A STRESSZ HATÁSA BETEGSÉGEK KIALAKULÁSÁBAN

A STRESSZ HATÁSA BETEGSÉGEK KIALAKULÁSÁBAN

Készítette és összeállította Erdőfi-Szabó Attila, BioLabor Biofizikai és Laboratóriumi Szolgáltatások Kft.

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A STRESSZ HATÁSA BETEGSÉGEK KIALAKULÁSÁBAN - tudományos magyarázatok, bizonyításokhivatkozott hazai és külföldi publikációkból

Kedvcsináló idézetek a figyelmes elolvasáshoz: „.. a betegségek is visszavezethetık lelki okokra. Innentıl már az orvos feladata eldönteni, mi volt elıbb, a tyúk, avagy a tojás, azaz a testi betegség vezetett a lelki betegséghez, vagy éppenséggel fordítva.” „A depressziós betegek ellenállóképessége romlik, és ez a gyakoribb gombás megbetegedésekben, és az influenza, pharyngitis, tonsillitis gyakoribb voltában is megnyilvánulhat.” „Beigazolódott, hogy az érzelmek csökkent kifejezése fokozottabb tumormitózissal és csökkent lymphocytainfiltrációval, nagyobb tumorvastagsággal jár együtt.” "Meyer és Haggerty (1962) már korán jelezte, hogy a tartósan fennálló családi konfliktusok, stress növelik a felsı légúti fetızések gyakoriságát." „A test szervi és mőködési zavarai nem választhatók el a szellemi-lelki állapottól, a szociális környezettıl, az egyéni sorstól és a teljes személyiségtıl. A pszichés élet elsıdleges zavarait a lelki izgalmak vagy a súlyos megterhelések okozzák. „ „A Hippokrateszi iskola a lelki történéseknek mindig elsıdleges, elızményi szerepet tulajdonított a szervi megbetegedések kialakulásában. „ „A legtipikusabb pszichoszomatikus megbetegedések – a teljesség igénye nélkül: ekcéma, hasmenés vagy gyomorhurut, gyomorfekély, légzési nehézségek (bronchitis, asthma), colitis (vastagbélgyulladás), a magas vérnyomás egyes fajtái, pajzsmirigy-túlmőködés, fejfájás, ízületi és végtagfájdalmak, herpes simplex, polio-vírus fertızés stb.”

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BioLabor Biofizikai és Laboratóriumi Szolgáltató Kft. / Erdőfi-Szabó Attila

DOKUMENTUMOK és IDÉZETEK

1. A közérzet/stressz által befolyásolt biológiai alrendszerek felsorolása, és a betegségek: 1.1.a dokumentum (Dr.Lázár Imre, adjunktus, SOTE MTud.Int.) szerint: immunrendszer, neuroendokrin belsıelválasztású mirigy rendszer, hormonrendszer, nyirokszervek (csontvelı, thymus), lép, autoimmunitás, anyagcsere folyamatok, limbikus rendszer, homeosztázis, sejtmőködés, szimpatikus idegrendszer, gyulladásos állapotok, sarcoidosis, Lupus - Szisztémás Lupusz Erythematózus, tumorpusztulási folyamat, daganatos megbetegedések, aluszékonyság, lethargia, depresszió, hálózatos önszabályzó folyamatok, hypophysectomia, adrenalectomia, allergiás encephalomyelitis, irritábilis bél szindróma,influenza, pharyngitis, tonsillitis, fertızéses megbetegedések, herpes, HIV, allergiás- atópiás megbetegedések: asthma bronchiale (extrinsic) rhinitis, eczema, urticaria. 1.1.b dokumentum (Prof.Dr. Kissgyörgy János, akadémikus) szerint: a test szervi és mőködési zavarai, szervi elváltozások, ekcéma, hasmenés, gyomorhurut, gyomorfekély, légzési nehézségek (bronchitis, asthma), colitis (vastagbélgyulladás), a magas vérnyomás egyes fajtái, pajzsmirigy-túlmőködés, fejfájás, ízületi és végtagfájdalmak, herpes simplex, polio-vírus fertızés. 1.1.c dokumenum (Prof.Dr. Kéri György, tudományok doktora) szerint: molekuláris betegségmechanizmusok, sejtek közötti kommunikáció. 1.1.d dokumentum (Prof.Dr. Kopp Mária, az orvostudomány kandidátusa) szerint: szív- érrendszeri megbetegedések, daganatos megbetegedések kórlefolyása, a csontok ásványi anyag sőrősége. 1.1.d2 dokumentum (Prof. Dr. Kopp Mária, az orvostudományok kandidátusa) szerint: depresszió. 1.1.e , f. dokumentumok (Prof.Dr.Kopp Mária, az orvostudományok kandidátusa) szerint: korai halálozási arány. 1.1.g dokumentum (A munkavédelemrıl szóló 1993. évi XCIII. törvény ) szerint: pszichoszociális kockázat, lelki eredető szervi (pszichoszomatikus) megbetegedés. 1.1.h dokumentum (Országos Munkavédelmi és Munkaügyi Fıfelügyelıség) szerint: depresszió, agresszió, zavartság, figyelmetlenség, vérnyomás emelkedése, fejfájás, emésztırendszeri, szív-érrendszeri megbetegedések. 1.1.i dokumentum (KSH-és MTA Ért. Szótár) szerint: A tudatnak kül. (különösképpen, fıképp) az egészségi állapotból eredı, a kedélyre is kiható általános állapota. 1.1.j dokumentum (Dr.Valló Ágnes) szerint: vércukor szint, mellékvese kéreg, izomtónus, fekélyek a bélrendszerben, gyomorban, irritábilis bél szindróma, szívinfarktus, fáradtság, kimerültség, gerincelváltozás, mozgásszervi panaszok, csökkenı ellenálló képesség, növekvı hajlam fertızésre. 1.1.k dokumentumok (külföldi egyetemek, intézetek) szerint (angol nyelven) : depresszió, kedélyzavar, lethargia, vegetatív rendszer, központi idegrendszer, hormon rendszer, emésztı rendszer, szívmőködés, atrythmia, keringés, immunrendszer, ellenálló képesség, limbikus rendszer, nyirokrendszer, autoimmunitás, anyagcsere folyamatok, ideg ingervezetı képesség, sejtmembrán akciós potenciál, receptor-proteinek –integrált membrán proteinek, effektor-proteinek-integrált membrán proteinek, bélflóra, légúti folyamatok és állapotok, asthma bronchiale, stroke, angiotens controller ensime, follikus stimuláló hormon, nemi hormonok, izomtónus, vércukor szabályozás, tápcsatorna mőködés, viselkedés mód, társas- és szociális viszony, agresszió, fájdalomérzet, vitalitás, apoptózis, leukocita aktivitás, extracelluláris közeg, colitis ulcerosa, irrritábilis bél szindróma, psychosomatikus betegségek, atópiás betegség, allergia, eczema, .

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1. 1. IDÉZETEK A TUDOMÁNYOS CIKKEKBİL (A dokumentumok teljes terjedelemben letölthetık) 1.1.a Dr. Lázár Imre, egyetemi adjunktus, PhD, SOTE Magatartástudományi Intézet, Neuroimmunmoduláció és pszichoimmunológia c. cikk, 2005.05.23 (TELJES DOKUMENTUM: 1-A-Pszicho-immunologia-Dr-LazarImre.pdf) „…a betegségek is visszavezethetık lelki okokra. Innentıl már az orvos feladata eldönteni, mi volt elıbb, a tyúk, avagy a tojás, azaz a testi betegség vezetett a lelki betegséghez, vagy éppenséggel fordítva.”

„Az egységes (pszicho)neuroimmun szabályozás tényére utal, hogy a neuroendokrin és immunmediátorok mindkét rendszerben (központi idegrendszerben és az immunrendszerben) termelıdnek, és egymás termelésére serkentı, illetve gátló hatást fejtenek ki, …”

„A hormonok a neuroendokrin-immun folyamatokat tartós átfogóbb "állapothatározó" hatásukkal tagolják a szervezet adaptív, anyagcsere folyamataiba.” . „Az érzelmi és magatartási folyamatok szervezıdésében oly fontos limbikus rendszer: a hippocampus, a gyrus dentatum, a kiterjesztetten értelmezett amygdala (centromediális amygdala, és a terminális striák nucleáris tartimánya) a gyrus cingulatus, a striatum ventrális része, a septum és a thalamus elülsı, és középsı magvai és a habenula bonyolult hálózatot alkotnak. Az immunmodulációban a hippocampalis-amygdala rendszer és a nucleus accumbens szerepe emelhetı ki.” . „A stressz folyamatok perifériáját képezi a hypophyseo-adrenális rendszer, melynek mőködését a CRH (corticoreleasing hormon) mellett potenciálják az angiotensin II, a cytokinek, és gyulladásos lipid mediátorok is. A glükokortikoidok a szervezet homeosztázisában és a stresszben is központi tényezık, és a HPA tengely basalis aktivitásában kulcsszerepet játszanak a stressz válasz negatív feed back-szerő lecsengetése mellett.” . „Az immuntörténés alatt a receptorsőrőség változik a sejtek felületén, mely a külsı jelzések összegzıdésének, és a sejt következményes belsı történéseinek, aktiváltságának eredıjeként állítja be a sejt érzékenységét, és közvetve meghatározza annak késıbbi viselkedését is.” . „A neuroimmun stresszfolyamat során a szimpatikus idegrendszer reciprok kapcsolatban áll a CRH rendszerrel, és aktiválódva az IL-6 szisztémás szekrécióját fokozza. Az IL-6 aktivációja a TNF alfa, és az IL-1 közvetlen gátlásával, és a HPA tengely aktiválásával szerepet játszik a stressz által elıidézett immunszuppresszióban.” . „Az adrenerg hatások tehát az elsıdleges nyirokszervekben zajló érési folyamatokra serkentı, míg a periférián a lymphocyta aktivitásra gátló hatást fejthetnek ki. A lép T sejtjeinek mitogénre adott válaszcsökkenését béta blokkolóval ( nadolol, propranolol) felfüggeszthetjük.”

„Fıbb immunserkentı hatású mediátorok: cholinerg agonisták, substance P, prolactin, növekedési hormon, Fobb immungátló hatású mediátorok: cortisol, VIP, adrenerg agonisták, somatostatin, vegyes hatású mediátorok beta endorphin, met enkephalin, „

„Stresszhormonok: A stresszfolyamat során a CRH (cortico-releasing hormon) az un. POMC (proopiomelanocortin) polipeptid hasításával szabadítja fel a glükokortikoidot mobilizáló ACTH-t, és a béta endorfint. A CRH közvetlen immunológiai befolyása is felvethetı, mivel a keringı fehérvérsejtekben kimutatható immunreaktív CRH (és az azt kódoló CRH mRNS is), mely a lymphocyták aktivációjával jelenik meg.”

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„A CRH perifériális szerepe a lokális szöveti gyulladásban is kifejezett lehet, ha carragenin provokálta kísérletes gyulladásos exsudatum mennyisége csökken a CRH immunneutralizálásával.(Karalis 1991) A gyulladást támogató hatással szemben a CRH csökkenti a Substance P kibocsátást. Mindez jelzi a stresszhormonok által hordozott üzenetek "szemantikai" többrétegőségét, és kontextus függıségét. Más streszhormonok is, mint az argvasopressin, prolactin, és a növekedési hormon befolyásolhatják az immunfolyamatokat. „ „A cortisol immunológiai hatásai Gátlás: 1. A lymphocyta közlekedés gátlása, a keringı lymphocyták száma átmenetileg csökken. 2. Az idegen , illetve saját eredető antigénekre adott T sejtes immunválasz csökken. 3. Csökken a mitogénre adott IL-1, IL-2, és a T sejtes növekedési faktor termelése. 4. Csökken a monocyta-macrophag átalakulás, és csökken a HLA-DR (Ia.) receptor megjelenítése, és a macrophag mitogén, illetve IL-1 iránti érzékenysége. 5. Csökken az autológ kevert lymphocyta reakció. 6. Gátló hatás a betegségek során jelentkezı a CD8 T sejtvonal Con A, és Pwm mitogénekre adott válaszát illetıen. 7. Csökken a B sejtes immunválasz, a Pwm mitogénre adott plakkképzés. 8. Fokozza az apoptozist, a T sejtklónok pusztulását. Serkentı hatás: 1. In vivo serkentı hatás az ADCC és NK sejtes aktivitásra. 2. In vitro serkent hatás nanomoláris koncentrációban az immunglobulinszintézisre.”

„A prolactin is stresszhormonnak tekinthetı, hiszen az akut fizikai vagy pszichoszociális stresszorhatás gyors, jelentıs és átmeneti prolactin elválasztáshoz vezet, bár a stresszorhatás ismétlıdése után az ingerre refrakter csökkenés jelentkezik. A krónikus stressz a prolactin elválasztását csökkenti, és ezt a dopamin antagonistával (haloperidol) fel lehet függeszteni.”

„A proimmun hormonok is befolyásolhatják a neuroimmun adaptációt. Az autoimmun folyamatokat serkentı hatású lehet a prolactin, ösztrogén és a progeszteron többlettermelıdés is. A prolactin ilyen szerepét észlelték hyperthyreosisban, sarcoidosisban, iritisben és SLE-ben szenvedı betegek esetében is, ..”

„Növekedési hormon: Ez a hormon (GH) is egyaránt tekinthetı stresszhormonnak és anyagcsere hormonnak, mely egyaránt fokozza a macrophagok antigénmegjelenítı képességét, az IL-1 termelését, és a tumorpusztító, baktericid szabadgyökgeneráló hatást. A növekedési hormon maga is hormon- illetve neuromediátor hatások fókuszában áll.” „Az érzelmi és kognitív folyamatokért felelıs neuroanatómiai szervezodések a pszichoimmunomodulációban is döntı jelentoséggel bírnak, melyek közvetítésében a neurpeptideknek fontos szerep jut. A peptiderg hatások lehetıségére utal az elsıdleges és másodlagos nyirokszervekben a SP, SS, VIP, neuropeptid Y, enkephalin, endorphin, vazopresszin immunfluoreszcens technikával kimutatható jelenléte. Ezeket a peptideket az enkefalinokkal együtt szimpatikus vegetatív idegrendszeri rostok is tartalmazzák, míg a paraszimpatikus beidegzés cholecystokinin, substance P, és TRH peptideket szállít. A nyirokszervekben a neuropeptid-tartalmazó idegrostok jelenléte tehát az immun célsejtek, illetve immunfolyamatok neuromoduláns hatásoknak való kiszolgáltatottságára utal.” „Az immuntörténést a hypothalamikus noradrenalin szint csökkenése kíséri. Ahogy neuroendokrin tényezıket láttunk lymphokin szerepkörben, úgy az immunmediátorok is közrejátszanak bizonyos idegi, viselkedéses jelenségek kialakulásában. Ilyen szerepe van az aluszékonyság, illetve a lassú hullámú alvás elmélyítésében az IL-1, interferon, és a muramyl dipeptidnek. Az alfa interferon közrejátszik a betegséget kísérı lethargia, depresszió kialakulásában sot kataton állapotot is elıidézhet. Az IL-2 és az IFN gátolja a hippocampus tartós potenciálását, ami közrejátszhat a daganat terápiában alkalmazott IL-2, IFN adását kísérı neuropszichiátriai mellékhatásokban.” „Mindezek az egyidejő mintázatszerő hatáshálók utalnak az immunrendszer, endokrin és idegrendszer nagyfokú összeszövıdöttségére, mely soktényezıs, interaktív, kölcsönös, és kiterjesztett oksági kapcsolatokkal jellemezhetı rendszerben mőködik. Ennek a rendszernek a viselkedése nehezen jósolható meg biztonsággal, bármelyik elem elhangolódása, befolyásoltsága felboríthatja ezt a túlbiztosítottnak tőnı, mégis kényes egyensúlyokkal dolgozó önszabályozást. A traumatizáló életesemények, elhúzódó stressz és az alkalmazkodási kudarc, represszív megküzdésmód, tanult segélytelenség nyomán csökkenı hypothalamikus NA szint éppen ezeket a visszacsatolási pályákat érintheti kedvezıtlenül.”

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„A szteroidok hatását, és a stressz során kifejtett immunszupresszív, a nyirokcsomók megkisebbedésében alakilag is tettenérhetı szerepét Selye fedezte fel, egyben tárgyunk alapmozzanatát is felvázolva. A depressziós betegek egy részében észlelt megváltozott DST próba a tartósan fokozott cortisol szekréció, és a betegeknél már említett IL-2 szint csökkenés jelzi a pszichés depresszió és az immunszuppresszió összekapcsolódását.”

„A krónikus gyulladásos betegségekre való fogékonyságot is értelmezhetjük Sternberg és Licinio (1995) összefoglalója alapján olyan zavart neuroimmun adaptációs folyamatnak, melyben az immunológiai adaptációt egyben fékezı hypophyseo-adrenális stresszreakció zavartan mőködik…. Ez a kiesı cortisol szerepe miatt az autoimmun folyamatok felerısödéséhez hozzájárulhat. A feed-back kör bármely szakaszán létrejött blokád elıidézheti a neuroimmun adaptáció zavarát, így a hypophysectomia, vagy az adrenalectomia akár fatálissá teheti például a salmonellafertızést, vagy a kísérletes allergiás encephalomyelitist.”

„Neuroimmun stresszmintázatok: … A tartós stresszhatás a fenti mellékhatások miatt válik kórképzıvé. A CRH (cortico-releasing hormon) peptid vezérlı szerepe mindebben igen fontos, hiszen ez a peptid koordinálja a viselkedéses, neuroendokrin vegetatív és immunológiai adaptáció folyamatát.”

„Ismert, hogy a korral illetve a depressziós állapot mértékével együtt nı noradrenerg aktivitás, és csökken az immunkompetencia. Mivel depresszióban fokozott a CRH szekréció, ezért e stresszregulátor szimpatikus idegrendszer közvetítette immunszuppresszív szerepe is szóba jön a depresszióban.”

„Az egyénre jellemzı lehet a CRH-t korlátozó feed back hatások gyengült volta. Így például a korai pszichoszociális, vagy egyéb környezeti traumák nyomán a hippocampus és a frontális kéreg glükocorticoid receptor gén expressziója is csökken, ami egyben a CRH (cortico-releasing hormon) és az arg-vasopressin szekrécióra való negatív-feedback csökkenését jelentheti. A glükocorticoidok vissza jelzése és gátló hatása iránt érzéketlenedett rendszer a stresszorra fokozott HPA aktivitással válaszolhat , mely az adott személy neuroendocrin jellemzıjévé válhat az immunszuppresszív következményekkel együtt. (Francis 1996)” „A depressziós betegek ellenállóképessége romlik, és ez a gyakoribb gombás megbetegedésekben, és az influenza, pharyngitis, tonsillitis gyakoribb voltában is megnyilvánulhat.” „A stressz okozta alvászavarok kedvezıtlenül hatnak vissza az immunvédelemre.” „A rák jelképes betegség, a határokat nem tisztelı dezorganizált szövet, mely egyszerre ragadozója, parazitája, gyilkosa és végül áldozata az elpusztult anyaszervezetnek- sajátos humán ökológiai jelkép. A civilizációs ártalmak: a környezet kémiai, vagy sugárzó carcinogénekkel való szennyezése, a szociális környezet szétesése, a korai anya-gyermek kapcsolat traumatizáltsága, az elidegenedettség, társtalanság, a szociális támogatottság hiányából fakadó immunvédekezés gyengülése a daganatos betegségeket a humán ökológia körébe vonja.” „A daganatképzıdés örökletes, bels onkogén tényezıit a szervezetben, mint belsı környezetben találjuk meg, míg a külsı természeti környezet vírus, vagy kémiai, vagy sugárzó onkogénekkel jelent fenyegetést a szervezetre. A daganatképzıdésre, fejlıdésre és a klinikai lefolyásra ható környezeti tényezıket a stressz mechanizmusok közvetítik a kóros sejtek és az ıket elhárító immunfolyamatok környezetébe.” „A neuroendokrin, metabolikus és más szervezeti állapotváltozás a sejtek daganatos átalakulásához vezethet, és a spontán tumorképzıdés arányát növelheti. Viselkedéses jelenségek befolyásolhatják a szervezet tumorellenes védekezését. A neuroimmuno-moduláció közvetíti ezeket a hatásokat elsısorban az NK sejt aktivitását befolyásolva, így a tumorellenes surveillance funkció a külsı pszichoszociális környezet befolyása alatt állhat.”

„A NK sejtek aktivitását csökkentı pszichoszociális befolyás így a szervezet "tumorátengedı" képességét, illetve a betegség progresszióját fokozza.”

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„A tartós hypercortisolaemia az IL1, IL2 szint csökkenésével járhat, ami tovább rontja a NK sejtek kompenzáló szerepét. A pszichoonkológiai vizsgálatok arra utalnak, hogy a letargiát panaszoló, a szociális támogatottságot nélkülözı személyeknél a NK sejt aktivitás alacsonyabb, és az áttétképzıdés intenzívebb.”

„Beigazolódott, hogy az érzelmek csökkent kifejezése fokozottabb tumormitózissal és csökkent lymphocytainfiltrációval, nagyobb tumorvastagsággal jár együtt.” „Fertızések, határfelületi védelem: A nyálkahártya (mucosa) által biztosított védelmi vonalban a humorális (IgA) védelem mellett az intraepitheliális sejtek –NA (natural killer) aktivitása is szerepet játszhat. A szájüregben a szájnyálkahártyán észlelt széles körő antigéntolerancia létrejöttében a szuppresszor T sejtek szerepe fontos. Ha stressz, pszichoimmun terhelés nyomán arányuk lecsökken, akkor fekélyek, gyulladásos jelenségek alakulhatnak ki.”

„A felületi immunitás romlását jelenti a légúti betegségrek gyakoriságának növekedése. Meyer és Haggerty (1962) már korán jelezte, hogy a tartósan fennálló családi konfliktusok, stress növelik a felsı légúti fetızések gyakoriságát. Graham 94 családot vizsgált meg, és a gyakoribb stressztol szenvedı csoportban a hőlések száma nagyobb volt. Clover és munkatársai a kaotikus, és rigid családok stresszterhes légkörében az influenza iránti fogékonyságot magasabbanak találták, mint a kiegyensúlyozott harmonikus családokban. (Clover 1989) Cohen(1993) szerint a stresszterhelés mellett a negatív érzéseknek is szerepe van a légúti beteg betegségek gyakoriságában, és súlyosságában.” „A herpes fertızés népbetegség jellegén túl lehetıséget nyújt a krónikus, visszatérı fertozı kórképek vizsgálatára. Jól követhetı a HSV antitesttiter szintje, a tünetek nyilvánvalóak, és közkelető és elfogadott az is, hogy a stresszkörülmények a herpes fertızés kiújulásához vezetnek. A látens fertızés aktiválódását a HSV antitest titerének növekedése jelzi. McLarnon, és Kaloupek(1988) genitális herpes prospektív vizsgálatakor találtak összefüggést a stressz és a betegség gyakoriság között.” „Az NK sejtek fordított arányosságot mutattak az AIDS betegségre összpontosuló figyelem beszőkülésével, és a fáradtsággal, tehetetlenségérzettel. Burack a helper T sejtszám csökkenését 38%-al gyorsabbnak találta a depressziós betegeknél szemben a nem depressziósakkal 1985 és 1991 között vizsgált 330 HIV pozitív homoszexuális körében. Kemény és mtsai HIV pozitív homoszexuálisok körében 5 éves követéses vizsgálatban észlelt hasonló tapasztalatok alapján kezdeményezett intenzív életminıségjavító és stressz kezelı csoporttherápiás programot. A vírus reaktiválódását jelzı P24 antigén (a HIV vírus része) szintjének növekedése arányban áll a depresszióval, félelemmel, és fordított arányosságot mutatott az aktív megküzdési stratégiákkal, a humort használó coping mechanizmussal. Temoshok egy másik vizsgálatában a T4 sejtek abszolút száma egyenes arányosságot mutatott az izgalmi szorongásos állapottal, a kevéssé kontrolált érzelmi élettel.” „Ha a fokozott arousalt, noradrenalin és adrenalin kibocsátást és a noradrenalin által fokozott NK sejt aktivitást a megfogyatkozott helper T sejtek funkcióját pótló tényezınek tekintjük, akkor érthetı, hogy a sztoikus, beletörıdı, és csökkent emócionalitású, a negatív érzelmeket kifejezni képtelen állapot miért jár rosszabb kilátásokkal.”

„Allergiás betegségek: A túlérzékenység (allergia) olyan indokolatlanul intenzív válasz egyébként ártalmatlan antigénre, vagy kórokozóra, gyógyszerre, mely magát a szervezetet is károsítja. .. Az antigénbehatásra azonnal bekövetkezı allergiás reakció, melyet IgE típusú antitest közvetít. A szabad Ig E felezési ideje néhány nap, míg a hízósejtekhez, basophil sejtekhez kötodött Ig E hetekig kimutatható, és mennyisége is nagyobb. A normális Ig E szint sem zárja ki az atópiás betegség diagnózisát. Az IgE mediált asthma bronchiale (extrinsic) rhinitis, eczema, urticaria, kórképeket nevezzük atópiás betegségeknek. Itt az allergénnel végzett borpróba tekinthetı a legbiztosabb diagnosztikus eszköznek. A borpróbák az allergiás betegben autogén tréning és relaxáció után javulást mutatnak.”

Dr. Lázár Imre, egyetemi adjunktus, PhD, SOTE Magatartástudományi Intézet: Neuroimmunmoduláció és pszichoimmunológia.

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1.1.b Prof. Dr. Kisgyörgy János, akadémikus, anatómus, ideggyógyász, pszichiáter, igazságügyi elmeszakértı, ny. egyetemi tanár PSB=Pszichoszomatikus Betegségek c. cikk (TELJES DOKUMENTUM: 1-A pszichoszomatikus betegsegek-Pr.Dr.KisgyorgyJanos.pdf)

„A test szervi és mőködési zavarai nem választhatók el a szellemi-lelki állapottól, a szociális környezettıl, az egyéni sorstól és a teljes személyiségtıl. A pszichés élet elsıdleges zavarait a lelki izgalmak vagy a súlyos megterhelések okozzák.” „A „PSB” (Pszichoszomatikus Betegségek ) lényege az egészséges állapotnak megfelelı harmónia megbomlása, illetve egyensúlyzavar létrejötte, melynek következményeként megváltozik a beteg kapcsolata a külvilággal is.” „A fı tünetek tulajdonképpen szervi panaszok, melyek mögött a munkához vagy a mindennapi élethez való alkalmazkodás zavara húzódik meg.”

„A szervi elváltozások kialakulását a kiváltó pszichés tényezı hosszan elhúzódó hatása miatt rögzült kóros válaszformák idézik elı. S ezek épp az egyén szervezetének legsebezhetıbb, leggyengébb ellenállású pontjain (latinul „locus minoris resistentiae”) jelentkeznek.” „A Hippokrateszi iskola a lelki történéseknek mindig elsıdleges, elızményi szerepet tulajdonított a szervi megbetegedések kialakulásában. „

„A legtipikusabb pszichoszomatikus megbetegedések – a teljesség igénye nélkül: ekcéma, hasmenés vagy gyomorhurut, gyomorfekély, légzési nehézségek (bronchitis, asthma), colitis (vastagbélgyulladás), a magas vérnyomás egyes fajtái, pajzsmirigy-túlmőködés, fejfájás, ízületi és végtagfájdalmak, herpes simplex, polio-vírus fertızés stb.”

„Az elsıdleges cél a munkaképesség visszaállítása, s az életminıség javítása. Ám a beteg szervi elváltozásainak észlelése és kezelése mellett, azzal egy idıben rendkívül fontos a beteg személyiségével való törıdés!”

Prof. Dr. Kisgyörgy János

. 1.1.c Prof. Dr. Kéri György, “a tudományok doktora”. Számos egyéb elismerés mellett 1986-ban a Kiváló Feltaláló Díj arany fokozatát, 1992-ben pedig a DEBIO PEPTID AWARD-ot nyerte el (megosztva) az Interlaken-i Európai Peptid Szimpoziumon “Új antitumor peptidhormon-származékok kifejlesztéséért”. 1974-tıl mindmáig a Semmelweis Egyetem I. sz. Kémiai-biokémiai Intézetében a Peptidbiokémiai Kutatócsoportban dolgozik, egyetemi tanár, az MTA doktora, tudományos tanácsadó, sok egyéb tisztsége mellett tagja az “Endocrine”, valamint a “Letters in Peptide Chemistry" folyóiratok szerkesztıbizottságának. Kommunikációs zavar a sejtekben c. cikk, és Jeltovábbítás terápia – új irányok a gyógyszerkutatásban c. publikáció-TELJES

„A molekuláris betegségmechanizmusok megismerése nyomán ugyanis világossá vált, hogy betegségeink hátterében többnyire - 80-85%-os gyakorisággal - jeltovábbítási zavar, azaz sejten belüli és sejtek közötti - talán hozzátehetjük: egyénen belüli és egyének közötti - kommunikációs zavar található. Ilyen kóros jeltovábbítási mechanizmusokra vezethetık vissza a daganatos, bizonyos érrendszeri, gyulladásos, és emésztorendszeri kórképek, számos központi idegrendszeri betegség, sıt a vírusos és bakteriális kórok jelentıs része is.”

„Ne feledkezzünk meg a neurodegeneratív rendellenességekhez kapcsolódó kórképekrıl és ezek összetett mechanizmusairól sem! Kimutatható ugyanis, hogy a központi idegrendszeri betegségek során - például az epilepszia és a skizofrénia esetében is - sejtek közötti kommunikációs rendellenességek vezetnek a betegség kialakulásához.”

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„Ha általánosságban nézzük az élı rendszereket, világossá válik, hogy kommunikáció nélkül nincs élet, az élet lényegéhez tartozik a kölcsönhatás, az interakció, és ez bizonyos szinten elvezet egészen az evolúció fogalmáig. Az élet ökoszisztémás rendszerben zajlik, és a különbözo szintő rendszerek fönnmaradásának és "fejlıdésének" alapja (a fejlıdés fogalmát most nem részletezve egyelıre maradjunk a komplexitás növekedésénél) a rendszeren belüli és rendszerek közötti interaktív kooperatív kölcsönhatás, azaz az interaktív kommunikáció. „ „Az egyed (jelen esetben a sejt) tehát az összetett jeltovábbítási rendszerek (interaktív kommunikáció) révén érzékeli az egész rendszer állapotát, és itt már eljutunk egyfajta holografikus, illetve holisztikus szemlélethez (a biológiai rendszerekben a holografikus szemlélet az információ tárolás holografikus elméletébol származik) amit egy taoista mondás is jól érzékeltet: "A tengerben benne van a csepp, és a cseppben benne van a tenger."

„A sejttársadalomban ha a rendszer egészséges, tiszta kommunikáció zajlik. Például ha az idegsejteknek cukorra van szükségük, és nincs elég cukor a vérben, akkor ezt közvetítı molekulákon keresztül jelzik az emésztorendszernek és a májnak, és ez az üzenet valós, és csak addig áll fenn, amíg valóban szükség van rá. Amikor a sejtek a külsı üzeneteket egymás között kis csatornákon továbbadják, ugyanazt az információt adják tovább, amit kaptak, vagy ha sejtosztódásra van szükség, ezek az üzenetek is valósak, és ha már nincs rá szükség, egy másik, szintén a valódi helyzetet tükrözı üzenet például a kontakt hatások révén leállítja az osztódási üzenetet.”

„Sokféle külsı, illetve belsı hatás vezethet a sejt, illetve a sejtek hibás mőködéséhez, ronthatja el, illetve zavarhatja meg a sejtek egy csoportjának kommunikációs rendszerét. Ha azonban a rendszer jó "kommunikációs állapotban" van, jól mőködik az immunrendszer, a hormonális rendszer, a kontakt hatások, a differenciációt indukáló faktorok stb., akkor a hamis üzenetet mimikáló vagy generáló sejtet a rendszer eliminálja, és nem fejlıdik ki a patológiás állapot. A jeltovábbítási terápia célja a rendszer tiszta kommunikációs állapotának helyreállítása, amit elsısorban a hamis jelek gátlásával igyekszik megvalósítani, másrészt bizonyos "pozitív" jelek stimulálásával, például immun stimulánsok, neuromodulátorok, hormonok révén is elérhetı a remélt egyensúlyi állapot.”

„A sejtkommunikáció holografikus elmélete az információtárolás, illetve a memória holografikus elméletébol ered. Az információ-tárolás molekuláris mechanizmusa a mai napig nem teljesen tisztázott, és a szinaptikus plaszticitás, valamint a holografikus elmélet a legáltalánosabban elfogadott elméletek közé tartozik. A holografikus elmélet szerint az információtárolás során az egyedi sejt (elektromágneses hullámok és sejt-sejt kölcsönhatások révén) érzékeli az egész agy ingerületi mintázatát, és így bizonyos egyedi idegsejtekben egy adott állapotban leképzodik az egész agy ingerületi mintázata, és innen elı is hívható - mint a holografikus képben, ahol a hologram egy elemében benne van az egész képe. Újabb feltételezések szerint az egész szervezet sejtjei közötti kommunikációs rendszerben is érvényesül az elektromágneses hullámok révén való kommunikáció és a holografikus elv, ami új prespektívákat nyit a rendszer biológiai szemlélete elıtt.”

„Befejezésül e gondolat jegyében egy taoista versikét szeretnék idézni: A betegség az egység hiánya. A betegség a Lélek magánya. A szellem, a lélek, a test és az értelem Egységben aranyvirágot terem. „

Prof. Dr. Kéri György

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1.1.d Prof. Dr. Kopp Mária, egyetemi tanár, tudományos igazgatóhelyettes, az orvostudomány kandidátusa, a Magyar Tudományos Akadémia doktora, SOTE Magatartástudományi Intézet igazgatója, Magyar Pszichofiziológiai és Egészséglélektani Társaság alapítója, elnöke, a WHO (Világ Egészségügyi Szervezet) szakértıje Stressz és megbirkózás: a közép- kelet-európai egészség paradoxon c. cikk (TELJES DOKUMENTUM: 1-Stressz és megbirkózás- a közép- kelet-európai egészség paradoxon.pdf)

„A WHO vizsgálatai alapján A 15-tıl 44 éves korosztályban a depressziós megbetegedések járulnak hozzá legnagyobb mértékben a betegségek és halálozás okozta évveszteséghez. 2020-ra a depresszió lesz a világon a második leggyakoribb tartós munkaképesség-csökkenést okozó megbetegedés (a szív- és érrendszeri betegségek után) a modern világ legfobb gyilkosai az un. civilizációs megbetegedések, amelyekben a magatartási, mentális tényezık szerepe alapvetı. (Mental Health: New understanding, new hope, The World Health Report 2001, WHO, Geneva, Kopp MS (Advisory Group member, Central-Eastern-European representative)”

„..a stressz akkor válik kórossá, ha nem vagyunk képesek megbirkózni az újszerő, veszélyeztetı helyzettel, illetve a krónikus stressz, a kimerülés fázisa egyértelmően károsító hatású.”

„Elsısorban a szív- érrendszeri megbetegedések esetében, de az összhalálozás szempontjából is, elsosırban a depresszió, de a szorongás kockázati szerepe is bizonyítható. A depresszió és szorongás tényleges kockázata lényegesen magasabb közvetlen élettani hatásánál, mivel a depresszió fokozza az ismert, egyéb veszélyeztetetı tényezık, a dohányzás, kóros alkoholfogyasztás, stressz-táplálkozás gyakoriságát is. Nem csupán a diagnosztizált depressziós megbetegedések, hanem a megfelelı klinikai skála alkalmazásával megállapított depressziós tünetegyüttes is fokozza a veszélyeztetettséget. Erre a célra az áttekintı tanulmányok alapján a legmegfelelıbb a széles körben alkalmazott Beck Depresszió Skála. Bár a legtöbb vizsgálat a kardiovaszkuláris megbetegedések és a depresszió összefüggéseit bizonyította, a depresszió kockázati szerepe további megbetegedések esetében is jelentıs, így a daganatos megbetegedések kórlefolyásának súlyosbításában. Szintén bizonyítottnak tekinthetı a csontok ásványi anyag sőrősége és a depresszió közötti összefüggés, azaz az osteoporózis veszélyeztetettség fokozódása, amelynek elsı, máig érvényes nemzetközi leírása a magyar Holló professzortól származik.” Prof. Dr. Kopp Mária 1.1.e Prof. Dr. Kopp Mária, egyetemi tanár, tudományos igazgatóhelyettes, az orvostudomány kandidátusa, a Magyar Tudományos Akadémia doktora, SOTE Magatartástudományi Intézet igazgatója, Magyar Pszichofiziológiai és Egészséglélektani Társaság alapítója, elnöke, a WHO (Világ Egészségügyi Szervezet) szakértıje, Férfiak lelki egészsége: Miért halnak meg idı elıtt a magyar férfiak c. cikK - TELJES DOKUMENTUM

„A negatív lelkiállapot kockázati szerepe: A férfiak esetében a súlyos depressziós tünetegyüttes 3-szor magasabb halálozással járt, a meghaltak közül 24 %- nak volt súlyos, 24 pont feletti Beck Depresszió pontszáma,..” Prof. Dr. Kopp Mária 1.1.f Prof. Dr. Kopp Mária, egyetemi tanár, tudományos igazgatóhelyettes, az orvostudomány kandidátusa, a Magyar Tudományos Akadémia doktora, SOTE Magatartástudományi Intézet igazgatója, Magyar Pszichofiziológiai és Egészséglélektani Társaság alapítója, elnöke, a WHO (Világ Egészségügyi Szervezet) szakértıje, A nık és férfiak egészsége ma Magyarországon c. cikK TELJES DOKUMENTUM

„Vizsgálatunk eredményeinek tükrében feltételezhetı, hogy a krónikus stressz az a láthatatlan kéz, amely a középkorú magyar férfiak tragikus korai halálozási arányát okozza. A krónikus stressz során felmerülı magatartási és lélektani változások szembetőnıen hasonlítanak a depresszió során tapasztalható krónikus változásokhoz.”

„..a tartós, krónikus stressz állapota jelentısen sietteti a biológiai és pszichológiai öregedést. A krónikus stressz helyzetek megélése az öregedés folyamatában alapvetı jelentıségő.” Prof. Dr. Kopp Mária

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1.1.g A munkavédelemrıl szóló 1993. évi XCIII. törvény (2008.01.01.) (TELJES DOKUMENTUM: A munkavédelemrıl szóló 1993. évi XCIII. törvény.pdf)

E törvény célja, hogy az Alkotmányban foglalt elvek alapján szabályozza az egészséget nem veszélyeztetıés biztonságos munkavégzés személyi, tárgyi és szervezeti feltételeit a szervezetten munkát végzık egészségének, munkavégzı képességének megóvása és a munkakörülmények humanizálása érdekében, megelızve ezzel a munkabaleseteket és a foglalkozással összefüggı megbetegedéseket.

82. § (1) A munkavédelmi hatóság munkavédelmi bírságot alkalmaz az egészséget nem veszélyeztetıés biztonságos munkavégzésre vonatkozó követelmények teljesítését elmulasztó, és ezzel a munkavállaló életét, testi épségét vagy egészségét súlyosan veszélyeztetı munkáltatóval szemben.

„87. § 1.bekezdés H.pontja: Pszichoszociális kockázat: a munkavállalót a munkahelyén érı azon hatások (konfliktusok, munkaszervezés, munkarend, foglalkoztatási jogviszony bizonytalansága stb.) összessége, amelyek befolyásolják az e hatásokra adott válaszreakcióit, illetıleg ezzel összefüggésben stressz, munkabaleset, lelki eredető szervi (pszichoszomatikus) megbetegedés következhet be.”

1.1.h A munkavédelemrıl szóló 1993. évi XCIII. törvény (2008.01.01.) Az Országos Munkavédelmi és Munkaügyi Fıfelügyelıség Tájékoztatása: I.pont 2. bekezdés: (TELJES DOKUMENTUM: Munkavédelemrıl szóló 1993. évi XCIII. törvény 2008. január 1.pdf) „a hosszú távú stressz hatás vezethet: -magatartási zavarokhoz: ingerlékenység, fokozott dohányzás, alkoholfogyasztás, alacsony munkateljesítmény, -pszichológiai hatásokhoz: depresszió, agresszió, zavartság, figyelmetlenség, -fizikai panaszokhoz, tünetekhez: vérnyomás emelkedése, fejfájás, -pszichoszomatikus megbetegedésekhez: emésztorendszeri, szív-érrendszeri megbetegedések. Ilyen, tartós stresszt a munkahelyi bizonytalanság, értékvesztés, képességgel arányban nem álló munkahelyi, társadalmi, családi elvárások, konfliktusos interperszonális kapcsolatok munkatársakkal, fınökkel, vagy a magánéletben, túlzott munkateher okozhatnak. Továbbá ide sorolandók az olyan kérdések is, mint: mennyi beleszólása van a munkavállalóknak abba, hogy miként végzik a munkájukat, értik-e vagy sem a feladatukat, részesülnek-e vagy sem a munkavállalók a kollégák és a vezetık részérıl kellı támogatásban, kaptak-e képzést a feladatok ellátásához stb.”

1.1.i Központi Statisztikai Hivatal: A gazdasági tevékenységek egységes ágazati osztályozási rendszere (TEÁOR) Egyéb személyi szolgáltatás/96.04. Fizikai közérzet javító szolgáltatás értelmezése, a Magyar Tudományos Akadémia Nyelvtudományi Intézet, MTA Nyelvmuvelıés Nyelvi Tanácsadó Kutatócsoport hivatkozás, Magyar Értelmezı Késziszótár (2003) szerint: „közérzet (fn) A tudatnak kül. (különösképpen, fıképp) az egészségi állapotból eredı, a kedélyre is kiható általános állapota.”

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1.1.j Dr. Valló Ágnes, pszichoszomatikus belgyógyász, természetgyógyász, életmódtanácsadó, egészségfejlesztı mentál-higiénikus, tréner, terapeuta, Semmelweis Egyetem Egészségtudományi (Fıiskolai) Karán tanított 12 éven át élettant, kórélettant, belgyógyászatot, gyógyszertant, és az általa kifejlesztett pszichoszomatikus tárgyakat. A Stressz c. cikk (TELJES DOKUMENTUM: 1-drvalloagnes-a-stressz.pdf) forrás: www.valloagnes.hu „Az orvostudomány a 20. században vette át a kifejezést, azonban itt kétféle értelemben is használták: a stresszt: jelenti a szervezetre ható külsı körülményeket (például magas hı, erıs ütés stb.), illetve az ezen körülmények hatására a szervezetben lezajló belsı változásokat is. Selye János (1983), választotta külön a hatást és a következményt: stressznek azt a nem specifikus választ tekinti, amit a szervezet a megterhelésre ad. A stressz ezen felfogása szerint a szervezetre ható külsı erıket, körülményeket stresszoroknak nevezzük. Selye szerint a stressz lényege az alkalmazkodás: annál erısebb stresszrol van szó, minél nagyobb mértékő alkalmazkodást kíván a szervezettıl. A pszichológiában, ill. a pszichoszomatikus szemlélető medicínában a stressz általában véve olyan eseményekre utal, amelyek megítélésünk szerint megterhelık, veszélyeztetik pszichikai és/vagy fizikai jóllétünket. Az ilyen események a stresszorok, a rájuk adott reakciók összessége pedig a stresszválasz. (Atkinson)” „A stressz mindennapi életünk része, alkotó energiáink forrása, mely cselekvésre sarkall, segíti küzdelmeinket. A stressz - kihívás, késztetés. Segít, hogy reggelente frissen, elevenen ébredjünk, hogy napközben lelkesek, pozitívak, kreatívak legyünk. Segít versenyt futni, elıadást tartani, még szerelmeskedni is. A stressz sarkall, hogy meneküljünk a tőz vagy az árvíz elıl, vagy elkészüljünk munkánkkal a kitőzött határidıre. A túlzott, mindent elborító, kontrollálhatatlan stressz azonban felmorzsolja energiáinkat, kiégést (burn out) okoz, tönkreteszi kapcsolatainkat, karrierünket, aláássa önbizalmunkat, végül - de nem utolsó sorban - súlyosan romboló hatással van egészségünkre.” „Belsı szerveink mőködését vegetatív idegrendszerünk irányítja. A vegetatív idegrendszer szimpatikus és paraszimpatikus oldalból tevıdik össze. A szimpatikus idegrendszer szakosodott a vészhelyzetek elhárítására, míg a paraszimpatikus elsısorban a táplálkozás, a regenerálódás szolgálatában áll. A "vészhelyzet" hatására, (pontosabban - mint késıbb látni fogjuk - annak hatására, amit vészhelyzetnek tartunk) a szimpatikus oldal, aktiválódik, ennek hatására gyorsul a légzés, a szívmőködés, emelkedik a vérnyomás, fokozódik az izomfeszülés. A szimpatikus idegrendszer "kihelyezett tagozata" a mellékvese velı nagy mennyiségu adrenalint termel, ami fokozza az izmok vérellátását, és biztosítja a megfelelo "üzemanyag-ellátásukat" is: a májban található raktárakból cukrot szabadít fel, növelve ezzel a vércukorszintet. Mindehhez a hormonrendszer megfelelı hátteret biztosít. Az agyalapi mirigy közbenjárására a mellékvese kéreg kortizolt termel, ami segíti és stabilizálja a szimpatikus hatásokat. Mindezen hatások összességeként szervezetünk készen áll a veszély elhárítására. Érzékszerveink kiélesednek, gondolkodásunk tisztul, reakcióink gyorsulnak, izmaink erıtıl duzzadnak, s elegendı cukor és oxigén áll rendelkezésükre a hatékony, gyors, erıteljes mőködéshez. Minden az izommőködés - a menekülés vagy küzdelem - szolgálatában áll. „

„Ha a stresszhelyzetet testi reakció - küzdés vagy menekülés - követi, akkor a szervezet egyáltalán nem vagy alig károsodik. Akkor sincs veszély, ha a harag, bosszúság, indulat csak átmeneti, könnyen lereagáljuk, vagy gyorsan túltesszük magunkat rajta. Ha azonban az élettani válasznak - a társadalmi következmények miatt - nincs szabad tere, tartós, vagy túl gyakran ismétlıdik, akkor a testet halmozódó negatív hatás éri. Tartós stresszhatás esetén egy bizonyos ideig a szervezet képes alkalmazkodni a stresszhez, ez az alkalmazkodóképesség azonban véges, és túlzott igénybevétel, megterhelés esetén kimerül. „

„az alkalmazkodási energia kimerül, ha a szervezetet túlságosan hosszú ideig túlságosan erıs stresszor hatása éri, (és/vagy ha a stresszorokkal szembeni cselekvés lehetetlen.) Újra megjelennek az alarm reakció jelei, megnagyobbodnak és túlmőködnek a mellékvesék, károsodik az immunrendszer fekélyek keletkeznek a gyomorban és a bélrendszerben.”

„Mitıl függ, hogy az ember melyik betegséget "választja", vagyis a bıséges "választékból" melyikben betegszik meg? A válasz több oldalról is megközelíthetı. Ez az a pont, ahol komolyan számításba jön a genetikai hajlam kérdése. Ez gyakorlati szempontból azt jelenti, hogy melyik szerv, szervrendszer a "leggyengébb láncszem", ami a külsı megterheléseknek legkevésbé tud ellenállni. Ez lesz az, ami leghamarabb "eltörik", vagyis amelyen a betegség megjelenik.”

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„Az állandó versenyhelyzet, az elfojtott indulatok, rohanás, idozavar például a szimpatikus idegrendszer túlaktiválódásához, s ezen keresztül magas vérnyomáshoz, infarktushoz vezethetnek. Ezeket nevezzük alarmvagy riadóbetegségeknek.”

„A túlzott aggodalmaskodás, elbizonytalanodás a paraszimpatikus idegrendszer általvezérelt emésztıszervekben okoz károsodást. Aki túlzottan aggodalmaskodik, az állandóan olyasmitol fél, ami soha sem - vagy csak nagyon ritkán - fog bekövetkezni. Mindig a legrosszabbat várja, és lélekben át is éli, anélkül, hogy az bekövetkezett volna. Ezzel nap mint nap megteremti, megsokszorozza, állandósítja önmaga számára a stresszt. Ezáltal az egyszeri hatás tartóssá válik, a vegetatív idegrendszer egyensúlya felbillen és a paraszimpatikus túlsúly következtében fekélybetegség, irritábilis bél szindróma alakulhat ki. „

„A közelmúltban végzett felmérésem számomra is meglepı eredményt hozott: a mozgásszervi panaszok sokkal szorosabb összefüggést mutattak a stresszel, mit a testsúllyal, a mozgásmennyiséggel vagy az életkorral. A stressz természetesen elsısorban izmainkra hat. Ha szorongunk, feszültek, idegesek vagyunk, izmaink megfeszülnek, tónusuk fokozódik. A tónusfokozódás az oxigénigény növekedésével jár, egyúttal több energiát fogyaszt, ezért estére olyan fáradtnak érezhetjük magunkat, mintha egész nap követ törtünk volna. Másrész a relatív oxigénhiány fájdalmakat is okozhat. Ha pedig stressz, tartós feszültség következtében az izmok megfeszülnek, a kisfokú gerincelváltozás is súlyos, alig elviselheto fájdalmakat okozhat.”

„A stressz károsan befolyásolja az immunrendszer mőködését is, és ezáltal elısegíti a fertızések sıt akár a rák kialakulását is.” „Több amerikai kutatóhelyen igazolták, hogy az egészséges fiatal egyetemisták vérében ill. nyálában kimutatható ellenanyagszint a vizsgaidıszakban fokozott stresszterhelés következtében csökken, tehát könnyebben kapják meg a fertızéseket. Érdekes megfigyelni, hogy az iskolai stressz milyen nagy fokban befolyásolja a 6-10 éves gyermekek ellenálló képességét. Egy szigorú, merev, büntetı tanítónı osztályában jóval nagyobb arányú a hiányzás, mint liberális, gyermekcentrikus, társnıjénél. Megkockáztatom: ha egy vállalatnál az évi rendes influenza-járvány idején a szokásosnál több a betegek száma, akkor egyrészt vizsgáljuk meg a klíma-berendezést, vajon nem szórja, terjeszti-e a kórokozókat, másrészt keressük meg azokat a stresszforrásokat, amelyek ronthatják a dolgozók hangulatát, közérzetét és ezáltal ellenállóképességét is.”

„A döntı tehát nem maga a stressz, hanem az, hogy valaki hogyan birkózik meg a stresszel. Betegség rendszerint akkor alakul ki, ha az egyén "megbirkózási technikája" hibás, túlzott, vagy nem felel meg a megoldandó problémának, azaz miként éli meg a helyzetet vagy állapotot.”

„Ritkán gondolunk arra, hogy étrendünk, is befolyásolja szellemi teljesítı képességünket, kedélyállapotunkat. Jó közérzetünkben az egészséges táplálkozásunknak is nagy szerepe van. Számos étel és ital tartalmaz stresszkeltı anyagokat., míg mások fokozzák stressztőrı képességünket. De attól is feszültek, ingerlékenyek lehetünk, ha munka közben nem jut idınk ebédelni. Az éhezés hatására ugyanis csökken a vércukorszint, ennek ellensúlyozására szervezet fokozott adrenalin-termeléssel válaszol. Az adrenalin fokozza a vércukorszintet, de stresszkeltı hatásai is érvényesülnek.” „A pszichoszomatikus zavarok megfelelı gyógyítása tehát midig többirányú. Természetesen magában foglalja a szervi károsodás biológiai szintő - tehát gyógyszeres, vagy ha szükséges, akár sebészi - gyógyítását, de ezzel egyenértékő szerepet kap a pszichológiai segítségnyújtás is. Mivel a pszichoszomatikus betegségek rendszerint krónikusak, vagy legalábbis kiújulásra hajlamosak, s ezért átszövik a beteg életvezetését, környezetéhez való viszonyulását, a gyógyításnak fontos szerepe van a rehabilitációban, a beteg számára megfelelı, személyiségének kiteljesedését biztosító életminıség biztosításában. Ez a komplex megközelítés teszi lehetıvé, hogy a beteg ne csak gyógyuljon, hanem meggyógyulhasson.” Dr. Valló Ágnes

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1.2. További nemzetközi tudományos kutatások dokumentumai (letölthetık, vagy CD-n átvehetı, összesen 1273 oldal) Understanding the interaction between psychosocial stress and immune... Stress and Health: Psychological and Biological Determinants... Protective and damaging effects of stress mediators- central role of the brain Psychological Stress and the Human Immune System If It Goes Up, Must It Come Down? University of British Columbia Out of Balance CD mellékletek 1-A Bayesian networks approach for predicting protein-protein interactions from genomic data.pdf 1-Acute inflammation and negative mood- mediation by cytokine activation.pdf 1-Acute psychological stress and exercise and changes in peripheral leukocyte.pdf 1-Children's cortisol levels and quality of child care provision.pdf 1-Chronic stress alters the immune response to influenza virus.pdf 1-chronic_pain_injury_ptsd.pdf 1-Clinical depression and regulation of the inflammatory response during acute stress.pdf 1-Could Stress Play a Role in IBD.pdf 1-Critical periods of special health relevance for psychoneuroimmunology.pdf 1-Depressive symptoms and production of proinflammatory cytokines by peripheral blood.pdf 1-Detection of acute stress by Heart Rate Variability using a prototype mobile ECG Sensor.pdf 1-Double-exposure to acute stress and chronic family stress is associated with immune.pdf 1-Estimation of Mental Stress Levels Based on Heart Rate Variability and Stress Factor.pdf 1-Examination stress results in altered cardiovascular responses to acute challenge and lower.pdf 1-Examining psychosocial factors related to cancer incidence and progression- in search of the.pdf 1-How does stress get inside the body to influence depression- Some answers from the .pdf 1-IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental.pdf 1-Individual differences in executive functioning- Implications for stress regulation.pdf 1-Individual differences, immunity, and cancer- lessons from personality psychology.pdf 1-Inflammation and Oxidative Damage During Exam Stress.pdf 1-IS GLUTATHIONE DEPLETION AN IMPORTANT PART OF THE PATHOGENESIS OF.pdf 1-LIFE STRESSES AND EFFECTS ON ULCERATIVE COLITIS.pdf 1-Optimism Is Associated With Mood, Coping, and Immune Change.pdf 1-Pain-induced stress- a barrier to wound healing.pdf 1-Population-based Controlled Study of Social Support, Selfperceived.pdf 1-Positive social interactions and the human body at work- Linking organizations and.pdf 1-Post-traumatic stress disorder Advances in psychoneuroimmunology.pdf 1-pr-dr-feinberg-Epigenetics at the Epicenter.pdf 1-Preliminary Evidence on the Direction of Effects Between Day-to-Day.pdf 1-Psychological Stress and Disease.pdf 1-PSYCHOLOGICAL STRESS AND IMMUNE FUNCTION AMONG MILD ASTHMATICS.pdf 1-Psychological stress and immunity.pdf 1-Psychological Treatment May Reduce the Need for.pdf 1-Psychology's Gateway to the Biomedical Future Janice K. Kiecolt-Glaser.pdf 1-Psychoneuroimmunology- Psychological influences on immune function and health.pdf 1-quality predict cardiovascular response in family caregivers of Alzheimer's disease victims.pdf 1-responses to social threat- Evolution of a psychological model in psychoneuroimmunology.pdf 1-Self-regulation processes and health- The importance of optimism and goal adjustment.pdf 1-status and inflammatory processes in childhood asthma- the role of psychological stress.pdf 1-Stress and Immunity in Humans- A Meta-Analytic Review.pdf 1-Stress effects on lung function in asthma are mediated by changes in airway inflammation.pdf 1-Stress inoculation training- A preventative and treatment approach.pdf 1-Stress- Sources, Appraisal, Coping, and Effects.pdf 1-Stress, age, and immune function- toward a lifespan approach.pdf 1-Stress, depression, the immune system, and.pdf

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1-Stress, immune reactivity and susceptibility to infectious disease.pdf 1-STRESS, INFECTIONS AND ASTHMA.pdf 1-Stress_and_Alopecia_Areata.pdf 1-Stressful life events are associated with low secretion rates of immunoglobulin A in saliva.pdf 1-Stress-Induced Immune Dysregulation- Implications.pdf 1-The immune system under stress.pdf 1-The role of immune system parameters in the relationship between depression and coronary.pdf 1-WELLNESS MILESTONES.pdf 1-WHY HUMAN GRANDMOTHERS MAY NEED LARGE BRAINS.pdf

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300 Desplanque, B.-N.Hautekeete és mtsai (2002):”Transgenic weed beets: possible, probable, avoidable?”Journal of Applied Ecology 39 (4): 561-571 301 Diaz, M. és P Casali (2002): Somatic immoglobulin hypermutation.” Current Opinion in Immunology 14: 235240. 302 Dutta, C. és A. Pan (2002): „Horizontal hene transfer and bacterial diversity.” Journal of Biosciences (balngalore) 27(1 Supplement 1):27-33. 303 Gearhart, P.J.(2002)”The roots of antibody diversity.” Nature 419:29-31. 304 Gogarten, J.P. (2003):”gene transfer: Gene swapping craze reaches eukaryotes.” Current Biology 13: R-53-R54. 305 Haygood, R.-A.R. Ives és mtsai (2003):”Consequences of recurrent gene flow from crops to wild relatives.” Proceedings of the Royal Society of London, Series B: Biological Sciences 270(1527): 1879-1886. 306 Heritage, J. (2004):”The fate of transgenes in the human gut.” Nature Biotechnology 22(2): 170skk 307 Jordanova, L.J. (1984): Lamarck. Oxford, Oxford University Press. 308 Lamarck, J.-B. de M. 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A pszichoimmunológiáról Dr. Lázár Imre: Neuroimmunmoduláció és pszichoimmunológia Pszichoimmunológia, depresszió, T-sejt A pszichoszomatika egyik alapelve, hogy amennyiben a testi (szomatikus) betegségek képesek pszichés problémákat kiváltani, úgy ez visszafelé is igaz: tehát a betegségek is visszavezethetık lelki okokra. Innentıl már az orvos feladata eldönteni, mi volt elıbb, a tyúk, avagy a tojás, azaz a testi betegség vezetett a lelki betegséghez, vagy éppenséggel fordítva. A lelki problémák az immunrendszert számos ponton gyengíthetik, elnyomhatják. A gyászra, elhagyatottságra, veszteség-élményre jelentkezı depressziótól szenvedı betegek esetében tartós csökkenést észleltek a T-sejtes (T lymphocyták; speciális, az immunválaszban szerepet játszó fehérvérsejtek) válaszreakció tekintetében. A depressziós betegek ellenállóképessége romlik, ez a gombás fertızések, az influenza, a torok- és mandulagyulladások gyakoribbá válásában is megnyilvánulhat. Az idegrendszer és az immunválasz kapcsolatára utal például annak a kísérletnek az eredménye is, melyben egy kísérleti állat bal agyféltekéjének kéregállományának roncsolásakor az ún. T-sejtes immunválasz 150 százalékos csökkenését észlelték, míg az ellenoldali, azaz a jobb oldali agykéreg roncsolása során, ugyanezen sejtek aktivitását 140 százalékkal magasabbnak találták, mint a kontroll állatnál. A fokozottabb immunaktivitásért tehát a bal agyfélteke a felelıs. Azonban a két félteke aktivitása személyenként eltérı, van, akinek a jobb, van, akinek a bal agyféltekéje az aktívabb. Vizsgálatokkal bizonyították, hogy depressziós, szorongó személyiségeknél, illetve a tartós stressznek kitetteknél éppen a jobb agyfélteke az aktívabb, amely tehát gátolja az immunválaszt. A stressz normális esetben akut veszélyek, kihívások leküzdésére adott válaszreakció. Hatására szorongás, nyugtalanság lép fel, ugyanakkor csökken az új környezet iránti érdeklıdés, felderítı magatartás, csökken az operáns tanulás, és emlékezet. A stresszt kísérı antireproduktív (szaporodásgátló), növekedésgátló, és immunoszuppresszív (immunrendszer mőködését gátló) hatások tartós stressz esetén válhatnak kórképzı, betegséget okozó tényezıkké. A stressz okozta alvászavarok pedig, tovább rontják a helyzetet, ugyanis kedvezıtlenül hatnak az immunrendszerre. A T-sejtek szerepe fontos az immunválaszban: ha stressz, pszichés megterhelés nyomán arányuk lecsökken, akkor fekélyek, gyulladások, fertızések alakulhatnak ki. A tartósan fennálló családi konfliktusok is gyengítik az immunaktivitást: növelik a felsı légúti fertızések gyakoriságát. 94 családot megvizsgálva a kutatók úgy találták, hogy a stressztıl gyakrabban szenvedı csoportban a nátha elıfordulási aránya nagyobb volt. Egy másik tanulmány szerint a rendezetlen, illetve rigid (merev) családok stresszterhes légkörében az influenza iránti fogékonyság magasabb, mint a kiegyensúlyozott, harmonikus családokban élık esetében. Ha pedig már a felsı légúti hurutoknál tartunk: az e tekintetben végzett felmérések arra utalnak, hogy az alacsonyabb énerıvel rendelkezı vizsgálati alanyoknál a felépülés elhúzódóbb, míg a meg nem felelés, a szociális elszigetelıdés e betegségek gyakoribbá válásához vezet. A tudósok évtizedek óta végzenek kísérleteket, melyekkel a lelki problémák és a testi betegségek kapcsolatát igazolják, pl. allergia, skizofrénia, krónikus fertızések, de rákos megbetegedések esetében is. E tények figyelembe vételével beláthatjuk, hogy rohanó világunkban milyen nagy jelentısége lehet a pozitív élményeknek, egy összetartó családnak, de akárcsak egy kedves szónak, vagy egy megnyugtató mosolynak. Dr. Lázár Imre: Neuroimmunmoduláció és pszichoimmunológia Forrás: Farkas, M.; InforMed Hírek 2003;1 InforMed 2005-05-23 23:52:25

SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

Neuroimmunmoduláció és pszichoimmunológia Dr Lázár Imre, egyetemi adjunktus, PhD SOTE Magatartástudományi Intézet

1.1. Kutatási elôzmények - magyar kutatók hozzájárulása 1896-ban London és Savchenko kísérletében a korábban antraxra immunizált patkány agykéreg ablációt követıen vált ismét fogékonnyá a lépfene bacillus iránt. A Pavlov tanítvány Metalnikov, Speranskij és Chorin a húszas évek végén igazolta a gyulladásos folyamatok kondícionálhatóságát. Az adrenalin lymphocytaszám emelı hatását Hatiegan 1917-ben, Frey és Tonietti 1925-ben már észlelte. 1929-ben Erich Wittkower írta le a szorongás, düh, gyász, sıt a fokozott öröm állapotában is észlelt fehérvérsejtszám emelkedést, melyet az "Affektleukocytose" fogalommal jelölt, és a szimpatikus idegrendszeri stimulációval magyarázott (Schedlowski 1994). A magyar kutatók is meghatározó szerepet játszottak a pszichoimmunológia kialakulásában. A negyvenes évek elején a vegetatív idegrendszernek a fehérvérsejtekre kifejtett hatását kolozsvári magyar és román kutatók, így Hadnagy és Baciu is vizsgálták. A pszichoneuro-immunológia hálózati modellje sejlik fel a Selye János által megfogalmazott Általános Adaptációs Szindróma tüneti triászában, ezt az összefüggést sejteti a mellékvesekéreg nagyobbodása és a nyirokszövetek egyidejû megkisebbedése. Hasonlóképpen meghatározó jelentıségû Szentiványi Andor kísérlete 1957-ben, aki az anterior hypothalamus sértésével kivédte az egyébként kikerülhetetlen anaphylaxiás shock választ a beadott lószérumra. Ezek a kísérletek mind megelızték a pszichoimmunológiai fogalmának megszületését, nélkülük azonban aligha beszélhetnénk ma errıl a tudományterületrıl. A testfelületi neuroimmun jelenségek, a neurogén gyulladásos jelenségek tanulmányozásával Jancsó Miklós jelentıs eredményekkel járult hozzá a neuroimmunmoduláció alapvetéséhez az ötvenes években. A kortársi neuroimmunomoduláció magyar kutatói közül Berczi István, Bohus Béla, Endrıczi, Fóris Gabriella, Korányi Lajos, Nagy Éva, Nyakas Csaba, Vizi E. Szilveszter, Szelényi Judit neve emelhetı ki a teljesség igénye nélkül.

A neuroimmunmoduláció a központi idegrendszer és az immunrendszer közötti kétirányú kommunikációval és befolyással, illetve e kommunikáció révén mûködı szervezetszintû neuroimmun szabályozással foglalkozik. Az egységes (pszicho)neuroimmun szabályozás tényére utal, hogy a neuroendokrin és immunmediátorok mindkét rendszerben termelıdnek, és egymás termelésére serkentı, illetve gátló hatást fejtenek ki, azaz "közös nyelv" elemei. A neuroimmun szabályozási körökben "sorba-kapcsolva" látunk interleukint, neurotranszmittert, releasing faktort, trophormont és hormont. Az immun-, és idegrendszer közötti kommunikációban a gyors, lökésszerû információt a neurotranszmitterek szolgáltatják, míg a neuropeptidek - a filogenetikusan ısibb- elnyúlóbb, és a neurotranszmitterek hatását moduláló befolyást fejtenek ki. A hormonok a neuroendokrin-immun folyamatokat tartós átfogóbb "állapothatározó" hatásukkal tagolják a szervezet adaptív, anyagcsere folyamataiba. A törzsfejlıdés során késıbb kialakuló immunfolyamatok számára az ısi neuropeptid humorális alkalmazkodási hírvivık, mint a substance P, endorfinok, cortisol már létezı mikrokörnyezetet képeznek. A teljes genom ezt lehetıvé teszi, hogy az immunsejtek éppúgy rendelkezzenek stresszhormontermelı potenciállal, mint az endokrin sejtek, de a lekötött génszakasz csak vírussal fertızıtt immunsejtekben aktiválódik. Ilyen "virocyták" képesek ACTH, és beta endorfin és trophormonok termelésére is (Blalock 1985).

Neuroimmunomoduláció

2. A neuroimmun kommunikáció - az immun és idegrendszer közötti interakcionista model


Neuroimmun információs csatornák Központi idegrendszer Hypophysis Vegetatív idegrendszer Agyi szekretumok FSH, LH acethylcholin corpus pineale szekrétumok (pl. elatonin) TSH -thyreoid hormonok noradrenalin somatostatin ACTH - glükokortikoidok serotonin neurotensin vasopressin somatostatin bombesin oxytocin VIP enkefalinok neurophysin enkefalinok + CCK beta-lipotropin substance P beta-endorfin cholecystokinin fibroblast GF thymocyta GF endothelial GF immunfolyamatok somatostatin VIP substance P tachykininek Szenzoros ganglionok Perifériás idegrendszer Bır "Bél" agy-GALT BALT MALT

1.1. Fejlıdéstani összefüggések Az adaptációs mintázatok evolúciója neuro-endokrin-immun információs tényezık integráltságát ırzi. Ez az integráltság a szervközi fejlıdési kapcsolatokban is érvényrejut. A velıpajzs sértése nyomán kialakuló immunzavarok, a thymectomia nyomán lecsökkent hypophysis hormonszint jelzi ezt. És erre az integráltáságra utal a kísérleti patkányokban megfigyelhetı sajátosság is, hogy a denervált lépben a thymus eredetû immunsejtek nem telepednek meg. Mindez jelzi, hogy a két rendszer érésése, kialakulása is igényli a másik jelenlétét, így egymás környezetei és feltételei is.

Thymus (csecsemımirigy): a T sejtvonal érésében döntı szerepet játszó mirigy, mely bıséges vegetatív beidegzése mellett, endokrin szerepû, illetve hormon-receptorokkal rendelkezı sejtjei révén neuro-endokrin-immun csatoló szerepet tölt be. A thymus lymphoendokrin szerepét bizonyítja, hogy thymulin, thymopoetin, TF V. faktorokat termel. Az endokrin funkció bizonyítéka, az is, hogy a korai thymus-eltávolítás az adenohypophysis hormonelválasztását befolyásolja (növeli a sejtek prolaktin granuláinak számát, és ellentétesen hat a növekedési hormon tartalmára). A thymus hiányában kialakult hormonszintváltozásokat (ACTH, cortisol, LH, tesztoszteron) a thymosin V. faktor szünteti. A hormontermelés tényének további igazolója, hogy egyes thymus sejtek a velıállományban és a subcapsuláris területen oxytocin és vazopresszin termelésre képesek.A thymushormont termelı sejtek idegi, peptiderg hatás alatt állnak, a pszichohumorális befolyás közvetítıi az endorfinok és az enkefalinok.A thymus és a neuroendokrin hatás hurokszerû kölcsönös befolyását jellemzi, hogy a thymosin-alfa-1, és V.faktorok nyomán a prolactin szekréció fokozódik, és a prolactin fokozza a thymulin elválasztását az epitheliális sejtekben. Ha újszülött korában a kísérleti állat thymusát eltávolítják, akkor a T3,4 pajzsmirigyhormonokban 50-80 %-os csökkenést észlelünk, csökken a mellékvesék tömege, a cortisol szintje és csökkenést észlelünk a nemi hormonok és serkentıhormonjaik szintjében is. Az újszülöttkori thymuseltávolítás a központi idegrendszerben is nyomot hagy. Immunsejt--idegsejt kölcsönhatásra utal az a tény, hogy ha a thymus eltávolítása miatt a lép T sejtekben szegénnyé válik, akkor a beidegzés megritkul, majd az arteriolák körüli állomány és a marginális sinus területén fluoreszcens technikával is alig lehet kimutatni idegrostokat.A lép beidegzésének fenntartásához szükséges a T lymphocyták jelenléte, melyet az általuk termelt SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

idegnövekedési tényezı, a NGF révén biztosítanak.

2.2. A neuroimmun rendszer információs anatómiája A féltekei kéregabláció lehetıséget kínál az agykérgi folyamatok és az immuntörténések kzötti kapcsolatok feltárására. Ennek jelentıségére utal Kang és Davidson megfigyelése, hogy a jobb féltekei (frontális alfa aktivitásban kifejezıdı) dominanciájú gyermekeknél az NK sejt aktivitás csökkent, és a depressziós viselkedéstendenciák voltak a jellemzık. Ha a kísérleti állat bal féltekéjének kéregállományát távolítjuk el, akkor a mitogénre adott Tsejtes immunválasz 150 %-os csökkenését észleljük, míg az ellenoldali kéreg eltávolítása, 140 %-os fokozódást mutat a T sejtek mitogénre adott válasza a sértetlen agyú kontrolállattal szemben. A féltekei szelektivitás hasonlóképpen érvényesül a humorális immunválasz esetén is, mert a bal féltekei roncsolás nyomán csökken az Ig G termelés, míg a jobb féltekei roncsolása fokozza az Ig G termelést. Egyes adatok tanusága szerint a jobb félteke parietooccipitális területének roncsolása nyomán az immunválasz csökkenése figyelhetı meg. Az érzelmi és magatartási folyamatok szervezıdésében oly fontos limbikus rendszer: a hippocampus, a gyrus dentatum, a kiterjesztetten értelmezett amygdala (centromediális amygdala, és a terminális striák nucleáris tartimánya) a gyrus cingulatus, a striatum ventrális része, a septum és a thalamus elülsı, és középsı magvai és a habenula bonyolult hálózatot alkotnak. Az immunmodulációban a hippocampalis-amygdala rendszer és a nucleus accumbens szerepe emelhetı ki. A limbikus rendszer az immunfolyamatok idegi hatásában is közvetítı szerppel bír. A dorsális hippocampus a glükokortikodiok HPA tengelyre kifejtett negatív feed-back hatását modulálja, aminek fontos immunológiai következményei lehetnek. (Jacobson, Sapolsky 1991) A tartós glücocorticoid expositió a hippocampális neuronokra kedvezıtlen hatást fejthet ki, ( Sapolsky 1990), és mindez csökkentheti a cortisol negativ feed back hatását a CRH-HPA tengely aktivitására. Az amygdala központi és mediális magva szintén szerepet játszik az ACTH szekréció szabályozásában.(Feldman 1994) A dorsális hippocampus és az amygdala komplex sértése a splenocyták, és thymocyták számának átmeneti növekedéséhez vezet (Brooks 1982), míg ezeket a hatásokat a hypophysectomia visszafordítja (Cross 1982). Az amygdala és a cortex cingulata kis elektrolitikus léziói nyomán észlet immunelváltozásokról Masek és mtsai számoltak be. (Masek 1992) A nucleus accumbens dopaminerg baloldali rostjainak károsítása csökkent lép NK sejt aktivitást vált ki, míg a striatum dopaminergiás rostjainak jobb oldali károsítása vezetett a lép lymphocytinak csökkent proliferációjához. ( Deleplanque 1994) A mélyebb agyalapi magvakat vizsgálva az anterior hypothalamus roncsolása gyengíti az antigénre adott immunválaszt, és a thymus és a lép sejtes állománya is csökkenést mutat. Még ısibb, noradrenerg rostokban gazdag és az arousal állapot felkeltésért felelıs központ a locus coeroleus, melynek roncsolása nyomán patkányban csökkent a bovin albumin ellenes antitest termelés, és csökken a thymus nagysága, és a CD4 T helper/inducer sejtarány is a periférián. Korneva a locus coeroleus roncsolása nyomán a immunsejtvonalba lépı ıssejtek számának csökkenését írta le. A stresszválasz központi csomópontjai a HPA (hypophyseo-adrenális) tengelyt vezérlı CRH neuronok (paragigantocelluláris magvak), az arg-vasopressin és CRH termeléséért felelıs paraventriculáris hypothalamus magvak és a szimpatikus idegrendszeri mozgósításért felelıs locus coeroleus. A CRH szekréció és a locus coeroleus között reciprok, feed-back viszony áll fenn. A CRH termelést csökkenti a központi idergendszerben termelıdı SP. A neuroimmun hatások között kell említenünk a szubakut CRH adás nyomán észlelt NK sejt aktivitás csökkenést, és a lymphocytaproliferáció gátló szerepét. Ezt nem lehetcsak az ACTH-cortisol tengelynek tulajdonítani, mert a szerzık észlelték adrenalectomizált és hypophysectomizált állaton is. (Jain 1991) A CRH nemcsak a HPA tengely révén éri el az immunrendszert, hanem a szimpatikus idegrendszer (NA/ NPY rostozat) révén is. Friedman és Irwin (1995) szerint az egyébként anxiogén CRH mint stresszhormon perifériás immunszuppresszív hatását a vegetatív idegrendszer szimpatikus rostozata útján közvetíti, melyet mind a kémiai szimpatektomia, mind a beta adrenerg blokád felfüggeszt. A szintén adrenerg aktivitás fokozódással járó idıskorban, illetve depresszióban észlelt immunszuppressziót is ezzel a jelenséggel magyarázhatónak vélik a szerzık. A stressz folyamatok perifériáját képezi a hypophyseo-adrenális rendszer, melynek mûködését a CRH mellett potenciálják az angiotensin II, a cytokinek, és gyulladásos lipid mediátorok is. A glükokortikoidok a szervezet homeosztázisában és a stresszben is központi tényezık, és a HPA tengely basalis aktivitásában kulcsszerepet játszanak. a stressz válasz negatív feed back-szerû lecsengetése mellett. A neuroimmun folyamatok vizsgálatának másik irányát nyújtják az ingerléses vizsgálatok. A hypothalamus ingerlésével a phagocytózis fokozódása jár együtt, míg a tuberális és mamilláris terület ingerlése fokozza a plazmasejtek antitesttermelését. A mesencephalikus területek vagy a posterior hypothalamus ingerlése csökkenti az antitesttermelést. SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

1. A katekolaminerg csatorna Az elsıdleges (csontvelı, thymus) és a másodlagos ( lép, nyirokcsomók, BALT, MALT, GALT) nyirokszervek beidegzése "huzalozott" kapcsolatot jelent az idegrendszer és az immunrendszer között, mely fıként, mintegy 90%-ban noradrenerg, és kisebb mértékben cholinerg és peptiderg rostok révén teljesül. A kéreg alatti magvakból induló noradrenerg pályák a gerincvelı középsı (intermediolaterális) szarvában húzódnak, majd átkapcsolódnak, és myelinmentes rostok a kiserek mentén lépnek be a nyirokszervekbe, mint a csontvelı, thymus, lép, és nyirokcsomók, és a T sejtek, illetve a pazmasejtek közelében végzıdnek. Közvetlen sejt-sejt kontaktus is lehetséges ("tight junction" kapcsolat), bár gyakoribb, ha a mediátor a receptorokhoz diffúziós úton jut el. Receptorok: Adrenerg receptor található T és B lymphocytákon, thymocytákon, granulocyta fehérvérsejteken. A lymphocytán található dopamin és szerotonin receptor is. Az immuntörténés alatt a receptorsûrûség változik a sejtek felületén, mely a külsı jelzések összegzıdésének, és a sejt következményes belsı történéseinek, aktiváltságának eredıjeként állítja be a sejt érzékenységét, és közvetve meghatározza annak késıbbi viselkedését is. A Con A mitogénre adott proliferáció nyomán a beta adrenoceptor sûrûség csökkent, míg a proliferáció gátlása ezt a jelenséget visszafordította. Ugyanakkor az immunfolyamat késûbbi idıszakában, az immuntörténés 2-3 napján a lymphocytán található beta adrenoceptorok sûrûsége 30-40%-al is nıhet, mely a negatív feed back részeként is értékelhetı. Pszichomotoros agitációval társuló endogén depreszióban szenvedı betegeknél a lymphocyta beta adrenoceptorok csökkent érzékenységét észlelték. Hatás: A noradrenerg hatások az elsıdleges nyirokszervekben (csontvelı, thymus) a béta adrenoceptorok által közvetített, az érési folyamatokat serkentı, míg az érett, az " immunperiférián" található sejteket a noradrenerg hatások gátolják. Heilig (1993) szerint a katekolaminok gátolják az antigén processzálást és prezentációt, az IL-2 termelést, és közvetve a T helper funkciót. A neuroimmun stresszfolyamat során a szimpatikus idegrendszer reciprok kapcsolatban áll a CRH rendszerrel, és aktiválódva az IL-6 szisztémás szekrécióját fokozza. Az IL-6 aktivációja a TNF alfa, és az IL-1 közvetlen gátlásával, és a HPA tengely aktiválásával szerepet játszik a stressz által elıidézett immunszuppresszióban. A szimpatikus beidegzés szerepet játszik a stressz immunszuppresszív hatásainak közvetítésében, sıt pathofiziológiai szerepe van a kísérletes és klinikai izületi gyulladás (Lorton 1996), vagy a kísérletes autoimmun myasthenia gravis (Agius 1987) kialakulásában és progressziójában. Allergiás (atópiás és asthmás) betegeknél a központi idegrendszer és az immunsejtek egyaránt csökkent mértékben termelnek katekolaminokat. A készenléti (arousal) állapotért felelıs NAerg centrum, a locus coeroleus kiírtása nyomán a lymphoid sejtvonalba a törzssejtek részérıl képzıdı utánpótlás lecsökken. Az adrenerg hatások tehát az elsıdleges nyirokszervekben zajló érési folyamatokra serkentı, míg a periférián a lymphocyta aktivitásra gátló hatást fejthetnek ki. A lép T sejtjeinek mitogénre adott válaszcsökkenését béta blokkolóval ( nadolol, propranolol) felfüggeszthetjük.

2. Cholinerg csatorna A cholinerg hatást a n. vagus rostjai közvetítik. A jelfogadásért a lymphocytákon kimutatható muscarinerg és nicotinerg cholinreceptorok felelısek. Ugyanakkor az immun rendszer nem rendelkezik cholinerg beidegzéssel. Egyes szerzık leírták a thymus cholinerg beidegzését (Bulloch 1988). Singh és Fatani (1988) szerint a thymusbeli lymphocytaérésre és az apoptozisra (Rinner 1994) a paraszimpatikus aktivitás is befolyást gyakorol. Általánosságban elmondható , hogy a lymphocyta intracelluláris cAMP szintjét növelı mediátorok gátló hatásúak, a cGMP szintet növelı anyagok serkentı hatást közvetítenek. Fıbb immunserkentı hatású mediátorok: cholinerg agonisták, substance P, prolactin, növekedési hormon, Fıbb immungátló hatású mediátorok: cortisol, VIP, adrenerg agonisták, somatostatin, vegyes hatású mediátorok beta endorphin, met enkephalin,

3. Stressz hormonok A stresszfolyamat során a CRH (cortico-releasing hormon) az un. POMC (proopiomelanocortin) polipeptid hasításával szabadítja fel a glükokortikoidot mobilizáló ACTH-t, és a béta endorfint. A CRH közvetlen immunológiai befolyása is felvethetı, mivel a keringı fehérvérsejtekben kimutatható immunreaktív CRH (és az azt kódoló CRH mRNS is), mely a lymphocyták aktivációjával jelenik meg. A néhol ellentmondásos adatokat összefoglalva a CRH a keringı fehérvérsejtekben az IL-1, IL-2 , a monocytákban az IL-6 termelést fokozza, mérsékli az LPS kiváltotta IL-1, IL-2 temelést a mononucleáris sejtekben, fokozza a lymphocyta proliferációt, és az IL-2 receptor expressziót. Továbbá gátolja az IL-2 indukálta splenocytaproliferációtm fokozza az SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

NK sejt kiváltotta sejtlízist, és indukálja a leukocyták ACTH és beta endorfin szintézisét. (Crofford 1995) A CRH kimutatható a capsaicin érzékeny (C-rostok) idegrostokban is, és a szimpatikus idegrendszerben.(Skofitsch 1984) A CRH perifériális szerepe a lokális szöveti gyulladásban is kifejezett lehet, ha carragenin provokálta kísérletes gyulladásos exsudatum mennyisége csökken a CRH immunneutralizálásával.(Karalis 1991) A gyulladást támogató hatással szemben a CRH csökkenti a Substance P kibocsátást. Mindez jelzi a stresszhormonok által hordozott üzenetek "szemantikai" többrétegûségét, és kontextusfüggıségét. Más streszhormonok is, mint az arg-vasopressin, prolactin, és a növekedési hormon befolyásolhatják az immunfolyamatokat.

3.1. A cortisol immunológiai hatásai Gátlás: 1. A lymphocyta közlekedés gátlása, a keringı lymphocyták száma átmenetileg csökken 2. Az idegen , illetve saját eredetû antigénekre adott T sjetes immunválasz csökken. 3. Csökken a mitogénre adott IL-1, IL-2, és a T sejtes növekedési faktor termelése. 4. Csökken a monocyta-macrophag átalakulás, és csökken a HLA-DR (Ia.) receptor megjelenítése, és a macrophag mitogén, illetve IL-1 iránti érzékenysége. 5. Csökken az autológ kevert lymphocyta reakció. 6. Gátló hatás a betegségek során jelentkezı a CD8 T sejtvonal Con A, és Pwm mitogénekre adott válaszát illetıen. 7. Csökken a B sejtes immunválasz, a Pwm mitogénre adott plakkképzés. 8. Fokozza az apoptozist, a T sejtklónok pusztulását. Serkentı hatás: 1. In vivo serkentı hatás az ADCC és NK sejtes aktivitásra. 2. In vitro serkentı serkentı hatás nanomoláris koncentrációban az immunglobulinszintézisre.

3.2. Prolactin A prolactin is stresszhormonnak tekinthetı, hiszen az akut fizikai vagy pszichoszociális stresszorhatás gyors, jelentıs és átmeneti prolactin elválasztáshoz vezet, bár a stresszorhatás ismétlıdése után az ingerre refrakter csökkenés jelentkezik. A krónikus stressz a prolactin elválasztását csökkenti, és ezt a dopamin antagonistával (haloperidol) fel lehet függeszteni. Az újabb megfigyelések alapján egyértelmûnek tûnik a prolactin immunstimuláns szerepe. Ha dopamingátló szer (sulpirid, metoclopramid ) adásával fokozzuk a prolactin elválasztást, a mitogénekre adott T sejtes válasz is fokozódik. A prolactin megfelelı dózisban képes ellensúlyozni a cyclosporin, és cortisol hatását is. Adagolására azonnali, azonnali génaktivációt, proliferációs sejtválaszt észlelünk. A csontvelıben a prolactin a hemopoezis fokozódását váltja ki, és serkentı hatást fejt ki a thymusban, és a lépben egyaránt.Berczi és Nagy (1994) szerint a csontvelıi, thymusbeli történések, immunfolyamatok során a növekedési tényezık, és cytokinek helyi termeléséhez a hypophyseális prolactin és növekedési hormon jelenléte szükséges. Clevenger és munkatársai (1992) in vitro igazolták, hogy a helper T sejt lymphocyta vonal proliferációjához az antigén, az IL-2 és a prolactin jelenléte egyaránt szükséges volt a sejttenyészetben. Az idıskorral csökkenı immuntevékenység, T sejt mitogénre adott válasza, és az IL-2 termelés helyreállítható prolactin adásával. Érdekes módon az élettaninál nagyobb prolactin koncentráció csökkentheti az NK sejt aktivitását, de az élettani koncentráció fokozza a cytotoxikus aktivitást. Bromocríptin adás csökkenti a T és B sejt választ. Ennek klinikai jelentıségét a tartós Parlodel kezelés alatt állóknál kell megvizsgálni. Igazolódott az is, hogy egyes T sejtvonalakban , illetve B lymphoblastoknál a prolactin elválasztás kimutatható, mely újabb bizonyítéke annak, hogy az idegrendszer és az immunrendszer legalább részben közös nyelvet beszél. Itt is, csak úgy mint az ACTH, a beta-endorfin egyaránt kell számolnunk hypophyseális, és helyi immunocyta eredetû endokrin-immun hatással.A proimmun hormonok is befolyásolhatják a neuroimmun adaptációt. Az autoimmun folyamatokat serkentı hatású lehet a prolactin, ösztrogén és a progeszteron többlettermelıdés is. A prolactin ilyen szerepét észlelték hyperthyreosisban, sarcoidosisban, iritisben és SLE-ben szenvedı betegek esetében is, az ilyenkor alkalmazott bromocryptin kezelés jótékony hatásúnak bizonyult. (Walker 1994 ) 3.3. Növekedés hormon Ez a hormon (GH) is egyaránt tekinthetı stresszhormonnak és anyagcsere hormonnak, mely egyaránt fokozza a macrophagok antigénmegjelenítı képességét, az IL-1 termelését, és a tumorpusztító, baktericid szabadgyökgeneráló hatást. A növekedési hormon maga is hormon- illetve neuromediátor hatások fókuszában áll. SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

Kettıs hypothalamikus szabályozás érvényesül, serkentı hatást gyakorol a GRF, a somatostatin gátló hatású Talán nem meglepı, hogy a keringı fehérvérsejtek, és a lép T sejtjei is rendelkeznek a GRF és a GH receptorával is, és termelnek növekedési hormont, melynek így az immunfolyamatokban is a sejtaktivitást, sejtérést fokozó szerepe érvényesül. A növekedési hormon fokozza a T lymphocyták cytolitikus aktivitását, az IL-2 szintézisét, a NK sejt aktivitását, a TNF termelését, vagy a thymulin (thymus hormon) szintézisét. A fehérvérsejt differentációját, illetve a macrophagok szabadgyök képzését a GH egyaránt fokozza, így a lymphocyták által termelt, lokálisan felszabaduló GH akár lymphokinnek is tekinthetı.

3.4. A melatonin A környezethez való alkalmazkodás az idıhöz való alkalmazkodást is jelenti, ilyen kronobiológiai jelentısége van a melatoninnak. A tobozmirigy termeli ezt a hormont, mely igen bıséges idegi kapcsolattal rendelkezik, egyebek között a látópálya felıl is. A megvilágítás megzavarhatja a melatonin elválasztás diurnális (24 óra alatti) ritmusát, és ezt a hatást valószínûleg adrenerg mechanizmus közvetíti, mert propranolollal is el lehet érni hasonló zavaró hatást. Emlıtumorban szenvedı nıbetegeknél észlelték, hogy az éjszakai melatonin szint emelkedése elmaradt. A melatonin ellensúlyozhatja a glükokortikoidok immunszuppresszív hatását, amit a melatonin-ID(immunderivált)opioid-immunocyta pályán vélnek a kutatók érvényrejutni. Állatkísérletben EMC vírussal fertızıtt és melatoninnal kezelt állatok zöme a kezeletlenekkel szemben a fertızést túlélte. Mivel a lymphocyták nem rendelkeznek melatonin receptorral, és a naltrexon felfüggeszti a melatonin immunserkentı hatását, ezért a melatonin hatásában az opioidok közvetítı szerepét tételezzük fel.

3.5. Insulin Az anyagcserehormonok között említésre méltó még az insulin, mely a T sejt növekedési faktorának tekinthetı, az insulin az aktivált T sejtek készültségi fázisát tartja fenn, és a lymphocyták cytotoxicitását serkenti. Az insulin jelentıségére utal az is, hogy insulin függı diabétesben az allergiás folyamatok enyhébbek, az átültetett szövet jobban megtapad, és a fertızésekre is fokozott hajlamot mutat a beteg.

3.6. Thyroxin A lymphocyták felületén van T3 receptor, és a thyreoid hormonok adása nyomán mitogén aktiválás nélkül is fokozódhat a T sejtes differentáció, és a plazmasejt aktiválódása.A thyroxin a thymus thymulin termelését fokozza. Thymus atrophia nyomán csökkent idıskori immunitás is javítható thyroxin adásával.

3.7. Szexuálhormonok A nemi érést követı thymusinvolució arra utal, hogy a nemi hormonok befolyásolják az immunrendszer állapotát. Az ösztrogén T lymphocyta funkciót csökkentı hatását a cytoplazmatikus ısztrogén receptorok közvetítik, melyek kimutathatók a thymus és a lép lymphocytáiban ugyanúgy, mint más mononucleáris sejtekben.A gyógyszeresen adott ösztrogén (pl prosztatarákban) is csökkenti a T helper sejtek számát, és az IL-2 szintézist, negatívan hat a thymus epiteliális rétegére. Fogamzásgátlót szedı nık esetében csökken a celluláris immunitás. Csökken a NK sejt aktivitás, és a szuppresszor sejtvonal aktivitása.Ez utóbbi magyarázhatja a fokozott humorális immunaktivitást. A nemi hormonok hatásának kasztráció útján történı megszüntetése nyomán a thymus eredeti tömegében, és szöveti szerkezetében, cellularitásában áll vissza. A szexuálszteroidok hatásáról Stimson, illetve Nelson és Steinberg összefoglalójában olvashatunk bıvebben a Berczi István és Kovács Kálmán által szerkesztett Hormones and Immunity (1986) kötetben.

4. Neuropeptid hatások Az érzelmi és kognitív folyamatokért felelıs neuroanatómiai szervezıdések a pszichoimmunomodulációban is döntı jelentıséggel bírnak, melyek közvetítésében a neurpeptideknek fontos szerep jut. A peptiderg hatások lehetıségére utal az elsıdleges és másodlagos nyirokszervekben a SP, SS, VIP, neuropeptid Y, enkephalin, endorphin, vazopresszin immunfluoreszcens technikával kimutatható jelenléte. Ezeket a peptideket az enkefalinokkal együtt szimpatikus vegetatív idegrendszeri rostok is tartalmazzák, míg a paraszimpatikus beidegzés cholecystokinin, substance P, és TRH peptideket szállít. A nyirokszervekben a neuropeptid-tartalmazó idegrostok jelenléte tehát az immun célsejtek, illetve immunfolyamatok neuromoduláns hatásoknak való kiszolgáltatottságára utal. A célsejt serkentését vagy gátlását SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

elıidézı neuropeptid származhat az említett helyi idegvégzıdésbıl, vagy elérheti a nyiroksejtet a hypothalamushypophysis tengelybıl a keringésbe jutva, s végül lehet forrása akár immunsejt is.

4.1.Az opioidok Stresszpeptidek analgetikus, euphorizáló, NK sejt aktivitás fokozó hatással. Szerepük nagy a korai szociális tanulás folyamatokban, és az imprintingben. Hatásukat felfüggesztve (naloxon, naltrexon) az ivadék az anya jelenlétében is szeparációs traumát él meg, az opioidok megfelelı szintje szükséges az imprinting létrejöttéhez. Ugyanakkor a tanult tehetetlenség immundepresszív kövretkezményekkel járó folyamatában is szerepe van a központi opioid folyamatoknak. T lymphocyták Met-enkefalin

antigénspecifikus cytolízis csökken aktív T sejt rozettaképzıdés nı Beta-endorfin PHA -okozta proliferáció csökken antigénspecifikus cytolízis csökken Con A -okozta proliferáció nı T sejtes szuppresszor aktivitás nı IL-2 szintézis nı Dynorphin Antigén specifikus cytolizis csökken PHA -okozta proliferáció nı B lymphocyták Alfa-endorfin antigén okozta antitestválasz csökken NK sejtek Met-enkefalin természetes cytotoxicitás nı ConA kiváltotta interferontermelés nı Leu-enkefalin természetes cytotoxicitás nı Alfa, Gamma endorfin természetes cytotoxicitás nı Beta-endorfin természetes cytotoxicitás nı ConA kiváltotta interferontermelés nı PHA, Poly I:C kiváltotta interferontermelés nı Granulocyták Met-enkefalin felületi tapadósság nı chemotaxis nı superoxid termelés nı Leu-enkefalin superoxid termelés nı Beta-endorfin chemotaxis nı felületi tapadósság nı superoxid termelés nı Dynorphin superoxid termelés Monocyták Met-enkefalin chemotaxis nı Leu-enkefalin fagocytozis csökken HLA-DR expresszió csökken Beta-endorfin chemotaxis nı phagocytózis csökken membrán HLA-DR expresszió csökken

5. A környéki idegrendszer immunmoduláns neuropeptidjei SP

chemotaxis fokozódik phagocytosis nı lymphocytaproliferáció nı gyulladásos jelenségek fokozódnak Somatostatin lymphocyta proliferációgátlás VIP lymphocyta migrációgátlás anergia Substance P SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

A szenzoros C rostok mediátora, a fájdalomérzet közvetítésében, a sérülés helyére a lymphocyták "regrutálásban" és a gyulladásos folyamatok felerısítésében van nagy szerepe. Tartós gyulladásos folyamatokban a központi idegrendszer Substance P tartalma is megnı, és ez gátló hatást fejthet ki a CRH-ra, megzavarva a gyulladásgátló negatív feed-back folyamatokat. Az autoimmun betegségek, és krónikus gyulladásos folyamatok (ld. rheumatoid arthritis, Crohn betegség) döntı tényezı a Substance P A bırbıl illetve a belsı nyálkahártyafelületekrıl környéki ingereket közvetítı C rostok is immunológiai hatású mediátorokat tartalmaznak, mint a substance P, és más tachykininek, továbbá a somatostatin, VIP. A Substance P különös jelentıségét az adja, hogy fıszereplıje a testfelszín, és belsı nyálkahártyafelszínek immunvédelmi vonalaiban szerepet játszó idegi tényezıknek. A gerincvelı hátsószarvi szenzoros, és nociceptív neuronjai tartalmazzák, de az idegrendszer szinte minden pontján megtalálható. Fıszerepet játszik a bır, a bélhuzam, a nyálkahártyák és az izületek gyulladásos történéseiben. A Substance P (SP) hatásai közé tartozik a gyulladásos reakció számos mozzanata, a vasodilatáció, exsudáció fokozása, a leukocyták, monocyták érfalhoz való kitapadása és a hízósejtek hisztaminszekréciójának fokozása. A SP fokozza a granulocyták superoxid képzését, és chemoattractáns hatással is rendelkezik, a sérülés, gyulladásos reakció helyére vonzza a sejteket. Az SP lehet felelıs a TNF, alfa és gamma interferon és az IL-1 termelés fokozásáért. Az SP fokozza a bélbıl izolált plazmasejtek Ig A termelését, a lépbıl izolált sejtek esetében ez az Ig A-ra és az Ig M-re egyaránt igaz. A helper és szuppresszor T, és a B lymphocyta egyaránt rendelkezik SP receptorral. Somatostatin A somatostatin gátolja a lymphocytaproliferációt, serkenti a hisztamin kibocsátását a hízósejtekbıl, de gátolja a basophil sejtek hisztamin szekrécióját. Mindezzel stabilizálja a szöveti sérülés folyamán fellépı gyulladásos reakciót. Korlátozó hatása az immunglobulin szintézisre is kihat. VIP A VIP (vasointestinális polipeptid) a folyamatokat felerısítı SP-vel szemben az immunfolyamatok lecsengetéséért felelıs, mert gátolja a T sejtek migrációját a mesenterális nyirokcsomókba, és a bél Peyer plakkjaiba. A neutrophilekbıl felszabaduló VIP lokális vasodilatációt eredményezhet, mely a mediátorok kimosását is elısegíti. Ugyanakkor a VIP gátolja a thymocyták proliferációját, a nyiroksejtek IL-2 termelését, és a Peyer plakkokban nı az Ig M és csökkent Ig G termelést mutatnak VIP hatására. A VIP gátolja az NK sejtek aktivitását, bár a VIP-el történt elıinkubáció nyomán az NK sejt aktivitás akár nıhet is. VIP a mononucleáris sejtekben, hízósejtekben, basophilekben is kimutatható, a VIP peptidvariánsok és a rájuk specifikus receptorok behatárolják az ilyen peptidek szerepét. Az immunocytákból származó VIP peptidek idegi hatása lehet egyszerû negatív feedback, mellyel a további VIP preszinaptikus felszabadulását gátolja az immunrendszer. Immuno-neurális stresszfolyamatok Az immunoneurális stresszfolyamatok fı tényezıi a TNF-alfa, Az IL-1, és az IL-6, melyek a HPA tengelyt egymással szinergiás módon módon serkentik. Hatásukat a CRH- neutralizáló antitestek, a prostanoidszintetázgátlók, és a glükokortikoidok egyaránt semlegesíteni tudják. Talán az IL-6 hatása a legkifejezettebb az HPA tengely immunstimulációja során. Az IL-6 nyomán elıálló ACTH és cortisol emlekdés jelentısebb, mint a CRH maximális serkentı dózisával elérhetı érték, ami más serkentı tényezık (pl. AVP) részvételét sejtetik. Mindez magyarázhatja a gyulladásos betegséget kísérı váratlan fokozott antidiuretikus hormon termeléssel jellemzett szindromát, a " SIADH" kórjelenségét is. Az immun-neurális feed-back csatolópontja lehet a vér-agy gát ablakjának tekinthetı eminentia mediana, vagy a lamina termiális circumventriculáris szervének erezetében végzıdı közti neuronok ingerlése. De ezek a cytokinek a megindított paracrin és autocrin folyamatok révén, az endothel sejtek, gliasejtek és cytokinerg neuronok közvetítésével is elérhetik a CRH illetve AVP szekretáló neuronokat. A tartós gyulladásos folyamatok során megfigyelt centrális Substance P koncentráció növekedés, és a megfigyelt CRH/AVP arány csökkenés hátterében a Substance P CRH csökkentı hatása is felmerül. Ezt a trypanosomiasis, az AIDS, és a kiterjedt gyulladásos folyamatok esetén is megfigyelték. A keringés kínálja az immun-neurális hatások egyik útját. A cytokinek esetében a vér-agy gát teheti kérdésessé az immuno-neurális hatásirányt, valójában azonban számos ablakot találunk a belsı környezetre, mint amilyen az eminentia mediana, az organum vasculosum laminae terminalis (OVLT) vagy a subfornicális szerv. Ugyanakkor Gutierrez felveti a cytokinek aktív transzportját a vér-agy gáton át. (Gutierrez 1994). Az eminentia mediana közvetlen idegi kapcsolatokkal rendelkezik a HPA tengely felé, míg az OVLT a lázreakció kiváltásában játszik szerepet. A hypothalamus és az agytörzs immun eredetû információkat fogadhat az area postrema és a szubfornicális szerv felıl is. A mesencephalikus locus coeroleus is ilyen fontos kapu az agyi és a zsigeri folyamatok integrációjában. Kérdés, hogy az IL-1 támadáspontjának tekinthetık-e ezek a noradrenerg strukturák, melyek érintkeznek a kapilláris fallal, azaz a szisztémás keringéssel. A másik fontos afferens pályát maga a környéki idegrendszer jelenti. Közvetítı funkciójához nics szükség cytokin szintváltozásra. A közvetítı csatorna lehet a vagus, vagy a szimpatikus pályákon szállított nociceptív afferentáció. A vagus szerepét bizonyítja, hogy a portális keringésbe juttatott IL-1beta fokozza a n. vagus hepatikus törzsének SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

aktivitását. (Niijima 1992) A nucleus tractus solitarius és nucleus raphe magnus közvetítésével a vagus eredetû információk a gerincvelı efferens pályáin a substance P, CCK hordozta információkkal érik el a perifériát. A vagus közvetítette információk a központot a hypothalamus nucleus paraventriculárisán keresztül érik el, ingerlik CRH sejteket, és így nem meglepı, ha a subdiaphragmális vagotomia gátolja a kisdózisú endotoxin kezelésre adott ACTH választ. (Gaykema 1995) A vagus így szerepet játszik az IL-1beta aktivitás glükokortikoid elválasztást fokozó hatásában, és az IL-1 beta hypothalamikus noradrenalin depléciót kiváltó szerepében. (Fleshner 1995) De szerepet játszik az LPS indukált betegségmagatartásban (Bluthe 1994), az IL-1 indukált hyperthermiában (Watkins 1995), és a cytokin indukált kondícionált ízaverzióban is (Goehler 1995). Az IL-1 másrészrıl az adrenerg-peptiderg közvetítıkkel hathat a központi idegrendszerre, más-részt közvetlenül is kifejti hatását a hypophysis hormontermelı sejtjeire. Hasonló immuno-neurális irányt jelez az IL-6 közvetlen mediátor hatása a hormontermelı sejtekre az agyalapi mirigyben. Az intravénásan alkalmazott rekombináns humán IL-1béta a thymushoz futó vagus idegrostok aktivitását fokozza. (Niijima 1995). Hasonlóképpen fokozódik a mellékvese és vese szimpatikus beidegzésének aktivitása 2-6 órás tartammal az IL-1béta iv alkalmazása nyomán. (Niijima 1991) Az IL-1béta serkenti a substance P felszabadulását, míg az IL-6 a noradrenalin termelıdést fokozza például a patkány jejunum myenterális plexusából. ( Rühl 1994) A cytokinek hatásai között éppúgy szerepelnek neuroendokrin válaszok, neuron növekedési tényezı hatások, mint a vegetatív funkciók, és a magatartási válaszok befolyásolása. Számolnunk kell az interleukinek substance P mediált fájdalomserkentı szerepével, és lokális fájdalomcsillapító hatásával is, mely az IL-1beta és CRH által fokozott opiáttermeléssel magyarázható.(Stein 1990). A gyulladásos történést kísérı perifériás idegi folyamatok közvetlenül is befolyásolhatják az immunválaszt, így a peptiderg (neurokinin A, VIP) aktivitás a lép antitest termelését modulálja. (Hikawa és Takenaka 1996) A gamma interferon, és egyes komplement faktorok is közrejátszanak a viselkedéses válasz, betegségmagatartás alakulásában. Ahogy a központi idegrendszer állapotváltozása befolyásolhatja az immun-rendszer mûködését, úgy az immuntörténésnek is tükrözıdnie kell az agyi aktivitásmintázatokban. Korneva és munka-társai mikroelektródos vizsgálattal igazolták, hogy a szubjektív panaszokat nem okozó, de immunmemorigén antigénhatás már az antigén expozíció elsı órájában megmutatkozik a hypothalamikus aktivitásmintázatok átrendezıdésében. A hátsó hypothalamikus terület, a ventromediális, mamilláris és supramamilláris magvak fogadják ezeket az információkat. Már az antigén bejuttatás órájában kezdetét veszi a neuronok aktivitásmintázatának változása, és csak a lezajlott immuntörténés 20. napja körül áll vissza a megelızı nyugalmi állapotba. Ez egybeesik az antitesttermelés önszabályozó leállítódásával. Tehát az impulzusmintázatok átrendezıdése híven követi az immunesemény fázisait. Az immuntörténést a hypothalamikus noradrenalin szint csökkenése kíséri. Ahogy neuroendokrin tényezıket láttunk lymphokin szerepkörben, úgy az immunmediátorok is közrejátszanak bizonyos idegi, viselkedéses jelenségek kialakulásában. Ilyen szerepe van az aluszékonyság, illetve a lassú hullámú alvás elmélyítésében az IL-1, interferon, és a muramyl dipeptidnek. Az alfa interferon közrejátszik a betegséget kísérı lethargia, depresszió kialakulásában sıt kataton állapotot is elıidézhet. Az IL-2 és az IFN gátolja a hippocampus tartós potenciálását, ami közrejátszhat a daganat terápiában alkalmazott IL-2, IFN adását kísérı neuropszichiátriai mellékhatásokban. (Bindoni 1988) A gyulladás során képzıdı complement származék peptidek, így a C3a és C5a utánozzák a dopamin és a noradrenalin hatását a perifornicális területen. A C5a phentolaminnal blokkolható étkezési választ provokál. A thymus hormonok közül a thymosin 5 frakció az ACTH és a cortisol szekréciójának fokozását váltja ki, míg a thymosin béta 4 az LH és testosteron termelést fokozza. Immunológiai eltéréseket pszichológiai vagy mentális zavarok kísérhetnek. Az autoimmun betegségek körében az SLE-vel társulhatnak pszichózisra emlékeztetı jelenségek. Immunpatho-genezisû az AIDS-ben tapasztalható elbutulás is, mely a neuronok és a helper T sejtek felületén egyaránt jelenlévı CD3 receptornak köszönhetı. Egyes kutatók az immunpathogenezis lehetıségét a schizophréniára is kiterjesztették, melyet késıbb részletezünk. Másrészrıl az aktivált immunsejtek, lymphocyták képesek hormonok és neuropeptidek elválasztására is, mint a vírussal aktivált lymphocyta ACTH és endorfin, és GH termelése. Mindez jelzi, hogy a hormon hírvivık is kétirányú kapcsolatot teremtenek ideg és immunrendszer között.

7.A neuroimmun szabályozási körök Az IL-1 hurkok Az immuno-neurális információs hurkok egyik fontos feladata az immuntörténés stabilizálása, és korlátozása. Az immunkommunikáció és az idegi szabályozás integráltságára utal, hogy az IL-1 központi idegrendszeri hatását prazosin adrenerg gátlószerrel felfüggeszthetjük. Az IL-1 -noradrenalin - CRH- ACTH- cortisol tengely aktiválásával lecsökkenti az immunmediátorok (IL-1, IL-2 ) további felszabadulását, így szinte minden vonalon fékezi az immunválasz intenzitását, a gyulladásos eredetû szövetdestrukciót, és véd a szükségtelen lymphoproliferációtól. Az IL-1 CRH mozgósító hatását arachidonsav származékok (PGE2) közvetítik, amit a nem szteroid gyulladáscsökkentık használatakor figyelembe kell vennünk, hiszen e természetes folyamatba beavatkozva nem zárható ki nem várt hatás. SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

Az adrenerg gátlószer az adrenerg szabályozás alatt álló CRH szintjén lép be ebbe a hurokba, így ez a mechanizmus az immuno-neuro-endokrin-immun szabályozási kör szép példáját adja. Az a tény, hogy az IL-1 egyaránt mobilizál a hypophysisbıl és aktivált B lymphocytából béta-endorfint, arra utal, hogy a peptid és lymphokin mediátorok egy közös nyelv szavai. Ezt igazolja az is, hogy a vírus, endotoxin sıt CRH hatása nyomán az aktivált keringı fehérvérsejtek, B lymphocyták is termelnek beta-, és gamma endorfin molekulát. Az IL-1 a béta endorfin hypophyseális felszabadításával így két hurkot is képez, egyrészrıl az IL-1-CRH-ACTHcortisol negatív feed-back körrel kell számolnunk, másrészrıl az IL-1- POMC-beta-endorfin hurok létrehozásával egy részben immunstimuláns hatásokat is hordozó szabályozási kört létesít. A mozgósított beta-endorfin C-terminális vége erıs kötıdésképességet mutat a phagocytozis fokozó vitronectin fehérjével, mely további IL-1 felszabadításával további kört zárhat be, melynek a szöveti sérülés helyén lehet nagy jelentısége. Az IL-1 nemcsak saját korlátozása végett hat a központi idegrendszerre, de a beteg állapothoz tartozó két fontos állapot, illetve viselkedéselem kialakulásáért is felelıs. Egyrészt a beteg aluszékonyságát váltja ki, mint a lassú hullámú alvást provokáló tényezı - ebben a szerepében osztozik a gamma interferon is, másrészrıl lázreakciót okoz. Az IL-1 hormonális hatásai perszen nemcsak önkorlátozó hatáshurkokat rajzolnak ki, hanem a növekedési hormon, és a prolactin hormon szintjének növelésével közvetve serkenthetik is az immunfolyamatokat. Mindezek az egyidejû mintázatszerû hatáshálók utalnak az immunrendszer, endokrin és idegrendszer nagyfokú összeszövıdöttségére, mely soktényezıs, interaktív, kölcsönös, és kiterjesztett oksági kapcsolatokkal jellemezhetı rendszerben mûködik. Ennek a rendszernek a viselkedése nehezen jósolható meg biztonsággal, bármelyik elem elhangolódása, befolyásoltsága felboríthatja ezt a túlbiztosítottnak tûnı, mégis kényes egyensúlyokkal dolgozó önszabályozást. A traumatizáló életesemények, elhúzódó stressz és az alkalmazkodási kudarc, represszív megküzdésmód, tanult segélytelenség nyomán csökkenı hypothalamikus NA szint éppen ezeket a visszacsatolási pályákat érintheti kedvezıtlenül. Az IL- 2 szabályozási körök Az immunválasz neuroimmun befolyásnak bıségesen kiszolgáltatott következı lépése az említett módon aktiválódott helper T sejtek interleukin-2 termelése. A nyugvó sejt nem termel IL-2-t, és ilyen receptort sem jelenít meg felületén. Az IL-2-nek kulcsszerepe, hogy az IL-2 receptorral rendelkezı sejtek proliferációját idézi elı. A folyamat szelektivitását az adja meg, hogy azok a sejtek jelenítenek meg IL-2 receptort , melyek a megfelelı antigénnel kerülnek kapcsolatba. Így együttesen a folyamat intenzitását,, az immunválasz szintjét és idıtartamát az IL-2 termelés és az IL-2 receptor megjelenítés együtt határozza meg.Az IL-2 a gamma interferon termelés fokozásán keresztül serkenti közvetve a NK sejteket, és a HLA-DR antigén további megjelenítését is. A cytotoxikus T sejtek klonális elszaporodásához az IL-2 jelenléte nélkülözhetetlen.Az IL-2 közvetlenül és közvetve is hat a B sejtvonalra. Az IL-2 is zár feed back hurkot a CRH-fel, mely mind a HPA tengely révén a cortisol, mind a szimpatikus idegrendszer révén noradrenerg közvetítéssel immunszuppresszív negatív feed back visszacsatolást mozgósíthat. Az IL-2 hatását cholinerg-NO(nitrogénmonoxid)erg-PGE- erg kapcsolatok közvetítik a CRH felé. A nagy depressziós kórképek körében mind az IL-2, mind az IL-2 receptor szérum szintjének csökkenését észleljük. Másrészrıl az immunfolyamatokat gátló gyógyszerek, melyeket az autoimmun betegségek, illetve a nyiroksejtes daganatok kezelésében választunk, a cyclophosphamid, a kortikoszteroidok, vagy a cyclosporin mind gátolják az IL-2 termelést. Ha a pszichoimmunológiában fontos hírvivı, mediátor anyagok támadáspontjait vizsgáljuk, akkor az IL-2 szekrécióra kifejtett hatás a leggyakoribb, és legmeghatározóbb. Az IL-6 vonatkozásában az epoxid származékok játszanak közvetítı szerepet. Az IL-6-nak a legintenzívebb a CRH mozgósító hatása, és neuroimmun stressz szerepére utal hogy depresszióban magas IL-6 szintet észlelünk.

8. Az immunrendszer mint hormonszerv Az aktivált immunsejt képes ACTH, endorphin, növekedési hormon, TSH, LH, FSH termelésére. A hormontermelı immunocyták viselkedése releasing tényezık, és a hormon feed back hatások tekintetében megfelel a hypophysis sejtek viselkedésének, ez a funkció paracrin, illetve autocrin jellegében immunmoduláns szerepet játszhat. Ugyanakkor e hormonoknak szerepük lehet a nem-kognitív ingerek (baktériumok, vírusok) neuroendokrin rendszer felé jelzésében. A hormontermelı szerep az aktiválódott sejtek nagy száma esetén számottevı befolyást gyakorolhat a környezı és a keringés révén a távolfekvı szervekre, szövetekre is. A termelt ACTH trophormon szerepe miatt ujabb feedback hurkok zárulnak be és ez igaz az endorfin több értékû immun szerepére is. Az immunrendszer sejtjei termelnek CRH, GnRH és TRH releasing hormonokat is (Blalock 1992). A releasing hormonokra érzékeny hormonreceptorok a rágcsálók splenocytáiban is kimutathatóak, és biológiai szepontból hatékonyak. In vitro a GnRH LH hormont szabadít fel a lymphocytákból. (Ebaugh 1987) In vivo a GnRH a patkány thymus involúcióját SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

részben kivédi. Így nemcsak az immunrendszer hormontermelı szerepe merül fel, hanem az is, hogy a neuropeptidek a lymphocyta hálózat paracrin kommunikációjában szerepet játszó tényezık. Sacerdote, és Panerai kutatásai jelzik, hogy az immunocytákban szintetizált beta-endorfin, az immunválaszra gátló hatást fejt ki. Az immunocyták beta endorfin szintézisét a dopaminerg és GABAerg hatás gátolja, és a szerotonin serkentöleg hat arra. A szerzık az egészségesnél mérhetı beta endorfin szintek felét-harmadát észlelték sclerosis multiplexes, Crohn beteg és rheumatoid arthritisben szenvedı személyek esetében. A szerzık fölvetik a beta endorfin szerepét Th1/Th2 lymphocyta sejtvonal átkapcsolásában is. ( Sacerdote 1997)

9. Gátló hatások A gátló neurotranszmitterek, mediátorok, mint a PGE2, neurotensin, és a VIP az intracelluláris cAMP szint emelésével a lymphocytaforgalmat szinte megbénítja. A PGE2, és a hisztamin a gyulladásos folyamatban azonban stimuláns szerepet is játszik keringési hatásaival, illetve az immunreakció beindítását serkentı szerepével. A szteroidok hatását, és a stressz során kifejtett immunszupresszív, a nyirokcsomók megkisebbedésében alakilag is tettenérhetı szerepét Selye fedezte fel, egyben tárgyunk alapmozzanatát is felvázolva. A depressziós betegek egy részében észlelt megváltozott DST próba a tartósan fokozott cortisol szekréció, és a betegeknél már említett IL-2 szint csökkenés jelzi a pszichés depresszió és az immunszuppresszió összekapcsolódását. Immunszuppresszió észlelhetı a morfinistáknál is, ahol a morfin hatása szintén az IL-2 szint csökkenésével jár, és feltehetıen kortikoid közvetítéssel érvényesül. A szteroidok az érett T lymphocyták magállományának károsítják. Ha a sejtállományt IL-2-vel telítjük, a sejtek pusztulását, "öngyilkosságát", az apoptozist megakadályozhatjuk. A VIP ( vasointestinális polipeptid ) szintén szuppresszív hatást fejt ki, A VIP gátolja az antitest termelést a bélben, a Peyer plakkokban, és gátlólag hat a tumor sejtekkel szembeni védıvonal sejtjére, a NK sejt aktivitására is.A VIP az immunválasz "lecsengetésében" játszhat szerepet, túltermelıdését teszik felelıssé az anergiás immunállapot kialakulásában. VIP nemcsak neuropeptiderg rostokban képzıdik, hanem hízósejtekben, és basophil sejtekben is termelıdik, mely peptidek szerkezeti és funkcionális tekintetben is változatokra oszthatók.A kutatás jelen állása szerint az ilyen VIP variánsok szerepét a rá specifikus receptor határozza meg, egy részrendszerre korlátozva annak hatását. A SS (somatostatin) közvetlen IL-2 gátló hatása kérdéses, de a T sejtes proliferáció gátlása, , és a kis koncentrációban jelentkezı lymphokin termeléscsökkentı hatása a gátló hatású befolyásolók közé sorozza.

10. Serkentı hatások Általánosságban elmondható, hogy a serkentı hatású neurotranszmitter, neuropeptid molekulák mint a serotonin, dopamin, illetve a bombesin, bradykinin, substance P, met-enkefalin a PI (foszfatidilinozitol), illetve cGMP (ciklikus guanidilmonofoszfát) membrán jelfogó-jelközvetítı rendszeren keresztül hatnak. Serkentik a nyirokcsomók lymphocyta forgalmát, és az antitest termelést. A fenti mediátorok érfali szabályozó szerepe, vazoaktivitása miatt joggal beszélhetünk neurovaszkuláris immun folyamatokról, mely a konkrét antigén-immunsejt történést a szöveti gyulladásos történés felé terjeszti ki. A stresszfolyamat során felszabaduló béta- endorfinok és enkefalinok a periférián az IL-2 szint emelésével az immunfolyamatok serkentéséhez is hozzájárulhatnak, míg centrálisan hatva (anterior hypothalamus, periaqueductalis szürkeállomány területén) valószínûleg noradrenerg idegi közvetítéssel a lép NK sejtjeinek gátló tényezıi. Ez utóbbi mechanizmus közvetíti az állatkísérletes tanult tehetetlenség immundepresszív hatását. Az endogén opioidok bizonytalan hatását a periférián a célsejt információs folyamatainak több támadásponton való modulációjával magyarázzuk. Az IL-2 iránti érzékenységet az anyagcsere szervezésében oly fontos insulin is fokozza. A krónikus gyulladásos betegségekre való fogékonyságot is értelmezhetjük Sternberg és Licinio (1995) összefoglalója alapján olyan zavart neuroimmun adaptációs folyamatnak, melyben az immunológiai adaptációt egyben fékezı hypophyseo-adrenális stresszreakció zavartan mûködik. A neuroimmun adaptációba épített önkorlátozó elem zavarát észleljük, ha a CRH elválasztást fokozó IL-1, IL-2, IL-6, vagy TNF hatásra nem jelentkezik a HPA (hypophysis-melékvesekéreg) tengely aktivitásfokozódása. (A thymosin alfa1 ellentétes hatást fejt ki.) Ez állatkísérletekben az ún. Lewis (LEW/N) patkánytörzsnél a fokozott arthritises fogékonyságban, vagy az ún. OS csirketörzsben már a fokozott gyakoriságú thyreoiditis elıtt is megfigyelhetı - IL-1-re, IL-6-ra adott - zavart hypophyseo-adrenális feed backben nyilvánul meg. Ez a kiesı cortisol szerepe miatt az autoimmun folyamatok felerısödéséhez hozzájárulhat. A feed-back kör bármely szakaszán létrejött blokád elıidézheti a neuroimmun adaptáció zavarát, így a hypophysectomia, vagy az adrenalectomia akár fatálissá teheti például a salmonellafertızést, vagy a kísérletes allergiás encephalomyelitist.


11. Neuroimmun stresszmintázatok Selye a tartós fizikai stressznek kitett állatoknál jelentkezı Általános Adaptációs Szindrómában a mellékvese megnagyobbodását (megnıtt ACTH és fokozott glükokortikoid termelés) és a nyirokcsomók megkisebbedését írta le. A stressz normális határok között akut veszélyek, kihívások leküzdésére szelektálódott neuroendokrin adaptív válasz. A stresszt kísérı viselkedésmintázat kialakításában a CRH-nak nagy szerepe van, és ez a funkció a HPA tengely aktiválásától független. A CRH anxiogén azaz szorongást, nyugtalanságot keltı hatását a locus coeroleus közvetítésével fejti ki. A centrálisan adott CRF agonisták nyomán csökken az új környezet iránti érdeklıdés, felderítı magatartás, és az állat visszahúzódik a már ismert területre. Csökken az operáns tanulás, és emlékezet. A stresszt kísérı, és a CRH által integrált antireproduktív, katabolikus, növekedésgátló, és immunoszuppresszív neuroendokrin hatások csak rövid távon tekinthetık adaptívnak. A tartós stresszhatás a fenti mellékhatások miatt válik kórképzıvé. A CRH peptid vezérlı szerepe mindebben igen fontos, hiszen ez a peptid koordinálja a viselkedéses, neuroendokrin vegetatív és immunológiai adaptáció folyamatát. Az akut stressz során a paraventriculáris CRH és AVP neuronok fokozzák az amygdala, és a mezokortikolimbikus rendszer aktivitását, mely utóbbi kulcsszerephez jut, mert negatív feed back révén korlátozza az amygdala és a CRH aktivitást. A melankoliás depresszió során azonban a mezokortiko-limbikus rendszer aktivitása gyengül változatlanul túlmûködı amygdala funkció mellett, melyhez a hippocampus alulmûködése is társul. Depressziós betegeknél jelentıs hippocampus atrófiát, és kicsi és hypofunkciós középsı frontális lebenyt találtak.( ) Ez a helyzet az ábra szerint a negatív feed-back hatások kiesése miatt tartós stresszhez vezethet. A szerzı nem foglal állást a herediter tányezık, illetve a környezeti hatások súlyának tekintetében. (Chrousos 1998) A CRH a szimpatikus idegrendszer révén fejt ki nem cortisol függı immunszuppresszív hatást, mely érinti a humorális és a celluláris sejtválaszt is. Ebben noradrenerg/neuropeptid Y rostozat, és a mellékvesébıl feszabaduló adrenalin egyaránt közvetítı csatornát képez. (Friedman 1995) Súlyos stresszt, illetve depressziót a keringı neuropeptid Y magasabb szintje kísér. (Irwin 1991) Ismert, hogy a korral illetve a depressziós állapot mértékével együtt nı noradrenerg aktivitás, és csökken az immunkompetencia. Mivel depressióban fokozott a CRH szekréció, ezért e stresszregulátor szimpatikus idegrendszer közvetítette immunszuppresszív szerepe is szóba jön a depresszióban. Az egyénre jellemzı lehet a CRH-t korlátozó feed back hatások gyengült volta. Így például a korai pszichoszociális, vagy egyéb környezeti traumák nyomán a hippocampus és a frontális kéreg glükocorticoid receptor gén expressziója is csökken, ami egyben a CRH és az arg-vasopressin szekrécióra való negatív-feedback csökkenését jelentheti. A glükocorticoidok vissza jelzése és gátló hatása iránt érzéketlenedett rendszer a stresszorra fokozott HPA aktivitással,válaszolhat , mely az adott személy neuroendocrin jellemzıjévé válhat az immunszuppresszív következményekkel együtt. (Francis 1996) A CRH és az AVP által ellenırzött HPA tengely immunmoduláns hatása is többrétû. E hormonok immunmoduláns hatását már részletesen tárgyaltuk korábban. A glükokortikoidok immunszuppresszív hatással rendelkeznek, másfelıl az akut stressz során ürülı, majd csökkent elválasztású stresszhormonnak tekinthetı prolactin, és a növekedési hormon serkentı, míg a béta-endorfinok, és a mellékvesevelıbıl felszabaduló met-enkefalin összetett hatást gyakorolnak az immunsejtekre. A stressz szituáció emléknyomait bevésı arg-vazopresszin egyaránt gyakorol serkentı hatást az ACTH és a béta-endorfinok elválasztására.

12. A depresszió

A depressziós betegek körében Kronfol vizsgálatai szerint a mitogénre adott proliferációs válasz csökkent mértékû, a helper/szuppresszor T sejt arány mérsékelt csökkenést mutat, és a NK sejt aktivitás is csökkent mértékû. (Kronfol 1989). Ezt Krueger is megerısítette, aki a T helper lymphocyták számát depressziósoknál csökkentnek találta. Kennes megfigyelése szerint a Hamilton skálával arányos változás észlelhetı a T helper/szuppresszor arány változásában. A Hamilton skála szerint legsúlyosabb depressziót mutató betegeknél a neutrophyl granulocyták fagocytózisa csökkentnek mutatkozik. A súlyos depressziós állapot jellemzıje, hogy az IL-2 szekréció csökken, és alacsonyabb az IL-2 receptor oldható frakciójának szérumszintje, míg az EB vírus ellenes, és anticardiolipin antitestek magasabb szintet mutatnak. A depressziós betegek ellenállóképessége romlik, és ez a gyakoribb gombás megbetegedésekben, és az influenza, pharyngitis, tonsillitis gyakoribb voltában is megnyilvánulhat. A gyász, a kívánt terhesség elvesztése, vagy a másik fél részérıl kierıszakolt válás, elhagyás tárgyvesztésre jelentkezı reaktív depressziós állapota esetén szintén tartós szuppressziót észlelünk a mitogénre adott T sejtes válaszreakció mutatójában. Ez gyász esetén 3 hónapos tartamú is lehet. A depresszió és a tanult segélytelenség közötti analógia feltehetıen a mélyben mûködı pszicho-biológiai mintázatok között is fennállhat. Nemcsak a depresszióval, de a mániás fázissal is együttjár a sejtes immunitás meggyengülése. Rihmer és munkatársai a maniaco-depresszívás betegeknél az ADCC (antigéndependens celluláris cytotoxicitás) SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

immunmutatóját csökkentnek találták mindkét fázisban. A depressziós betegeknél talált immunszuppresszió dinamikájának idıi feltérképezése fontossá vált, mert az immunszuppresszió itt nem jelent egyszersmint anergiát, sıt fokozott gyakran éppen a gyulladásos folyamatok kísérıje. Muller és mtsai (1993) 23 endogén depressziós beteg vizsgálata során eltérı jelenségeket észlelt. A T és B sejtvonal együttes provokációjakor a CD4/CD8 arány növekedését, és a szuppresszor aktivitás csökkenését észlelték, mely kapcsán az affektív pszichózis folyamán fellépı zavart immunológiai kontrolfolyamatokra hívták fel a figyelmet. Hasonló következtetésre jutott Maes vizsgálatsorozata értékelésekor, amikor a depressziós kórkép során észlelt immunszuppressziót következményes jellegûnek értékelte, és a folyamat során fokozott T sejt aktivációt, CD4/CD8 arányt, fokozott akut fázis reakciót tapasztalt. Az immunszuppressziót következményesnek tekintve az IL1beta, IL-6 cytokinek nyomán másodlagosan fokozódó HPA választ tartja az immunszuppresszív jelenséget magyarázó tényezınek(Maes 1993, 1995) A szerzık hangsúlyozták a PWM és PHA mitogénekre adott csökkent szuppresszor aktivitás jelentıségét is, és a depresszióban a pszichoimmunológiai eltéréseket a depresszió eltérı etiológai alcsoportjaival hozták kapcsolatba. Cover (1994) 38 depressziós betegnél az alvászavar és az NK sejt aktivitás között mutatott ki fordított korrelációt. Maes és mtsai (1993) a major depresszióban észlelt hyperhaptoglobinaemiát a betegség akut szakaszának indikátoraként értelmezi, és jelentıs összefüggést talált a testsúlycsökkenés, anorexia, alvás-, és pszichomotoros zavarok és a haptoglobin szint között. A fokozott IL6 szint, a hyperhaptoglobinaemia, hypotransferrinémia és a hypophyseoadrenális tengely fokozott aktivitása közötti összefüggésre is találunk az irodalomban adatot. Berk és mtsai a gyulladásos folyamat szerológiai tényezıit, az akut fázis proteinek viselkedését vizsgálták, és a depressziós betegek körében a kontrollhoz képest jelentısen emelkedett C4 komplement, illetve IL 6, és C reaktív protein szintet találtak. (Berk 1997) Ugyanakkor a depressziót jellemzı hormonális elváltozások szerepét nehéz figyelmen kívül hagyni, hiszen a depressziós betegek közel felét kóros cortisol szekréció jellemzi, ahol a napi cortisol szekréció kétszerese az átlagnak, és a szekréciós kiugrások az átlagos 6-7 helyett elérik a tizenkettıt is. Hasonlóképpen a depressziósoknál magasabb béta-endorfin szintek mérhetık. Herbert és Cohen (1993) elvégezte a számottevı eltérést mutató celluláris immunitással járó klinikai depresszióról beszámoló közlemények meta-elemzését. A csökkent mitogénre adott T sejtes proliferációt mutató, és csökkent NK sejt aktivitásról beszámoló és metodológiailag nem támadható tanulmányokat tették a szerzık vizsgálat tárgyává. Az immuneltérések a hospitalizált és az idısebb betegek körében voltak kifejezettebbek. Egyértelmû lineáris arányosságot észleltek a depresszió súlyossága és a celluláris immunitás gátoltsága között.

13. Schizophrénia A schizophrénia pathogenezisében is felmerült az autoimmun kórjelleg lehetısége. A kórképben tartósan emelkedett és a beteg állapotának rendezıdésével egyidejûleg lecsökkent liquor IgA, illetve IgM szint fölveti autoimmun történés lehetıségét. Ilyen elváltozást SLE során is lehet észlelni, ami azért elgondolkodtató, mert ez az autoimmun kórkép pszichotikus tünettekel is együtt járhat. A pszichoneuroimmunológiai vizsgálatok Muller és Ackenheil szerint 20 -50%-ban találtak a schizofrén betegeknél immunológiai eltéréseket, azonban a szerzık a különbözı alcsoportok meghatározásának fontosságára hívják fel a figyelmet. (Muller 1995) Fabisch és mtsai kutatásai során immunológiai eltéréseket a paranoid betegekkel szemben fıként a nemdifferenciált és a dezorganizált klinikai altípusoknál talált. (Fabisch 1997), míg Wilke fıként a paranoid schizophrén csoportban észlelt csökkent IL 2 szintet. (Wilke 1996) A szerum és liquor immunglobulinok tekintetében ellentmondásos adatokat találhatunk az összefoglalókban. Fessel a schizophréniásoknál az antigammaglobulin, és a RF (rheumatoid faktor) antitesteket emelkedettnek találta. Más szerzık agonista viselkedésû dopaminreceptor ellenes autoantitesteknek tulajdonítanak szerepet. A vírusinfekciók mint az AIDS vagy a Lyme betegség nyomán fellépı pszichotikus állapotok is felvetik az immunopszichés befolyás lehetıségét. Számos tanulmány jelzi, hogy schizofrén betegeknél egyes virusok (HSV, kanyaró, CMV, varicella, borna virus) elleni antitest titer emelkedett, és egyes vizsgálatok az antitest titer liquor/szerum arányát magasnak találták, ami agyi lokalizációjú ellenanyagtermelésre utal. Mindez fölveti a lehetıségét, hogy a vírusos fertızés nyomán az idegi strukturák antigénszerkezete megváltozik, és a fenti adatok összeegyeztethetık a schizofrénia egyes eseteit illetı autoimmun pathogenezis lehetıségével is. A hatvanas években etiológiai lehetıségként felvetıdött az anti-agyszöveti globulinok detektálása nyomán Heath és Krupp (1967) tanulmányában. Muller a schizophrén betegek mintegy harmadában tartja valószí nûnek az autoimmun-folyamatok kórszerepét. (Muller 1995) Az akut pszichotikus betegek 28 %-ban található agyszövetellenes antitest, míg az egészséges véradóknál ez csak 10 %.Vartanian vizsgálatában 5o schizophréniás közül 5 esetben tudott kimutatni agyszövetellenes antitestet. Vartanian a schizofrénia és a celluláris illetve humorális immunitás közötti összefüggéseket egyaránt érintette. (Vartanian 1978) Baron munkatársaival a boncolt schizophréniásoknál az agyban radioimmunofixációs technikával agyszövetellenes antitestet tudott kimutatni a septális régióban a depressziós, normális elméjû elhaltak agyában találtakkal szemben. Úgy tûnik, hogy fıként a dopamin transzmisszióval jellemezhetı területek az érintettek, és SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

felvetıdött az anti-dopamin receptor stimuláló autoantitestek szerepe is Kelley munkájában (1987). A receptorszelektivitással jellemezhetı autoantitestek állatkísérletben a célterületnek megfelelı tünetképzést váltják ki. Az agyi sejtes elemekre reaktív antitestek nemcsak a schizophréniában, hanem a demenetiában, Huntington choreában, Parkinson betegségben is kimutathatók. Ha nem az immunpathogenezis felıl vizsgáljuk a kórképet, hanem figyelmünket a schizophrénia immunológiai következményeire irányítjuk, akkor magasabb IL1, és alacsonyabb IL 2 szintet észlelünk az ilyen betegek jelentıs részében. Rabin és munkatársai azoknál észleltek alacsonyabb IL 2 szintet, akiknél az autoantitestek szintje magasabb volt. Ezeknél a betegeknél az T sejtek IL 2 receptordenzitásának fokozódása arra utal, hogy a jelenség más mechanizmussal magyarázható, mint a depreszióban észlelt IL 2 szint csökkenés. Az IL 2 szint csökkenést Villemain (1989) és Ganguli (1987) is megfigyelte. A schizophrénia akut szakaszában észlelt IL 2 csökkenést csak a betegség heveny szakaszában tudta Ganguli kimutatni egy másik vizsgálatában, mely csökkenés a keringı autoantitestek megjelenésével társult. Bessler és mtsai (1995) az IL 2 termelés csökkenését a gyógyszermentes betegeknél kifejezettebb találták. Shintani és mtsai (1991) a szérum IL 6 szintjét kórosan emelkedettnek találták a betegek egy részében, míg Ganguli (1994) szerint az IL 6 szint emelkedett volta korrelációt mutat a betegség tartamával. Maes és mtsai az IL 6 szintet nemcsak a schizophreniásoknál hanem a heveny mániás betegek körében is emelkedettnek találták. Az IL 6 jelentıségét fokozza, hogy in vitro fokozza az idegsejtek dopamin kibocsátását, és in vivo a frontál kéreg, és a hippocampus dopamin forgalmát. (Zalcman 1994) A hippocampus IL-6 receptorsûrûsége a legkifejezettebb az agyban. Természetesen találunk ellentmondó adatokat is az irodalomban. Barak (1995), és Gattaz (1992) nem talált schizophreniával társuló IL 2 szint változást. A schizophréniás betegek liquorjában Licinio (1993) emelkedett IL 2 szintet talált. A centrálisan emelkedett IL 2 szint ismeretében emlékeztetünk arra a tényre, hogy a rekombináns IL 2 -vel kezelt rákos betegek schizopréniát utánzó tüneteket tapasztalnak. ( Denicoff 1987) Az ellentmondásos kép ellenére felvethetı, hogy a schizophrenia egyes alcsoportjaiban az IL 2 és interferon termelés zavarai összefüggést mutatnak a klinikai állapot változásaival. Muller (1997) a központi idegrendszerbe aktiv transzport útján bejutó, és az aktivált glia sejtekbıl felszabaduló cytokineknek a kórfolyamatban is szerepet tulajdonít, mivel az agyi cytokin kaszkád folyamat befolyásolhatja a dopaminerg, noradrenerg és szerotoninerg neurotranszmissziót és a HPA tengelyt is. Erre utal véleménye szerint az a tény, hogy a liquor IL 2 koncentráció szorosabb összefüggést mutat a schizophréniás relapsussal, mint azt a katekolamin metabolitok esetében tapasztaljuk. Ugyanakkor az aktivált glia sejtek IL 6 termelését az agyi noradrenalin is fokozza, mely a stresszfolyamatok neurotranszmitter-cytokin integrált modelljét az agyszövetekben is kirajzolja számunkra. Az agyi cytokin receptorok lokalizációja segíthet a cytokinek szerepének azonosításában. Egyébként az IL 2-nek Merrill (1992) szerepet tulajdonít a normális agyi fejlıdésben, és épp a schizophrenia vonatkozásában érdeklıdést keltı hippocampus gazdag IL 2 receptorokban (Lapchek 1991). A jelenséget magyarázhatja az egyik feltevés, mely szerint a pszichozis akut fázisában Th1 lymphocytavonal mitogén-ingerlésre elmaradó interleukin 2 termelésének csökkenése épp a sejtvonal kimerülésének lenne az eredménye. Mivel a Th2 lymphocytavonalra jellemzı IL 10 termelése sem emelkedett, inkább csökkent, ezért a két sejt vonal közötti feltételezett antagonizmus nem lehet oka a jelenségnek. Rabin neuroleptikus kezelés után emelkedett CD4 (helper) T sejt frakciót és fokozott CD4/CD8 arányt észlelt a kezeletlen esetekkel szemben. Müller és Ackenheil (1995) 55 frissen felvett és kezeletlen schizofréniás betegnél vizsgálta a T sejtarányokat, és a kezelés elıtti és utáni értékeket. Az észlelt és a betegek többségénél változást nem mutató emelkedett CD4 sejtcsoport arány hátterében a szerzık fokozott immunaktiváció lehetıségét vetik fel a kezeletlen betegeknél is. A gyógyszerelt és a kezeletlen schizophréniások körében egyaránt csökkent NK sejt aktivitás volt észlelhetı. A neurózisok pszichoimmunológiája A nagy pszichiátriai kórképek mellett a pszichoimmunológia figyelme nem kerülte el a szélesebb lakosságkört érintı neurózisok, szorongásos kórképek körét sem. Schmidt-Traub (1991) 34 viselkedésterápiával kezelt fóbiás beteget vizsgált meg ilyen szempontból. A betegek körében a poliallergiás immunológiai kép gyakorisága szembetûnı a vizsgált mintában. A 31 poliallergiás tünetekkel is küzdı fóbiás betegnél a szerzı a kognitív tényezıket a szorongás és az allergiás folyamatok közös közvetítı tényezıjeként értelmezte. Brambilla és mtsai (1992) 17 pánikbetegnél vizsgálták az immunológiai és endokrinológiai változókat (DST, növekedési hormon, prolactin szint). Nem észleltek az egészséges kontrolhoz képest immunológiai változást, az ACTH, GH hormon magasabb szintet mutatott, míg a CRH hatásra csökkent érzékenységet észleltek az ACTH és a cortisol válaszban, ami azonban javult az alprazolam kezelést követıen a pánik rohamok ritkulásával párhuzamosan. Ramesh pánikbetegeknél a kontrolcsoporthoz képest a lymphocyták számát alacsonyabbanak, míg az IgA szint emelkedett voltát észlelte. (Ramesh 1991) Marazziti és mtsai (1992) a depressziós betegeknél a CD3, és CD8 T sejtpopuláció csökkent voltát észlelte, míg a vizsgált 10 pánikbetegnél a CD4 sejtcsoport alacsonyabb arányát állapította meg. Schmidt-Traub és Bamler a pánikbetegek allergiával társuló komorbiditását vizsgálták, és a 79 pánikbeteg 70%-ában találtak I típusú allergiás SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

betegséget szemben a kontrollcsoportnál talált 29 %-al. A vizsgált összes allergiás beteg mintegy tíz százaléka bizonyult pánikbetegnek. A pánibetegség és a vazomotoros allergiás reakciók közötti összefüggés szignifikánsnak mutatkozott. (Schmidt-Traub 1997) A kényszeres neurotikusok esetében, az obszesszív-kompulzív betegeknél Maes és mtsai lényeges változást az egészséges kontrolhoz képest nem tudtak megállapítai. A kompulzivitás súlyossága és az IL 6, és a solubilis IL 6 receptor szintje arányosságot mutatott, míg a betegeknél a cortisol és az IL2 receptor között fordított összefüggés mutakozott. A negatív önértékelés egészséglélektani szerepét sokan hangsúlyozzák. A szorongó, diszfóriás személyeknél ez a kép visszatérı, vezetı tünet depressziós tendenciák nélkül is. A meg nem felelés érzete a magatartásepidemiológiai vizsgálatokan is igen nagy gyakoriságot mutat. A önreferencia stimulusok (Ss) alkalmazása után Strauman és mtsai (1993) az NK sejt aktivitást mérték. A szerzık a diszforiás személyeknél észlelték a legnagyobb eltérést az ideális és az aktuális énkép között, míg a szorongó személyeknél a legnagyobb eltérés az aktuális és a kívülrıl elvárt teljesítmény között volt. Az NK aktivitás mindkét csoportban alacsonyabb volt, és ez fokozottan jelentkezett a szorongásos személyeknél. A kontrol csoportban az Ss az NK sejtek fokozódását váltotta ki. Figyelmet érdemel a "krónikus fáradtság szindroma" is, melynek organikus illetve pszichiátriai eredetét illetıen megoszlanak a vélemények. Herbert Weiner szerint a krónikus fáradtság/ fibromyalgia szindróma (CFS), a neurasthenia a krónikus EBV infekció ugyanazon szindróma részét képezi (idézi Solomon 1995). A Herberman által leírt "alacsony NK sejt szindrómát" is krónikus fáradtság és társuló testi tünetek jellemzik, ahol az alacsony NK sejt szinthez a serum interferon magas szintje társul, mely felelıssé tehetı a fáradtságért, és a pszichiátriai tünetekért is. A krónikus fáradtság szindrómában az IL 6, a TNF, és a beta 2 mikroglobulin emelkedett szintjérıl is beszámoltak. A stressz okozta alvászavarok kedvezıtlenül hatnak vissza az immunvédelemre. A krónikus fáradtság szindromában a lassu hullámú alvást alfa hullámok törik meg gyakran. A testgyakorlás, edzésprogramok melyek növelik az NK sejt aktivitást, egyben az alvászavarokat is rendezik. Taerk és mtsai (1994) kísérletet tettek a pszichológiai és élettani jellemzık integrálására egy, a korai tárgykapcsolat zavarát feltételezı analitikus modell keretében. A közölt két esettanulmány igazolni látszik a korai kapcsolati zavar feltárásának jelentıségét és a beteg-orvos kötıdés facilitáló szerepét a klinikai javulásban. Lutgendorf és mtsai (1995) a kognitív funkciók és a mitogénre adott proliferatív T sejtválasz között talált arányosságot. A klinikai tünetesség és az immun és kognitív mutatók együtt változtak.

14. Pszichoonkológia A rák jelképes betegség, a határokat nem tisztelı dezorganizált szövet, mely egyszerre ragadozója, parazitája, gyilkosa és végül áldozata az elpusztult anyaszervezetnek- sajátos humán ökológiai jelkép. A civilizációs ártalmak: a környezet kémiai, vagy sugárzó carcinogénekkel való szennyezése, a szociális környezet szétesése, a korai anya-gyermek kapcsolat traumatizáltsága, az elidegenedettség, társtalanság, a szociális támogatottság hiányából fakadó immunvédekezés gyengülése a daganatos betegségeket a humán ökológia körébe vonja. A daganatképzıdés örökletes, belsı onkogén tényezıit a szervezetben, mint belsı környezetben találjuk meg, míg a külsı természeti környezet vírus, vagy kémiai, vagy sugárzó onkogénekkel jelent fenyegetést a szervezetre. A daganatképzıdésre, fejlıdésre és a klinikai lefolyásra ható környezeti tényezıket a stressz mechanizmusok közvetítik a kóros sejtek és az ıket elhárító immunfolyamatok környezetébe. A neuroendokrin, metabolikus és más szervezeti állapotváltozás a sejtek daganatos átalakulásához vezethet, és a spontán tumorképzıdés arányát növelheti. Viselkedéses jelenségek befolyásolhatják a szervezet tumorellenes védekezését. A neuroimmuno-moduláció közvetíti ezeket a hatásokat elsısorban az NK sejt aktivitását befolyásolva, így a tumorellenes surveillance funkció a külsı pszichoszociális környezet befolyása alatt állhat. A Bahnson által elfojtással magyarázott, Cassier szerint a kezelhetetlen helyzetet "érzelmi dermedtséggel" kezelı, a kihívásra passzív copinggal reagáló személy érzelmi kifejezésében gátolttá válik, érzelmileg bénul. Ez a dermedési reakció ellentétje a harcosságnak, a "fight or flight" reakciónak. Mindez elhúzódó depresszió, gátolt érzelmi kifejezıdés képében jelenik meg, mely rontja a szociális támogatottság érzetét. Az érzelmek elfojtása mellett a "freeze" reakció a fenyegetettség elhûzódó élményével jár együtt, mely a szimpatikus idegrendszer tartós aktivációját eredményezi. A veszély tartós elıvételezése a megoldás lehetısége nélkül a reménytelenség helyzethez vezet, mely a daganatos betegségben szenvedıkre jellemzı. Ezek a tényezık közrejátszhatnak a lelassult tumornövekedés újraindulásában. A metasztázisképzést és a betegség lefolyását a stressz és/vagy depresszió, illetve a beteg megküzdési jellemzıi egyaránt képesek befolyásolni.. A szervezetben spontán, és állandóan képzıdı vírusos vagy kémiai, fizikai provokáló hatásra pedig fokozódó tumorképzıdéssel szemben a szervezet fıképpen a természetes immunitásával fejti ki ellenállását. A daganatos átalakulás nem jár szükségképpen a sejt fenotípusának megváltozásával, és az immunfelismerés számára hozzáférhetı immunogén antigénszerkezet kialakulásával. Sıt az immunogenitás kialakulása esetén is gyakran kell felismerési képtelenséggel, hatásatlan immunválasszal, vagy toleranciával számolnunk. A tumorellenes immunvédelem fı vonala a NK és az NC sejtekhez kötıdik. A NK (natural killer) sejtek a T SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

sejtvonalhoz tartozónak mondhatók, míg a NC (natural cytotoxic) a macrophágok közé sorolhatók. Ezek a sejtek az elsı vonalbeli tumorellenes védekezés kulcstényezıi. Közrejátszanak a transzplantált daganat kilökıdésében (állatkísérletekben), és hátráltatják az áttétek kialakulását. Aktivitásukat az IL-2, és az interferon fokozza, de szerepük a daganatos betegség elırehaladásával csökken. Hatásukat sejt-sejt kontaktus révén fejtik ki. A NK sejtek aktivitását csökkentı pszichoszociális befolyás így a szervezet "tumorátengedı" képességét, illetve a betegség progresszióját fokozza. A tumorellenes aktivitásban szerepet tulajdonítunk még a macrophagoknak is, amelyek közvetlen úton, cytolitikus faktorok révén, de az ADCC reakció végrehajtó sejtjeként is szerepet játszanak a tumorsejtek elhárításában. Ezt számos pszichoneurohumorális tényezı által befolyásolt lymphokin (IL2, interferon) serkenti. Egyes polimorphonucleáris (PMN) sejtek is az ADCC reakció killer sejtjeiként fejtik ki tumorellenes hatásukat. A LAK sejtek (lymphokin aktivált killersejtek - cytotoxikus T lymphocyták) a tumorsejteket nem az MHC antigének segítségével ismerik fel, így képesek a NK sejteknek ellenálló tumorsejteket is elpusztítani. Az adaptív tumorasszociált antigénfelismerésen alapuló immunitás erıteljes pszichoimmun be-folyás alatt áll, hiszen itt is az MHC strukturával együtt történik a felismerés az IL1, IL2 mediátorok által szervezetten. Mindezek alapján nem meglepı, hogy az un. represszív coping stílussal jellemezhetı, a negatív érzelmek jelzésére képtelen, indulatait elfojtó, lemondó, tehetetlenségérzettel telt, megfelelı szociális támogatottságot nélkülözı depressziós személyeknél-az AIDS ismeretetése során már említett módon- a daganatellenes védelem gyengülésének kockázata nıhet. A tartós hypercortisolaemia az IL1, IL2 szint csökkenésével járhat, ami tovább rontja a NK sejtek kompenzáló szerepét. A pszichoonkológiai vizsgálatok arra utalnak, hogy a letargiát panaszoló, a szociális támogatottságot nélkülözı személyeknél a NK sejt aktivitás alacsonyabb, és az áttétképzıdés intenzívebb. Kulturális antropológiai jelentıséggel bír az a tény, amit Hay így foglalt már nagyon korán össze: ' a rák megoszlását vizsgálva a Föld különbözı népeinél azt találjuk, hogy ez a betegség a civilizált életmóddal egyenes arányban fordul elı.' Az akulturációs stressz jelentıségét igazolhatja, hogy Bigelow és Lombard vizsgálata szerint, a legveszélyeztettebbek a második generációs személyek, akiknek szülei bevándorlók voltak. (idézi Kulcsár 1995) Ez a szociális kohézió jelentıségét húzza alá. Kiterjedt kutatások hozza kapcsolatba a daganatos betegségek kapcsolatát a tárgyvesztéssel, gyásszal, biztonságvesztéssel, a mobilis 'centrifugális' családszerkezet, azaz a gyenge kötéssel jellemezhetı, bizonytalan családi kapcsolatok szerepével. A szülık korai elveszítése, kényszerû, nem kívánt környezetváltozás és más tárgyvesztéses helyzetek példázzák, hogy valamilyen fontos kötelék felszakadása nyomán elızetes szenzibilizálódás (ld állapotfüggı tanulás, tanult tehetetlenség) után fokozott pszichoonkológiai kockázathoz vezethet. LeShan vizsgálatai alapján tesztekkel vak vizsgálatban váratlan biztonsággal lehetett elkülöníteni a rákos beteget, az egyéb betegségben szenvedıtıl, vagy egészséges személytıl. ( Le Shan 1977) A LeShan által leírt személyiségkép lényegében megfeleltethetı a C típusú személyiség-min-tázatnak. A korábban tárgyalt C típusú személyiség és a malignus melanoma közti kapcsolatra utal Temoshok(1985) megfigyelése, akik a kérdıíves vizsgálatban egyaránt elemezte a környezeti kihívásra adott érzelmi, viselkedéses fizikális és kognitív válaszelemeket. Beigazolódott, hogy az érzelmek csökkent kifejezése fokozottabb tumormitózissal és csökkent lymphocytainfiltrációval, nagyobb tumorvastagsággal jár együtt. Azonban más pszichobiológiai tényezık is szerepet játszhatnak, Dilman a feltételezetten elhangolódott cortisolCRF-ACTH szabályozási kör miatt endokrinimmun tényezık mellett a tartós aktivációs állapot miatt megnıtt szabadzsírsav szint carcinogén szerepére hívja fel a figyelmet. A DNS javító mechanizmusok sérülése, a szöveti proliferációs regulátorok változása, az antionkogén tényezık inaktiválása, az apoptozis megzavarása miatt túlélı kóros sejtalakok valószínûségének növekedése mind jelzi, hogy a pszichoneuroimmun modellezés sem egyszerûsítheti le a pszicho-biológiai befolyást egyetlen, vagy néhány tényezıre (NK sejt, IL-2). Bár az adatok nem ellentmondásmentesek, mégis elgondolkodtató hogy a depressziós elmebetegek körében gyakoribb tumorelıfordulás mellett az IL-2 , és IL-2 receptor szint, valamint az NK sejtes, és ADCC aktivitás is csökkent. 2020 személy 20 éves követése után a kutatók azt találták, hogy az MMPI tesztben magasabb depresszió értéket mutatók körében 17 év (Shekele 1981), és 20 év után (Persky 1987) kétszer annyian haltak meg daganatos betegségben, mint a depressziótól mentes személyek. Sem a daganat típusa, sem helye, sem egyéb jellemzık ( dohányzás) tekintetében a két csoport között különbséget ki mutatni nem lehetett. Grossarth-Maticek(1983, 1985) szerint a tartós tehetetlenséget és depressziót panaszolók gyakrabban betegszenek meg daganatos betegségben az általa végzett tíz éves követéses vizsgálat tanusága szerint. Ezzel ellentétes eredményeket mutató vizsgálati eredmények is ismertek. (Zonderman 1989, Hahn és Pettiti 1988) Ugyanakkor a depresszió mint a daganatbetegséggel szövıdı társbetegség rövidebb túléléssel ( Derogatis 1979), felgyorsult progresszióval ( Levy 1985) jár együtt. A daganatos betegek ellátásában is nagy jelentısége van a pszichobiológiai megközelítésnek. Már a diagnózis feldolgozása olyan kognitív feladatot ró a beteget vezetı orvosra, melyben az esélytelenség tudatának felszámolása, azaz a helyzetet súlyosbító pszichoimmun kockázati állapot megszûntetése elsıdleges fontosságú. A daganatbetegeket a halálos betegség vélelme miatt gyakran elkerülik, korábban is szegényes szociális SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

kapcsolati hálójuk tovább szakadozik. Ez az elmagányosodás sokszor a családon belül is megfigyelhetı. Pedig Levy szerint a szociális támogatottság élménye prognosztikus tényezı (Levy 1985), és hosszabb túlésssel társul a fokozott társas támogatás (Funch et al 1983, Weisman et al.1975). A betegséggel szembeni küzdelem igényével fellépı betegek nagyobb túlélési idıvel, és jobb életminıséggel jellemezhetık. A hosszabb túlélést mutató daganatbetegek esetében Stavraky az emocionális kontrol megtartása mellett észlelt hosztilitást, Greer a harcias szellemet, az elutasítást, Visintainer a problémamegoldó magatartást, Derogatis az aggresszív, nem compliens, panaszkodó magatartást, Ikemi az elkötelezett vallásosságot találta jellemzınek, míg a rosszabb prognózishoz Reynolds a szociális izoláltságot, Greer a sztoikus elfogadást, segélytelen-reménytelen attitûdöt, Temoshok az elfogadó, aggressziógátolt, kórosan kedves C típusú szeméyiséget, Jensen az érzelmek elfojtását, Schonfield a szociális befelé fordulást kötötte. (Fox 1988) Fawzy 66 melanomás betegnél végzett vizsgálatban igazolta, hogy a betegoktatás, stresszkezelés, a coping készségek fejlesztését célzó hat másfél órás ülés után a hat hónappal a betegeknél csökkent pszichológiai distresszt, fokozott immunfunkciót (NK sejt aktivitás) találtak a kezeletlen kontroll csoporthoz képest. A hat év után elvégzett vizsgálat szerint a magatartásterápia csökkentette a visszaesés gyakoriságát, és növelte a túlélést is. (Fawzy 1993) Spiegel és munkatársai áttétes emlırákos nıbetegek körében találta eredményesnek a heti egy alkalommal, és egy éven keresztül folytatott magatartásterápia szerepét, a kontrollcsoporttal szemben a terápia 18 hónapos többlettúlélést eredményezett. (Spiegel 1989) A korai trauma jelentıségét elızı fejezeteinkben ismertettük, klinikai kutatást igényel a feltáró, illetve katarzis therápiák, és az állapotfüggı tanulás és emlékezet vizsgálata a daganatellenes immunitás befolyásolásában, egyben a megváltozott coping magatartáshoz rendelıdı pszicho-endokrinimmun változások elıidézésében. A fájdalomcsillapításban és az élményfeldolgozásban, a beteg életminıségének javításában a hypnózis a hypnabilitás függvényében igen hatásos módszert kínál. A Simonton-féle módszer, az irányított imagináció és más, a késıbbiekben érintett therápiás technikák közös jelentısége, hogy biztosítja a beteg részvételét a kezelésben, és a kontrol lehetséges visszaszerzésében. Ez megnyilvánulhat a fájdalom csökkenésében, vagy a pánikállapot oldódásában, az énerı fokozódásában és az egzisztenciális-kognitív alapállás változtatásban is. A betegség okozta pszichoszociális izoláció stresszét is oldjuk. Az alkalmazott mélyrelaxáció igazolt nyeresége, az NK sejtek aktivitásának fokozódása is számottevı szerepet játszhat a progresszió lassításában, vagy akár fordulat elérésében, mint a szükséges daganatellenes beavatkozásokat (mûtét, irradiáció vagy kemoterápia) kiegészítı terápia. Nagyon nagy jelentısége lehet a pozitív állapotfüggı élmények pszichoendokrin vonzatú mobilizálásának hypnózisban, illetve a pozitív élményt nyújtó környezet kialakításának (lakás fény, színviszonyai, filmek, könyvek, zene stb). A beteg-orvos viszony indulatáttételi jellemzıi, a regressziós jelenségek a hypnotherapeuta számára is feldolgozást, sıt pszichoimmunológiai kockázatot jelentenek (erıs érzelmi bevonódás, fenyegetı tárgyvesztés), amit Bálint csoport segítségével oldhat a kezelı.

15. Fertızı betegségek 15.1. A határfelületi védelem A nyálkahártya (mucosa) által biztosított védelmi vonalban a humorális (IgA)védelem mellett az intraepitheliális sejtek natural killer aktivitása is szerepet játszhat. A szájüregben a szájnyálkahártyán észlelt széles körû antigéntolerancia létrejöttében a szuppresszor T sejtek szerepe fontos. Ha stressz, pszichoimmun terhelés nyomán arányuk lecsökken, akkor fekélyek, gyulladásos jelenségek alakul-hatnak ki. Ilyen lehet a "trench mouth", a lövészárkokban súlyosan legyengült szervezetû embereknél kialakult fekélyes szájüregi gyulladás. A felületi immunitás romlását jelenti a légúti betegségrek gyakoriságának növekedése. Meyer és Haggerty (1962) már korán jelezte, hogy a tartósan fennálló családi konfliktusok, stress növelik a felsı légúti fetızések gyakoriságát. Graham 94 családot vizsgált meg, és a gyakoribb stressztıl szenvedı csoportban a hûlések száma nagyobb volt. Clover és munkatársai a kaotikus, és rigid családok stresszterhes légkörében az influenza iránti fogékonyságot magasabbanak találták, mint a kiegyensúlyozott harmonikus családokban. (Clover 1989) Cohen(1993) szerint a stresszterhelés mellett a negatív érzéseknek is szerepe van a légúti beteg betegségek gyakoriságában, és súlyosságában. Látens, krónikus fertızések aktiválódása A herpes fertızés népbetegség jellegén túl lehetıséget nyújt a krónikus, visszatérı fertızı kórképek vizsgálatára. Jól követhetı a HSV antitesttiter szintje, a tünetek nyilvánvalóak, és közkeletû és elfogadott az is, hogy a stresszkörülmények a herpes fertızés kiújulásához vezetnek. A látens fertızés aktiválódását a HSV antitest titerének növekedése jelzi. McLarnon, és Kaloupek(1988) genitális herpes prospektív vizsgálatakor találtak összefüggést a stressz és a betegség gyakoriság között. Kemény és munkatársai 36 személyt követtek fél éves vizsgálati idıszak alatt, és havonként vizsgálták a pszichológiai stresszorok, hangulatváltozások, egészségmagatartás, és a herpes vírus fertızések közötti SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

összefüggést. A negatív hangulati változások azonban inkább a T CD8, azaz a cytotoxikus/szuppresszor sejtvonal csökkenését váltották ki, ez történt a szorongás, a depresszió és a düh esetében egyaránt. Kemény szerint a herpes kiújulásában a T CD8 cytotoxikus sejtvonal elégtelen mûködése játszhat szerepet. A depressziós hangulatváltozás vonta magával leginkább a T CD8 sejtvonal csökkenését. Kiecolt-Glaser és munkatársai (1984) a vizsgaidıszak pszichoszociális terhelése során vizsgálták a HSV-1 ellenes antitesttitert, mely emelkedettnek bizonyult. Ezt a szerzık a latens herpes vírussal szemben gyengült celluláris immunitással magyarázták. KiecoltGlaser és munkatársai (1986) másik vizsgálatukban a vizsgaidıszak alatt a helper T, és szuppresszor /cytotoxikus sejtvonalat egyaránt csökkentnek találták csökkent mitogén válaszkészség, és csökkent NK sejtes aktivitás mellett. A lymphocyta interferon termelés, mely a NK sejtek szabályozójának tekinthetı, szintén csökkentnek bizonyult a megterhelés ideje alatt. Az egyéb moduláns hatásokat, mint az alvás, étkezési szokások szintén mérlegelték a kutatók, de lényeges befolyásukat nem észlelték. Állatkísérletben hidegstressznek, (a hûlés állatkísérletes modellje ) kiszolgáltatott állatnál figyelték meg az egyébként nem invázív gyengített arbovírus nyomán fellépı idegi viraemiát. Az encephalitis a vér-agy gát megnyílásának, és a vírus "envelope" proteinjében beállt változásnak köszönhetı a szerzık szerint. Ez sajátos interakciót sejtet a stresszmediátorok, a kórokozó és egyes barrier mechanizmusok között. A herpes vírus fertızés mellett már korai epidemiológiai vizsgálatok jelezték a negatív hangulati, érzelmi állapotok, és a TBC fellépése, lefolyása közötti kapcsolat létét. A felsı légúti hurut, és a mononucleosis infectiosa tekintetében végzett vizsgálatok arra utaltak, hogy az alacsony énerıvel jellemezhetı vizsgálati alanyoknál a felépülés elhúzódó, és a megoldatlan szerepzavarok, a meg nem felelés, a szociális izoláció is a fertızı légúti betegségek gyakoribb voltához vezet. Levy és munkatársai szerint a tartósan alacsonyabb NK sejt aktivitás része az un."krónikus fáradtság szindromának". Fiatal, egészséges férfiak csoportját vizsgálva, 88 személy esetében 15%-ban észleltek tartósan alacsonyabb aktivitást, alacsonyabb noradrenalin elválasztást, és fokozott depressziót. Ezeknél a személyeknél az EB-vírus ellenes antitest titere is magasabb volt.

15.2. AIDS AIDS betegeknél is szembetûnı az érzelmi tényezık szerepe. A társas-lelki hatások közvetítésében egyesek a látens vírusok reaktiválódásának, és a helper T sejtproliferációnak, majd következményesen a HIV vírus nyomán bekövetkezı számbeli csökkenésnek tulajdonítanak szerepet. Mindez a HIV fertızés virulenciájának potenciálását jelentené. Solomon, Temoshok és munkatársai AIDS betegek 5 hetes követéses vizsgálata során többszörös regresszióanalízissel azt találták, hogy az alacsonyabb szorongás és feszültségszint a T sejtek magasabb számával társult, és hasonlóképpen fordított összefüggést találtak a depresszió, fáradtság és düh, aggresszivitás tekintetében. A szuppresszor/cytotoxikus T lymphocyta sejtvonal együtt-mozgott a rendszeres testgyakorlással, jó erınléttel, a kifelé irányultsággal, a kedvelt idıtöltések gyakorlásával. A természetes ölıképességgel rendelkezı sejtek (LGL, NK sejtek) nagyobb aktivi-tásával jár együtt a csökkent szorongásos feszültség, a stresszhatások csökkenése, a fokozott énerı, "feldobottság".A NK sejtek fordított arányosságot mutattak az AIDS betegségre összpontosuló figyelem beszûkülésével, és a fáradtsággal, tehetetlenségérzettel. Burack a helper T sejtszám csökkenését 38%-al gyorsabbnak találta a depressziós betegeknél szemben a nem depressziósakkal 1985 és 1991 között vizsgált 330 HIV pozitív homoszexuális körében. Kemeny és mtsai HIV pozitív homoszexuálisok körében 5 éves követéses vizsgálatban észlelt hasonló tapasztalatok alapján kezdeményezett intenzív életminıségjavító és stressz kezelı csoporttherápiás programot. A vírus reaktiválódását jelzı P24 antigén (a HIV vírus része) szintjének növekedése arányban áll a depresszióval, félelemmel és fordított arányosságot mutatott az aktív megküzdési stratégiákkal, a humort használó coping mechanizmussal. Temoshok egy másik vizsgálatában a T4 sejtek abszolút száma egyenes arányosságot mutatott az izgalmi szorongásos állapottal, a kevéssé kontrolált érzelmi élettel. A szerzık felhívták a figyelmet arra, hogy a betegség különbözı idıszakaiban eltérı pszichoimmunológiai kölcsönhatások játszhatnak szerepet. A bır fokozott vezetéses (conductance) választ mutató paramétere a betegeknél az NK sejtek nagyobb cytolitikus aktivitásával mutatott egyenes arányosságot. Ez a paraméter akár a prognózis egyik mutatója is lehet a szerzık szerint. Ha a fokozott arousalt, noradrenalin és adrenalin kibocsátást és a noradrenalin által fokozott NK sejt aktivitást a megfogyatkozott helper T sejtek funkcióját pótló tényezınek tekintjük, akkor érthetı, hogy a sztoikus, beletörıdı, és csökkent emócionalitású, a negatív érzelmeket kifejezni képtelen állapot miért jár rosszabb kilátásokkal. Miután a fent jelzett és rosszabb esélyekkel társuló mintázat a represszív coping stílussal mutat egyezı jeleket, míg a jobb prognózis az un. elkötelezett, énerıs, céltudatos, kontrolra törı attitûddel, a "hardiness" mintázatával egyezik. Az AIDS alakulásában szerepet játszó tényezık hasoníthatók a daganatos betegségnél észlelt pszichoimmunológiai összefüggésekhez.


16. Az allergiás betegségek A túlérzékenység (allergia) olyan indokolatlanul intenzív válasz egyébként ártalmatlan antigénre, vagy kórokozóra, gyógyszerre, mely magát a szervezetet is károsítja. 1. I. típusú túlérzékenységi reakció Az antigénbehatásra azonnal bekövetkezı allergiás reakció, melyet IgE típusú antitest közvetít. A szabad Ig E felezési ideje néhány nap, míg a hízósejtekhez, basophil sejtekhez kötıdött Ig E hetekig kimutatható, és mennyisége is nagyobb. A normális Ig E szint sem zárja ki az atópiás betegség diagnózisát. Az IgE mediált asthma bronchiale (extrinsic) rhinitis, eczema, urticaria, kórképeket nevezzük atópiás betegségeknek. Itt az allergénnel végzett bırpróba tekinthetı a legbiztosabb diagnosztikus eszköznek. A bırpróbák az allergiás betegben autogén tréning és relaxáció után javulást mutatnak. Az IgE termelıdését T sejtek szabályozzák, és az atópiában észlelhetı fokozott Ig E termelést a szuppresszor T sejtek csökkent mûködésével hozzák kapcsolatba. Egyes T helper alcsoportok az Ig E szintézisért szelektíve lehetnek felelısek. A természetes anti -IgE ellenanyagok segíthetnek az IgE közömbösítésében, vagy az azt termelı B sejtek eliminálásában. Stadler szerint neuroendokrin tényezık kontrolálják az Ig E szintézis szintjén az allergiás folyamatokat. A hisztamin immunregulációs szerepe is figyelembe veendı. a nyálkahártya szenzoros idegrostjai, a C rostok substance P szerû anyagok, tachikininek révén a hízósejtekbıl hisztamint mobilizálnak, és ezzel lokális gyulladásos jelenségeket váltanak ki. A substance P, a neurokininek, tachykininek venodilatációt, exsudációt, a nyákelválasztás fokozását és bronchokonstrikciót okoznak az immunsejtek aktivizálása mellett. A helyi szöveti túlérzékenységi reakciók sejtes és vaszkuláris folyamatai pszichofiziológiai úton szétválaszthatók. Clarkson egy 18 éves tojásérzékeny nıbetegnél az intradermális injekcióra adott allergiás választ gátolta hypnózis alkalmazásával. Ha szuggesztiót nem alkalmazták, akkor az erythéma ismét megjelent. Zeller kontrolvizsgálata során nem tudta megerısíteni a Clarkson által tapasztaltakat. Azonban a két vizsgálat nem vethetı össze, hiszen az alanyok hypnabilitását nem vizsgálták objektív eszközökkel. Bowers és Kelly szerint az erıs hypnabilitás szerepet játszhat az immunválasz pszichés befolyásolhatóságában. Mason és Black pollenallergiában szenvedı, szénanátha és asthma tüneteit produkáló nıbeteget kezelt a pollenszezont megelızı héttel kezdıdıen, és a szuggesztió az allergén kiváltotta tüneteket gátolta. A hypnózist karlevitációs technikával, azaz a kar fokozódó könnyûségének szuggesztiójával mélyítették el. A karon az allergén ismételt alkalmazása mellett sem észleltek erythémát, míg ugyanannak az allergénnek váratlan, a hypnózistól független alkalmazása lábon a szokott méretû erythémához vezetett. Ha a poszthypnotikus szuggesztiót kiterjesztették az egész testre, az allergiás válasz testszerte elmaradt. A hypnotizáltból vett szérummal inficiált nem-allergiás vizsgálati alanyon urticariát észleltek a szerzık. Black I. típusú túlérzékenységi reakciónál direkt hypnotikus szuggesztióval a kísérı oedémás duzzanat szignifikáns csökkentését érte el, ezt a vizsgálatot a IV típusú (közvetett vagy sejtes) immunválaszra (Mantoux próba) is kiterjesztette. A túlérzékenységi reakciók másik formája, mely a diagnosztikai gyakorlatban is szerephez jut, a közvetett, vagy sejtes immunitás közvetítette túlérzékenység. Itt az allergénre adott válasz az antigénprezentáló sejtek nyomán felkínált antigénrészletre (epitopra) adott T sejtes , celluláris válaszkészséget, illetve túlérzékenységet jelzi. Black (1963) biopsziát végzett azoknál, akiknél a direkt hypnotikus szuggesztió alatt elmaradt a pozitív reakció. Ez azt igazolta, hogy a hypnotikus hatás csak a vaszkuláris választ és az exszudációt érintette, míg a sejtes immunfolyamat, a celluláris infiltráltság nem változott. Zachariae és munkatársai korszerûbb vizsgálati eszközökkel is megerısítették ezt az észlelést. A szuggesztió szerint a hisztamin intracután adására a jobb kézen adott hisztamin injekció nyomán kialakult duzzanat csökken, míg a bal kézen az allergiás duzzanat nı. Csak a csökkenés bizonyult szignifikánsnak. Ha 72 óra után vizsgálták a IV. típusú túlérzékenységi reakciót, mind az erythéma felülete, mind a duzzanat, beszûrıdés mélysége csökkent. Lézer, doppler áramlásméréssel és ultrahanggal mérték ezeket a paramétereket. A hízósejtek és a basophilek a belsı testfelszínek (tüdı, bél, gasztrointesztinális rendszer) és a bırben lelhetık fel a legnagyobb sûrûségben.Az IgE-vel egyenlı intenzitású a SP és a somatostatin hisztamin mobilizáló hatása in vitro patkány peritoneális hízósejtjén. A somatostatin is hisztaminmobilizáló a hízósejtekben , de gátló a hatást gyakorol a basophilekre. Mivel az SP-vel együtt szabadul fel a szenzoros ideg ingerlésekor, szerepe korlátozó. A substance P venodilatatív hatású, hisztamin mobilizálása és általános immunsejt serkentı szerepe így kiegyenlítıdik. A folyamatot a szenzoros neuronból szintén felszabaduló VIP "csengeti le". A neurogén gyulladás ismert jelensége is ezekhez a tényezıkhöz köthetı. Figyelembe kell vennünk, hogy a hypnoterápiás technikák csak hyperaemia, oedema, és a hisztaminhatások vonatkozásában mutattak eredményt, a celluláris infiltrációt nem érintették. A capsaicin lokális alkalmazása (SP depléció) csökkenti az oedémát. A hisztamin mozgósítja a SP-t, és ez pozitív feed back hatásként fokozza a vazodilatációt. SOTE Magatartástudományi Intézet Dr Lázár Imre, egyetemi adjunktus, PhD

Kroger (1964) csokoládéra és macskaszırre allergiás gyermeknél poszthypnotikus szuggesztióval elérte, hogy az zavartalanul játszhatott a macskával, fogyaszthatott csokoládét.Ha amnéziássá tették a gyermeket a hypnotikus szuggesztióra, mintegy visszavonva azt, akkor az urticaria újra jelentkezett. Spiegelmann és Perloff egy 10 éves gyermek allergiáját kezelte irányított imaginációval, és egyidejû deszenzitizációval eredményesen, teljes tünetmentességet ért el. Emocionális tényezık kiválthatják, és súlyosbíthatják az urticáriát Kaneko és Takaishi szerint.A szerzık vizsgálatukban 27 betegbıl hypnózissal 5 esetben teljes tünetmentességet, 9 esetben közel tünetmentességet, 8 esetben nagyfoku javulást tapasztaltak, és csak 5 esetben bizonyult a kezelés eredménytelennek. A 7 hónapos követés alatt csak néhány visszaesés adódott.Minél hosszabb ideje állt fenn a betegség , annál kevésbé volt hatékony a hypnózis.Az eredmények hasonló korrelációt mutattak a hypnabilitással. A relaxációs szuggesztiók eredményei elmaradtak a tünetszüntetést célzó hypnózisszuggesztiók során elért eredményektıl. Más vizsgálat során a szerzık olyan betegeknél, ahol a tapasztalat szerint az urticáriát meleg, illetve érzelmi konfliktusok váltották ki- a konfliktushelyzet hypnotikus szuggesztiójával, illetve melegszuggesztióval elı tudták idézni. Idiopáthiás urticáriában (53 eset) , ahol provokáló antigén nem volt kimutatható, az IgE számos esetben magas értéket mutatott. Mason gyógyíthatalannak ismert ichtyotikus erythroderma hypnozissal való kezelésére vállakozott, a szelektív hypnotikus szuggesztióval ( elıbb a bal kézre irányítva) szelektív tünetcsökkenést, majd az egész testre kiterjesztve a szuggesztiót változó 50-95%-os javulást ért el. A beteg egy éves követése során nem tapasztalt visszaesést.Az ichtyotikus erythroderma javulása arányban áll a hypnabilitással. Az angioneurotikus oedema kiváltásában is szerepe lehet az emocionális stressznek, bár itt a rendellenes complement tényezık aktiválódásához járul hozzá a stressz nyomán elıálló neuroendokrin befolyás, triggerhatás.

Dr Lázár Imre, egyetemi adjunktus, PhD SOTE Magatartástudományi Intézet


PSB

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PSZICHOSZOMATIKUS BETEGSÉG! Tények: • • •

Egyre gyakoribb diagnózis a PSB. Hazánkban a lakosság 10–30%-át érinti. Fıként fiatal nık és idısebb férfiak szenvednek tıle.

A kifejezés egy görög eredető szóösszetétel (psyhe = lélek; soma = test). Maga a megbetegedés a lélek és a test oda-vissza kölcsönhatásának zavarából ered. Ennek megfelelıen a kezelés is elsısorban a lelki okokra irányul, noha emellett a fizikai tünetek is enyhíthetıek.

A test szervi és mőködési zavarai nem választhatók el a szellemi-lelki állapottól, a szociális környezettıl, az egyéni sorstól és a teljes személyiségtıl. A pszichés élet elsıdleges zavarait a lelki izgalmak vagy a súlyos megterhelések okozzák. Ezek valódi szervi tüneteket is eredményezhetnek a létfontosságú mőködéseket - például a keringést, a légzést, az emésztést, a belsı elválasztású mirigyeket stb.) szabályozó, ún. vegetatív idegrendszer (az agykéregtıl a szervekhez menı) pályáin keresztül. A „PSB” lényege az egészséges állapotnak megfelelı harmónia megbomlása, illetve egyensúlyzavar létrejötte, melynek következményeként megváltozik a beteg kapcsolata a külvilággal is. A fı tünetek tulajdonképpen szervi panaszok, melyek mögött a munkához vagy a mindennapi élethez való alkalmazkodás zavara húzódik meg. A leggyakoribb tünetek a vizsgálatok során objektíven kimutatható szervi elváltozások, míg kisebb részben szervi elváltozás nélküli betegség lép fel. A szervi elváltozások kialakulását a kiváltó pszichés tényezı hosszan elhúzódó hatása miatt rögzült kóros válaszformák idézik elı. S ezek épp az egyén szervezetének legsebezhetıbb, leggyengébb ellenállású pontjain (latinul „locus minoris resistentiae”) jelentkeznek. A Hippokrateszi iskola a lelki történéseknek mindig elsıdleges, elızményi szerepet tulajdonított a szervi megbetegedések kialakulásában. Ezek lehetnek konfliktusok, csalódások, gátlások, félelmek, fóbiák, szorongások, depresszió… A legtipikusabb pszichoszomatikus megbetegedések – a teljesség igénye nélkül: ekcéma, hasmenés vagy gyomorhurut, gyomorfekély, légzési nehézségek (bronchitis, asthma), colitis (vastagbélgyulladás), a magas vérnyomás egyes fajtái, pajzsmirigy-túlmőködés, fejfájás, ízületi és végtagfájdalmak, herpes

simplex, polio-vírus fertızés stb. A mindennapi nyelvhasználat is híven tükrözi, hogy milyen szoros kapcsolat áll fenn lelkiállapotunk és például az emésztıszerveink között. Gyakran használunk ilyen kifejezéseket: „remeg a gyomrom az idegességtıl, egy falatot sem tudnék lenyelni, gombóc van a torkomban” stb. Az elsıdleges cél a munkaképesség visszaállítása, s az életminıség javítása. Ám a beteg szervi elváltozásainak észlelése és kezelése mellett, azzal egy idıben rendkívül fontos a beteg személyiségével való törıdés! A pszichoterápia egy olyan beszélgetésterápia, amely segít a betegnek, hogy felismerje és megértse a problémáit, hogy új tapasztalatokat szerezzen, újabb viszonyítási alapot nyerjen, és másfajta viselkedési módokat sajátíthasson el. A terápia során bekövetkezı lelki változásokkal összefüggésben gyakran a testi panaszok is fokozatosan megszőnnek. A betegség fajtájától függıen az orvos komplex kezelést végez, melynek részét képezheti a pszichoterápia valamelyik formája is: csoportos-, családi-, viselkedési terápia, hipnózis, autogén tréning stb. Bizonyos esetekben az is elıfordulhat, hogy már nem kerülhetı el a mőtéti beavatkozás (pl. gyomorfekély súlyosabb formái). A pszichoszomatikus és a civilizációs betegségek korrelálnak, hasonlóan növekvı tendenciát mutatnak. Minden terápia ellenére a PSB-ben szenvedık abszolút száma folyamatosan emelkedik, jelenleg az össznépesség 10–30%-át teszik ki. Számos tényezı hozzájárult e tendencia kialakulásához, többek között az új, megváltozott élethelyzetek, a rendszerváltás okozta speciális lét(fenntartási) kérdések, az alkalmazkodási nehézségek, az esetleges átképzési kényszer, a munkanélküliség, az utcára kerülés, a válások növekvı száma, s ezzel együtt az elmagányosodás, az elidegenedés. Mindemellett érdekesség, hogy a nıknél inkább fiatalabb, míg a férfiaknál inkább idısebb korban fordulnak elı pszichoszomatikus betegségek. Fentieket összegezve elmondhatjuk, hogy az egyre gyakoribbá váló, és sokszor súlyos, igen változatos tüneteket produkáló pszichoszomatikus megbetegedéseket komolyan kell vennünk, nem tekinthetünk rájuk, mint véletlen, múló „kellemetlenségekre”. A lelki és testi történéseink kölcsönhatásaiból kialakuló kedvezıtlen változások és állapotok komplex kezelése orvosilag elengedhetetlenül szükséges! Prof. Dr. Kisgyörgy János Tel.: 407-3174 (16 óra után)

Prof. Dr. Kisgyörgy János akadémikus, anatómus, ideggyógyász, pszichiáter, igazságügyi elmeszakértı, ny. egyetemi tanár.

Dr. Valló Ágnes

A stressz „Mindenkinek van, mindenki beszél róla, mégiscsak kevesen vették a fáradtságot, hogy utánanézzenek, valójában mi is a stressz.” – kezdi Selye János „Stressz distressz nélkül” című könyvét Nézzük meg tehát, hogy valójában mit is jelent a stressz? A stressz szó eredetileg az angol és a latin nyelvben egy ige, melynek jelentése: megsérteni, bántani, szorítani. A fogalmat később a természettudományokban használták, elsősorban a fizikában, ahol a tárgyra ható külső nyomással hozták összefüggésbe. Az orvostudomány a 20. században vette át a kifejezést, azonban itt kétféle értelemben is használták: a stresszt: jelenti a szervezetre ható külső körülményeket (például magas hő, erős ütés stb.), illetve az ezen körülmények hatására a szervezetben lezajló belső változásokat is. Selye János (1983), választotta külön a hatást és a következményt: stressznek azt a nem specifikus választ tekinti, amit a szervezet a megterhelésre ad. A stressz ezen felfogása szerint a szervezetre ható külső erőket, körülményeket stresszoroknak nevezzük. Selye szerint a stressz lényege az alkalmazkodás: annál erősebb stresszről van szó, minél nagyobb mértékű alkalmazkodást kíván a szervezettől. A pszichológiában, ill. a pszichoszomatikus szemléletű medicínában a stressz általában véve olyan eseményekre utal, amelyek megítélésünk szerint megterhelők, veszélyeztetik pszichikai és/vagy fizikai jóllétünket. Az ilyen események a stresszorok, a rájuk adott reakciók összessége pedig a stresszválasz. (Atkinson)

A „jó” és a „rossz” stressz A stressz jelensége egyre erőteljesebben van jelen a köztudatban, a médiában. És meg kell hagyni, hogy meglehetősen rossz sajtója, rossz "PR"-ja van. Az utóbbi években szinte közhellyé vált a stressz káros, megbetegítő hatása. Ami nemcsak igazságtalan, hanem félrevezető is. Tegyük fel a kérdést: vajon egyértelműen ártalmas-e a stressz? Biztos, hogy megbetegít? Ha így lenne, minden bizonnyal kihalt volna már az emberiség. Hiszen stresszmentes élet nincs. A stressz hiánya - maga a halál. A stressz mindennapi életünk része, alkotó energiáink forrása, mely cselekvésre sarkall, segíti küzdelmeinket. A stressz - kihívás, késztetés. Segít, hogy reggelente frissen, elevenen ébredjünk, hogy napközben lelkesek, pozitívak, kreatívak legyünk. Segít versenyt futni, előadást tartani, még szerelmeskedni is. A stressz sarkall, hogy meneküljünk a tűz vagy az árvíz elől, vagy elkészüljünk munkánkkal a kitűzött határidőre. A túlzott, mindent elborító, kontrollálhatatlan stressz azonban felmorzsolja energiáinkat, kiégést (burn out) okoz, tönkreteszi kapcsolatainkat, karrierünket, aláássa önbizalmunkat, végül - de nem utolsó sorban - súlyosan romboló hatással van egészségünkre. Olyan ez, mint a tűz: hasznunkra fordíthatjuk, ha korlátozzuk, és ellenőrzésünk alatt tartjuk. Hiszen a tűz világít, megsüti ételünket, fűti lakásunkat. De ha mindent elborít, elszabadul ellenőrzésünk alól akkor pusztító tűzvész válhat belőle.

Stresszorok Stresszoroknak a szervezetre ható külső erőket, körülményeket, vagyis azokat az ingereket nevezzük, amelyek a stresszválaszt létrehozzák. Elvileg - a helyzetnek tulajdonított jelentéstől függően - bármilyen inger kiválthat stresszválaszt. Az, hogy egy inger, esemény vagy helyzet mikor válik stresszorrá attól függ, hogy mennyire befolyásolható, bejósolható, mennyire változtatja meg az életünket, illetve mekkora belső konfliktust eredményez. A stresszkeltő események befolyásolhatatlannak tűnnek. Már a puszta hit, hogy befolyásolhatjuk az eseményeket, még akkor is csökkenti a szorongást, ha ezzel a lehetőségünkkel sosem élünk. Egy kísérletben például a kísérleti személyek két csoportját hangos, nagyon kellemetlen zajnak tették ki. Az egyik csoport egy gombbal kikapcsolhatta volna a zajt, de kérték őket, hogy ezt csak akkor tegyék, ha nagyon muszáj. A másik csoport nem tudta kikapcsolni a zajt. Végül az első csoport tagjai sem éltek a lehetőséggel, senki sem kapcsolta ki Dr. Valló Ágnes - A Stressz

a hangot, tehát mindkét csoport ugyanannyi zajnak volt kitéve. Az ezt követő probléma-megoldási feladat során a befolyással nem rendelkező csoport sokkal rosszabb teljesítményt nyújtott, ami arra utal, hogy számukra sokkal nagyobb stresszt okozott a zaj, mint azoknak, akik úgy érezték, hogy képesek irányítani az eseményeket. Ezért jelentős stresszor például, ha szigorú utasítások szerint kell dolgoznunk, és nincs befolyásunk arra, hogy milyen módszerrel, ütemezéssel végezzük a munkát. A kiszolgáltatottság, tehetetlenség az egyik legerősebb stresszforrás. Állatkísérletes adatok is bizonyítják, hogy a tehetetlenségérzés számos súlyos betegség, (pl. a rák) kifejlődésének egyik központi momentuma lehet. Két kísérleti patkányt helyeztek két egymás melletti, de elválasztott ketrecbe. Mindkét patkány hátbőre alá daganatsejteket injektáltak. Mindkét ketrecbe egyazon áramkörön keresztül áramot vezettek, s a kísérletvezetők időnként áramütésnek tették ki az állatokat. A két fülkét egyidejű, azonos számú, időtartamú és intenzitású áram érte. A különbség csak az volt, hogy az egyik ketrecben elhelyeztek egy áram-megszakító pedált. Az itt elhelyezett "A" patkány hamar megtanulta, hogy a pedál megnyomásával megszüntetheti a kellemetlen áramütést - mindkét ketrecben. A másik ("B") patkánynak ilyen lehetőség nem állt rendelkezésére. Bár mindkét állat azonos mennyiségű és erősségű áramütést kapott - hiszen "A" patkány mindkettejük számára megszakította az áramkört, a mesterségesen beültetett daganatsejtek mégis jóval nagyobb arányban tapadtak meg "B"-nél, mint "A"-nál. A különbség pedig nem áll másból, minthogy A patkány a pedál révén aktívan tudta befolyásolni a helyzetet, míg "B" mindvégig a külső körülményeknek kiszolgáltatott tehetetlen helyzetben volt. A stresszkeltő események bejósolhatatlanok. Miért fontos a bejósolhatóság? Egyrészt a figyelmeztető jelzés lehetővé teszi valamilyen előkészítő folyamat beindítását, ami kivédheti vagy csökkentheti a kellemetlen inger hatását. (Általában megkérjük az orvost vagy fogorvost, hogy szóljon előre, ha valami fájdalmas, vagy kellemetlen beavatkozás következik.) Másrészt bejósolható stressz esetén vannak ún. biztonságos időszakok is, amikor megnyugodhatunk, hiszen nincs vészjelzés: semmi rossz nem történhet. Ebből a szempontból (is) különösen stresszkeltő például a mentősök, rendőrök munkája, amelynek során bármikor előállhat vészhelyzet. Életkörülményeink változása, minden jelentős alkalmazkodást igénylő esemény stresszkeltőnek tekinthető. Holmes és Rahe feltérképezték és értékelték a stresszterhes események skáláját. A legmagasabb pontszámokkal a házastárs halála, a válás, különélés baleset vagy betegség szerepel a skálán, de stresszkeltőnek tekinthetők olyan örömteli események is, mint a kibékülés, terhesség, új családtag érkezése, kiemelkedő siker, sőt a nyaralás is. A stresszkeltő lehet mindaz, ami belső konfliktusokat okoz, pl. ha egymással összeegyeztethetetlen célok között kell választanunk. De az is, ha egy feladat képességeink határait súrolja. Ilyenkor ugyanis úgy érezzük, hogy a feladat meghaladja a rendelkezésünkre álló erőforrásokat, tudásunkat, képességünket. Viszonylag nagy tehát a kudarc esélye, ami negatívan befolyásolhatja őnmagunkról kialakított képünket.

A stressz élettani hatásai Hogyan befolyásolja a stressz a szervezet működését? Az állatvilágban, de még a primitív emberi társadalmakban is az életben maradás feltétele az, hogy az egyén azonnal felismerje a veszélyt és eldöntse: küzd vagy menekül. Veszélyhelyzetekben az ideg- és hormonrendszer azonnal adrenalint és mellékvese-kéreg hormonokat (kortizolt) mozgósít, s minden szerv működését a küzdés vagy menekülés szolgálatába állítja. Példaképpen idézzük emlékezetünkbe, mi történik, ha békésen sétálunk az utcán, és a kerítésnek nekiront egy vérszomjasan ugató, vicsorgó kutya. Szívünk hevesen, szinte a torkunkban dobog, gyorsabban kapkodjuk a levegőt, gyomrunk összeszorul, s még hátunkon is feláll a szőr. (Hasonló - bár nem ennyire drámai, viszont tartósabb - hatást válthat ki főnökünk packázása vagy anyósunk állandó zsörtölődése is.) Lássuk tehát pontosabban, mi is játszódik le szervezetünkben. Belső szerveink működését vegetatív idegrendszerünk irányítja. A vegetatív idegrendszer szimpatikus és paraszimpatikus oldalból tevődik össze. A szimpatikus idegrendszer szakosodott a vészhelyzetek elhárítására, míg a paraszimpatikus elsősorban a táplálkozás, a regenerálódás szolgálatában áll. A "vészhelyzet" hatására, (pontosabban - mint később látni fogjuk Dr. Valló Ágnes - A Stressz

annak hatására, amit vészhelyzetnek tartunk) a szimpatikus oldal, aktiválódik, ennek hatására gyorsul a légzés, a szívműködés, emelkedik a vérnyomás, fokozódik az izomfeszülés. A szimpatikus idegrendszer "kihelyezett tagozata" a mellékvese velő nagy mennyiségű adrenalint termel, ami fokozza az izmok vérellátását, és biztosítja a megfelelő "üzemanyag-ellátásukat" is: a májban található raktárakból cukrot szabadít fel, növelve ezzel a vércukorszintet. Mindehhez a hormonrendszer megfelelő hátteret biztosít. Az agyalapi mirigy közbenjárására a mellékvese kéreg kortizolt termel, ami segíti és stabilizálja a szimpatikus hatásokat. Mindezen hatások összességeként szervezetünk készen áll a veszély elhárítására. Érzékszerveink kiélesednek, gondolkodásunk tisztul, reakcióink gyorsulnak, izmaink erőtől duzzadnak, s elegendő cukor és oxigén áll rendelkezésükre a hatékony, gyors, erőteljes működéshez. Minden az izomműködés - a menekülés vagy küzdelem - szolgálatában áll. Mindez roppant hasznos, sőt elengedhetetlen a nyúl számára, ha farkas elől menekül, a macskának, ha kutyával kerül szembe, két vetélkedő szarvasbika küzdelme esetén, sőt az ősembernek sem volt más választása, ha mamuttal találkozott, mint elfutni, vagy harcba szállni vele. A mai stressz természete azonban nagymértékben változott. Ritkán kerülünk szembe olyan szituációval, ahol a fizikai harc vagy menekülés megoldást jelentene. Bár valószínűleg gyakran szívesen orrba vágnánk a közlekedési dugóban pofátlanul előző sofőrt, vagy szeretnénk világgá szaladni az állandóan csengő telefon elől - a társadalmi játékszabályok rákényszerítenek, hogy uralkodjunk magunkon. Ha a stresszhelyzetet testi reakció - küzdés vagy menekülés - követi, akkor a szervezet egyáltalán nem vagy alig károsodik. Akkor sincs veszély, ha a harag, bosszúság, indulat csak átmeneti, könnyen lereagáljuk, vagy gyorsan túltesszük magunkat rajta. Ha azonban az élettani válasznak - a társadalmi következmények miatt - nincs szabad tere, tartós, vagy túl gyakran ismétlődik, akkor a testet halmozódó negatív hatás éri. Tartós stresszhatás esetén egy bizonyos ideig a szervezet képes alkalmazkodni a stresszhez, ez az alkalmazkodóképesség azonban véges, és túlzott igénybevétel, megterhelés esetén kimerül. Selye írta le az ún. Általános Adaptációs Szindrómát. E szerint az alkalmazkodásnak három egymástól elkülöníthető szakasza van: 1. alarm reakció: A szervezetben a stresszorral való találkozás jellegzetes tünetei jelentkeznek: gyorsul a szívverés, emelkedik a vérnyomás, nő a vércukorszint, stb. 2. ellenállási szakasz: ha a stresszor folyamatos hatása mellett lehetséges az alkalmazkodás, akkor kifejlődhet a megfelelő ellenállás. Az alarm reakció jelei látszólag eltűnnek, és az ellenállóképesség a normális szint fölé emelkedik. 3. kimerülés szakasza: az alkalmazkodási energia kimerül, ha a szervezetet túlságosan hosszú ideig túlságosan erős stresszor hatása éri, (és/vagy ha a stresszorokkal szembeni cselekvés lehetetlen.) Újra megjelennek az alarm reakció jelei, megnagyobbodnak és túlműködnek a mellékvesék, károsodik az immunrendszer fekélyek keletkeznek a gyomorban és a bélrendszerben. A szervezetben stressz hatására mindig a „leggyengébb láncszeme szakad el”, kialakul a betegség, végül – segítség nélkül – akár halál is bekövetkezhet.

Stressz és betegség Már az állatvilágban is megfigyelhetők stresszel összefüggő megbetegedések. Az anyjuktól túl korán elszakított kiscicáknál pl. az emberi asztmához nagyon hasonló légzési nehézségeket észleltek, míg a szüntelen kutyaugatásnak kitett macskák 50%-ban magas vérnyomásban betegszenek meg. A szállítással együtt járó félelem a disznóknál gyomorfekélyt, a lovaknál foltos “kopaszodást” (alopecia) okozhat. Egy igen heves és hosszantartó vihart követően több ezer sirály holttestét találták a francia tengerparton. A boncolás kimutatta, hogy a rémület és a kimerülés következtében vérző gyomorfekélyt (stresszulcus) kaptak, és ez okozta halálukat. A legmeggyőzőbben azonban egy igen érdekes - és a kutatók számára is meglepő eredménnyel zárult állatkísérlet is igazolta a stressz szerepét, mégpedig nem is akármilyen betegség, hanem a rák kialakulásában A rákkutatás céljaira egy speciális, a rákra genetikailag fogékony egérfajt tenyésztettek ki. Erre az egértörzsre az a jellemző, hogy - szokásos laboratóriumi körülmények között általában kb. 70%-ban betegszenek meg rákban. Rendszerint a különböző daganat-ellenes gyógyszerek hatását vizsgálják rajtuk. Dr. Vernon Riley a Washingtoni Egyetemen azonban arra volt kíváncsi, hogy milyen mértékben befolyásolja a stressz a daganatképződést. Dr. Valló Ágnes - A Stressz

Ezért az egereket születésük után két csoportra osztotta. Az egyik csoportot nagyfokú stressznek tette ki, (zsúfoltság, szűk ketrec, váratlan zajok, rázkódás, rendszertelen táplálás stb.) A kutatók azt várták, hogy a daganat előfordulása kb. 80%-os lesz. Az eredmények jócskán meghaladták várakozásukat, mivel az egerek 96%-a betegedett meg rákban. Az igazi meglepetést azonban nem ez okozta. Az egerek másik csoportját a kutatók kellemes, stresszmentes környezetbe helyezték. Igazi egér-paradicsomot varázsoltak az állatkáknak. (Bőséges tér, hinták, mászókák szórakozás céljára, kellemes egyenletes hőmérséklet, rendszeres táplálék) A kutatók azt várták, hogy a daganatok keletkezése ebben a csoportban talán néhány százalékkal alacsonyabb lesz, de voltaképpen csak a stressznek kitett csoport eredményeit akarták velük kontrolálni. Az eredmény megdöbbentő volt. A genetikailag terhelt egértörzsnek mindössze 7 (nem tévedés, hetes!) %-ában alakult ki rák. Mitől függ, hogy az ember melyik betegséget "választja", vagyis a bőséges "választékból" melyikben betegszik meg? A válasz több oldalról is megközelíthető. Ez az a pont, ahol komolyan számításba jön a genetikai hajlam kérdése. Ez gyakorlati szempontból azt jelenti, hogy melyik szerv, szervrendszer a "leggyengébb láncszem", ami a külső megterheléseknek legkevésbé tud ellenállni. Ez lesz az, ami leghamarabb "eltörik", vagyis amelyen a betegség megjelenik. Más megközelítés szerint (Alexander) összefüggésbe hozhatunk bizonyos betegségeket meghatározott személyiségjegyekkel illetve konfliktus-szituációkkal. Az állandó versenyhelyzet, az elfojtott indulatok, rohanás, időzavar például a szimpatikus idegrendszer túlaktiválódásához, s ezen keresztül magas vérnyomáshoz, infarktushoz vezethetnek. Ezeket nevezzük alarmvagy riadóbetegségeknek. A vészhelyzet hatására ugyanis megszólal szervezetünkben egy rejtett "csengő", a szimpatikus idegrendszer aktiválódik, és minden erőforrásunkat a veszély leküzdésére mozgósítja. Emelkedik a vérnyomás, a szív szaporábban és erőteljesebben dobog, megnő a vércukor mennyisége stb. Nincs gond, ha az izgalom, a vészhelyzet csak átmeneti; különösen akkor nem, ha feszültségeinket, indulatainkat le tudjuk vezetni, vagy legalábbis bánni tudunk velük. Ha azonban az izgalom, feszültség tartóssá válik vagy állandóan ismétlődik, és levezetése is akadályba ütközik, akkor megbillen a vegetatív idegrendszer egyensúlya, szimpatikus túlsúly alakul ki. Ez az állandóan visszafojtott feszültség alarm betegségekhez vezethet. Az utóbbi évtizedekben az infarktus jól ismert rizikófaktorain (dohányzás, magas kolesztrinszint, elhízás, magas vérnyomás, cukorbetegség, ülő életmód) kívül egy újabbat is számításba szokás venni, ez pedig az úgynevezett "A" típusú viselkedés. Az A típusú személyiséggel rendelkező egyén lázasan tevékeny, örökké siet, egyszerre mindig többfélét csinál, (pl. borotválkozás közben telefonál, reggelizik, újságot olvas és rádiót hallgat), türelmetlen, versengő természetű, hirtelen haragú, ellenséges indulatokkal küzd. Tökéletességre törekszik, nagy követelményeket támaszt másokkal, de még nagyobbakat önmagával szemben, valójában állandó készenlétben él, egy percig sem képes lazítani. (Figyeljük meg: az itt leírt személyiségkép voltaképpen korunk hőse, a „very busy businessman”) A további kutatások azt mutatják, hogy az A tipus jellemzői közül kiemelkedő jelentősége van az ellenségességnek. S így önmagában jobb előrejelzője a szív-koszorúér betegségeknek. A teljesítményorientáció, a versengés önmagában nem veszélyeztető, ha barátságossággal, együttműködési készséggel párosul. Az esetek többségében az A típusú magatartás csak egy a rizikófaktorok közül, azonban az is előfordul, hogy a szélsőségesen A típusú viselkedés önmagában, más rizikófaktorok nélkül is infarktushoz vezethet. A szélsőségesen A típusú, túlzottan teljesítmény- és sikerorientált, ellenséges indulatokkal küzdő személyiségben nem működnek a “biztosítékok”, s így a túlterhelés magát a „szerkezetet” károsítja. Az előbbiekkel ellentétben az emésztőszervi betegségek inkább a két tűz közé szorított középvetetőket és a beosztottakat veszélyeztetik. (Egy gyakran idézett anekdota szerint Selye János egyszer megkérdezte egy zsarnoki természetű, önkényeskedő admirálistól, hogy van-e gyomorfekélye. "Nekem nincs" - felelte az admirális - "de a beosztottaimnak van". Az az ember, aki túlzottan befelé fordul, vagyis minden problémáját "lenyeli", de nem tudja azokat "megemészteni", tehát szükségképpen "megfekszik a gyomrát", fekélybetegségre veszélyeztetett. A túlzott aggodalmaskodás, elbizonytalanodás a paraszimpatikus idegrendszer általvezérelt emésztőszervekben okoz károsodást. Aki túlzottan aggodalmaskodik, az állandóan olyasmitől fél, ami soha sem - vagy csak nagyon ritkán fog bekövetkezni. Mindig a legrosszabbat várja, és lélekben át is éli, anélkül, hogy az bekövetkezett volna. Ezzel nap mint nap megteremti, megsokszorozza, állandósítja önmaga számára a stresszt. Ezáltal az egyszeri hatás tartóssá válik, a vegetatív idegrendszer egyensúlya felbillen és a paraszimpatikus túlsúly következtében fekélybetegség, irritábilis bél szindróma alakulhat ki. Dr. Valló Ágnes - A Stressz

Napjainkban egyre gyakoribbá váltak a mozgásszervek fájdalommal és mozgáskorlátozottsággal járó betegségei. Ennek számos civilizációs oka van: a túlsúly, a mozgásszegény, ülő életmód, stb. A közelmúltban végzett felmérésem számomra is meglepő eredményt hozott: a mozgásszervi panaszok sokkal szorosabb összefüggést mutattak a stresszel, mit a testsúllyal, a mozgásmennyiséggel vagy az életkorral. A stressz természetesen elsősorban izmainkra hat. Ha szorongunk, feszültek, idegesek vagyunk, izmaink megfeszülnek, tónusuk fokozódik. A tónusfokozódás az oxigénigény növekedésével jár, egyúttal több energiát fogyaszt, ezért estére olyan fáradtnak érezhetjük magunkat, mintha egész nap követ törtünk volna. Másrész a relatív oxigénhiány fájdalmakat is okozhat. Ha pedig stressz, tartós feszültség következtében az izmok megfeszülnek, a kisfokú gerincelváltozás is súlyos, alig elviselhető fájdalmakat okozhat. A stressz károsan befolyásolja az immunrendszer működését is, és ezáltal elősegíti a fertőzések sőt akár a rák kialakulását is. Régóta ismert, hogy természeti katasztrófák, háborúk után hatalmas járványok söpörtek végig országokon, kontinenseken. Elég csak az I. világháborút követő spanyol-influenza járványra gondolni, melynek több halálos áldozata volt, mint magának a világégésnek. E járványokban a higiénés állapotok romlása kedvezett a kórokozók szaporodásának és fertőzőképességének, az éhezés, az alultápláltság, valamint a katasztrófa, a háború okozta nagyfokú stressz pedig gyengítette az áldozatok immunrendszerét. Igen érdekes, hogy a fertőzések nagy többsége nem a háború alatt, hanem azt követően alakul ki. Úgy tűnik, hogy az állandó veszélyt, készenléti állapotot követő kimerültség az, ami kedvez a kórokozóknak. Erre utal az a francia megfigyelés is, hogy az I. világháború alatt a visszavonuló - tehát letört, kimerült, reményvesztett - alakulatoknál jóval több tüdőgyulladásról számoltak be, mint a harcoló - tehát aktuálisan több stressznek kitett, állandó készenléti állapotban élő - csapatoknál. Mindezek alapján arra következtethetünk, hogy a közvetlen életveszély elmúltával az általános adaptációs szindrómával terhelt katonák védekezőképessége nem regenerálódott, hanem a 2. ellenállási szakaszból a 3. kimerülési fázisba csapott át. Egyetemeken, főiskolákon jól ismert, hogy vizsgaidőszakban a hallgatók gyakorta halasztanak vizsgákat lázas fertőző betegségek miatt. Vajon a felső légúti hurutok megszaporodása a vizsgaidőszakban csupán a lustaságot leplezni kívánó hallgatói kifogás, netán valami furcsa járvány következménye? Korántsem. Több amerikai kutatóhelyen igazolták, hogy az egészséges fiatal egyetemisták vérében ill. nyálában kimutatható ellenanyagszint a vizsgaidőszakban fokozott stresszterhelés következtében csökken, tehát könnyebben kapják meg a fertőzéseket. Érdekes megfigyelni, hogy az iskolai stressz milyen nagy fokban befolyásolja a 6-10 éves gyermekek ellenálló képességét. Egy szigorú, merev, büntető tanítónő osztályában jóval nagyobb arányú a hiányzás, mint liberális, gyermekcentrikus, társnőjénél. Megkockáztatom: ha egy vállalatnál az évi rendes influenza-járvány idején a szokásosnál több a betegek száma, akkor egyrészt vizsgáljuk meg a klíma-berendezést, vajon nem szórja, terjeszti-e a kórokozókat, másrészt keressük meg azokat a stresszforrásokat, amelyek ronthatják a dolgozók hangulatát, közérzetét és ezáltal ellenállóképességét is. A stressz a testi betegségeken kívül számos pszichológiai hatást is kiválthat. Ide sorolható akár a kirobbanó öröm, megelégedettség is, ha sikerül egy nehéz helyzetet, feladatot, kihívást megoldani. Ha a stresszhelyzet tartósan fennáll, akkor szorongás, harag, agresszió, fásultság, vagy akár depresszió is kialakulhat. A szorongás testi tünetekben is megnyilvánuhat ilyen lehet pl. torokban érzett “gombóc”, a fejfájás, vagy az alvászavar, de vezethet akár pánikrohamokhoz is. A stresszhelyzetekre adott másik általános reakció a gyakran agresszióba torkolló harag. Állatkísérletek is igazolták, hogy a frusztráció, a tehetetlenség agressziót válthat ki. Gyerekek gyakran válnak agresszivvá, ha frusztrálják őket. Felnőtteknél közlekedési dugókban figyelhető meg a – szerencsére általában csak verbális – agresszió. A frusztráció hatására megjelenhet az agresszióval ellenkező véglet, a visszahúzódás, és fásultság, mely gyakran teljesítményromláshoz, súlyos esetben pedig depresszióhoz vezet.

Coping: Megküzdés a stresszel. Valóban a stressz az, ami megbetegít? Nemcsak az a fontos, hogy mi történik velünk, hanem az is, hogy a történteket hogyan éljük át. Az, hogy miként hatnak ránk egyes helyzetek, elsősorban attól függ, hogyan gondolkodunk róluk, milyen jelentést tulajdonítunk neki, és - nem utolsó sorban - az, hogy képesek vagyunk-e befolyásolni az eseményeket. Dr. Valló Ágnes - A Stressz

A stressz csak előkészíti a talajt a betegség számára, de nem maga a stressz okozza a betegséget. Nincsenek - vagy alig vannak - önmagukban betegség-okozó helyzetek, hanem csak olyan magatartások, szokások, amelyekkel az ember a helyzetre reagál. A helyzet rendezését, megoldását pedig nagymértékben befolyásolja annak egyéni jelentése. Vagyis nem magára a helyzetre reagálunk, hanem arra, amit az számunkra jelent. Mást jelent az állásvesztés 20 illetve 50 éves korban, mást a kistelepülésen élő szakképzetlen bedolgozónak és mást a magasan képzett menedzsernek, aki után fejvadászcégek kapkodnak. Mást jelent a nyugdíjazás annak, akinek élete értelme volt a munka, mint annak, aki kínos kötelezettségek tömegétől szabadul meg, és alig várja, hogy végre horgászszenvedélyének élhessen. Mást jelent egy meghiúsult üzletkötés, füstbe ment szerződés virágzó üzletmenet idején, s megint mást akkor, ha a csőd fenyeget. A teljesítmény-kihívásokat is igen eltérően ítélik meg az emberek attól függően, hogy mekkora az önbizalmuk, becsvágyuk, s mennyi örömöt találnak tevékenységükben. A döntő tehát nem maga a stressz, hanem az, hogy valaki hogyan birkózik meg a stresszel. Betegség rendszerint akkor alakul ki, ha az egyén "megbirkózási technikája" hibás, túlzott, vagy nem felel meg a megoldandó problémának, azaz miként éli meg a helyzetet vagy állapotot. Megküzdés alatt a személy azon erőfeszítéseit értjük, melyek arra irányulnak, hogy legyőzze a rá ható külső vagy belső fenyegetéseket. A megküzdési folyamat révén az emberek új készségeket, képességeket sajátíthatnak el, vagyis azt mondhatjuk, hogy amennyiben a stressz hatékony megküzdéshez vezet, úgy hosszabb távon pozitívnak tekinthető, hiszen fejlődéshez segítette hozzá az egyént. A megküzdés módját is az határozza meg, hogyan értelmezzük, értékeljük a helyzetet. A folyamat első szakasza az elsődleges értékelés azt tisztázza, hogy a helyzet mit jelent, mekkora a jelentősége. Fontos-e számunkra, ami történt, érinti-e a személyes céljainkat, és ha igen, milyen mértékben tér el az adott hatás az elvárttól. Lényegében arra a kérdésre kell megtalálni a választ, hogy „bajban vagyok-e?”. Az elsődleges értékelés határozza meg, hogy milyen érzelmekkel reagálunk a helyzetre. A másodlagos értékelésben azt elemezzük, hogy mi a teendő? Tudunk-e egyáltalán tenni valamit? Itt dől el, hogy véleményünk szerint meg tudunk-e küzdeni az elsődleges értékelésben fenyegetőnek ítélt helyzettel. Eldöntjük, hogy kontrollálható-e a helyzet, s ki vagy mi az okozója. Számba vesszük az erőforrásainkat. (Ilyen megküzdési forrás bármi lehet, például egy másik személy vagy csoport segítsége, támogatása, anyagi javak, kulturális források, stb.) A kérdés: Mit tehetek én ebben a szituációban? A másodlagos értékelést követi a döntés, hogy milyen megküzdési stratégiát fogunk használni. Ha az értékelés alapján úgy tűnik, hogy kezelhető a helyzet, akkor problémaközpontú megküzdést fogunk alkalmazni, ha nem, akkor inkább érzelemközpontú stratégiákhoz folyamodunk. Majd megtörténik a tulajdonképpeni megküzdés, melyről az újraértékelés során dől el, hogy a várt eredményre vezetett-e, s ha nem, akkor új megküzdési próbálkozás következik. Problémaközpontú megküzdés Az egyén akkor választja ezt a stratégiát, ha úgy érzi, hogy van esélye befolyásolni a fennálló vagy fenyegető stresszhelyzete4t. Arra összpontosít tehát, hogy megkísérelje azt elkerülni, vagy megváltoztatni. Ennek során először is pontosan meghatározza a problémát, lehetséges megoldási módokat dolgoz ki, ezek közül választ, majd végrehajtja a kiválasztott megoldást. A problémaközpontú megküzdésnek leggyakoribb módjai: tárgyalás (a helyzet többi résztvevőjére irányuló akciók, például mások meggyőzése, kompromisszumos megállapodás), a cselekvés (a probléma megoldására irányuló erőfeszítés), az óvatosság gyakorlása (több kárt, mint hasznot hozó cselekvések visszatartása) önmagunkban változtatunk meg valamit: pl. tanulással igyekszünk megszerezni valamilyen hiányzó készséget, képességet. Érzelemközpontú megküzdés Az idetartozó megküzdési stratégiák célja enyhíteni a stresszkeltő helyzethez kapcsolódó érzelmi reakciót, megváltoztatni a helyzet értelmezését, ha magát a helyzetet nem tudja megváltoztatni. Mindannyiunk életében előfordulnak olyan szomorú események, mint például egy szeretett hozzátartozó elvesztése, ahol magán a problémán változtatni nem tudunk. Megküzdésünk ilyenkor arra irányul, hogy saját fájdalmas, kellemetlen érzelmeinket csökkentsük, vagyis, hogy jobban érezzük magunkat. Ide olyan (adaptív és kevésbé adaptív) Dr. Valló Ágnes - A Stressz

viselkedési stratégiák tartoznak, mint testmozgás, társas támaszkeresés (barátokhoz, rokonokhoz fordulás), alkohol, drog, gyógyszer, stb. Érzelemközpontú gondolkodási stratégiáink olyanok lehetnek, mint: - panaszkodás, támaszjeresés, kibeszélés - figyelemelterelés, - tagadás, - a probléma félre tétele, - a helyzet jelentésének megváltoztatása, - humor, - vallásos hit, - alkohol, drog, gyógyszer, stb. Az emberek a legtöbb alapvető megküzdési stratégiát használják valamennyi feszültségkeltő helyzetben, vannak azonban specifikus stresszorokhoz kötődő megoldások. Az érzelemközpontú megküzdést választunk, ha nincs hatásunk az eseményekre például egyértelmű kár és veszteség, pl. rokon, barát halála esetén. Problémamegoldó stratégia gyakoribb olyan helyzetben, amit kihívásként értelmezünk. Ha megváltoztathatónak látjuk a körülményeket, akkor problémafókuszú stratégiákat használunk. A nyugati kultúrában hajlamosak vagyunk arra, hogy kizárólag a problémafókuszú stratégiákat tekintsük valódi megküzdésnek, vagyis leértékeljük az érzelemközpontúakat. Ez azonban sajnálatos tévedés. A problémafókuszú megküzdés ugyanis csak akkor csökkenti a stresszt, ha sikeres! A különböző stresszhelyzetekhez való leghatékonyabb alkalmazkodás akkor várható az adott személytől, ha minél többféle megküzdési készséggel rendelkezik, és rugalmasan tudja ezeket használni a helyzet követelményeinek megfelelően, akár többet is egyszerre. Nem mondhatjuk tehát, hogy bármelyik megküzdési stratégia általánosságban hatékonyabb lenne a többinél.

Stresszoldás, stresszkezelés Ritkán gondolunk arra, hogy étrendünk, is befolyásolja szellemi teljesítő képességünket, kedélyállapotunkat. Jó közérzetünkben az egészséges táplálkozásunknak is nagy szerepe van. Számos étel és ital tartalmaz stresszkeltő anyagokat., míg mások fokozzák stressztűrő képességünket. De attól is feszültek, ingerlékenyek lehetünk, ha munka közben nem jut időnk ebédelni. Az éhezés hatására ugyanis csökken a vércukorszint, ennek ellensúlyozására szervezet fokozott adrenalin-termeléssel válaszol. Az adrenalin fokozza a vércukorszintet, de stresszkeltő hatásai is érvényesülnek. Néhány vitamin jelentős szerepet tölt be lelki egyensúlyunk biztosításában, stressztűrő képességünk fokozásában. Hiányuk esetén számos negatív hatással kell szembenéznünk. Fokozhatjuk stressztűrő képességünket gyógynövényekkel, illóolajokkal is. A helytelen tartás, amit az íróasztal és a számítógép billentyűzete fölötti tartós görnyedés okoz, gyakran nemcsak izomgörcshöz, fájdalomhoz, hanem a stressz fokozódásához is vezet. A masszázs a fizikai fájdalom és az izomfeszülés egyik leghatásosabb ellenszere, egyúttal oldja a stresszt is. Megtanulhatunk egy olyan 5-10 perces önmasszázst is, amit akár munka közben is alkalmazhatunk. De mindenképpen nyújtózzunk minél gyakrabban, és az ajtókeret segítségével nyújtsuk meg fáradt hátizmainkat is. Mindennapi környezetünk nagymértékben befolyásolja hangulatunkat, otthonunkat lehetőség szerint úgy kell berendeznünk, hogy lehetővé tegye a pihenést, kikapcsolódást, feltöltődést. Néhány apró fortéllyal a leglehangolóbb irodát is vonzóbbá, vidámabbá varázsolhatjuk. A zaj jelentősen fokozza a feszültséget. A fény is jelentősen befolyásolja közérzetünket. A szobanövények a lakásban és az irodában is meghittséget, otthonosságot sugároznak, ezen kívül egészségesek is, mivel növelik a levegő páratartalmát. Sokak számára rendkívül pihentető, megnyugtató egy szépen "berendezett" akvárium látványa. Mozogjunk, sportoljunk minél többet! A testi, fizikai megterhelés jó mederbe tereli, és ezzel semlegesíti a szervezet stresszre adott válaszreakcióit. Ezzel csökkenti a stressz okozta ártalmakat, és növeli a stressztűrő képességet. Olyan sportot válasszunk, ami örömet okoz! Ha a mozgás, a sport, amit esetleg orvosunk tanácsára, egészségünk megőrzése céljából űzünk, nem más, mint egy újabb kínos kötelesség, feladat, nyűg, "púp a hátunkon" - akkor semmit sem ér. Legfeljebb azt érjük el, hogy roppant edzetten kapjuk meg - esetleg éppen futás közben - az infarktust. A különböző testgyakorlások között különleges helyet foglal el a jóga. A jóga erősíti és rugalmasabbá teszi a testet, ellazítja, megnyugtatja a lelket, fokozza a szellemi tudatosságot és koncentrálóképességet. Dr. Valló Ágnes - A Stressz

A megfelelő tervezés, szervezés hiánya, az állandó időzavar első helyen áll a munkavégzéssel kapcsolatos stressz okai között. Ha úgy érezzük, hogy összecsapnak fejünk felett a hullámok, tegyünk fel magunknak néhány kérdést: Tényleg nekem kell mindezt elvégeznem? Mire mondhatnék nemet? Miért nem merek nemet mondani? Valóban nem bízhatnám másra? Kire bízhatnám? Sokan egészen kiváló képességekkel rendelkezünk, amikkel nagymértékben fokozni tudjuk a minket érő stresszt. A legtöbben egészen rendkívüli stratégiákkal jó alaposan fel tudjuk idegesíteni magunkat. Ehelyett inkább tanuljunk meg egy igen egyszerű légzéskontrol gyakorlatot! Néhány egyszerű gyakorlat csodákat tehet: szorongásunk, indulatunk oly mértékben csökken, hogy képesek leszünk objektíven, szinte kívülről szemlélni az eseményeket. Ha már elfelejtettünk volna, tanuljunk meg tehát újra örülni, nevetni, kikapcsolódni. Szánjunk rá időt: fedezzük fel, mi jelent igazi örömöt számunkra. Ne becsüljük le a szórakozás, a kikapcsolódás értékét. Mindennapi gondjaink, bajaink közepette használjuk humorérzékünket, próbáljuk meg a történteket humoros oldaláról nézni. Megtanulhatunk relaxálni. A relaxáció nem kizárólag izomlazítást jelent, hanem teljes idegi és lelki ellazítást is. A különféle relaxációs módszerek kiválóan alkalmasak a feszültség, a szorongás kóros köreinek áttörésére. Végül – de egyáltalán nem utolsó sorban - részt vehetünk stresszoldó, stresszkezelő tréningeken. Ezeken megtanulhatjuk az előzőket, és fokozhatjuk megküzdő képességünket. A stresszel való hatékony megküzdés tehát nem egyszerűen segít a stressz káros hatásainak elkerülésében, hanem hozzájárul a személyiség fejlődéséhez, növekedéséhez.

A stresszkezelés szintjei A Dilts piramis logikai szintjei jól használhatók arra, hogy az egészségfejlesztésről, a stresszről, illetve a stresszel való megbirkózásról gondolkodjunk. Számba vehetjük, milyen tényezőket befolyásolhatunk, és mely szinteken érhetjük el a kívánt változást. A környezet. Ide tartozik a belégzett levegő, az elfogyasztott ételek minősége, lakásunk, irodánk berendezése, hangulata. A munkahelyi környezet nagymértékben befolyásolja a dolgozók hangulatát, munkakedvét, munkavégző képességét. A szürke, személytelen, ingerszegény környezet éppúgy nyomasztóan hat, mint a túlzsúfoltság, a zaj, a rossz szellőzés, vagy az alkalmatlan, kényelmetlen bútorok. Viselkedés, magatartás öleli fel mindazt, amit megteszünk illetve nem teszünk meg egészségünkért. Azt, hogy mit, és mennyit eszünk, mozgunk, dohányzunk-e, stb. De az is, hogy hogyan bánunk önmagunkkal és környezetünkkel, hogyan kommunikálunk, milyen kapcsolatokat alakítunk ki magunk körül. Mit csinál az egyén és a szervezet, ami stresszt okoz? Mit tehetne, a stresszcsökkentés, optimalizálás érdekében. Hogyan óvhatná menedzserei, dolgozói egészségét pl. menedzserszűrések, sportolási alkalmak teremtésével. Képességek. Ha tudjuk, mit kellene tennünk, de nem tudjuk, hogyan tegyük, akkor a képességek szintjére érkeztünk. Ide magatartáscsoportok, szokásrendszerek, általánosan alkalmazott stratégiák tartoznak. Például nem vagyunk képesek leszokni a dohányzásról. Miközben tudjuk, hogy milyen fontos a mozgás, a sport, mégsem vagyunk képesek időt szakítani rá. Nem tudunk lazítani, ezzel szemben kiváló stratégiáink vannak önmagunk felidegesítésére. Ezen a szinten készíthetjük el azokat a stratégiákat, amelyek segítségével lefogyhatunk, leszokhatunk a dohányzásról, amelyek segítenek csökkenteni a stresszt, illetve amelyek segítségével könnyebben tudunk megbirkózni vele. Sokan egészen kiváló képességekkel rendelkeznek, amikkel nagymértékben fokozni tudják az őket – ill. a környezetüket - érő stresszt. Képességeink azonban nem velünk születnek, mindent meg Dr. Valló Ágnes - A Stressz

tudunk tanulni, amit akarunk! Megtanulhatunk pl. relaxálni, vagy fejleszthetjük kommunikációs készségünket, illetve szert tehetünk bármely, az egészségi állapotunkat, stresszkezelésünket, hatékonyságunkat pozitívan befolyásoló képességre. Meggyőződések és értékek. A negyedik szint a meggyőződések és értékek szintje. Ide tartozik mindaz, amit önmagunkról és a világról gondolunk, hiszünk. Ezektől a cselekedeteinket befolyásoló alapelvektől függ, hogyan szemléljük önmagunkat, hogyan értelmezzük tapasztalatainkat, hogyan reagálunk másokra. Meggyőződéseink nagymértékben befolyásolják egészségünket is. A placebo-hatás igen ékes bizonyítéka annak, hogy a gyógyszerbe vetett hit önmagában gyógyítani képes, függetlenül attól, hogy van-e a gyógyszernek tényleges élettani hatása. Egészségünk nagymértékben függ attól, hogy mennyire hiszünk abban, hogy képesek vagyunk egészségi állapotunkat aktívan befolyásolni. Korlátozó hiedelmeink alááshatják egészségünket, megnehezíthetik, gátolhatják megbirkózási stratégiáinkat. Az értékek azok a dolgok, amik fontosak a számunkra. Ilyen az egészség, a boldogság, a szeretet, a siker, a jólét, a pénz, a karrier, a hatalom - és még sorolhatnánk vég nélkül. Értékeink, és azok fontossági sorrendje (hierarchiája) döntően megszabja magatartásunkat. Az, hogy mekkora érték számunkra az egészség, döntően meghatározza, hogy mit vagyunk hajlandók megtenni érte. A szervezet oldaláról pedig az, hogy mekkora értéket képvisel számára dolgozóinak jóléte ill. jól-léte. Identitás. Ez a szint jelenti önmagunkról alkotott képünket, öntudatunkat. Legfontosabb értékeink, meggyőződéseink tartoznak ide, amelyek meghatároznak bennünket és küldetésünket az életben. A szervezet identitása, a szervezeti kultúra nagymértékben meghatározza a stresszhez való viszonyt, stresszmenedzsment technikáit – és ezzel végső soron a szervezet hatékonyságát is. A különböző szintek egymást kölcsönösen áthatják. Természetesen minél magasabb szinten tudunk beavatkozni, annál jelentősebb, tartósabb, mélyrehatóbb változást érhetünk el.

A pszichoszomatikáról A pszichoszomatika a testi betegségek hátterében megbúvó lelki tényezőkkel foglalkozik. A pszichoszomatikus zavarok közös sajátossága, hogy többféle ok együttesen játszik szerepet kialakulásukban, de a lelki tényezők, a stressz kulcsfontosságúak a betegség keletkezésében, kiújulásában és súlyosbodásában. Ha pedig így van, akkor ennek a gyógyulás, gyógyítás során is meg kell nyilvánulnia. Minden orvos egyetért abban, hogy a hatékony gyógyítás - amennyire ez egyáltalán lehetséges - a betegség okát próbálja meg kiküszöbölni. Éppen ezért, a pszichoszomatikus betegségek esetén a hagyományos gyógyítás önmagában rendszerint nem elegendő. A hagyományos, akadémikus gyógyítás ugyanis a csak a testet, a szerveket, a betegséget veszi célba, s egyre újabb és hatékonyabb gyógyszerek segítségével próbálja meg helyreállítani az egészséget. Kizárólag gyógyszeres kezeléssel azonban gyakran nem születhet tartós eredmény, hiszen ez a szemlélet a betegséget provokáló, kiváltó lelki tényezőket figyelmen kívül hagyja. A pszichoszomatikus zavarok megfelelő gyógyítása tehát midig többirányú. Természetesen magában foglalja a szervi károsodás biológiai szintű - tehát gyógyszeres, vagy ha szükséges, akár sebészi - gyógyítását, de ezzel egyenértékű szerepet kap a pszichológiai segítségnyújtás is. Mivel a pszichoszomatikus betegségek rendszerint krónikusak, vagy legalábbis kiújulásra hajlamosak, s ezért átszövik a beteg életvezetését, környezetéhez való viszonyulását, a gyógyításnak fontos szerepe van a rehabilitációban, a beteg számára megfelelő, személyiségének kiteljesedését biztosító életminőség biztosításában. Ez a komplex megközelítés teszi lehetővé, hogy a beteg ne csak gyógyuljon, hanem meggyógyulhasson. Dr. Valló Ágnes

Dr. Valló Ágnes, pszichoszomatikus belgyógyász, természetgyógyász, életmódtanácsadó, egészségfejlesztő mentálhigiénikus, tréner, terapeuta, Semmelweis Egyetem Egészségtudományi (Főiskolai) Karán tanított 12 éven át élettant, kórélettant, belgyógyászatot, gyógyszertant, és az általa kifejlesztett pszichoszomatikus tárgyakat.

Dr. Valló Ágnes - A Stressz

BRAIN, BEHAVIOR, and IMMUNITY Brain, Behavior, and Immunity 21 (2007) 1009–1018 www.elsevier.com/locate/ybrbi

Named Series: Twenty Years of Brain, Behavior, and Immunity

Understanding the interaction between psychosocial stress and immune-related diseases: A stepwise progression Margaret E. Kemeny

a,*

, Manfred Schedlowski

b

a

b

Health Psychology Program, Department of Psychiatry, University of California, Laurel Heights Campus, 3333 California Street, Suite 465, San Francisco, CA 94143-0848, USA Institute of Medical Psychology & Behavioral Immunobiology, University of Duisburg-Essen, Medical Faculty, 45122 Essen, Germany Received 9 May 2007; received in revised form 3 July 2007; accepted 4 July 2007 Available online 21 September 2007

Abstract For many years, anecdotal evidence and clinical observations have suggested that exposure to psychosocial stress can affect disease outcomes in immune-related disorders such as viral infections, chronic autoimmune diseases and tumors. Experimental evidence in humans supporting these observations was, however, lacking. Studies published in the last 2 decades in Brain, Behavior and Immunity and other journals have demonstrated that acute and chronic psychological stress can induce pronounced changes in innate and adaptive immune responses and that these changes are predominantly mediated via neuroendocrine mediators from the hypothalamic–pituitary– adrenal axis and the sympathetic–adrenal axis. In addition, psychological stress has predicted disease outcomes using sophisticated models such as viral challenge, response to vaccination, tracking of herpesvirus latency, exploration of tumor metastasis and healing of experimental wounds, as well as epidemiological investigations of disease progression and mortality. These studies have contributed significantly to our understanding that the neuroendocrine–immune interaction is disturbed in many pathophysiological conditions, that stress can contribute to this disturbance, and that malfunction in these communication pathways can play a significant role in the progression of disease processes. There are, however, significant gaps in the extant literature. In the coming decade(s), it will be essential to further analyze neuroendocrine–immune communication during disease states and to define the specific pathways linking the central nervous system to the molecular events that control important disease-relevant processes. This knowledge will provide the basis for new therapeutic pharmacological and non-pharmacological behavioral approaches to the treatment of chronic diseases via specific modulation of nervous system–immune system communication. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Stress; Leukocytes; Cytokines; Catecholamines; Glucocorticoids; Arthritis; Tumor; HIV; Psychoimmunology; Infection; Autoimmune

1. Introduction The notion that stressful life experiences and one’s psychological state can influence the onset and progression of disease has existed for centuries, despite a paucity of evidence. Research conducted over the past 20 years in the field of psychoneuroimmunology has carefully examined this premise, leading to a much clearer picture of its strengths and weaknesses. The last 2 decades of research

*

Corresponding author. Fax: +1 415 476 7744. E-mail address: [email protected] (M.E. Kemeny).

0889-1591/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.bbi.2007.07.010

in the field of psychoneuroimmunology have been exciting, beginning with rigorous evidence that stress can affect the immune system, followed by intensive investigation of mediating mechanisms and extrapolation to disease processes. This short review focuses on the effects of psychological stress on immune functions and the etiology and progression of immune-mediated diseases since Brain, Behavior and Immunity (BBI) was first published in 1987. We will mainly concentrate on human work, in particular on the effects of stressors on viral infections, autoimmune diseases, wound healing and cancer. Since we are limited in the number of citations, we will predominantly cite review articles and apologize to all those colleagues who

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M.E. Kemeny, M. Schedlowski / Brain, Behavior, and Immunity 21 (2007) 1009–1018

contributed to the findings but whose work could unfortunately not be cited due to page and reference limitations. 1.1. Psychosocial stress, neuroendocrine–immune interactions In response to stressful circumstances, the neuroendocrine system stimulates a series of adaptive responses involving behavioral, cardiovascular, metabolic, and immunological changes. Pituitary hormones such as prolactin and growth hormone, and neuropeptides like corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), neuropeptide Y (NPY) and the opioids can be released during stressor exposure and can affect cellular and humoral immune responses (Malarkey and Mills, 2007; Kelley et al., 2007; Blalock and Smith, 2007; see Fig. 1). Experimental data in rodents and humans demonstrate that: (1) primary and secondary lymphoid organs are innervated by sympathetic noradrenergic nerve fibers, (2) all lymphoid cells express b-adrenoceptors and some subsets express a-adrenoreceptors, and (3) adrenaline and noradrenaline can alter circulation of leukocyte subpopulations and the functional capacity of immuncompetent cells, including cytokine production and release (Glaser and Kiecolt-Glaser, 2005; Sanders and Kavelaars, 2007). Increased sympathetic adrenal activity appears to play a major role in immune changes observed after acute psychological stress. Hypothalamic–Pituitary–Adrenal (HPA) axis-activity, resulting in enhanced release of glucocorticoids, together with sympathetic mechanisms are mainly responsible for the inhibition of cellular and humoral immune responses after chronic psychological stress exposure (Glaser and Kiecolt-Glaser, 2005) (Fig. 1). Glucocorticoids regulate multiple aspects of immune cell functions. For example, they regulate innate immune responses to bacterial and viral infection and can cause a shift in the adaptive immune response from T-helper-1 (Th-1) to T-helper-2 (Th-2) cell activity by inhibiting the production of pro-inflammatory cytokines such as Interleukin 12 (IL-12) and Tumor Necrosis Factor (TNF) or IL-2 and by stimulating the synthesis of the Th-2 cytokines IL-10 or IL-4 (Glaser and Kiecolt-Glaser, 2005). Sensory peptides, such as Substance P (SP), also interact with the immune system and may play a role in the link between stress and inflammatory processes. The primary role of SP in the periphery is to promote inflammation in order to protect tissue from irritants and pathogens. Many immune cell types express receptors for SP and SP afferents innervate immune organs. Binding of SP to its receptor upregulates pro-inflammatory cytokines, and influences a variety of other immunological processes that support inflammation. SP also plays a role in moderating stress pathways, such as the HPA-axis (see Rosenkranz, in press). Glaser et al. (1987) published the first study on stress and immune functions in humans in BBI, demonstrating an inhibition of cellular immune functions and poorer cel-

lular immune control of herpesvirus latency during examination stress in medical students. This first report in BBI confirmed earlier studies of this group and others demonstrating a suppression of humoral and cellular immune responses in individuals exposed to psychological stress. Over the last 20 years, the concept of immunosuppression following prolonged psychological stress has been demonstrated by numerous studies employing different stress models (e.g., examination, caregiving, marital conflict, bereavement) and parameters of the innate and adaptive immune response (e.g., circulation of leukocyte subpopulations, lymphocyte activity, cytokine production; Glaser and Kiecolt-Glaser, 2005). At approximately the time that BBI was first published, an increasing number of publications reported effects of acute psychological stress on human peripheral immune functions. These studies, using public speech, mental arithmetic or naturalistic stressors such as a parachute jump, demonstrated a transient activation in innate immune responses, such as an increase in natural killer (NK) cell activity and NK cell and granulocyte numbers. Over the last 2 decades we have learned a remarkable amount about how immune responses change during and after stressful events. However, there is still considerable debate over the normal versus pathological nature of these shifts in immunity. In healthy individuals, the changes in immune response following exposure to an acute psychological stressor are generally evaluated as an evolutionary adaptive process, indicating that immune responses are highly sensitive and quickly responsive to environmental stimuli, such as stressful or threatening circumstances. And the healthy immune system is capable of compensating for prolonged exposure to psychosocial stress-induced immune inhibition. However, experimental data in humans clearly indicate that the risk for illness due to the adverse effects of stress on the immune system can be increased. Not only from animal experiments but also from human studies, we recognize today, however, that even exposure to acute stressors can have prolonged effects on the immune response to pathogens (Edwards et al., 2006). In addition, numerous studies demonstrate that maladaptive neuroendocrine hyper- or hypoactive responses of the HPA or the sympathetic nervous system (SNS) to stress, including glucocorticoid resistance, can function as risk factors for the initiation and progression of specific diseases, in particular viral infection and chronic, inflammatory autoimmune diseases. 2. The first decade 1987–1996 2.1. Stress and chronic inflammatory diseases The etiology of chronic inflammatory diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) has been and remains unclear. Clinical observations suggest that stressful life events are associated with the onset and aggravation of symptoms in these autoimmune


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Fig. 1. Acute and sustained psychosocial stress affects the circulation and activity of immuncompetent cells via the release of neuroendocrine mediators. The major neural efferent pathways, through which stress can affect peripheral immune functions, are the neocortical–sympathetic–immune axis, the hypothalamus–pituitary–adrenal immune axis, and the brain stem–vagus–cholinergic pathway with the release of the major mediators noradrenaline, cortisol and acetylcholine. These hormones and neurotransmitters can subsequently modulate the inflammatory process in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis or skin disease, affect the immune response during infection and may influence tumor development and progression. ACTH, adrenocorticotropic hormone; Ach, acetylcholine; NE, noradrenaline.

disorders. Twenty years ago, however, experimental data investigating the effects of stress on neuroendocrine and immunological responses and disease outcome in patients with RA or SLE were rare. Most of our knowledge came from work with experimental animals demonstrating that stress effects on these inflammatory processes seem to be predominantly mediated via two neuroendocrine communication pathways. Chronic inflammatory processes appeared to be associated with a dysfunction of the HPA-axis, resulting in an altered secretion pattern of CRH, ACTH and glucocorticoids, which in turn modulated immune functions in the autoimmune process. In addition, animal data clearly showed an involvement of the SNS and adrenoceptor mediated mechanisms, in particular in chronic inflammatory processes. Treatment with badrenoceptor antagonists in experimentally induced arthritis in rats significantly decreased disease symptoms. In contrast, the application of adrenaline exacerbated arthritis in rats via b2-adrenergic mechanisms (Wilder, 1995). Most of the studies in humans on the effects of stress and disease outcomes were retrospective. However these studies

suggested that stress can be a disease permissive and aggravating factor in particular in juvenile idiopathic arthritis (JIA) and less so in RA. These findings were experimentally confirmed in studies demonstrating a disturbed, b2-adrenoceptor mediated SNS–immune system interaction in JIA patients in response to stress (Kuis et al., 1996). Researchers investigated the effects of stress on the exacerbation and the subsequent development of brain lesions in patients with multiple sclerosis (MS). Also here, a number of clinical, mainly retrospective studies indicated that critical life events preceded the onset or exacerbation of MS (Grant et al., 1989). Again, 20 years ago, experimental data on the effects of stress in MS patients were lacking and hypotheses regarding these effects and possible underlying mechanisms could only be generated from animal experiments. These data in experimental allergic encephalomyelitis (EAE), an animal model of MS, showed that exposure to stress such as restraint stress or maternal deprivation influenced the development of EAE in rats. However, these data also underscored the importance of effects of sex, strain, time of the onset of the stressor and subsequent

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kinetics of the immune response on disease exacerbation (Griffin et al., 1993). Although clinical evidence suggested an association between psychosocial stressors, immunological functions and other chronic inflammatory diseases such as skin diseases (psoriasis or atopic dermatitis; Gaston et al., 1987) or inflammatory bowel diseases (IBD), no systematic approach to investigation in these areas had been undertaken during the first decade of BBI. A number of human studies also published in BBI during the first decade demonstrated that acute psychological stress induced a transient activation in particular innate immune responses such as increased natural killer and granulocyte numbers. In contrast, sustained psychosocial stress was documented to suppress humoral and cellular immune responses and inflammatory reactions. Against the background of inconclusive results from retrospective studies on the effects of stress on the onset or aggravation of symptoms in patients with chronic inflammatory diseases however, the mechanisms underlying effects of stress on inflammatory processes in these conditions were largely unknown during this first decade. 2.2. Stress and infectious disease A number of paradigms have been utilized to examine the effects of stressful life experience on infectious disease outcomes. The most rigorous of these have involved viral challenge, response to vaccinations, and a focus on reactivation of latent viruses. Viral challenge studies involve inoculating healthy individuals with a virus under controlled conditions and quarantine and then examining individuals for evidence of infection and symptoms on a daily basis. The advantages of this approach are its ability to control viral exposure, verify effects observed in naturalistic studies and test for physiological mediators. In this early period, Cohen et al. (1991) found that greater levels of stress (defined on the basis of stressful life events, perceived stress and negative affect) predicted greater susceptibility to rhinovirus infection, lower neutralizing antibody titers and higher cold symptoms. During this same time period, Stone and colleagues found that stressful events, but not perceived stress, predicted rhinovirus virus infection using a similar paradigm. Another excellent model involves measuring the immune response to vaccinations against influenza or Hepatitis B, since there is important variability in the extent to which individuals develop protective immunity following vaccination. Antibody titers following vaccination with Hepatitis B and/or influenza were predicted by acute stress (medical student exams), chronic stress (caregiving for a family member with Alzheimer’s Disease), as well as perceived stress (Glaser, 2005). Other relevant immune processes in this context, such as virus-specific IL-2 and IL-1b levels, were also related to chronic stress. A third important model is reactivation of latent herpesviruses, such as the Epstein–Barr virus (EBV), capable of

causing mononucleosis, the herpes simplex virus (HSV), and the cytomegalovirus (CMV). Early work examined predictors of EBV infection and illness in West Point cadets and found that psychological factors such as a high motivation to achieve and poor academic performance predicted seroconversion, EBV titers and length of hospitalization. Glaser and colleagues reported effects of examination stress on herpesvirus latency beginning in 1984. Subsequent studies showed that academic exam stress and other stressors were capable of reactivating latent EBV as well as HSV-1 and CMV (see Glaser, 2005). Another latent virus, HIV-1, has been a focus for a number of studies in PNI. HIV-1 infection is an important model for understanding the potential impact of stressors on disease because immune and virologic processes that play a significant role in disease pathogenesis are known and easily accessible to investigation. In addition, there is a great deal of unexplained variability in disease course even in those on an adequate medical regimen, suggesting that factors such as stress may be capable of affecting disease course. HIV positive individuals are exposed to profoundly stressful circumstances (e.g., death of loved ones to HIV, stigma) which can be a focus for investigation. While there were a few studies documenting a link between exposure to AIDS-related bereavement and markers of HIV progression, the data demonstrating a relationship between stressful life events more generally and indices of HIV progression was limited during this period (see Cole and Kemeny, 2001). However, those stress studies that incorporated measures of stressor context so that the stressfulness of the event could be more readily assessed were better able to predict CD4 T cell decline and time to onset of AIDS, controlling for relevant alternative explanations (see Leserman et al., 2000). Particular psychological responses to the risk of HIV progression, such as HIV-specific pessimism about one’s future health, have been shown to predict onset of HIV-related symptoms and mortality, particularly among those who experienced the death of a close other to AIDS (e.g., Reed et al., 1994). 2.3. Stress and cancer There is a long history of interest in whether psychological factors can affect the etiology and progression of cancer. Very early studies suggested links between personality types and cancer etiology; however, interpretation of these findings has been significantly hampered by methodological problems in many of these studies. A great deal of important work has taken place in this area over the past 2 decades with a tremendous acceleration of studies demonstrating potential effects of stress on tumor metastasis, the tumor microenvironment, and regulation of cell growth. 2.3.1. Cancer etiology During this decade and before, the data linking stressor exposure to cancer etiology was quite inconsistent and


most reviews failed to find a relationship (Reiche et al., 2004), although evidence may have been stronger for severe life events, such as death of a child or spouse (see Lutgendorf et al., 2007). Also, depression and other psychological factors were not found to be consistent predictors (see Lutgendorf et al., 2007). 2.3.2. Cancer progression The strongest relations with course of cancer were found for social support and emotional expression (see Sephton and Spiegel, 2003). For example, higher levels of social support (e.g., emotional support, presence of supportive persons, marriage) have been associated with survival time in breast, colorectal and lung cancer. Important studies were conducted on the effects of psychological interventions and cancer prognosis during this early period. Spiegel and colleagues utilized a supportive–expressive group therapy approach in studies of women with metastatic breast cancer. This therapeutic approach involves expressing and dealing with negative emotions in a supportive group environment. They found that participation in this intervention predicted longer survival time, with support group members surviving an average of 18 months longer than those assigned to the control condition (Spiegel et al., 1989). The impact of a psychoeducational group intervention for patients with malignant melanoma was evaluated in relation to mood, the natural killer cell system, recurrence and survival over a 6-year period (Fawzy et al., 1993). The intervention involved health education, training in problem-solving skills, stress management, and social support. Those randomly assigned to the 6-week intervention showed improved mood relative to the controls, as well as increases in the number of NK cells and in IFN-a augmentation of NK cell activity at 6 months. Most importantly, the intervention group had fewer deaths than controls at 6 years post treatment. 3. The second decade 1997–2007 3.1. Stress and chronic inflammatory diseases Based on knowledge of the kinetics and potential mechanisms of the way stress affects the immune response in the healthy individual, further research activities demonstrated that leukocytes from individuals with chronic inflammatory diseases such as RA or SLE differ in their response to acute psychological stress or adrenergic and corticoid stimulation in comparison to immuncompetent cells from healthy subjects (Straub et al., 2005). This can be explained by a disturbed neuroendocrine–immune interaction in these chronic inflammatory states based on an inadequate HPA-axis and SNS response to stress. For example, RA patients with a recent diagnosis showed a significantly impaired stress- or dexametasone-induced ACTH or cortisol increase, with this insensitivity apparently located both at a hypothalamic/pituitary and at an adrenal level (Dekkers et al., 2001). Similarly, the SNS response to acute psy-

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chological stress seemed to differ in RA and SLE patients in comparison to healthy controls. The expression of badrenoceptors on peripheral and synovial immune cells appeared to be decreased in patients and the numbers of b-adrenoceptors on peripheral blood mononuclear cells (PBMC) significantly increased in healthy subjects but not in SLE patients after stress exposure (Pawlak et al., 1999). In addition, an up-regulation of a-adrenoceptors on monocytes of patients with JIA has been reported. Due to this shift from b- to a-adrenoceptors, the immunosuppressive effect of noradrenaline by activation of badrenoceptors might be prevented in these patients (Kuis et al., 1996; Straub et al., 2005). In addition, patients with SLE or RA react differently in terms of leukocyte numbers in circulation, activity and cytokine release to acute psychological stress in comparison to healthy controls, underscoring the disturbed communication pathway between the brain, the neuroendocrine system and the immune system (Pawlak et al., 1999). In particular, the disturbed SNS– immune pathway seemed to be partly due to an altered receptor sensitivity mediated by the activity of G-proteincoupled receptor kinases (GRK) and protein expression. For example, in RA patients, the pro-inflammatory signaling pathway mediated through G-protein coupled receptors (i.e., b2-adrenoceptors) are less efficiently turned off by the GRK/b-arrestin desensitization machinery (Lombardi et al., 1999). Moreover, the inflammatory process in vivo induces a tissue-specific down-regulation of GRKs in lymphocyte subpopulations in these patients (Lombardi et al., 2001). All together, these data demonstrate that, in the healthy individual, acute psychological stress leads to various forms of immune system activation, whereas sustained stress exposure inhibits key immune responses. In conditions of chronic inflammation such as in the rheumatoid diseases (RA, JIA or SLE) however, experimental evidence in humans demonstrates disturbed neuroendocrine– immune communication during stress exposure. These data show an inadequate secretion of cortisol as well as increased sympathetic tone at rest but an inadequate response during stress exposure, a functional loss of synovial sympathetic nerve fibers, a local b- to a- adrenergic shift, and a disturbed adrenoceptor intracellular signaling cascade in leukocytes, which seemed to generate the basis for stress-induced aggravation of these chronic inflammatory rheumatoid diseases (Straub et al., 2005). Similar to inflammatory rheumatoid diseases, the pathogenesis of MS remains unclear and is most likely heterogeneous. However, there is increasing evidence during the last decade that stressful life events correlate with exacerbations in MS. Also, here we see the disruption in the communication between the peripheral immune system and the two major stress response systems, the HPA and the SNS. Disturbed glucocorticoid and b-adrenergic modulation of immune responses during stress exposure may be mainly responsible for the overshooting inflammatory process in MS. In addition, hyperreactivity of the HPA-axis in

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MS might be responsible, in part, for the neurodegenerative process and increased disability (Gold et al., 2005). It has been recently suggested that the impact of stress on disease outcome in MS may be related to the temporal relationship of the stressor, the stress response and the disease outcome. This may include the onset of the stressor and the temporal course from acute to chronic and the resolution of the stress response with a unique neuroendocrine–immune interaction influencing the exacerbation process in MS (Mohr and Pelletier, 2006). During the last decade, increasing experimental evidence indicated that patients with inflammatory skin diseases such as psoriasis or atopic dermatitis also differ in their response to psychological stress (Buske-Kirschbaum et al., 2007) and that stress exposure can trigger or aggravate the inflammatory skin process (Paus et al., 2006). Although the mechanisms underlying the impact of stress on the inflammatory process in the skin are still largely unknown, the activity of mast cells, NK cells or dendritic cells in the skin are regulated by neuroendocrine mediators such as CRH, Substance P, ACTH, glucocorticoids and catecholamines, mediating the brain–skin cross talk (Paus et al., 2006). Psychological stress has long been suggested to increase the likelihood of relapse in patients with inflammatory bowl diseases (IBD) such as Crohn’s disease or ulcerative colitis. However, experimental data in humans providing evidence of a causal link between stress exposure, and neuroendocrine and immune responses in these patients are rare. However, preliminary evidence also indicates disturbed adrenoceptor-mediated cytokine production in these patients. 3.2. Stress and infectious disease The relations between stress and response to viral challenge were replicated and extended in the second decade by Cohen and colleagues (see Cohen, 2005). In a viral challenge study including 276 individuals, for example, Cohen and colleagues found that exposure to chronically stressful life events (of one month or longer duration) predicted greater susceptibility to infection. Extending this paradigm to influenza virus, they found that greater levels of psychological stress were associated with greater symptom scores and mucus weights, as well as higher levels of IL-6. In addition, the greater the diversity of one’s social network (defined by types of social groups) the lower the susceptibility to viral infection using this model. Thus far, little is known about the physiological mediators of these effects since attempts to link hormonal and immunologic processes to viral outcomes in this paradigm have been largely unsuccessful. However, animal studies conducted by Sheridan and colleagues suggest three major pathways linking stress exposure to natural resistance to influenza viral infection—the response of pro-inflammatory cytokines, b-chemokines, and natural killer cells. In addition, the adaptive immune response, involving antigen-specific T cell activation, also plays a role in this process (see Bailey et al.,

2007). These may be important targets for future influenza viral challenge studies in humans. In the second decade, the chronic stress of caregiving, other stressors and certain psychological factors continued to demonstrate relationships to response to vaccination (in most but not all studies; Glaser, 2005). An interesting study published in BBI found that an acute laboratory stress followed by influenza vaccination increased antibody titers at 4 and 20 weeks (Edwards et al, 2006), but only in women. On the other hand, distress on the days after the vaccination but not before may contribute to an inadequate response to vaccination (Miller et al., 2004). It is interesting to note that the antibody response to a Hepatitis B vaccination can be enhanced by a brief psychological intervention provided after the vaccination. Following on the findings in the first decade on stress effects on EBV in West Point cadets, Glaser et al. (1999) published a paper in BBI, examining effects of West Point training and final exam stress during training on herpesvirus latency. They found that exam stress was associated with increases in EBV-titer but not HSV-1 or human herpesvirus 6 (HHV)-6 titers. Based on a recent meta-analytic review of the research on the effects of stress on the immune system, there appear to be relatively consistent effects of stress on antibody titer to the EBV virus (Segerstrom and Miller, 2004). Overall, about seven studies of brief naturalistic stressors, primarily examination stress, demonstrated a significant relationship between stress exposure and elevated EBV antibody titers. In the second decade of research on predictors of HIV progression, a number of studies utilized measures of stressful events that incorporated measures of subjective experience and found that stress predicted a more rapid loss of the CD4 T cells, and onset of AIDS-related conditions (see Sloan et al., 2007). These studies have been bolstered by studies of Rhesus macaques inoculated with the Simian immunodeficiency virus (SIV), showing that social stressors such as housing changes and separation predict accelerated disease progression and alterations in relevant immune processes (e.g., Capitanio and Lerche, 1998). Depression has also been shown to predict accelerated disease course in some, but not all studies, and effects appear to depend on stage of disease. A wide range of other psychological responses to the presence of HIV infection have been examined as predictors of disease course. For example, cognitive and emotional reactions associated with negative views of the self, stigmatization or rejection predicted virologic and immunologic evidence of disease progression and mortality as well as a weaker response to anti-viral therapy in terms of HIV viral load (e.g., Cole et al., 2003). Effects were not explained by health behavior, demographics, medication regimen or general levels of stress or depression. Higher levels of distress have also been associated with alterations in HIV-relevant immune parameters, such as CD4 and CD8 T cells, and NKCA. While HPA activity has been invoked as a potential mediator of such effects since corticosteroids can enhance viral replication and


may prolong viral gene expression and HPA activity has predicted disease progression in both the HIV and SIV models, cortisol levels have not been found to mediate the relations between stress and disease progression noted above. An alternative proposed pathway is via SNS reactivity. Cole and colleagues have conducted intensive investigation of the role of the SNS in HIV replication and disease progression, taking these studies from the epidemiological to the molecular (see Sloan et al., 2007). They have found that SNS activity predicts viral load and CD4 responses to anti-retroviral therapy and mediates some of the effects of psychological factors on disease course. In vitro studies showed that NE can enhance HIV replication in a dose–response relationship. This relationship involves the cyclic AMP/protein kinase A signaling pathway. In terms of interventions, both short and longer term psychological interventions have been associated with immunologic or virologic benefit in HIV positive individuals. The intervention program Cognitive Behavioral Stress Management (CBSM) has undergone intensive investigation by a team of researchers including Antoni, Schneiderman, Ironson, Esterling and others. CBSM focuses on modifying stress-related cognitive appraisals and teaching effective coping skills (Antoni, 1997). For example, in HIV positive individuals, CBSM has been shown to result in a decrease in antibody titers to herpesviruses EBV and HSV-2 along with reductions in negative mood. Also, CBSM + adherence training versus adherence training alone reduced HIV viral load in gay men treated with HAART (Antoni et al., 2007). Goodkin and colleagues found that a 10 week supportive–expressive program combined with coping skills training was associated with decreased cortisol, increased CD4 counts, and decreased viral load relative to controls in recently bereaved HIV infected gay men (see Antoni et al., 2007). At the same time, there have been many intervention studies with HIV+ samples that have not found effects on relevant virologic or immune processes (Carrico and Antoni, in press). No studies have reported intervention effects on mortality outcomes. 3.3. Stress and cancer 3.3.1. Cancer etiology A few recent studies suggest a relationship between stress and the onset of cancer (e.g., a 20 year longitudinal study of a very large sample of Isrealis who experienced the death of an adult son due to accidents or related to war). However, overall, the relationship between stressor exposure and the etiology of cancer in humans is weak (Reiche et al., 2004). If there is such a relationship, it is highly likely that it will only be detectable if considered in conjunction with known risk factors such as genetics, gender, site of cancer, age and health behaviors, such as smoking. 3.3.2. Cancer progression In the second decade, a few well conducted studies do support a relation between stress and cancer progression.

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For example, one interesting model involved examining effects on human papilomavirus (HPV)-associated cervical intraepithelial neoplasia (CIN), a precursor to cervical cancer. Stress and pessimism have predicted greater severity of CIN (see Antoni et al., 2007). In women coinfected with HIV and HPV, greater negative life events predicted declines in NK number, greater risk of outbreak of genital herpes, as well as persisting CIN over a year follow-up. However, overall, the relationship between stress and cancer prognosis has not been strengthened by the recent evidence. For example, some of the effects of interventions on cancer progression found during the first decade were not replicated in more recent studies. One study, using the Spiegel supportive–expressive intervention, did not show effects on breast cancer survival despite psychological benefits. Overall, the potential benefit of psychological interventions for slowing cancer progression and increasing survival is unknown, since there are well designed studies that demonstrate effects on survival and those that do not (see Spiegel, 2002). A promising area of current research evaluates the relationship between stress and immune function in cancer patients, including in the tumor microenvironment (see Lutgendorf et al., 2005). Lutgendorf and colleagues have found stress to be associated with lower NKCA in tumor-infiltrating lymphocytes from patients with ovarian cancer, while social support has been associated with higher NKCA. Impaired NKCA has been linked with progression of this tumor in previous research. In a study reported in BBI, TNF-a, which is associated with tumor regression and survival time, was found to be decreased in breast cancer patients with social disruption at cancer diagnosis (Marucha et al., 2005). A number of studies have found that interventions can influence important immune parameters relevant to cancer progression in cancer patients, for example, the lymphocyte proliferative response. Studies of stress effects in healthy humans on processes important to cancer also support potential mechanistic pathways. For example, acute stress has been shown to alter the response of leukocytes to factors that induce apoptosis, a process that plays an important role in defense against the development of malignant cells. In addition, Kiecolt-Glaser and colleagues found greater impairment of DNA repair mechanisms in those with psychiatric illness compared to healthy controls (see Reiche et al., 2004) suggesting that this critically important cancer-relevant process may be amenable to influence by psychological factors. The animal literature appears to show a more robust and consistent relation between stress, tumor growth and metastases. Animal studies have demonstrated effects of stress on tumor growth or metastasis, with stressors such as restraint, forced swim and social isolation (see Reiche et al., 2004). For example, Ben-Eliyahu and colleagues have demonstrated that surgical and psychological stress can suppress NK activity in rats, and this suppression compromises resistance to tumor progression. NK effects in this tumor model can be mediated by catecholamines, which

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suppress NK activity by elevating cAMP levels. More recently, in BBI, these researchers report on a successful method for preventing the negative effects of stressors on metastasis utilizing a product that causes NK cells to be partially resistant to suppression by agents that increase cAMP. These findings may have clinical utility in humans. Studies of human cancer cell lines have also provided an important opportunity to investigate potential pathways between stress and tumor cell outcomes. Intriguing findings demonstrate that noradrenaline can promote processes related to metastases in vitro, such as cancer cell migration. NE acts on the b-adrenergic receptor-cyclic AMP–protein kinase A pathway in ovarian cancer cell lines, with effects abolished by a b blocker. Also HPA effects on apoptosis of lymphocytes, survival genes that protect cancer cells from chemotherapy effects, oncogenic viruses, and immune responses to tumors may play a role in tumor initiation, growth and survival (Antoni et al., 2006). In BBI, Sephton and Spiegel (2003) proposed an interesting hypothesis that stress-related alterations in hormonal and immunological circadian rhythms could play a role in cancer progression. Stressful life experiences, depression and other psychiatric disorders have been shown to disrupt circadian rhythms of the HPA. There is some evidence of abnormal circadian rhythms in individuals at high risk for breast cancer and predicting cancer outcomes. For example, a flattened cortisol rhythm has predicted early mortality up to 7 years after assessment as well as decrements in number and activity of NK cells, which also predicted mortality. These HPA alterations were associated with poor sleep and prior marital disruption. In addition, animals with mutations in circadian clock genes are at increased risk for tumor development and shortened survival. Clearly, animal studies and in vitro work are pointing to mechanisms that would allow stress and psychological factors to affect tumor progression, at least with certain forms of cancer. Future directions in this area may include an attempt to integrate the molecular level investigation with the human experimental study paradigms in order to begin to define the pathway from stress to the molecular events controlling tumor progression. 3.4. Stress and wound healing Wound healing became a very important outcome in PNI research in this second decade (see Marucha and Engeland, 2007). The initial study in this area conducted by Kiecolt-Glaser, Marucha and colleagues showed that the chronic stress of caregiving for a person with Alzheimer’s Disease was associated with a delay in wound healing. Punch biopsy wounds healed about 25% more slowly in the chronically stressed group, and these individuals also produced lower blood levels of IL-1b, which may have played a role in the wound healing effect. These investigators have also examined the impact of examination stress on wound healing, and found that oral wounds placed 3

days before exams healed 40% more slowly on average when compared to those placed during the less stressful summer vacation. In addition, higher perceived stress and cortisol levels have been associated with slower wound healing, consistent with the evidence that glucocorticoids have an inhibitory effect on wound healing via effects on recruitment and bacterial killing. Physiological processes taking place within the wound, for example, levels of IL-1b, IL-8, and MMP-9, have also been found to be associated with level of perceived stress. The role of pro-inflammatory cytokines as mediators of effects of stress on wound healing is supported by animal studies. For example, in a study published in BBI, Padgett et al. (1998) demonstrated that restraint stress lowers levels of pro-inflammatory cytokines, such as IL-1b in wounds with effects due to glucocorticoids. However, evidence also published in BBI by these investigators suggests that HPA induced effects on pro-inflammatory cytokines are not the sole mediators. In another paper published in BBI, these researchers show that stress effects on iNOS gene expression in mice have also been implicated in dermal wound healing effects, suggesting a role for stress induced SNS effects on tissue oxygen levels. Overall, these results provide strong support for a link between stressor exposure and physiological processes that regulate the wound healing process (see Marucha and Engeland, 2007). 3.5. Future directions for the next decade(s) Overall, research conducted in the decade encompassing 1987–1996 laid down a research foundation indicating a relationship between stress and specific diseases and disease-related processes, such as infectious disease, antibody response to vaccinations, and latent virus reactivation. Results of such studies in the area of autoimmune disease and cancer were weaker. In the second decade, 1997– 2007, neuroendocrine and immunologic mechanisms were more carefully specified and the complexities of these relationships began to be revealed. Important mechanistic work was conduced in cancer (including a focus on the tumor microenvironment, and in vitro studies of cancer cell lines), autoimmune disease, wound healing, HIV-1 and other latent viruses. These data clearly indicate that neuroendocrine and immune system interactions are relevant to the etiology and course of many immunological diseases. It is interesting to note that epidemiological evidence remains weak is some of these areas (e.g., autoimmune disease, cancer) probably as a result of the multiple, interacting factors controlling disease etiology and progression (genetics, lifestyle and environmental factors, etc.). One of the major challenges for future research activities is to elucidate the hierarchical, temporal and spatial communication patterns linking the brain, our stress-perceiving system, and the neuroendocrine and peripheral immune responses to acute and chronic psychosocial stress in the different diseases. We must understand in more detail how, where and when the brain–immune axis is disturbed


in the different, immune-related diseases. It is important to identify the basic psychological mechanisms that are associated with the relevant brain structures and signaling that are subsequently processed via neuroendocrine efferent pathways to immuncompetent cells in the periphery. Thus far, we know very little about the role of the CNS in orchestrating these neuro-immune responses to emotionally provocative circumstances. Borrowing concepts and tools from affective and cognitive neuroscience would facilitate the integration of neuroscience into these investigations. In addition, it is important to focus on how these stress-induced neuroendocrine signals alter downstream receptor physiology, intracellular signaling cascades and gene expression in normal physiological states and in pathophysiological conditions. Based on this knowledge, new pharmacological and non-pharmacological diagnostic and treatment options can be developed that result in a specific modulation of the nervous system–immune system communication. On a behavioral level in particular, this knowledge will provide the basis for new specific behavioral intervention strategies for the treatment of chronic diseases (Pacheco-Lopez et al. 2006). References Antoni, M.H., 1997. Cognitive behavioral stress management for gay men learning of their HIV-1 antibody test results. In: Spira, J. (Ed.), Group Therapy for Patients with Chronic Medical Diseases. Guildford Press, New York, pp. 55–91. Antoni, M.H., Lutgendorf, S.K., Cole, S.W., Dhabhar, F.S., Sephton, S.E., McDonald, P.G., Stefanek, M., Sood, A.K., 2006. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat. Rev. Cancer 6, 240–248. Antoni, M.H., Schneiderman, N., Penedo, F., 2007. Behavioral interventions: immunologic mediators and disease outcomes. In: Ader, R. (Ed.), Psychoneuroimmunology. Academic Press, San Diego, pp. 675–703. Bailey, M.T., Padgett, D.A., Sheridan, J.F., 2007. Stress-induced modulation of innate resistance and adaptive immunity to influenza viral infection. In: Ader, R. (Ed.), Psychoneuroimmunology. Academic Press, San Diego, pp. 1097–1124. Blalock, J.E., Smith, E.M., 2007. Conceptual development of the immune system as a sixth sense. Brain Behav. Immun. 21, 23–33. Buske-Kirschbaum, A., Kern, S., Ebrecht, M., Hellhammer, D.H., 2007. Altered distribution of leukocyte subsets and cytokine production in response to acute psychosocial stress in patients with psoriasis vulgaris. Brain Behav. Immun. 21, 92–99. Capitanio, J.P., Lerche, N.W., 1998. Social separation, housing relocation, and survival in simian AIDS: a retrospective analysis. Psychosomatic Med. 60, 235–244. Carrico, A.W., Antoni, M.H., in press. The effects of psychological interventions on neuroendocrine hormone regulation and immune status in HIV-positive persons: a review of randomized controlled trials. Psychosom. Med. Cohen, S., 2005. Keynote presentation at the eight international congress of behavioral medicine: the Pittsburgh common cold studies: psychosocial predictors of susceptibility to respiratory infectious illness. Int. J. Behav. Med. 12, 123–131. Cohen, S., Tyrrel, D.A.G., Smith, A.P., 1991. Psychological stress and susceptibility to the common cold. N. Eng. J. Med. 325, 606–612. Cole, S.W., Kemeny, M.E., 2001. Psychological influences on the progression of HIV infection. In: Ader, R., Felten, D.L., Cohen, N. (Eds.), Psychoneuroimmunology. Academic Press, New York, pp. 583–612.

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Reed, G.M., Kemeny, M.E., Taylor, S.E., Wang, H.Y., Visscher, B.R., 1994. Realistic acceptance as a predictor of decreased survival time in gay men with AIDS. Health Psychol. 13, 299–307. Reiche, E.M.V., Nunes, S.O.V., Morimoto, H.K., 2004. Stress, depression, the immune system, and cancer. Lancet Oncol. 5, 617–625. Rosenkranz, M.A., in press. Dysregulation of Substance P in chronic inflammatory disease and affective disorders. Psychol. Bull. Sanders, V.M., Kavelaars, A., 2007. Adrenergic regulation of immunity. In: Ader, R., Felten, D.L., Cohen, N. (Eds.), Psychoneuroimmunology. Academic Press, New York. Segerstrom, S.C., Miller, G.E., 2004. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psych. Bull. 130, 601–630. Sephton, S., Spiegel, D., 2003. Circadian disruption in cancer: a neuroendocrine–immune pathway from stress to disease? Brain Behav. Immun. 17, 321–328. Sloan, E., Collado-Hidalgo, A., Cole, S., 2007. Psychobiology of HIV infection. In: Ader, R. (Ed.), Psychoneuroimmunology. Academic Press, San Diego, pp. 869–895. Spiegel, D., 2002. Effects of psychotherapy on cancer survival. Nat. Rev. Cancer 2, 383–389. Spiegel, D., Bloom, J.R., Kraemer, H.C., Gottheil, E., 1989. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 2, 888–891. Straub, R.H., Dhabhar, F.S., Bijlsma, J.W., Cutolo, M., 2005. How psychological stress via hormones and nerve fibers may exacerbate rheumatoid arthritis. Arthritis Rheum. 52, 16–26. Wilder, R.L., 1995. Neuroendocrine–immune system interactions and autoimmunity. Annu. Rev. Immunol. 13, 307–338.

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Annu. Rev. Clin. Psychol. 2005. 1:607–28 doi: 10.1146/annurev.clinpsy.1.102803.144141 c 2005 by Annual Reviews. All rights reserved Copyright First published online as a Review in Advance on November 1, 2004

STRESS AND HEALTH: Psychological, Behavioral, and Biological Determinants Neil Schneiderman, Gail Ironson, and Scott D. Siegel Department of Psychology, University of Miami, Coral Gables, Florida 33124-0751; email: [email protected], [email protected], [email protected]

Key Words psychosocial stressors, stress responses, homeostasis, psychosocial interventions, host vulnerability-stressor interactions ■ Abstract Stressors have a major influence upon mood, our sense of well-being, behavior, and health. Acute stress responses in young, healthy individuals may be adaptive and typically do not impose a health burden. However, if the threat is unremitting, particularly in older or unhealthy individuals, the long-term effects of stressors can damage health. The relationship between psychosocial stressors and disease is affected by the nature, number, and persistence of the stressors as well as by the individual’s biological vulnerability (i.e., genetics, constitutional factors), psychosocial resources, and learned patterns of coping. Psychosocial interventions have proven useful for treating stress-related disorders and may influence the course of chronic diseases.

CONTENTS INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PSYCHOLOGICAL ASPECTS OF STRESS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stressors During Childhood and Adolescence and Their Psychological Sequelae . Stressors During Adulthood and Their Psychological Sequelae . . . . . . . . . . . . . . . Variations in Stress Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BIOLOGICAL RESPONSES TO STRESSORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute Stress Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Stress Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PSYCHOSOCIAL STRESSORS AND HEALTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Respiratory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Human Immunodeficiency Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammation, the Immune System, and Physical Health . . . . . . . . . . . . . . . . . . . . Inflammation, Cytokine Production, and Mental Health . . . . . . . . . . . . . . . . . . . . . HOST VULNERABILITY-STRESSOR INTERACTIONS AND DISEASE . . . . . . TREATMENT FOR STRESS-RELATED DISORDERS . . . . . . . . . . . . . . . . . . . . . . BEHAVIORAL INTERVENTIONS IN CHRONIC DISEASE . . . . . . . . . . . . . . . . . . Morbidity, Mortality, and Markers of Disease Progression . . . . . . . . . . . . . . . . . . . CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1548-5943/05/0427-0607$14.00

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INTRODUCTION Claude Bernard (1865/1961) noted that the maintenance of life is critically dependent on keeping our internal milieu constant in the face of a changing environment. Cannon (1929) called this “homeostasis.” Selye (1956) used the term “stress” to represent the effects of anything that seriously threatens homeostasis. The actual or perceived threat to an organism is referred to as the “stressor” and the response to the stressor is called the “stress response.” Although stress responses evolved as adaptive processes, Selye observed that severe, prolonged stress responses might lead to tissue damage and disease. Based on the appraisal of perceived threat, humans and other animals invoke coping responses (Lazarus & Folkman 1984). Our central nervous system (CNS) tends to produce integrated coping responses rather than single, isolated response changes (Hilton 1975). Thus, when immediate fight-or-flight appears feasible, mammals tend to show increased autonomic and hormonal activities that maximize the possibilities for muscular exertion (Cannon 1929, Hess 1957). In contrast, during aversive situations in which an active coping response is not available, mammals may engage in a vigilance response that involves sympathetic nervous system (SNS) arousal accompanied by an active inhibition of movement and shunting of blood away from the periphery (Adams et al. 1968). The extent to which various situations elicit different patterns of biologic response is called “situational stereotypy” (Lacey 1967). Although various situations tend to elicit different patterns of stress responses, there are also individual differences in stress responses to the same situation. This tendency to exhibit a particular pattern of stress responses across a variety of stressors is referred to as “response stereotypy” (Lacey & Lacey 1958). Across a variety of situations, some individuals tend to show stress responses associated with active coping, whereas others tend to show stress responses more associated with aversive vigilance (Kasprowicz et al. 1990, Llabre et al. 1998). Although genetic inheritance undoubtedly plays a role in determining individual differences in response stereotypy, neonatal experiences in rats have been shown to produce long-term effects in cognitive-emotional responses (Levine 1957). For example, Meaney et al. (1993) showed that rats raised by nurturing mothers have increased levels of central serotonin activity compared with rats raised by less nurturing mothers. The increased serotonin activity leads to increased expression of a central glucocorticoid receptor gene. This, in turn, leads to higher numbers of glucocorticoid receptors in the limbic system and improved glucocorticoid feedback into the CNS throughout the rat’s life. Interestingly, female rats who receive a high level of nurturing in turn become highly nurturing mothers whose offspring also have high levels of glucocorticoid receptors. This example of behaviorally induced gene expression shows how highly nurtured rats develop into low-anxiety adults, who in turn become nurturing mothers with reduced stress responses. In contrast to highly nurtured rats, pups separated from their mothers for several hours per day during early life have a highly active hypothalamic-pituitary

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adrenocortical axis and elevated SNS arousal (Ladd et al. 2000). These deprived rats tend to show larger and more frequent stress responses to the environment than do less deprived animals. Because evolution has provided mammals with reasonably effective homeostatic mechanisms (e.g., baroreceptor reflex) for dealing with short-term stressors, acute stress responses in young, healthy individuals typically do not impose a health burden. However, if the threat is persistent, particularly in older or unhealthy individuals, the long-term effects of the response to stress may damage health (Schneiderman 1983). Adverse effects of chronic stressors are particularly common in humans, possibly because their high capacity for symbolic thought may elicit persistent stress responses to a broad range of adverse living and working conditions. The relationship between psychosocial stressors and chronic disease is complex. It is affected, for example, by the nature, number, and persistence of the stressors as well as by the individual’s biological vulnerability (i.e., genetics, constitutional factors) and learned patterns of coping. In this review, we focus on some of the psychological, behavioral, and biological effects of specific stressors, the mediating psychophysiological pathways, and the variables known to mediate these relationships. We conclude with a consideration of treatment implications.

PSYCHOLOGICAL ASPECTS OF STRESS Stressors During Childhood and Adolescence and Their Psychological Sequelae The most widely studied stressors in children and adolescents are exposure to violence, abuse (sexual, physical, emotional, or neglect), and divorce/marital conflict (see Cicchetti 2005). McMahon et al. (2003) also provide an excellent review of the psychological consequences of such stressors. Psychological effects of maltreatment/abuse include the dysregulation of affect, provocative behaviors, the avoidance of intimacy, and disturbances in attachment (Haviland et al. 1995, Lowenthal 1998). Survivors of childhood sexual abuse have higher levels of both general distress and major psychological disturbances including personality disorders (Polusny & Follett 1995). Childhood abuse is also associated with negative views toward learning and poor school performance (Lowenthal 1998). Children of divorced parents have more reported antisocial behavior, anxiety, and depression than their peers (Short 2002). Adult offspring of divorced parents report more current life stress, family conflict, and lack of friend support compared with those whose parents did not divorce (Short 2002). Exposure to nonresponsive environments has also been described as a stressor leading to learned helplessness (Peterson & Seligman 1984). Studies have also addressed the psychological consequences of exposure to war and terrorism during childhood (Shaw 2003). A majority of children exposed to war experience significant psychological morbidity, including both post-traumatic

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stress disorder (PTSD) and depressive symptoms. For example, Nader et al. (1993) found that 70% of Kuwaiti children reported mild to severe PTSD symptoms after the Gulf War. Some effects are long lasting: Macksound & Aber (1996) found that 43% of Lebanese children continued to manifest post-traumatic stress symptoms 10 years after exposure to war-related trauma. Exposure to intense and chronic stressors during the developmental years has long-lasting neurobiological effects and puts one at increased risk for anxiety and mood disorders, aggressive dyscontrol problems, hypo-immune dysfunction, medical morbidity, structural changes in the CNS, and early death (Shaw 2003).

Stressors During Adulthood and Their Psychological Sequelae It is well known that first depressive episodes often develop following the occurrence of a major negative life event (Paykel 2001). Furthermore, there is evidence that stressful life events are causal for the onset of depression (see Hammen 2005, Kendler et al. 1999). A study of 13,006 patients in Denmark, with first psychiatric admissions diagnosed with depression, found more recent divorces, unemployment, and suicides by relatives compared with age- and gender-matched controls (Kessing et al. 2003). The diagnosis of a major medical illness often has been considered a severe life stressor and often is accompanied by high rates of depression (Cassem 1995). For example, a meta-analysis found that 24% of cancer patients are diagnosed with major depression (McDaniel et al. 1995). Stressful life events often precede anxiety disorders as well (Faravelli & Pallanti 1989, Finlay-Jones & Brown 1981). Interestingly, long-term follow-up studies have shown that anxiety occurs more commonly before depression (Angst & Vollrath 1991, Breslau et al. 1995). In fact, in prospective studies, patients with anxiety are most likely to develop major depression after stressful life events occur (Brown et al. 1986).

LIFE STRESS, ANXIETY, AND DEPRESSION

Lifetime exposure to traumatic events in the general population is high, with estimates ranging from 40% to 70% (Norris 1992). Of note, an estimated 13% of adult women in the United States have been exposed to sexual assault (Kilpatrick et al. 1992). The Diagnostic and Statistical Manual (DSM-IV-TR; American Psychiatric Association 2000) includes two primary diagnoses related to trauma: Acute Stress Disorder (ASD) and PTSD. Both these disorders have as prominent features a traumatic event involving actual or threatened death or serious injury and symptom clusters including re-experiencing of the traumatic event (e.g., intrusive thoughts), avoidance of reminders/numbing, and hyperarousal (e.g., difficulty falling or staying asleep). The time frame for ASD is shorter (lasting two days to four weeks), with diagnosis limited to within one month of the incident. ASD was introduced in 1994 to describe initial trauma reactions, but it has come under criticism (Harvey & Bryant 2002) for weak empirical and theoretical support. Most people who have symptoms of PTSD shortly

DISORDERS RELATED TO TRAUMA

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after a traumatic event recover and do not develop PTSD. In a comprehensive review, Green (1994) estimates that approximately 25% of those exposed to traumatic events develop PTSD. Surveys of the general population indicate that PTSD affects 1 in 12 adults at some time in their life (Kessler et al. 1995). Trauma and disasters are related not only to PTSD, but also to concurrent depression, other anxiety disorders, cognitive impairment, and substance abuse (David et al. 1996, Schnurr et al. 2002, Shalev 2001). Other consequences of stress that could provide linkages to health have been identified, such as increases in smoking, substance use, accidents, sleep problems, and eating disorders. Populations that live in more stressful environments (communities with higher divorce rates, business failures, natural disasters, etc.) smoke more heavily and experience higher mortality from lung cancer and chronic obstructive pulmonary disorder (Colby et al. 1994). A longitudinal study following seamen in a naval training center found that more cigarette smoking occurred on high-stress days (Conway et al. 1981). Life events stress and chronically stressful conditions have also been linked to higher consumption of alcohol (Linsky et al. 1985). In addition, the possibility that alcohol may be used as self-medication for stress-related disorders such as anxiety has been proposed. For example, a prospective community study of 3021 adolescents and young adults (Zimmerman et al. 2003) found that those with certain anxiety disorders (social phobia and panic attacks) were more likely to develop substance abuse or dependence prospectively over four years of follow-up. Life in stressful environments has also been linked to fatal accidents (Linsky & Strauss 1986) and to the onset of bulimia (Welch et al. 1997). Another variable related to stress that could provide a link to health is the increased sleep problems that have been reported after psychological trauma (Harvey et al. 2003). New onset of sleep problems mediated the relationship between post-traumatic stress symptoms and decreased natural killer (NK) cell cytotoxicity in Hurricane Andrew victims (Ironson et al. 1997).

Variations in Stress Responses Certain characteristics of a situation are associated with greater stress responses. These include the intensity or severity of the stressor and controllability of the stressor, as well as features that determine the nature of the cognitive responses or appraisals. Life event dimensions of loss, humiliation, and danger are related to the development of major depression and generalized anxiety (Kendler et al. 2003). Factors associated with the development of symptoms of PTSD and mental health disorders include injury, damage to property, loss of resources, bereavement, and perceived life threat (Freedy et al. 1992, Ironson et al. 1997, McNally 2003). Recovery from a stressor can also be affected by secondary traumatization (Pfefferbaum et al. 2003). Other studies have found that multiple facets of stress that may work synergistically are more potent than a single facet; for example, in the area of work stress, time pressure in combination with threat (Stanton et al. 2001), or high demand in combination with low control (Karasek & Theorell 1990).

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Stress-related outcomes also vary according to personal and environmental factors. Personal risk factors for the development of depression, anxiety, or PTSD after a serious life event, disaster, or trauma include prior psychiatric history, neuroticism, female gender, and other sociodemographic variables (Green 1996, McNally 2003, Patton et al. 2003). There is also some evidence that the relationship between personality and environmental adversity may be bidirectional (Kendler et al. 2003). Levels of neuroticism, emotionality, and reactivity correlate with poor interpersonal relationships as well as “event proneness.” Protective factors that have been identified include, but are not limited to, coping, resources (e.g., social support, self-esteem, optimism), and finding meaning. For example, those with social support fare better after a natural disaster (Madakaisira & O’Brien 1987) or after myocardial infarction (Frasure-Smith et al. 2000). Pruessner et al. (1999) found that people with higher self-esteem performed better and had lower cortisol responses to acute stressors (difficult math problems). Attaching meaning to the event is another protective factor against the development of PTSD, even when horrific torture has occurred. Left-wing political activists who were tortured by Turkey’s military regime had lower rates of PTSD than did nonactivists who were arrested and tortured by the police (Baso˘glu et al. 1994). Finally, human beings are resilient and in general are able to cope with adverse situations. A recent illustration is provided by a study of a nationally representative sample of Israelis after 19 months of ongoing exposure to the Palestinian intifada. Despite considerable distress, most Israelis reported adapting to the situation without substantial mental health symptoms or impairment (Bleich et al. 2003).

BIOLOGICAL RESPONSES TO STRESSORS Acute Stress Responses Following the perception of an acute stressful event, there is a cascade of changes in the nervous, cardiovascular, endocrine, and immune systems. These changes constitute the stress response and are generally adaptive, at least in the short term (Selye 1956). Two features in particular make the stress response adaptive. First, stress hormones are released to make energy stores available for the body’s immediate use. Second, a new pattern of energy distribution emerges. Energy is diverted to the tissues that become more active during stress, primarily the skeletal muscles and the brain. Cells of the immune system are also activated and migrate to “battle stations” (Dhabar & McEwen 1997). Less critical activities are suspended, such as digestion and the production of growth and gonadal hormones. Simply put, during times of acute crisis, eating, growth, and sexual activity may be a detriment to physical integrity and even survival. Stress hormones are produced by the SNS and hypothalamic-pituitary adrenocortical axis. The SNS stimulates the adrenal medulla to produce catecholamines (e.g., epinephrine). In parallel, the paraventricular nucleus of the hypothalamus produces corticotropin releasing factor, which in turn stimulates the pituitary to

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produce adrenocorticotropin. Adrenocorticotropin then stimulates the adrenal cortex to secrete cortisol. Together, catecholamines and cortisol increase available sources of energy by promoting lipolysis and the conversion of glycogen into glucose (i.e., blood sugar). Lipolysis is the process of breaking down fats into usable sources of energy (i.e., fatty acids and glycerol; Brindley & Rollan 1989). Energy is then distributed to the organs that need it most by increasing blood pressure levels and contracting certain blood vessels while dilating others. Blood pressure is increased with one of two hemodynamic mechanisms (Llabre et al.1998, Schneiderman & McCabe 1989). The myocardial mechanism increases blood pressure through enhanced cardiac output; that is, increases in heart rate and stroke volume (i.e., the amount of blood pumped with each heart beat). The vascular mechanism constricts the vasculature, thereby increasing blood pressure much like constricting a hose increases water pressure. Specific stressors tend to elicit either myocardial or vascular responses, providing evidence of situational stereotypy (Saab et al. 1992, 1993). Laboratory stressors that call for active coping strategies, such as giving a speech or performing mental arithmetic, require the participant to do something and are associated with myocardial responses. In contrast, laboratory stressors that call for more vigilant coping strategies in the absence of movement, such as viewing a distressing video or keeping one’s foot in a bucket of ice water, are associated with vascular responses. From an evolutionary perspective, cardiac responses are believed to facilitate active coping by shunting blood to skeletal muscles, consistent with the fight-or-flight response. In situations where decisive action would not be appropriate, but instead skeletal muscle inhibition and vigilance are called for, a vascular hemodynamic response is adaptive. The vascular response shunts blood away from the periphery to the internal organs, thereby minimizing potential bleeding in the case of physical assault. Finally, in addition to the increased availability and redistribution of energy, the acute stress response includes activation of the immune system. Cells of the innate immune system (e.g., macrophages and natural killer cells), the first line of defense, depart from lymphatic tissue and spleen and enter the bloodstream, temporarily raising the number of immune cells in circulation (i.e., leukocytosis). From there, the immune cells migrate into tissues that are most likely to suffer damage during physical confrontation (e.g., the skin). Once at “battle stations,” these cells are in position to contain microbes that may enter the body through wounds and thereby facilitate healing (Dhabar & McEwen 1997).

Chronic Stress Responses The acute stress response can become maladaptive if it is repeatedly or continuously activated (Selye 1956). For example, chronic SNS stimulation of the cardiovascular system due to stress leads to sustained increases in blood pressure and vascular hypertrophy (Henry et al. 1975). That is, the muscles that constrict the vasculature thicken, producing elevated resting blood pressure and response stereotypy, or a tendency to respond to all types of stressors with a vascular response. Chronically

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elevated blood pressure forces the heart to work harder, which leads to hypertrophy of the left ventricle (Brownley et al. 2000). Over time, the chronically elevated and rapidly shifting levels of blood pressure can lead to damaged arteries and plaque formation. The elevated basal levels of stress hormones associated with chronic stress also suppress immunity by directly affecting cytokine profiles. Cytokines are communicatory molecules produced primarily by immune cells (see Roitt et al. 1998). There are three classes of cytokines. Proinflammatory cytokines mediate acute inflammatory reactions. Th1 cytokines mediate cellular immunity by stimulating natural killer cells and cytotoxic T cells, immune cells that target intracellular pathogens (e.g., viruses). Finally, Th2 cytokines mediate humoral immunity by stimulating B cells to produce antibody, which “tags” extracellular pathogens (e.g., bacteria) for removal. In a meta-analysis of over 30 years of research, Segerstrom & Miller (2004) found that intermediate stressors, such as academic examinations, could promote a Th2 shift (i.e., an increase in Th2 cytokines relative to Th1 cytokines). A Th2 shift has the effect of suppressing cellular immunity in favor of humoral immunity. In response to more chronic stressors (e.g., long-term caregiving for a dementia patient), Segerstrom & Miller found that proinflammatory, Th1, and Th2 cytokines become dysregulated and lead both to suppressed humoral and cellular immunity. Intermediate and chronic stressors are associated with slower wound healing and recovery from surgery, poorer antibody responses to vaccination, and antiviral deficits that are believed to contribute to increased vulnerability to viral infections (e.g., reductions in natural killer cell cytotoxicity; see Kiecolt-Glaser et al. 2002). Chronic stress is particularly problematic for elderly people in light of immunosenescence, the gradual loss of immune function associated with aging. Older adults are less able to produce antibody responses to vaccinations or combat viral infections (Ferguson et al. 1995), and there is also evidence of a Th2 shift (Glaser et al. 2001). Although research has yet to link poor vaccination responses to early mortality, influenza and other infectious illnesses are a major cause of mortality in the elderly, even among those who have received vaccinations (e.g., Voordouw et al. 2003).

PSYCHOSOCIAL STRESSORS AND HEALTH Cardiovascular Disease Both epidemiological and controlled studies have demonstrated relationships between psychosocial stressors and disease. The underlying mediators, however, are unclear in most cases, although possible mechanisms have been explored in some experimental studies. An occupational gradient in coronary heart disease (CHD) risk has been documented in which men with relatively low socioeconomic status have the poorest health outcomes (Marmot 2003). Much of the risk gradient in CHD can be eliminated, however, by taking into account lack of perceived job

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control, which is a potent stressor (Marmot et al. 1997). Other factors include risky behaviors such as smoking, alcohol use, and sedentary lifestyle (Lantz et al. 1998), which may be facilitated by stress. Among men (Schnall et al. 1994) and women (Eaker 1998), work stress has been reported to be a predictor of incident CHD and hypertension (Ironson 1992). However, in women with existing CHD, marital stress is a better predictor of poor prognosis than is work stress (Orth-Gomer et al. 2000). Although the observational studies cited thus far reveal provocative associations between psychosocial stressors and disease, they are limited in what they can tell us about the exact contribution of these stressors or about how stress mediates disease processes. Animal models provide an important tool for helping to understand the specific influences of stressors on disease processes. This is especially true of atherosclerotic CHD, which takes multiple decades to develop in humans and is influenced by a great many constitutional, demographic, and environmental factors. It would also be unethical to induce disease in humans by experimental means. Perhaps the best-known animal model relating stress to atherosclerosis was developed by Kaplan et al. (1982). Their study was carried out on male cynomolgus monkeys, who normally live in social groups. The investigators stressed half the animals by reorganizing five-member social groups at one- to three-month intervals on a schedule that ensured that each monkey would be housed with several new animals during each reorganization. The other half of the animals lived in stable social groups. All animals were maintained on a moderately atherogenic diet for 22 months. Animals were also assessed for their social status (i.e., relative dominance) within each group. The major findings were that (a) socially dominant animals living in unstable groups had significantly more atherosclerosis than did less dominant animals living in unstable groups; and (b) socially dominant male animals living in unstable groups had significantly more atherosclerosis than did socially dominant animals living in stable groups. Other important findings based upon this model have been that heart-rate reactivity to the threat of capture predicts severity of atherosclerosis (Manuck et al. 1983) and that administration of the SNS-blocking agent propranolol decreases the progression of atherosclerosis (Kaplan et al. 1987). In contrast to the findings in males, subordinate premenstrual females develop greater atherosclerosis than do dominant females (Kaplan et al. 1984) because they are relatively estrogen deficient, tending to miss ovulatory cycles (Adams et al. 1985). Whereas the studies in cynomolgus monkeys indicate that emotionally stressful behavior can accelerate the progression of atherosclerosis, McCabe et al. (2002) have provided evidence that affiliative social behavior can slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. This rabbit model has a genetic defect in lipoprotein clearance such that it exhibits hypercholesterolemia and severe atherosclerosis. The rabbits were assigned to one of three social or behavioral groups: (a) an unstable group in which unfamiliar rabbits were paired daily, with the pairing switched each week; (b) a stable group, in which littermates were paired daily for the entire study; and (c) an individually

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caged group. The stable group exhibited more affiliative behavior and less agonistic behavior than the unstable group and significantly less atherosclerosis than each of the other two groups. The study emphasizes the importance of behavioral factors in atherogenesis, even in a model of disease with extremely strong genetic determinants.

Upper Respiratory Diseases The hypothesis that stress predicts susceptibility to the common cold received support from observational studies (Graham et al. 1986, Meyer & Haggerty 1962). One problem with such studies is that they do not control for exposure. Stressed people, for instance, might seek more outside contact and thus be exposed to more viruses. Therefore, in a more controlled study, people were exposed to a rhinovirus and then quarantined to control for exposure to other viruses (Cohen et al. 1991). Those individuals with the most stressful life events and highest levels of perceived stress and negative affect had the greatest probability of developing cold symptoms. In a subsequent study of volunteers inoculated with a cold virus, it was found that people enduring chronic, stressful life events (i.e., events lasting a month or longer including unemployment, chronic underemployment, or continued interpersonal difficulties) had a high likelihood of catching cold, whereas people subjected to stressful events lasting less than a month did not (Cohen et al. 1998).

Human Immunodeficiency Virus The impact of life stressors has also been studied within the context of human immunodeficiency virus (HIV) spectrum disease. Leserman et al. (2000) followed men with HIV for up to 7.5 years and found that faster progression to AIDS was associated with higher cumulative stressful life events, use of denial as a coping mechanism, lower satisfaction with social support, and elevated serum cortisol.

Inflammation, the Immune System, and Physical Health Despite the stress-mediated immunosuppressive effects reviewed above, stress has also been associated with exacerbations of autoimmune disease (Harbuz et al. 2003) and other conditions in which excessive inflammation is a central feature, such as CHD (Appels et al. 2000). Evidence suggests that a chronically activated, dysregulated acute stress response is responsible for these associations. Recall that the acute stress response includes the activation and migration of cells of the innate immune system. This effect is mediated by proinflammatory cytokines. During periods of chronic stress, in the otherwise healthy individual, cortisol eventually suppresses proinflammatory cytokine production. But in individuals with autoimmune disease or CHD, prolonged stress can cause proinflammatory cytokine production to remain chronically activated, leading to an exacerbation of pathophysiology and symptomatology.

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Miller et al. (2002) proposed the glucocorticoid-resistance model to account for this deficit in proinflammatory cytokine regulation. They argue that immune cells become “resistant” to the effects of cortisol (i.e., a type of glucocorticoid), primarily through a reduction, or downregulation, in the number of expressed cortisol receptors. With cortisol unable to suppress inflammation, stress continues to promote proinflammatory cytokine production indefinitely. Although there is only preliminary empirical support for this model, it could have implications for diseases of inflammation. For example, in rheumatoid arthritis, excessive inflammation is responsible for joint damage, swelling, pain, and reduced mobility. Stress is associated with more swelling and reduced mobility in rheumatoid arthritis patients (Affleck et al. 1997). Similarly, in multiple sclerosis (MS), an overactive immune system targets and destroys the myelin surrounding nerves, contributing to a host of symptoms that include paralysis and blindness. Again, stress is associated with an exacerbation of disease (Mohr et al. 2004). Even in CHD, inflammation plays a role. The immune system responds to vascular injury just as it would any other wound: Immune cells migrate to and infiltrate the arterial wall, setting off a cascade of biochemical processes that can ultimately lead to a thrombosis (i.e., clot; Ross 1999). Elevated levels of inflammatory markers, such as C-reactive protein (CRP), are predictive of heart attacks, even when controlling for other traditional risk factors (e.g., cholesterol, blood pressure, and smoking; Morrow & Ridker 2000). Interestingly, a history of major depressive episodes has been associated with elevated levels of CRP in men (Danner et al. 2003).

Inflammation, Cytokine Production, and Mental Health In addition to its effects on physical health, prolonged proinflammatory cytokine production may also adversely affect mental health in vulnerable individuals. During times of illness (e.g., the flu), proinflammatory cytokines feed back to the CNS and produce symptoms of fatigue, malaise, diminished appetite, and listlessness, which are symptoms usually associated with depression. It was once thought that these symptoms were directly caused by infectious pathogens, but more recently, it has become clear that proinflammatory cytokines are both sufficient and necessary (i.e., even absent infection or fever) to generate sickness behavior (Dantzer 2001, Larson & Dunn 2001). Sickness behavior has been suggested to be a highly organized strategy that mammals use to combat infection (Dantzer 2001). Symptoms of illness, as previously thought, are not inconsequential or even maladaptive. On the contrary, sickness behavior is thought to promote resistance and facilitate recovery. For example, an overall decrease in activity allows the sick individual to preserve energy resources that can be redirected toward enhancing immune activity. Similarly, limiting exploration, mating, and foraging further preserves energy resources and reduces the likelihood of risky encounters (e.g., fighting over a mate). Furthermore, decreasing food intake also decreases the level of iron in the blood, thereby decreasing bacterial replication. Thus, for a limited period, sickness behavior may be looked upon as an adaptive response to the stress of illness.

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Much like other aspects of the acute stress response, however, sickness behavior can become maladaptive when repeatedly or continuously activated. Many features of the sickness behavior response overlap with major depression. Indeed, compared with healthy controls, elevated rates of depression are reported in patients with inflammatory diseases such as MS (Mohr et al. 2004) or CHD (Carney et al. 1987). Granted, MS patients face a number of stressors and reports of depression are not surprising. However, when compared with individuals facing similar disability who do not have MS (e.g., car accident victims), MS patients still report higher levels of depression (Ron & Logsdail 1989). In both MS (Fassbender et al. 1998) and CHD (Danner et al. 2003), indicators of inflammation have been found to be correlated with depressive symptomatology. Thus, there is evidence to suggest that stress contributes to both physical and mental disease through the mediating effects of proinflammatory cytokines.

HOST VULNERABILITY-STRESSOR INTERACTIONS AND DISEASE The changes in biological set points that occur across the life span as a function of chronic stressors are referred to as allostasis, and the biological cost of these adjustments is known as allostatic load (McEwen 1998). McEwen has also suggested that cumulative increases in allostatic load are related to chronic illness. These are intriguing hypotheses that emphasize the role that stressors may play in disease. The challenge, however, is to show the exact interactions that occur among stressors, pathogens, host vulnerability (both constitutional and genetic), and such poor health behaviors as smoking, alcohol abuse, and excessive caloric consumption. Evidence of a lifetime trajectory of comorbidities does not necessarily imply that allostatic load is involved since immunosenescence, genetic predisposition, pathogen exposure, and poor health behaviors may act as culprits. It is not clear, for example, that changes in set point for variables such as blood pressure are related to cumulative stressors per se, at least in healthy young individuals. Thus, for example, British soldiers subjected to battlefield conditions for more than a year in World War II showed chronic elevations in blood pressure, which returned to normal after a couple of months away from the front (Graham 1945). In contrast, individuals with chronic illnesses such as chronic fatigue syndrome may show a high rate of relapse after a relatively acute stressor such as a hurricane (Lutgendorf et al. 1995). Nevertheless, by emphasizing the role that chronic stressors may play in multiple disease outcomes, McEwen has helped to emphasize an important area of study.

TREATMENT FOR STRESS-RELATED DISORDERS For PTSD, useful treatments include cognitive-behavioral therapy (CBT), along with exposure and the more controversial Eye Movement Desensitization and Reprocessing (Foa & Meadows 1997, Ironson et al. 2002, Shapiro 1995).

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Psychopharmacological approaches have also been suggested (Berlant 2001). In addition, writing about trauma has been helpful both for affective recovery and for potential health benefit (Pennebaker 1997). For outpatients with major depression, Beck’s CBT (Beck 1976) and interpersonal therapy (Klerman et al. 1984) are as effective as psychopharmacotherapy (Clinical Practice Guidelines 1993). However, the presence of sleep problems or hypercortisolemia is associated with poorer response to psychotherapy (Thase 2000). The combination of psychotherapy and pharmacotherapy seems to offer a substantial advantage over psychotherapy alone for the subset of patients who are more severely depressed or have recurrent depression (Thase et al. 1997). For the treatment of anxiety, it depends partly on the specific disorder [e.g., generalized anxiety disorder (GAD), panic disorder, social phobia], although CBT including relaxation training has demonstrated efficacy in several subtypes of anxiety (Borkovec & Ruscio 2001). Antidepressants such as selective serotonin reuptake inhibitors also show efficacy in anxiety (Ballenger et al. 2001), especially when GAD is comorbid with major depression, which is the case in 39% of subjects with current GAD (Judd et al. 1998).

BEHAVIORAL INTERVENTIONS IN CHRONIC DISEASE Patients dealing with chronic, life-threatening diseases must often confront daily stressors that can threaten to undermine even the most resilient coping strategies and overwhelm the most abundant interpersonal resources. Psychosocial interventions, such as cognitive-behavioral stress management (CBSM), have a positive effect on the quality of life of patients with chronic disease (Schneiderman et al. 2001). Such interventions decrease perceived stress and negative mood (e.g., depression), improve perceived social support, facilitate problem-focused coping, and change cognitive appraisals, as well as decrease SNS arousal and the release of cortisol from the adrenal cortex. Psychosocial interventions also appear to help chronic pain patients reduce their distress and perceived pain as well as increase their physical activity and ability to return to work (Morley et al. 1999). These psychosocial interventions can also decrease patients’ overuse of medications and utilization of the health care system. There is also some evidence that psychosocial interventions may have a favorable influence on disease progression (Schneiderman et al. 2001).

Morbidity, Mortality, and Markers of Disease Progression Psychosocial intervention trials conducted upon patients following acute myocardial infarction (MI) have reported both positive and null results. Two meta-analyses have reported a reduction in both mortality and morbidity of approximately 20% to 40% (Dusseldorp et al. 1999, Linden et al. 1996). Most of these studies were carried out in men. The major study reporting positive results was the Recurrent Coronary Prevention Project (RCPP), which employed group-based CBT, and decreased hostility and depressed affect (Mendes de Leon et al. 1991), as well as the composite medical end point of cardiac death and nonfatal MI (Friedman et al. 1986).

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In contrast, the major study reporting null results for medical end points was the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial (Writing Committee for ENRICHD Investigators 2003), which found that the intervention modestly decreased depression and increased perceived social support, but did not affect the composite medical end point of death and nonfatal MI. However, a secondary analysis, which examined the effects of the psychosocial intervention within gender by ethnicity subgroups, found significant decreases approaching 40% in both cardiac death and nonfatal MI for white men but not for other subgroups such as minority women (Schneiderman et al. 2004). Although there were important differences between the RCPP and ENRICHD in terms of the objectives of psychosocial intervention and the duration and timing of treatment, it should also be noted that more than 90% of the patients in the RCPP were white men. Thus, because primarily white men, but not other subgroups, may have benefited from the ENRICHD intervention, future studies need to attend to variables that may have prevented morbidity and mortality benefits among gender and ethnic subgroups other than white men. Psychosocial intervention trials conducted upon patients with cancer have reported both positive and null results with regard to survival (Classen 1998). A number of factors that generally characterized intervention trials that observed significant positive effects on survival were relatively absent in trials that failed to show improved survival. These included: (a) having only patients with the same type and severity of cancer within each group, (b) creation of a supportive environment, (c) having an educational component, and (d) provision of stressmanagement and coping-skills training. In one study that reported positive results, Fawzy et al. (1993) found that patients with early stage melanoma assigned to a six-week cognitive-behavioral stress management (CBSM) group showed significantly longer survival and longer time to recurrence over a six-year follow-up period compared with those receiving surgery and standard care alone. The intervention also significantly reduced distress, enhanced active coping, and increased NK cell cytotoxicity compared with controls. Although published studies have not yet shown that psychosocial interventions can decrease disease progression in HIV/AIDS, several studies have significantly influenced factors that have been associated with HIV/AIDS disease progression (Schneiderman & Antoni 2003). These variables associated with disease progression include distress, depressed affect, denial coping, low perceived social support, and elevated serum cortisol (Ickovics et al. 2001, Leserman et al. 2000). Antoni et al. have used group-based CBSM (i.e., CBT plus relaxation training) to decrease the stress-related effects of HIV+ serostatus notification. Those in the intervention condition showed lower distress, anxiety, and depressed mood than did those in the control condition as well as lower antibody titers of herpesviruses and higher levels of T-helper (CD4) cells, NK cells, and lymphocyte proliferation (Antoni et al. 1991, Esterling et al. 1992). In subsequent studies conducted upon symptomatic HIV+ men who were not attempting to determine their HIV serostatus, CBSM decreased distress, dysphoria, anxiety,

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herpesvirus antibody titers, cortisol, and epinephrine (Antoni et al. 2000a,b; Lutgendorf et al. 1997). Improvement in perceived social support and adaptive coping skills mediated the decreases in distress (Lutgendorf et al. 1998). In summary, it appears that CBSM can positively influence stress-related variables that have been associated with HIV/AIDS progression. Only a randomized clinical trial, however, could document that CBSM can specifically decrease HIV/AIDS disease progression.

CONCLUSION Stress is a central concept for understanding both life and evolution. All creatures face threats to homeostasis, which must be met with adaptive responses. Our future as individuals and as a species depends on our ability to adapt to potent stressors. At a societal level, we face a lack of institutional resources (e.g., inadequate health insurance), pestilence (e.g., HIV/AIDS), war, and international terrorism that has reached our shores. At an individual level, we live with the insecurities of our daily existence including job stress, marital stress, and unsafe schools and neighborhoods. These are not an entirely new condition as, in the last century alone, the world suffered from instances of mass starvation, genocide, revolutions, civil wars, major infectious disease epidemics, two world wars, and a pernicious cold war that threatened the world order. Although we have chosen not to focus on these global threats in this paper, they do provide the backdrop for our consideration of the relationship between stress and health. A widely used definition of stressful situations is one in which the demands of the situation threaten to exceed the resources of the individual (Lazarus & Folkman 1984). It is clear that all of us are exposed to stressful situations at the societal, community, and interpersonal level. How we meet these challenges will tell us about the health of our society and ourselves. Acute stress responses in young, healthy individuals may be adaptive and typically do not impose a health burden. Indeed, individuals who are optimistic and have good coping responses may benefit from such experiences and do well dealing with chronic stressors (Garmezy 1991, Glanz & Johnson 1999). In contrast, if stressors are too strong and too persistent in individuals who are biologically vulnerable because of age, genetic, or constitutional factors, stressors may lead to disease. This is particularly the case if the person has few psychosocial resources and poor coping skills. In this chapter, we have documented associations between stressors and disease and have described how endocrine-immune interactions appear to mediate the relationship. We have also described how psychosocial stressors influence mental health and how psychosocial treatments may ameliorate both mental and physical disorders. There is much we do not yet know about the relationship between stress and health, but scientific findings being made in the areas of cognitive-emotional psychology, molecular biology, neuroscience, clinical psychology, and medicine will undoubtedly lead to improved health outcomes.

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ACKNOWLEDGMENTS Preparation of this manuscript was supported by NIH grants P01-MH49548, P01HL04726, T32-HL36588, R01-MH66697, and R01-AT02035. We thank Elizabeth Balbin, Adam Carrico, and Orit Weitzman for library research. The Annual Review of Clinical Psychology is online at http://clinpsy.annualreviews.org LITERATURE CITED Adams DB, Bacelli G, Mancia G, Zanchetti A. 1968. Cardiovascular changes during naturally elicited fighting behavior in the cat. Am. J. Physiol. 216:1226–35 Adams MR, Kaplan JR, Koritnik DR. 1985. Psychosocial influences on ovarian, endocrine and ovulatory function in Macaca fascicularis. Physiol. Behav. 35:935–40 Affleck G, Urrows S, Tennen H, Higgins P, Pav D, Aloisi R. 1997. A dual pathway model of daily stressor effects on rheumatoid arthritis. Ann. Behav. Med. 19:161–70 American Psychiatric Association. 2000. Diagnostic and Statistical Manual of Mental Disorders IV-TR, 4th ed. Washington, DC: Am. Psychiatr. Assoc. Angst J, Vollrath M. 1991. The natural history of anxiety disorders. Acta Psychiatr. Scand. 84:446–52 Antoni MH, Baggett L, Ironson G, LaPerriere A, Klimas N, et al. 1991. Cognitive behavioral stress management intervention buffers distress responses and elevates immunologic markers following notification of HIV-1 seropositivity. J. Consult. Clin. Psychol. 59:906–15 Antoni MH, Cruess DG, Cruess S, Lutgendorf S, Kumar M, et al. 2000a. Cognitive behavioral stress management intervention effects on anxiety, 24-hour urinary catecholamine output, and T-cytotoxic/suppressor cells over time among symptomatic HIV-infected gay men. J. Consult. Clin. Psychol. 68:31–45 Antoni MH, Cruess S, Cruess DG, Kumar M, Lutgendorf S, et al. 2000b. Cognitivebehavioral stress management reduces distress and 24-hour urinary free cortisol output

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Editorial

D

ear Colleagues,

In spite of its apparent simplicity, the word “stress” can convey a wide variety of meanings and connotations in modern psychiatry. • As a symptom, stress expresses the reaction to external circumstances (stressful events), or to internal factors (for instance when the individual’s psychological and somatic defense mechanisms are overwhelmed, such as in angina pectoris). • Stress can also be understood as a disorder. Post-traumatic stress disorder was covered in a previous issue of Dialogues in Clinical Neuroscience (DCNS Vol 2, No 1). • Stress can trigger complex psychiatric disorders (for instance, recurring episodes of a mood disorder, or acute delusional episodes, etc). • Through an effect on neuroplasticity, the accumulation of stress can predispose to depressive disorders. The elucidation of this pathogenetic mechanism has led to new hypotheses and treatment options in depression. In addition to defining stress and its clinical consequences, it is also important to understand the biological mechanisms that are responsible for or associated with stress. Research into the etiology of stress involves genetics, and the study of structures such as the prefrontal cortex, the amygdala, and the hypothalamo-pituitary-adrenal axis, which have been shown to play key roles in the genesis of stress. The discovery of the interaction between the accumulation of stress and disturbances of neuroplasticity was one of the key scientific advances in recent years, and it paved the way for the development of new hypotheses and treatment methods in depression. We felt that it was important to dedicate an issue of DCNS to the question of “stress.” This issue was coordinated by David Rubinow (University of North Carolina, USA). We are grateful to him for bringing together such an outstanding panel of experts, and would like to thank all the authors for their brilliant contributions. Sincerely yours, Jean-Paul Macher, MD

Marc-Antoine Crocq, MD 361

Dialogues in Clinical Neuroscience is a quarterly publication that aims to serve as an interface between clinical neuropsychiatry and the neurosciences by providing state-of-the-art information and original insights into relevant clinical, biological, and therapeutic aspects. Each issue addresses a specific topic, and also publishes free contributions in the field of neuroscience as well as other non–topic-related material. All contributions are reviewed by members of the Editorial Board and submitted to expert consultants for peer review. Indexed in MEDLINE, Index Medicus, EMBASE, Scopus, Elsevier BIOBASE, and PASCAL/INIST-CNRS. EDITORIAL OFFICES Editor in Chief Jean-Paul MACHER, MD FORENAP - Institute for Research in Neuroscience and Neuropsychiatry BP29 - 68250 Rouffach - France Tel: + 33 3 89 78 70 18 / Fax: +33 3 89 78 51 24 Secretariat, subscriptions, and submission of manuscripts Marc-Antoine CROCQ, MD FORENAP - Institute for Research in Neuroscience and Neuropsychiatry BP29 - 68250 Rouffach - France Tel: +33 3 89 78 71 20 (direct) or +33 3 89 78 70 18 (secretariat) Fax: +33 3 89 78 51 24 / E-mail: [email protected] Annual subscription rates: Europe €150; Rest of World €170. Production Editor Catriona DONAGH, BAppSc Servier International - Medical Publishing Division 192 avenue Charles-de-Gaulle 92578 Neuilly-sur-Seine Cedex - France Tel: +33 1 55 72 32 79 / Fax: +33 1 55 72 62 57 E-mail: [email protected] PUBLISHER Les Laboratoires Servier 22 rue Garnier - 92578 Neuilly-sur-Seine Cedex - France E-mail: [email protected] Copyright © 2006 by Les Laboratoires Servier All rights reserved throughout the world and in all languages. No part of this publication may be reproduced, transmitted, or stored in any form or by any means either mechanical or electronic, including photocopying, recording, or through an information storage and retrieval system, without the written permission of the copyright holder. Opinions expressed do not necessarily reflect the views of the publisher, editors, or editorial board. The authors, editors, and publisher cannot be held responsible for errors or for any consequences arising from the use of information contained in this journal. ISSN 1294-8322 Printed on acid-free paper. Design: Christophe Caretti / Layout: Graphie 66 Imprimé en France par SIP 1, rue Saint Simon - 95310 Saint-Ouen-l’Aumône

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Contents Page

361 365 367

Editorial

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Basic Research

397 407 417 433 445 463 478

Jean-Paul Macher, Marc-Antoine Crocq

In this issue David Rubinow

State of the Art Protective and damaging effects of stress mediators: central role of the brain Bruce S. McEwen (USA)

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress Sean M. Smith,Wylie W.Vale (USA) Behavioral control, the medial prefrontal cortex, and resilience Steven F. Maier, Jose Amat, Michael V. Baratta, Evan Paul, Linda R.Watkins (USA) Angst and the amygdala Jay Schulkin (USA) Experimental models of stress Vladimir K. Patchev,Alexandre V. Patchev (Germany)

Clinical Research Genetics of stress response and stress-related disorders Marcus Ising, Florian Holsboer (Germany) Traumatic stress: effects on the brain J. Douglas Bremner (USA) Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior A. Leslie Morrow, Patrizia Porcu, Kevin N. Boyd, Kathleen A. Grant (USA)

Poster Estrogen enhances stress-induced prefrontal cortex dysfunction: relevance to Major Depressive Disorder in women Rebecca M. Shansky, Amy F. T. Arnsten (USA)

ISSUE COORDINATED BY: David Rubinow

363

Contributors Bruce S. McEwen, PhD

Florian Holsboer, MD, PhD

Author affiliations: Alfred E. Mirsky Professor and Head, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA

Author affiliations: Max Planck Institute of Psychiatry, Munich, Germany

Wylie W. Vale, PhD

J. Douglas Bremner, MD

Author affiliations: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California, USA

Author affiliations: Departments of Psychiatry and Behavioral Sciences and Radiology, and the Emory Center for Positron Emission Tomography, Emory University School of Medicine, Atlanta, Ga, and the Atlanta VAMC, Decatur, Ga, USA

Steven F. Maier, PhD

A. Leslie Morrow, PhD

Author affiliations: Department of Psychology and Center for Neuroscience, University of Colorado at Boulder, Colorado, USA

Author affiliations: Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Curriculum in Toxicology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Jay Schulkin, PhD

Rebecca M. Shansky, PhD

Author affiliations: Department of Physiology and Biophysics, Georgetown University, School of Medicine, Washington, DC, USA; Clinical Neuroendocrinology Branch, National Institute of Mental Health, Bethesda, Md, USA

Author affiliations: Mount Sinai School of Medicine, New York, NY, USA

Vladimir K. Patchev, MD

Author affiliations: Corporate Research, Bayer Schering Pharma, Berlin, Germany

364

In this issue... It is empirical truth for most that stress is not good for us, and, further, we now recognize that stress comes in different flavors and cannot be considered a unitary phenomenon. Nothing new there. What is new, however, is the recognition that the stress response is not simply an amplifier of behavioral and affective symptoms but is instead critical to their development and expression. What are the isomorphs between stress maladaptation and psychophathology, how does stress change how the brain learns, and what are the molecules and circuits of the stress response? In this issue of Dialogues in Clinical Neuroscience, these questions are answered by authors who both decompose the stress response, identifying its chemical and neural mediators, and demonstrate the centrality of stress adaptation to compromised as well as resilient psychological functioning. In the State of the art opening article, Bruce McEwen describes the brain as not only the director of the stress response, but also its target. The cumulative demands of everyday life combine with the efficiency of one’s management of stressors to generate what Dr McEwen calls “allostatic overload,” the consequences of which include both chemical and structural remodeling of the brain. Current knowledge of this process is sufficient to argue for the implementation of societal policies to reduce allostatic overload. In the first Basic research article, Sean Smith and Wylie Vale deconstruct the stress response by first describing the pharmacology of its hormonal components, particularly the corticotropin-releasing factor (CRF) family of peptides, largely discovered through the work of Dr Vale and colleagues. The authors then clearly and comprehensively describe the neuroendocrine and neuronal regulation of the hypothalamic-pitutary-adrenal (HPA) axis. With this background, the diversity of the stress response becomes clear, as different stressors activate different neurocircuitry, with different behavioral and physiological consequences. In the second Basic research article, Steven Maier and colleagues, in a tour de force, describe the central role of the medial prefrontal cortex in the perception of control and in the subsequent inhibition of the adverse consequences of stress. Further, they demonstrate that the activation of the medial prefrontal cortex, rather than the controllability of the stressor, is what determines both the acute response to stressor and the response to subse-

quent stressors. These “behavioral immunization” studies provide a unique framework for understanding the development and expression of resilience or psychopathology in the face of repeated exposure to traumatic stressors. In the third Basic research article, Jay Schulkin redirects our attention from the prefrontal cortex to the amygdala. Known for years to be central to the fear response, the amygdala has increasingly been implicated in a variety of psychiatric disorders, including depression and post-traumatic stress disorder (PTSD). Dr Schulkin first describes the anatomical complexity of the amygdala and the implications of the differential “wiring.” He then suggests how stress-induced glucocorticoid secretion may, in the proper genetic context, increase corticotropin-releasing hormone (CRH) expression in the amygdala and, by so doing, result in exaggerated subsequent amygdala responses to stress, with concomitant alterations in both the perception of and response to life events. Some of the ambiguities in stress research are explained in the fourth Basic research article by Vladimir and Alexandre Patchev, who systematically review existing animal models for the stress response. These authors first describe the multitude of outcome measures that have been employed and then the variety of experimental approaches to stress induction .While no perfect model exists, appreciation of the major sources of variance permits the integration of what otherwise might be viewed as disparate findings. In the first Clinical research article, Marcus Ising and Florian Holsboer review the heritability and genetic association studies of the stress response before arguing that the study of stress-related disorders—hypertension, coronary artery disease, and affective illness (bipolar and unipolar)—reveals genes relevant to the stress response that would not otherwise be identified. The authors describe how burgeoning technical capabilities must be dovetailed with clinical investigations that assess gene-gene and gene-environment interactions if we are to understand the role of genetic context in the etiopathogenesis of the stress response. In the second Clinical research article, J. Douglas Bremner uses brain imaging data to trace the neurocircuitry of the response to (and consequences of) traumatic stress in humans. The brain regions so identified are then exam-

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In this issue... ined in PTSD as mediators of learning, targets of stressrelated hormones, and possible sites of action of pharmacotherapies. Of particular note are the neural consequences of early abuse as well as the different expression of these consequences (eg, deficient activation of the medial prefrontal cortex) in the presence and absence of PTSD. Neurosteroids are neuroactive metabolites of the stressactivated hormone deoxycorticosterone and progesterone. These hormones are powerful modulators of 웂aminobutyric acid (GABA)-mediated chloride ion channel activity and, hence, behavior. In the third Clinical research article, Leslie Morrow and colleagues present a

strong argument for the role of neuroactive steroids in the behavioral response to alcohol and in the susceptibility to alcoholism. Data presented in this article suggest the possible therapeutic use of neurosteroids in alcohol withdrawal or relapse prevention. Finally, in the Poster, Rebecca Shansky and Amy Arnsten present an elegant example of modulation of the stress response, namely estradiol-dependent increased sensitivity to the detrimental effects of stress on the prefrontal cortex (PFC). These findings may, in part, explain both the increased sensitivity to stress-induced PFC dysfunction in female rats and the increased susceptibility in women to stress-related disorders (eg, depression).

David Rubinow, MD

366

State of the art Protective and damaging effects of stress mediators: central role of the brain Bruce S. McEwen, PhD

“S

tress” is a commonly used word that generally refers to experiences that cause feelings of anxiety and frustration because they push us beyond our ability to successfully cope. “There is so much to do and so little time!” is a common expression. Besides time pressures and daily hassles at work and home, there are stressors related to economic insecurity, poor health, and interpersonal conflict. More rarely, there are situations that are life-threatening—accidents, natural disasters, violence—and these evoke the classical “fight or flight” The mind involves the whole body, and two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Stress is a condition of the mind-body interaction, and a factor in the expression of disease that differs among individuals. It is not just the dramatic stressful events that exact their toll, but rather the many events of daily life that elevate and sustain activities of physiological systems and cause sleep deprivation, overeating, and other health-damaging behaviors, producing the feeling of being “stressed out.” Over time, this results in wear and tear on the body, which is called “allostatic load,” and it reflects not only the impact of life experiences but also of genetic load, individual lifestyle habits reflecting items such as diet, exercise, and substance abuse, and developmental experiences that set life-long patterns of behavior and physiological reactivity. Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation by the process known as allostasis, but in the long run allostatic load causes changes in the body that can lead to disease. The brain is the key organ of stress, allostasis, and allostatic load, because it determines what is threatening and therefore stressful, and also determines the physiological and behavioral responses. Brain regions such as the hippocampus, amygdala, and prefrontal cortex respond to acute and chronic stress by undergoing structural remodeling, which alters behavioral and physiological responses. Translational studies in humans with structural and functional imaging reveal smaller hippocampal volume in stress-related conditions, such as mild cognitive impairment in aging and prolonged major depressive illness, as well as in individuals with low selfesteem. Alterations in amygdala and prefrontal cortex are also reported. Besides pharmaceuticals, approaches to alleviate chronic stress and reduce allostatic load and the incidence of diseases of modern life include lifestyle change, and policies of government and business that would improve the ability of individuals to reduce their own chronic stress burden. © 2006, LLS SAS

Dialogues Clin Neurosci. 2006;8:367-381.

Keywords: stress; stress hormone; allostasis; hippocampus; amygdala; prefrontal cortex Author affiliations: Alfred E. Mirsky Professor and Head, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA Copyright © 2006 LLS SAS. All rights reserved

Address for correspondence: Prof Bruce E. McEwen, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10021, USA (e-mail: [email protected])

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www.dialogues-cns.org

State of the art Selected abbreviations and acronyms ACTH BDNF CRS CRF CRH NCAM

acetylcholine brain-derived neurotrophic factor chronic restraint stress corticotropin-releasing factor corticotropin-releasing hormone neural cell adhesion molecule

response. In contrast to daily hassles, these stressors are acute, and yet they also usually lead to chronic stress in the aftermath of the tragic event. The most common stressors are therefore ones that operate chronically, often at a low level, and that cause us to behave in certain ways. For example, being “stressed out” may cause us to be anxious and or depressed, to lose sleep at night, to eat comfort foods and take in more calories than our bodies need, and to smoke or drink alcohol excessively. Being stressed out may also cause us to neglect to see friends, or to take time off or engage in regular physical activity as we, for example, sit at a computer and try to get out from under the burden of too much to do. Often we are tempted to take medications— anxiolytics, sleep-promoting agents—to help us cope, and, with time, our bodies may increase in weight… The brain is the organ that decides what is stressful and determines the behavioral and physiological responses, whether health-promoting or health-damaging. And the brain is a biological organ that changes under acute and chronic stress, and directs many systems of the body— metabolic, cardiovascular, immune—that are involved in the short- and long-term consequences of being stressed out. What does chronic stress do to the body and brain? This review summarizes some of the current information, placing emphasis on how the stress hormones can play both protective and damaging roles in brain and body, depending on how tightly their release is regulated, and it discusses some of the approaches for dealing with stress in our complex world.

Definition of stress, allostasis, and allostatic load “Stress” is an ambiguous term, and has connotations that make it less useful in understanding how the body handles the events that are stressful. Insight into these processes can lead to a better understanding of how best to intervene, a topic that will be discussed at the end of this article. There are two sides to this story1: on the one

hand, the body responds to almost any event or challenge by releasing chemical mediators—eg, catecholamines that increase heart rate and blood pressure—that help us cope with the situation; on the other hand, chronic elevation of these same mediators—eg, chronically increased heart rate and blood pressure—produce chronic wear and tear on the cardiovascular system that can result, over time, in disorders such as strokes and heart attacks. For this reason, the term “allostasis” was introduced by Sterling and Eyer2 to refer to the active process by which the body responds to daily events and maintains homeostasis (allostasis literally means “achieving stability through change”). Because chronically increased allostasis can lead to disease, we introduced the term “allostatic load or overload” to refer to the wear and tear that results from either too much stress or from inefficient management of allostasis, eg, not turning off the response when it is no longer needed.1,3,4 Other forms of allostatic load are summarized in Figure 1, and involve not turning on an adequate response in the first place, or not habituating to the recurrence of the same stressor, and thus dampening the allostatic response.

Protection and damage as the two sides of the response to stressors Thus, protection and damage are the two contrasting sides of the physiology involved in defending the body against the challenges of daily life, whether or not we call them “stressors.” Besides adrenaline and noradrenaline, there are many mediators that participate in allostasis, and they are linked together in a network of regulation that is nonlinear (Figure 2), meaning that each mediator has the ability to regulate the activity of the other mediators, sometimes in a biphasic manner. Glucocorticoids produced by the adrenal cortex in Figure 1. Four types of allostatic load. The top panel illustrates the normal allostatic response, in which a response is initiated by a stressor, sustained for an appropriate interval, and then turned off. The remaining panels illustrate four conditions that lead to allostatic load: top left—repeated “hits” from multiple stressors; top right—lack of adaptation; bottom left—prolonged response due to delayed shut down; and bottom right—inadequate response that leads to compensatory hyperactivity of other mediators (eg, inadequate secretion of glucocorticoid, resulting in increased levels of cytokines that are normally counter-regulated by glucocorticoids). Reproduced from reference 1: McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998; 338:171-179. Copyright © Massachusetts Medical Society 1998.

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State of the art response to acetylcholine (ACTH) from the pituitary gland is the other major “stress hormone.” Pro- and antiinflammatory cytokines are produced by many cells in the body; they regulate each other and are, in turn, regulated by glucocorticoids and catecholamines. Whereas catecholamines can increase proinflammatory cytokine production, glucocorticoids are known to inhibit this production.5 Yet, there are exceptions—proinflammatory effects of glucocorticoids that depend on dose and cell or tissue type.6,7 The parasympathetic nervous system also plays an important regulatory role in this nonlinear network of allostasis, since it generally opposes the sympathetic nervous system and, for example, slows the heart and also has anti-inflammatory effects.8,9 What this nonlinearity means is that when any one mediator is increased or decreased, there are compensatory changes in the other mediators that depend on time course and level of change of each of the mediators. Unfortunately, we cannot measure all components of this system simultaneously, and must rely on measurements of only a few of them in any one study. Yet the nonlinearity must be kept in mind in interpreting the results.

Stress in the natural world The operation of allostasis in the natural world provides some insight into how animals use this response to their own benefit or for the benefit of the species. As an example of allostasis, in spring, a sudden snowstorm causes stress to birds and disrupts mating, and stress hormones are pivotal in directing the birds to suspend reproduction, to find a source of food, and to relocate to a better mating site, or at least to delay reproduction until the weather improves.10 As an example of allostatic load, bears preparing to hibernate for the winter eat large quantities of food and put on body fat to act as an energy source during the winter.11 This accumulation of fat is used, then, to survive the winter and provide food for gestation of young; this is in contrast to the fat accumulation that occurs in bears that are captive in zoos and eating too much, partially out of boredom, while not exercising.4 The accumulation of fat under these latter conditions can be called “allostatic overload,” referring to a condition that is associated with pathophysiology. However, allostatic overload can also have a useful pur-

Metabolism eg, diabetes obesity

CNS function eg, cognition depression aging diabetes Alzheimer’s disease

Cortisol DHEA

Inflammatory cytokines

Sympathetic

Anti-inflammatory cytokines

Parasympathetic

Oxidative stress

Cardiovascular function eg, endothelial cell damage atherosclerosis

Immune function eg, immune enhancement immune suppression

Figure 2. Nonlinear network of mediators of allostasis involved in the stress response. Arrows indicate that each system regulates the others in a reciprocal manner, creating a nonlinear network. Moreover, there are multiple pathways for regulation—eg, inflammatory cytokine production is negatively regulated via anti-inflammatory cytokines as well as via parasympathetic and glucocorticoid pathways, whereas sympathetic activity increases inflammatory cytokine production. Parasympathetic activity, in turn, restrains sympathetic activity. DHEA, dehydroepiandrosterone

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pose for the preservation of the species, such as in migrating salmon or the marsupial mouse, which die of excessive stress after mating—the stress, and allostatic load, being caused for salmon, in part, by the migration up the rapidly flowing rivers, but also because of physiological changes that represent accelerated aging.12-14 The result is freeing up food and other resources for the next generation. In the case of the marsupial mouse, it is only the males that die after mating, due apparently to a response to mating that reduces the binding protein, corticosteroid-binding globulin (CBG), for glucocorticoids and renders them much more active throughout the body.15

Being “stressed out,” especially sleep deprivation and its consequences The common experience of being “stressed out” has as its core the elevation of some of the key systems that lead to allostatic load—cortisol, sympathetic activity, and proinflammatory cytokines, with a decline in parasympathetic activity. Nowhere is this better illustrated than for sleep deprivation, which is a frequent result of being “stressed out.” Sleep deprivation produces an allostatic overload that can have deleterious consequences. Sleep restriction to 4 hours of sleep per night increases blood pressure, decreases parasympathetic tone, increases

Environmental stressors

evening cortisol and insulin levels, and promotes increased appetite, possibly through the elevation of ghrelin, a proappetitive hormone, and decreased levels of leptin.16-18 Proinflammatory cytokine levels are increased, along with performance in tests of psychomotor vigilance, and this has been reported to result from a modest sleep restriction to 6 hours per night.19 Reduced sleep duration was reported to be associated with increased body mass and obesity in the NHANES study.20 Sleep deprivation also causes cognitive impairment. The brain is the master regulator of the neuroendocrine, autonomic, and immune systems, along with behaviors that contribute to unhealthy or health lifestyles, which, in turn, influence the physiological processes of allostasis (Figure 3).2 Alterations in brain function by chronic stress can, therefore, have direct and indirect effects on the cumulative allostatic overload. Allostatic overload resulting from chronic stress in animal models causes atrophy of neurons in the hippocampus and prefrontal cortex, brain regions involved in memory, selective attention, and executive function, and causes hypertrophy of neurons in the amygdala, a brain region involved in fear and anxiety, as well as aggression.21 Thus, the ability to learn and remember and make decisions may be compromised by chronic stress, and may be accompanied by increased levels of anxiety and aggression.

Major life events

Trauma, abuse

(work, home, neighborhood)

Perceived stress (threat, no threat) (helplessness) (vigilance)

Individual differences

Behavioral responses (fight or flight) (personal behavior—diet, smoking, drinking, exercise)

(genes, development, experience)

Physiologic responses Allostasis

Adaptation Allostatic load

Figure 3. Central role of the brain in allostasis and the behavioral and physiological response to stressors. Reproduced from reference 1: McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:171-179. Copyright © Massachusetts Medical Society 1998.

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State of the art Although sleep deprivation has not yet been studied in terms of all these aspects, there is increasing evidence, not only for cognitive impairment resulting from sleep restriction, but also for altered levels of cytokines, oxidative stress markers, glycogen levels, and structural changes in the form of reduced dentate gyrus neurogenesis. With respect to proinflammatory cytokines, IL-1β messenger ribonucleic acid (mRNA) levels in brain are reported to increase following sleep deprivation by gentle handling and to be higher in daytime (during the normal sleep period in rodents) than in darkness (during the normal activity time for rodents).22 Closely related to inflammatory processes through the actions of reduced nicotinamide adenine nucleotide phosphate (NADPH) oxidase23,24 is oxidative stress involving the generation of free radicals. Sleep deprivation in mice for 72 hours by the “flowerpot” or platform method has been reported to increase oxidative stress in hippocampus, as measured by increased lipid peroxidation and increased ratios of oxidized to reduced glutathione.25 Another noteworthy effect of sleep deprivation is regulation of the level of glycogen, found predominantly in white matter, which is reported to decrease by as much as 40% in rats deprived of sleep for 24 hours by novelty and gentle handling, and reversed by recovery sleep.26,27 It is noteworthy that glycogen in astrocytes is able to sustain axon function during glucose deprivation in central nervous system (CNS) white matter.28 Sleep deprivation in rats using a treadmill for 96 hours has been reported to decrease proliferation of cells in the dentate gyrus of the hippocampal formation by as much as 50%.29 A similar effect has also been reported by keeping rats in a slowly rotating drum, but here again, there is a question of how much physical activity and physical stress may have contributed to the suppression of cell proliferation.30 Nevertheless, sleep restriction by novelty exposure, a more subtle method, prevented the increased survival of new dentate gyrus neurons promoted by spatial training in a Morris water maze.31 Indeed, with respect to memory and cognitive performance, there are numerous reports of impairments following sleep deprivation. For example, sleep deprivation by the platform (or flowerpot) method resulted in impaired retention of passive avoidance memory, a context-dependent fear memory task,25 as well as impaired performance of spatial memory in the Morris water maze32 and a reduction in long-term potentiation in the CA1 region of the hippocampus.33

Sleep deprivation by gentle stimulation or novelty in the aftermath of contextual fear conditioning has been reported to impair memory consolidation.34 Moreover, a 6-hour period of total sleep deprivation by novelty exposure impaired acquisition of a spatial task in the Morris water maze.35 Furthermore, a 4-hour period of sleep deprivation by gentle stimulation impaired the late-phase long-term potentiation (LTP) in the dentate gyrus 48 hours later, but had the opposite effect of enhancing latephase LTP in the prefrontal cortex.36 Sleep deprivation has also been associated with increases in fighting behavior after deprivation of rapid eye movement (REM) sleep;37 there is also a report of increased aggression in the form of muricide after phencyclidine administration after sleep deprivation.38 These findings may be related to the finding of increased aggression among cagemates in rats subjected to 21 days of 6 hours per day of chronic restraint stress during the resting period when some sleep deprivation may occur.39 Interestingly, a 12-hour sleep deprivation that is applied by using a slowly rotating drum which minimizes physical stress, but does produce locomotor activity, reversed the decreased open-field behavior induced by a single social defeat.40

Key role of the brain in response to stress The brain is the key organ of the stress response because it determines what is threatening, and therefore, stressful, and also controls the behavioral and physiological responses that have been discussed earlier in this article (see Figure 3). There are enormous individual differences in the response to stress, based upon the experience of the individual early in life and in adult life. Obviously, positive or negative experiences in school, at work, or in romantic and family interpersonal relationships can bias an individual towards either a positive or negative response in a new situation. For example, someone who has been treated badly in a job by a domineering and abusive supervisor and/or has been fired will approach a new job situation quite differently than someone who has had positive experiences in employment. Early life experiences perhaps carry an even greater weight in terms of how an individual reacts to new situations. Early life physical and sexual abuse imposes a lifelong burden of behavioral and pathophysiological problems.41,42 Cold and uncaring families produce long-lasting emotional problems in children.43 Some of these effects

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are seen on brain structure and function, and in the risk for later depression and post-traumatic stress disorder (PTSD).44-46 Animal models have been useful in providing insights into behavioral and physiological mechanisms. Early life maternal care in rodents is a powerful determinant of life-long emotional reactivity and stress hormone reactivity, and increases in both are associated with earlier cognitive decline and a shorter lifespan.47,48 Effects of early maternal care are transmitted across generations by the subsequent behavior of the female offspring as they become mothers, and methylation of deoxyribonucleic acid (DNA) on key genes appears to play a role in this epigenetic transmission.49 Furthermore, in rodents, abuse of the young is associated with an attachment, rather than an avoidance, of the abusive mother, an effect that increases the chances that the infant can continue to obtain food and other support until weaning.50 Moreover, other conditions that affect the rearing process can also affect emotionality in offspring. For example, uncertainty in the food supply for rhesus monkey mothers leads to increased emotionality in offspring and possibly an earlier onset of obesity and diabetes. 51 So far, we have emphasized the important role of the environment and experiences of individuals in the health outcomes, but clearly genetic differences also play an important role. Different alleles of commonly occurring genes determine how individuals will respond to experiences. For example, the short form of the serotonin transporter is associated with a number of conditions such as alcoholism, and individuals who have this allele are more vulnerable to respond to stressful experiences by developing depressive illness.52 In childhood, individuals with an allele of the monoamine oxidase A gene are more vulnerable to abuse in childhood and more likely to themselves become abusers and to show antisocial behaviors compared with individuals with another commonly occurring allele.53 Yet another example is the consequence of having the Val66Met allele of the brainderived neurotrophic factor (BDNF) gene on hippocampal volume, memory, and mood disorders.54-57

The brain as a target of stress The hippocampus One of the ways that stress hormones modulate function within the brain is by changing the structure of neurons.

The hippocampus is one of the most sensitive and malleable regions of the brain, and is also very important in cognitive function.Within the hippocampus, the input from the entorhinal cortex to the dentate gyrus is ramified by the connections between the dentate gyrus and the CA3 pyramidal neurons. One granule neuron innervates, on the average, 12 CA3 neurons, and each CA3 neuron innervates, on the average, 50 other CA3 neurons via axon collaterals, as well as 25 inhibitory cells via other axon collaterals. The net result is a 600-fold amplification of excitation, as well as a 300-fold amplification of inhibition, that provides some degree of control of the system.58 As to why this type of circuitry exists, the dentate gyrus (DG)-CA3 system is believed to play a role in the memory of sequences of events, although long-term storage of memory occurs in other brain regions.59 However, because the DG-CA3 system is so delicately balanced in its function and vulnerability to damage, there is also adaptive structural plasticity, in that new neurons continue to be produced in the dentate gyrus throughout adult life, and CA3 pyramidal cells undergo a reversible remodeling of their dendrites in conditions such as hibernation and chronic stress.58,60,61 The role of this plasticity may be to protect against permanent damage. As a result, the hippocampus undergoes a number of adaptive changes in response to acute and chronic stress. One type of change involves replacement of neurons.The subgranular layer of the dentate gyrus contains cells that have some properties of astrocytes (eg, expression of glial fibrillary acidic protein) and which give rise to granule neurons.62,63 After BrdU administration to label DNA of dividing cells, these newly born cells appear as clusters in the inner part of the granule cell layer, where a substantial number of them will go on to differentiate into granule neurons within as little as 7 days. In the adult rat, 9000 new neurons are born per day, and survive with a half-life of 28 days.64 There are many hormonal, neurochemical, and behavioral modulators of neurogenesis and cell survival in the dentate gyrus including estradiol, insulin-like growth factor (IGF)-1, antidepressants, voluntary exercise, and hippocampal-dependent learning.65-67 With respect to stress, certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in the dentate gyrus, and the mediators of these inhibitory effects include excitatory amino acids acting via N-methyl-D-aspartate (NMDA) receptors and endogenous opioids.68 Another form of structural plasticity is the remodeling of dendrites in the hippocampus. Chronic restraint stress

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State of the art causes retraction and simplification of dendrites in the CA3 region of the hippocampus.58,69 Such dendritic reorganization is found in both dominant and subordinate rats undergoing adaptation of psychosocial stress in the visible burrow system, and it is independent of adrenal size.70 What this result emphasizes is that it is not adrenal size or presumed amount of physiological stress per se that determines dendritic remodeling, but a complex set of other factors that modulate neuronal structure. Indeed, in species of mammals that hibernate, dendritic remodeling is a reversible process, and occurs within hours of the onset of hibernation in European hamsters and ground squirrels, and it is also reversible within hours of wakening of the animals from torpor.60,61,71 This implies that reorganization of the cytoskeleton is taking place rapidly and reversibly, and that changes in dendrite length and branching are not “damage,” but a form of structural plasticity. Regarding the mechanism of structural remodeling, adrenal steroids are important mediators of remodeling of hippocampal neurons during repeated stress, and exogenous adrenal steroids can also cause remodeling in the absence of an external stressor. The role of adrenal steroids involve many interactions with neurochemical systems in the hippocampus, including serotonin, γaminobutyric acid (GABA), and excitatory amino acids.21,58 Probably the most important interactions are those with excitatory amino acids such as glutamate. Excitatory amino acids released by the mossy fiber pathway play a key role in the remodeling of the CA3 region of the hippocampus, and regulation of glutamate release by adrenal steroids may play an important role.58 Among the consequences of restraint stress is the elevation of extracellular glutamate levels, leading to induction of glial glutamate transporters, as well as increased activation of the nuclear transcription factor, phosphoCREB.72 Moreover, 21d chronic restraint stress (CRS) leads to depletion of clear vesicles from mossy fiber terminals and increased expression of presynaptic proteins involved in vesicle release.73-75 Taken together with the fact that vesicles that remain in the mossy fiber terminal are near active synaptic zones and that there are more mitochondria in the terminals of stressed rats, this suggests that CRS increases the release of glutamate.73 Extracellular molecules play a role in remodeling. Neural cell adhesion molecule (NCAM) and its polysialatedNCAM (PSA-NCAM), as well as L1 are expressed in the dentate gyrus and CA3 region, and the expression of both NCAM, L1, and PSA-NCAM are regulated by 21d CRS.76

Tissue plasminogen activator (tPA, see below) is an extracellular protease and signaling molecule that is released with neural activity and is required for chronic stress-induced loss of spines and NMDA receptor subunits on CA1 neurons.77 Within the neuronal cytoskeleton, the remodeling of hippocampal neurons by chronic stress and hibernation alters the acetylation of microtubule subunits that is consistent with a more stable cytoskeleton,78 and alters microtubule associated proteins, including the phosphorylation of a soluble form of tau, which is increased in hibernation and reversed when hibernation is terminated.71 Neurotrophic factors also play a role in dendritic branching and length in that BDNF +/- mice show a less branched dendritic tree and do not show a further reduction of CA3 dendrite length with chronic stress, whereas wild-type mice show reduced dendritic branching (Magarinos and McEwen, unpublished data). However, there is contradictory information thus far concerning whether CRS reduces BDNF mRNA levels, some reporting a decrease79 and other studies reporting no change.80,81 This may reflect the balance of two opposing forces, namely, that stress triggers increased BDNF synthesis to replace depletion of BDNF caused by stress.82 BDNF and corticosteroids appear to oppose each other—with BDNF reversing reduced excitability in hippocampal neurons induced by stress levels of corticosterone.83 Corticotropin-releasing factor (CRF) is a key mediator of many aspects related to stress.84 CRF in the paraventricular nucleus regulates ACTH release from the anterior pituitary gland, whereas CRF in the central amygdala is involved in control of behavioral and autonomic responses to stress, including the release of tPA that is an essential part of stress-induced anxiety and structural plasticity in the medial amygdala.85 CRF in the hippocampus is expressed in a subset of GABA neurons (Cajal-Retzius cells) in the developing hippocampus, and early life stress produces a delayed effect that reduces cognitive function and the number of CA3 neurons, as well as decreased branching of hippocampal pyramidal neurons.86,87 Indeed corticotropin-releasing hormone (CRH) inhibits dendritic branching in hippocampal cultures in vitro.88 Prefrontal cortex and amygdala Repeated stress also causes changes in other brain regions, such as the prefrontal cortex and amygdala. Repeated stress causes dendritic shortening in medial

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prefrontal cortex.89-95 but produces dendritic growth in neurons in amygdala,95 as well as in orbitofrontal cortex.96 Along with many other brain regions, the amygdala and prefrontal cortex also contain adrenal steroid receptors; however, the role of adrenal steroids, excitatory amino acids, and other mediators has not yet been studied in these brain regions. Nevertheless, in the amygdala, there is some evidence regarding mechanism, in that tPA is required for acute stress to activate not only indices of structural plasticity but also to enhance anxiety.97 These effects occur in the medial and central amygdala and not in basolateral amygdala, and the release of CRH acting via CRH1 receptors appears to be responsible.85 Acute stress induces spine synapses in the CA1 region of hippocampus98 and both acute and chronic stress also increases spine synapse formation in amygdala,95-99 but chronic stress decreases it in hippocampus.77 Moreover, chronic stress for 21 days or longer impairs hippocampaldependent cognitive function58 and enhances amygdaladependent unlearned fear and fear conditioning,100 which are consistent with the opposite effects of stress on hippocampal and amygdala structure. Chronic stress also increases aggression between animals living in the same cage, and this is likely to reflect another aspect of hyperactivity of the amygdala.39 Behavioral correlates of remodeling in the prefrontal cortex include impairment in attention set shifting, possibly reflecting structural remodeling in the medial prefrontal cortex.95

frontal cortex and amygdala (Figure 4).104-106 Interestingly, amygdala volume has been reported to increase in the first episode of depression, whereas hippocampal volume is not decreased.107,108 It has been known for some time that stress hormones, such as cortisol, are involved in psychopathology, reflecting emotional arousal and psychic disorganization rather than the specific disorder per se.109 We now know that adrenocortical hormones enter the brain and produce a wide range of effects upon it. In Cushing’s disease, there are depressive symptoms that can be relieved by surgical correction of the hypercortisolemia.110,111 Both major depression and Cushing’s disease are associated with chronic elevation of cortisol that results in gradual loss of minerals from bone and abdominal obesity. In major depressive illness, as well as in Cushing’s disease, the duration of the illness, and not the age of the subjects, predicts a progressive reduction in volume of the hippocampus, determined by structural magnetic resonance imaging.103,112 Moreover, there are a variety of other anxiety-related disorders, such as PTSD113,114 and borderline personality disorder,115 in which atrophy of the hippocampus has been reported, suggesting that this is a common process reflecting chronic imbalance in the activity of adaptive systems, such as the hypothalamo-pituitaryadrenocortical (HPA) axis, but also including endogenous neurotransmitters, such as glutamate. The brain under stress: structural remodeling

Translation to the human brain Much of the impetus for studying the effects of stress on the structure of the human brain has come from the animal studies summarized thus far.Although there is very little evidence regarding the effects of ordinary life stressors on brain structure, there are indications from functional imaging of individuals undergoing ordinary stressors, such as counting backwards, that there are lasting changes in neural activity.101 Moreover, the study of depressive illness and anxiety disorders has also provided some insights. Life events are known to precipitate depressive illness in individuals with certain genetic predispositions.52,102,103 Moreover, brain regions such as the hippocampus, amygdala, and prefrontal cortex show altered patterns of activity in positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), and also demonstrate changes in volume of these structures with recurrent depression: decreased volume of hippocampus and pre-

Prefrontal cortex

Hippocampus atrophy

Atrophy

Amygdala Hippocampus

Amygdala, hypertrophy and later atrophy

Figure 4. Brain regions that are involved in perception and response to stress, and which show structural remodeling as a result of stress.

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State of the art Another important factor in hippocampal volume and function is glucose regulation. Poor glucose regulation is associated with smaller hippocampal volume and poorer memory function in individuals in their 60s and 70s who have “mild cognitive impairment” (MCI),116 and both MCI and type 2, as well as type 1, diabetes are recognized as risk factors for dementia.117-119

Positive affect, self-esteem, and social support Having a positive outlook on life and good self-esteem appear to have long-lasting health consequences,120 and good social support is also a positive influence on the measures of allostatic load.121 Positive affect, assessed by aggregating momentary experiences throughout a working or leisure day, was found to be associated with lower cortisol production and higher heart rate variability (showing higher parasympathetic activity), as well as a lower fibrinogen response to a mental stress test.122 On the other hand, poor self-esteem has been shown to cause recurrent increases in cortisol levels during a repetition of a public speaking challenge in which those individuals with good self-esteem are able to habituate, ie, attenuate their cortisol response after the first speech.123 Furthermore, poor self-esteem and low internal locus of control have been related to a 12% to 13% smaller volume of the hippocampus, as well as higher cortisol levels during a mental arithmetic stressor.124,125 Related to both positive affect and self-esteem is the role of friends and social interactions in maintaining a healthy outlook on life. Loneliness, often found in people with low self-esteem, has been associated with larger cortisol responses to wakening in the morning and higher fibrinogen and natural killer cell responses to a mental stress test, as well as sleep problems.126 On the other hand, having three or more regular social contacts, as opposed to zero to two such contacts, is associated with lower allostatic load scores.121

Conclusions: what can one do about being stressed out? If being stressed out has such pervasive effects on the brain as well as the body, what are the ways that individuals, as well as policymakers in government and business, can act to reduce the negative effects and enhance the ability of the body and brain to deal with stress with min-

imal consequences? The answers are simple and obvious, but often difficult to achieve. From the standpoint of the individual, a major goal should be to try to improve sleep quality and quantity, have good social support and a positive outlook on life, maintain a healthy diet, avoid smoking, and have regular moderate physical activity. Concerning physical activity, it is not necessary to become an extreme athlete, and seemingly almost any amount of moderate physical activity helps.127,128 Regarding self-esteem, although this is still early in the story, efforts to build self-esteem in individuals might have long-term benefits for physical as well as mental health. From the standpoint of policy, the goal should be to create incentives at home and in work situations and build community services and opportunities that encourage the development of the beneficial individual lifestyle practices. As simple as the solutions seem to be, changing behavior and solving problems that cause stress at work and at home is often difficult, and may require professional help on the personal level, or even a change of job or profession. Yet these are important issues because the prevention of later disease is very important for full enjoyment of life, and also to reduce the financial burden on the individual and on society. Nevertheless, many people often lack the proactive, longterm view of themselves and/or feel that they must maintain a stressful lifestyle and, if they deal with these issues at all, they want to treat their problems with “a pill.” Are there any medications to treat being stressed out? In fact, there are many useful pharmaceutical agents: sleeping pills, anxiolytics, β-blockers, and antidepressants are all drugs that are used to counteract some of the problems associated with being stressed out. Likewise, drugs that reduce oxidative stress or inflammation, block cholesterol synthesis or absorption, and treat insulin resistance or chronic pain can help deal with the metabolic and neurologic consequences of being stressed out. All are valuable to some degree, and yet each one has its side effects and limitations that are based in part on the fact that all of the systems that are dysregulated in allostatic overload are also systems that interact with each other and perform normal functions when properly regulated. Because of the nonlinearity of the systems of allostasis, the consequences of any drug treatment may be either to inhibit the beneficial effects of the systems in question or to perturb other systems that interact with it in a direction that

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promotes an unwanted side effect. So the best solution would seem to be not to rely solely on such medications and find ways to change lifestyle in a positive direction. Being able to change lifestyle and associated behavior is not just an individual matter, and might become easier with changes via another level of intervention, namely, policies in government and business. The Acheson Report129 from the United Kingdom in 1998 recognized that no public policy should be enacted without considering the implications for health of all citizens. Thus, basic education, housing, taxation, setting of a minimum wage, and policies and programs addressing occupational health and safety and environmental pollution regulations are all likely to affect health via a myriad of mechanisms. At the same time, providing higher-quality food and making it affordable and accessible in poor as well as affluent neighborhoods is necessary for people to eat better, providing they also learn what types of food to eat. Likewise, making neighborhoods safer and more congenial and supportive130 can improve opportunities for positive social interactions and increased recreational physical activity. However, governmental policies are not the only way to reduce allostatic load. For example, businesses that

encourage healthy lifestyle practices among their employees are likely to gain reduced health insurance costs and possibly a more loyal workforce.131-133 Above all, policymakers and business leaders need to be made aware of their broader issues of improving health and preventing disease and the fact that they make economic sense as well as being “the right thing to do.” Finally, there are programs in existence that combine some of the key elements just described, namely, education, physical activity and social support, along with one other ingredient that is hard to quantify: namely, finding meaning and purpose in life. One such program is the Experience Corps which takes elderly volunteers and trains them as teachers’ assistants for younger children in the neighborhood schools.134 Not only does this program improve the education of the children, it also benefits the elderly volunteers and improves their physical and mental health.135 This program has now been adopted as a key part of a political campaign for the governorship of the state of Maryland.136 One can only hope that politicians and business leaders will listen to and heed the advice of science, which often is reinforcing common sense, in helping to address the pervasive problems of stress in our world. ❏

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State of the art Efectos protectors y dañinos de los mediatores del estrés: papel central del cerebro La mente se extiende a todo el cuerpo y a la comunicación bilateral entre el cerebro y los aparatos cardiovascular, sistema inmunitario y otros a través de mecanismos neurales y endocrinos. El estrés es un estado de interacción entre la mente y el cuerpo e interviene en la expresión diferente de la enfermedad entre las personas. No son únicamente los sucesos estresantes más llamativos los que cuestan más, sino más bien los múltiples episodios de la vida cotidiana que elevan y sostienen la actividad de los sistemas fisiológicos y determinan una privación del sueño, sobrealimentación y otras conductas dañinas para la salud que producen una sensación de “agotamiento por estrés”. Con el tiempo, el organismo desgasta por la llamada “carga alostática”, que refleja no sólo el impacto de las experiencias vitales sino también de la carga genética, de los hábitos personales de vida —que traducen aspectos como la alimentación, el ejercicio y el abuso de sustancias— y de las experiencias del desarrollo que fijan los patrones duraderos de conducta y reactividad fisiológica. Las hormonas asociadas al estrés y a la carga alostática protegen el organismo a corto plazo y fomentan la adaptación a través de un proceso llamado alostasia pero, a la larga, la carga alostásica determina cambios corporales que pueden causar enfermedades. El cerebro es el órgano destinatario del estrés, la alostasia y la carga alostática, porque decide qué información resulta amenazadora y, en consecuencia, estresante y determina, además, las respuestas fisiológicas y conductuales. Las regiones cerebrales, como el hipocampo, la amígdala (núcleo amigdalino) y la corteza prefrontal, responden al estrés agudo y crónico sometiéndose a una remodelación estructural que modifica las respuestas comportamentalesl y fisiológicas. Los estudios translacionales de imágenes estructurales y funcionales de seres humanos revelan un volumen hipocámpico más reducido en los estados de estrés, por ejemplo una ligera alteración cognitiva con el envejecimiento y el trastorno depresivo mayor prolongado, así como entre las personas que se subestiman. Se han descrito también alteraciones de la amígdala y de la corteza prefrontal. Además del enfoque farmacéutico, las medidas para aliviar el estrés crónico y reducir la carga alostásica así como la incidencia de las enfermedades de la vida moderna se basan en cambios en los hábitos de vida y políticas gubernamentales y empresariales para mejorar la capacidad del individuo y reducir la carga propia y crónica del estrés.

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Effets protecteurs et délétères des médiateurs du stress : rôle central du cerveau L’esprit implique le corps entier, et il existe une intercommunication entre le cerveau, les systèmes cardiovasculaire, immunitaire et d’autres, par des mécanismes neuraux et endocriniens. Le stress est la manifestation d’une interaction entre l’esprit et le corps et un facteur d’expression de maladies qui diffère selon les individus. Les événements de la vie quotidienne, plus que les stress aigus ou intenses de la vie, élèvent et entretiennent les niveaux d’activité des systèmes physiologiques, entraînant privation de sommeil, boulimie et autres comportements néfastes pour la santé qui donnent le sentiment d’être « dépassé par les événements ». Avec le temps, ceci entraîne une usure du corps appelée « charge allostatique », qui reflète non seulement l’impact des expériences de la vie mais aussi la charge génétique, les habitudes de vie quotidienne comme le régime, l’exercice, l’usage de drogues et le vécu au cours du développement qui mettent en place tout au long de la vie des schémas de comportement et de réactivité physiologique. Les hormones associées au stress et à la charge allostatique protègent le corps à court terme et favorisent l’adaptation par un procédé nommé allostase mais à long terme, les modifications somatiques dues à la charge allostatique peuvent entraîner l’apparition d’une maladie. Le cerveau est l’organe clé du stress, de l’allostase et de la charge allostatique car il détermine ce qui est menaçant et donc stressant ainsi que les réponses physiologiques et comportementales. Les régions cérébrales comme l’hippocampe, l’amygdale et le cortex préfrontal répondent au stress aigu et chronique par un remodelage structural qui modifie les réponses physiologiques et comportementales. Des études réalisées chez l’homme par imagerie structurale et fonctionnelle montrent que le volume de l’hippocampe est diminué dans des situations de stress comme il l’est dans les déficits cognitifs légers dus à l’âge, les dépressions majeures prolongées et les individus qui se sous-estiment. Des altérations de l’amygdale et du cortex préfrontal sont aussi rapportées. Outre les traitements pharmacologiques, les modifications du mode de vie, les politiques gouvernementales et de travail pouvant améliorer la capacité individuelle à réduire la charge de stress chronique de chacun, sont autant d’approches visant à alléger le stress chronique et réduire la charge allostatique et l’incidence des maladies liées à la vie moderne.

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Basic research The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress Sean M. Smith, PhD; Wylie W. Vale, PhD

S

Animals respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Corticotropinreleasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, CRF initiates a cascade of events that culminate in the release of glucocorticoids from the adrenal cortex. As a result of the great number of physiological and behavioral effects exerted by glucocorticoids, several mechanisms have evolved to control HPA axis activation and integrate the stress response. Glucocorticoid feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release. In addition to glucocorticoid feedback, the HPA axis is regulated at the level of the hypothalamus by a diverse group of afferent projections from limbic, midbrain, and brain stem nuclei. The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenomedullary circuits, and parasympathetic systems. In summary, the aim of this review is to discuss the role of the HPA axis in the integration of adaptive responses to stress. We also identify and briefly describe the major neuronal and endocrine systems that contribute to the regulation of the HPA axis and the maintenance of homeostasis in the face of aversive stimuli. © 2006, LLS SAS

Copyright © 2006 LLS SAS. All rights reserved


tress is commonly defined as a state of real or perceived threat to homeostasis. Maintenance of homeostasis in the presence of aversive stimuli (stressors) requires activation of a complex range of responses involving the endocrine, nervous, and immune systems, collectively known as the stress response.1,2 Activation of the stress response initiates a number of behavioral and physiological changes that improve an individual’s chance of survival when faced with homeostatic challenges. Behavioral effects of the stress response include increased awareness, improved cognition, euphoria, and enhanced analgesia.1,3 Physiological adaptations initiated by activation of this system include increased cardiovascular tone, respiratory rate, and intermediate metabolism, along with inhibition of general vegetative functions such as feeding, digestion, growth, reproduction, and immunity.4,5 Due to the wide array of physiologic and potentially pathogenic effects of the stress response, a number of neuronal and endocrine systems function to tightly regulate this adaptive process.

Anatomy of the stress response The anatomical structures that mediate the stress response are found in both the central nervous system and peripheral tissues. The principal effectors of the stress response are localized in the paraventricular Keywords: stress; corticotropin-releasing factor; adrenocorticotropic hormone; glucocorticoid; hypothalamus; pituitary gland; adrenal gland Author affiliations: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, Calif, USA Address for correspondence: Wylie W. Vale, PhD, Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA (e-mail: [email protected])

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Basic research Selected abbreviations and acronyms ACTH BNST cAMP CeA CNS CRF DMH GR HPA LC LS MeA NTS POA PVN SFO

The CRF family of peptides

adrenocorticotropic hormone bed nucleus of stria terminalis cyclic adenosine monophosphate central nuclei of amygdala central nervous system corticotropin-releasing factor dorsomedial hypothalamic nucleus glucocorticoid receptor hypothalamic-pituitary-adrenal locus coeruleus lateral septum medial nuclei of the amygdala nucleus of solitary tract preoptic area paraventricular nucleus subfornical organ

Corticotropin-releasing factor is a 41 amino acid peptide that was originally isolated from ovine hypothalamic tissue in 1981.8 Since this initial identification, CRF has been shown to be the primary regulator of ACTH release from anterior pituitary corticotropes9 and has also been implicated in the regulation of the autonomic nervous system, learning and memory, feeding, and reproductionrelated behaviors.13-19 CRF is widely expressed through-

Hypothalamus

PVN

PVN

III

AVP

AVP

CRF

nucleus (PVN) of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland. This collection of structures is commonly referred to as the hypothalamic-pituitary-adrenal (HPA) axis (Figure 1). In addition to the HPA axis, several other structures play important roles in the regulation of adaptive responses to stress. These include brain stem noradrenergic neurons, sympathetic andrenomedullary circuits, and parasympathetic systems.5-7

CRF Portal system

Pituitary

Anterior lobe CRFR1 cAMP IP , DAG V1B 3

ACTH MC2-R

cA M P

MP cA

Adrenal

MC2-R

The HPA axis Hypophysiotropic neurons localized in the medial parvocellular subdivision of the PVN synthesize and secrete corticotropin-releasing factor (CRF), the principle regulator of the HPA axis.8,9 In response to stress, CRF is released into hypophysial portal vessels that access the anterior pituitary gland. Binding of CRF to its receptor on pituitary corticotropes induces the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. The principal target for circulating ACTH is the adrenal cortex, where it stimulates glucocorticoid synthesis and secretion from the zona fasciculata. Glucocorticoids are the downstream effectors of the HPA axis and regulate physiological changes through ubiquitously distributed intracellular receptors.10,11 The biological effects of glucocorticoids are usually adaptive; however, inadequate or excessive activation of the HPA axis may contribute to the development of pathologies.10,12

Glucocorticoids

Figure 1. Schematic representation of the hypothalamic-pituitaryadrenal (HPA) axis. Hypophysiotropic neurons localized in the paraventricular nucleus (PVN) of the hypothalamus synthesize corticotropin-releasing factor (CRF) and vasopressin (AVP). In response to stress, CRF is released into hypophysial portal vessels that access the anterior pituitary gland. Binding of CRF to the CRF type 1 receptor (CRFR1) on pituitary corticotropes activates cyclic adenosine monophosphate (cAMP) pathway events that induce the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. In the presence of CRF, AVP elicits synergistic effects on ACTH release that are mediated through the vasopressin V1b receptor. Circulating ACTH binds to the melanocortin type 2 receptor (MC2-R) in the adrenal cortex where it stimulates glucocorticoid synthesis and secretion into the systemic circulation. Glucocorticoids regulate physiological events and inhibit further HPA axis activation (red lines) through intracellular receptors that are widely distributed throughout the brain and peripheral tissues. IP3, inositol triphosphate; DAG, diacylglycerol

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The HPA axis and stress - Smith and Vale

out the central nervous system (CNS) and in a number of peripheral tissues. In the brain, CRF is concentrated in the medial parvocellular subdivision of the PVN and is also localized in the olfactory bulb, bed nucleus of the stria terminalis (BNST), medial preoptic area, lateral hypothalamus, central nucleus of the amygdala, Barington’s nucleus, dorsal motor complex, and inferior olive.20 In the periphery, CRF has been detected in the adrenal gland, testis, placenta, gastrointestinal tract, thymus, and skin.21-23 Three additional members of the CRF peptide family have recently been identified.These include urocortin (Ucn) 124 and the recently cloned Ucn 225 and Ucn 3,26 which are also known as stresscopin-related peptide and stresscopin,27 respectively. In the mammalian brain, Ucn 1 is predominantly expressed in the Edinger-Westphal nucleus24 and Ucn 2 expression is restricted to the PVN and locus coeruleus.25 Ucn 3 has a wider distribution in the brain and is localized in the perifornical area of the hypothalamus, BNST, lateral septum (LS), and amygdala.28 The widespread anatomical distribution of CRF and the urocortins correlates well with the diverse array of physiological functions associated with this peptide family. CRF receptors The physiological actions of the CRF family of peptides are mediated through two distinct receptor subtypes belonging to the class B family of G-protein coupled receptors.29 The CRF type 1 receptor (CRFR1) gene encodes one functional variant (α) in humans and rodents along with several nonfunctional splice variants.30-32 The CRF type 2 receptor (CRFR2) has three functional splice variants in human (α, β, and γ) and two in rodents (α and β) resulting from the use of alternate 5’ starting exons.33,34 CRFR1 is expressed at high levels in the brain and pituitary and low levels in peripheral tissues. The highest levels of CRFR1 expression are found in the anterior pituitary, olfactory bulb, cerebral cortex, hippocampus, and cerebellum. In peripheral tissues, low levels of CRFR1 are found in the adrenal gland, testis, and ovary.35,36 In contrast, CRFR2 is highly expressed in peripheral tissues and localized in a limited number of nuclei in the brain.37 In rodents, the CRF type 2α splice variant is preferentially expressed in the mammalian brain and is localized in the lateral septum, BNST, ventral medial hypothalamus, and mesencephalic raphe nuclei.36 The CRF type 2β

variant is expressed in the periphery and is concentrated in the heart, skeletal muscle, skin, and the gastrointestinal tract.29,38,39 Radioligand binding and functional assays have revealed that CRFR1 and CRFR2 have different pharmacological profiles. CRF binds to the CRFR1 with higher affinity than to CRFR2.29,33 Ucn1 has high affinity for both CRFR1 and CRFR2 and is more potent than CRF on CRFR2.24,33 Ucn 2 and Ucn 3 are highly selective for CRFR2 and exhibit low affinities for CRFR1. In addition, Ucn 2 and Ucn 3 minimally induce cyclic adenosine monophosphate (cAMP) production in cells expressing either endogenous or transfected CRFR1.25-27 The neuroendocrine properties of CRF are mediated through CRFR1 in the anterior pituitary. Binding of CRF to the type 1 receptor results in the stimulation of adenylate cyclase and a subsequent activation of cAMP pathway events that culminate with the release of ACTH from pituitary corticotropes.29,39,40 The integral role of CRFR1 in the regulation of ACTH release was confirmed by the phenotype of CRFR1-deficient mice. Mice deficient for CRFR1 have a severely attenuated HPA response to stress and display decreased anxietylike behaviors.41,42 The role of CRFR2 in the regulation of the HPA axis and adaptive responses to stress is less clear. Mice deficient for CRFR2 have an amplified HPA response to stress and display increased anxiety-like behaviors.43-45 However, administration of CRFR2 agonists and antagonists into discrete brain regions reveal both anxiolytic and anxiogenic roles for CRFR2.45 Vasopressin Vasopressin (AVP) is a nonapeptide that is highly expressed in the PVN, supraoptic (SON), and suprachiasmatic nuclei of the hypothalamus.46,47 Magnocellular neurons of the PVN and SON project to the posterior lobe of the pituitary and release AVP directly into the systemic circulation to regulate osmotic homeostasis.48,49 In addition to magnocellular neurons, parvocellular neurons of the PVN synthesize and release AVP into the portal circulation, where this peptide potentiates the effects of CRF on ACTH release from the anterior pituitary.7,50,51 The synergistic effects of AVP on ACTH release are mediated through the vasopressin V1b (also known as V3) receptor on pituitary corticotropes.52 Binding of AVP to

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Basic research the V1b receptor activates phospholipase C by coupling to Gq proteins. Activation of the phospholipase C stimulates protein kinase C, resulting in the potentiation of ACTH release.53 Several investigators have reported that the expression of AVP in parvocellular neurons of the PVN and V1b receptor density in pituitary corticotropes is significantly increased in response to chronic stress.54-58 These findings support the hypothesis that AVP plays an important role in the stress response by maintaining ACTH responsiveness to novel stressors during periods of chronic stress. Adrenocorticotropic hormone Pro-opiomelanocortin (POMC) is a prohormone that is highly expressed in the pituitary and the hypothalamus. POMC is processed into a number of bioactive peptides including ACTH, β-endorphin, β-lipotropic hormone, and the melanocortins.59-61 In response to CRF, ACTH is released from pituitary corticotropes into the systemic circulation where it binds to its specific receptor in the adrenal cortex. ACTH binds to the melanocortin type 2 receptor (MC2-R) in parenchymal cells of the adrenocortical zona fasciculata. Activation of the MC2-R induces stimulation of cAMP pathway events that induce steroidogenesis and the secretion of glucorticoids, mineralcorticoids, and androgenic steroids.62,63 Specifically, ACTH promotes the conversion of cholesterol into δ-5 pregnenolone during the initial step of glucocorticoid biosynthesis.61,64 Glucocorticoids Glucocorticoids, cortisol in humans and corticosterone in rodents, are a major subclass of steroid hormones that regulate metabolic, cardiovascular, immune, and behavioral processes.3,4 The physiological effects of glucocorticoids are mediated by a 94kD cytosolic protein, the glucocorticoid receptor (GR). The GR is widely distributed throughout the brain and peripheral tissues. In the inactive state, the GR is part of a multiprotein complex consisting of several different molecules of heat shock proteins (HSP) that undergo repeated cycles of dissociation and ATP-dependent reassociation.11,65,66 Ligand binding induces a conformational change in the GR, resulting in the dissociation of the receptor from the HSP complex and translocation into the nucleus. Following translocation, the GR homodimer binds to specific DNA motifs

termed glucocorticoid response elements (GREs) in the promoter region of glucocorticoid responsive genes and regulates expression through interaction with transcription factors.11,67,68 The GR has also been shown to regulate activation of target genes independent of GRE-binding through direct protein-protein interactions with transcription factors including activating protein 1 (AP-1) and nuclear factor-κB (NF-κB).69-71

Endocrine regulation of the HPA axis Activation of the HPA axis is a tightly controlled process that involves a wide array of neuronal and endocrine systems. Glucocorticoids play a prominent role in regulating the magnitude and duration of HPA axis activation.72 Following exposure to stress, elevated levels of circulating glucocorticoids inhibit HPA activity at the level of the hypothalamus and pituitary. The HPA axis is also subject to glucocorticoid independent regulation. The neuroendocrine effects of CRF are also modulated by CRF binding proteins that are found at high levels in the systemic circulation and in the pituitary gland.73,74 Glucocorticoid negative feedback The HPA axis is subject to feedback inhibition from circulating glucocorticoids.72 Glucocorticoids modulate the HPA axis through at least two distinct mechanisms of negative feedback. Glucocorticoids have traditionally been thought to inhibit activation of the HPA axis through a delayed feedback system that is responsive to glucocorticoid levels and involves genomic alterations. There is increasing evidence for an additional fast nongenomic feedback system that is sensitive to the rate of glucocorticoid secretion; however, the exact mechanism that mediates rapid feedback effects has not yet been characterized.11,72,75 The delayed feedback system acts via transcriptional alterations and is regulated by GR localized in a number of stress-responsive brain regions.76 Following binding of glucocorticoids, GRs modulate transcription of HPA components by binding to GREs or through interactions with transcription factors.11,72 Glucocorticoids have a low nanomolar affinity for the GR and extensively occupy GRs during periods of elevated glucocorticoid secretion that occur following stress.77 Mineralocorticoid receptors (MRs) have a subnanomolar affinity for glucocorticoids, a restricted expression pattern in the brain, and bind glu-

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cocorticoids during periods of basal secretion.76,77 The distinctive pharmacologies of these two receptors suggest that MRs regulate basal HPA tone while GRs mediate glucocorticoid negative feedback following stress.75,78,79 GRs are widely expressed in the brain, and thus the precise anatomical locus of glucocorticoid negative feedback remains poorly defined. However, two regions of the brain appear to be key sites for glucocorticoid feedback inhibition of the HPA axis. High levels of GR are expressed in hypophysiotropic neurons of the PVN, and local administration of glucocorticoids reduce PVN neuronal activity and attenuate adrenalectomy-induced ACTH hypersecretion.80-83 These findings suggest that the PVN is an important site for glucocorticoid feedback inhibition of the HPA axis. The hippocampus has been implicated as a second site for glucocorticoid negative feedback regulation of the HPA axis. The hippocampus contains a high concentration of both GR and MR, and infusion of glucocorticoids into this strructure reduces basal and stress induced glucocorticoid release.84-86 CRF binding proteins Two soluble proteins have been identified that bind the members of the CRF family of peptides with high affinity. The CRF binding protein (CRF-BP) is a highly conserved 37kD glycoprotein that binds both CRF and Ucn 1 with high affinity.74,87,88 The CRF-BP was originally identified in maternal plasma where it functions to inhibit HPA axis activation stemming from the elevated circulating levels of placenta-derived CRF.89,90 The CRF-BP is highly expressed in the pituitary, and recombinant CRF-BP attenuates CRF-induced ACTH release from dispersed anterior pituitary cells in culture.74 These findings suggest the CRF-BP may function to sequester CRF at the level of the pituitary and reduce CRFR activity. Our laboratory has recently identified a transcript that encodes a soluble splice variant of the CRFR2 receptor (sCRFR2α) in the mouse brain.73 Soluble CRFR2α is a predicted 143 amino acid protein generated from a predicted 143 amino acid protein generated from exons 3-5 of the extracellular domain of CRFR2움 gene and a unique 38 amino acid hydrophilic C-terminal tail. High levels of sCRFR2α expression are found in the olfactory bulb, cortex, and midbrain regions that have been shown to express CRFR1.36 Recombinant sCRFR2α binds CRF with low

nanomolar affinity and inhibits cellular responses to both CRF and Ucn 1 in signal transduction assays,73 suggesting that sCRFR2α may function as a decoy receptor for the CRF family of peptides.

Neuronal regulation of the HPA axis Hypophysiotropic neurons in the PVN are innervated by a diverse constellation of afferent projections from multiple brain regions. The majority of afferent inputs to the PVN originate from four distinct regions: brain stem neurons, cell groups of the lamina terminalis, extra-PVN hypothalamic nuclei, and forebrain limbic structures.20,91 These cell groups integrate and relay information regarding a wide array of sensory modalities to influence CRF expression and release from hypophysiotropic neurons of the PVN (Figure 2). Brain stem neurons Brain stem catecholaminergic centers play an important role in the regulation of the HPA axis. Neurons of the nucleus of the solitary tract (NTS) relay sensory information to the PVN from cranial nerves that innervate large areas of thoracic and abdominal viscera. The NTS also receives projections from limbic structures that regulate behavioral responses to stress including the medial prefrontal cortex and the central nucleus of the amygdala.92 Accordingly, neuronal populations in the NTS are activated following lipopolysaccharide injection,93,94 hypotension,95 forced swim, and immobilization stress paradigms.96 Stress-receptive neurons in the A2/C2 region of the NTS densely innervate the medial parvocellular subdivision of the PVN.97,98 Findings from both in vivo and in vitro studies demonstrate that catecholaminergic input represents a major excitatory drive on the HPA axis and induces CRF expression and protein release through an α-1 adrenergic receptor-dependent mechanism.99-101 Nonaminergic NTS neurons also innervate the PVN and contribute to HPA axis regulation. Glucagon-like peptide 1 containing neurons in the NTS are activated by physiological stressors and have been shown to induce ACTH release in vivo.102,103 The neuropeptides somatostatin, substance P, and enkephalin are also expressed in NTS neurons that innervate the PVN and have been shown to have regulatory effects on the HPA axis.104-106

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Basic research The lamina terminalis

Hypothalamus

A series of interconnected cell groups including the subfornical organ (SFO), median preoptic nucleus (MePO), and the vascular organ of the lamina terminalis are localized on the rostral border of the third ventricle and make up the lamina terminalis.107 Cell groups of the lamina terminalis lie outside of the blood-brain barrier and relay information concerning the osmotic composition of blood to the PVN.108 The medial parvocellular subdivision of the PVN receives rich innervation from the SFO and to a lesser extent from the OVLT and MePO.109 Neurons in the SFO that project to the PVN are angiotensinergic, and promote CRF secretion and biosynthesis.110,111 This afferent pathway has parallel input to the magnocellular division of the PVN, and had been hypothesized to serve as a link between HPA and neurohypophysial activation.112-114

The medial parvocellular subdivision of the PVN receives afferent projections from γ-aminobutyric acid (GABA)-ergic neurons of the hypothalamus.115 Hypophysiotropic neurons of the PVN express GABAA receptor subunits116 and hypothalamic injection of the GABA-A receptor agonists inhibit glucocorticoid secretion following exposure to stressors.117,118 These studies suggest that GABA plays a prominent role in hypothalamic stress integration. Hypothalamus: DMH and POA GABAergic neurons in the dorsomedial hypothalamic nucleus (DMH) and preoptic area (POA) project to the medial parvocellular division of the PVN, and are activated following exposure to stressors.115,117 Lesions of

Humoral Visceral Limbic (Glu)

Psychological

SFO

(Ang, Glu)

BNST (GABA)

NTS (NE, GLP-1)

PVN CRF

Endocrine

HYPO (GABA)

C1 (Epi) PIT

ACTH

Figure 2. Depiction of the major brain regions and neurotransmitter groups that supply afferent innervation to the medial parvocellular zone of the paraventricular nucleus (PVN). Cell groups of the nucleus of the solitary tract (NTS) and ventral medulla (C1) relay visceral information to the PVN though noradrenergic (NE), adrenergic (Epi), and glucagon-like peptide 1 (GLP-1)containing neurons. Hypothalamic nuclei (HYPO) encode information from endocrine systems and send mainly γ-aminobutyric acid (GABA)-ergic (GABA) projections to the PVN. Cell groups of the lamina terminalis relay information concerning the osmotic composition of blood to the PVN through glutamatergic (Glu) and angiotensinergic (Ang) neurons. Limbic structures including the hippocampus, prefrontal cortex, and the amygdala contribute to the regulation of PVN neurons through intermediary neurons of the bed nucleus of the stria terminalis (BNST). PIT, pituitary Adapted from reference 20: Sawchenko PE, Imaki T, Potter E, Kovacs K, Imaki J, Vale W. The functional neuroanatomy of corticotropin-releasing factor. Ciba Found Symp. 1993;172:5-21; discussion 21-29. Copyright © John Wiley and Sons 1993.

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hypothalamic regions encompassing the DMH and the POA amplify HPA responses to stress.119,120 Furthermore, glutamate microstimulation of DMH neurons produces inhibitory postsynaptic potentials in hypophysiotropic neurons of the PVN,121 and stimulation of the POA attenuates the excitatory effects of medial amygdalar stimulation of glucocorticoid release.122 The POA is a potential site of integration between gonadal steroids and the HPA axis. Accordingly, neurons of the POA are activated by gonadal steroids and express high levels of androgen, estrogen, and progesterone receptors.123,124 Hypothalamus: feeding centers Hypothalamic centers involved in the regulation of energy homeostasis directly innervate PVN neurons. Neurons in the arcuate nucleus are sensitive to circulating levels of glucose, insulin, and leptin These cells also synthesize neuropeptide Y (NPY), agouti-related peptide (AGRP), αmelanocyte stimulating hormone (αMSH), and cocaineand amphetamine-regulated transcript (CART) which play critical roles in the regulation of feeding behaviors.125-127 In addition to their roles in energy homeostasis, arcuate neuropeptides have significant effects on HPA axis activity. Central injection of the orexigenic factor NPY results in HPA axis activation128,129 and infusion of AGRP significantly increases CRF release from hypothalamic explants.130 The anorectic peptides αMSH and CART have been reported to increase circulating levels of ACTH and corticosterone,130-132 induce cAMP binding protein phosphorylation in CRF neurons,133 and stimulate CRF release from hypothalamic neurons.130,134 These studies suggest that the HPA axis is activated in response to positive and negative states of energy balance. The limbic system Limbic structures of the forebrain contribute to the regulation of the HPA axis. Neuronal populations in the hippocampus, prefrontal cortex, and amygdala are the anatomical substrates for memory formation and emotional responses, and may serve as a link between the stress system and neuropsychiatric disorders.86,135 The hippocampus, prefrontal cortex, and amygdala have significant effects on glucocorticoid release and behavioral responses to stress.84,136,137 However, these limbic structures have a limited number of direct connections with hypophysiotropic neurons of the PVN and are thought

to regulate HPA axis activity through intermediary neurons in the BNST, hypothalamus, and brain stem.20,138,139 Limbic system: hippocampus The hippocampus plays an important role in the terminating HPA axis responses to stress.84,139 Stimulation of hippocampal neurons decreases neuronal activity in the parvocellular division of the PVN and inhibits glucocorticoid secretion.140-142 Hippocampal lesions produce elevated basal levels of circulating glucocorticoids,143,144 increase parvocellular CRF and AVP expression,145 and prolong ACTH and corticosterone release in response to stress.141,146 The regulatory effects of the hippocampus on the HPA axis are mediated through a multisynaptic pathway and appear to be stressor-specific.139 Hippocampal outflow to the hypothalamus originates in the ventricle subiculum and CA1 regions of the hippocampus.139,147 These regions send afferent projections to GABAergic neurons of BNST and the peri-PVN region of the hypothalamus that directly innervate the parvocellular division of the PVN.139,147,148 Hippocampal lesions encompassing the ventral subiculum produce exaggerated HPA responses to restraint and open field exposure, but not to hypoxia or ether exposure, suggesting that hippocampal neurons respond to distinct stress modalities.146,149,150 Limbic system: prefrontal cortex The prefrontal cortex also regulates HPA responses to stress. Neurons of the medial prefrontal cortex are activated and release catecholamines following exposure to acute and chronic stressors.117,151,152 Bilateral lesions of the anterior cingulate and prelimbic cortex increase ACTH and glucocorticoid responses to stress,85,153 demonstrating that the prefrontal cortex has inhibitory effects on the HPA axis. Anatomic tracing studies reveal that the there is an intricate topographic organization of prefrontal cortex output to HPA regulatory circuits. Afferents from the infralimbic cortex project extensively to the BNST, amygdala, and the NTS.154,155 In contrast, the prelimbic/anterior cingulate cortex projects to the POA and the DMH but fails to synapse with the BNST, NTS, or amygdalar neurons.139,154,155 The prefrontal cortex may also play a role in glucocorticoid feedback inhibition of the HPA axis. High densities of GR are expressed in layers II, III, and VI of the

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Basic research prefrontal cortex.156 Infusion of glucocorticoids into the medial prefrontal cortex attenuates ACTH and corticosterone responses to restraint stress, but has no significant effect on HPA responses to ether.85,157 Similarly to the hippocampus, it appears that neurons of the prefrontal cortex are subject to modality-specific regulation of glucocorticoid feedback inhibition of the HPA axis.139 Limbic system: amygdala In contrast to the hippocampus and the prefrontal cortex, the amygdala is thought to activate the HPA axis. Stimulation of amygdalar neurons promotes glucocorticoid synthesis and release into the systemic circulation.158,159 The medial (MeA) and central (CeA) nuclei of the amygdala play a key role in HPA axis activity and contribute the majority of afferent projections from the amygdala to cortical, midbrain, and brain stem regions that regulate adaptive responses to stress.160,161 The MeA and CeA respond to distinct stress modalities and are thought to have divergent roles in HPA regulation.139 Neurons in the MeA are activated following exposure to “emotional” stressors including predator, forced swim, social interaction, and restraint stress paradigms.117,162-165 In contrast, the CeA appears to be preferentially activated by “physiological” stressors, including hemorrhage and immune challenge.166,167 The CeA exerts its regulatory effects on the HPA axis through intermediary neurons in the brain stem.139 Afferent projections from the CeA densely innervate the NTS and parabrachial nucleus.92,168 The MeA sends a limited number of direct projections to the parvocellular division of the PVN169; however, this subnucleus innervates a number of nuclei that directly innervate the PVN. Neurons of the MeA project to the BNST, MePO, and ventral premammillary nucleus.169 The amygdala is a target for circulating glucocorticoids and the CeA and MeA express both GR and MR. In contrast to the effects on hippocampal and cortical neurons, glucocorticoids increase expression of CRF in the CeA and potentiate autonomic responses to chronic stressors. Glucocorticoid infusion into the CeA does not acutely effect HPA activation but may play a feed-forward role to potentiate HPA responses to stress.139,157,170

Sympathetic circuits and the stress response Activation of brain stem noradrenergic neurons and sympathetic andrenomedullary circuits further contribute to the body’s response to stressful stimuli. Similarly to the HPA axis, stress-evoked activation of these systems promotes the mobilization of resources to compensate for adverse effects of stressful stimuli.3,171 The locus coeruleus (LC) contains the largest cluster of noradrenergic neurons in the brain and innervates large segments of the neuroaxis.172 The LC has been implicated in a wide array of physiological and behavioral functions including emotion, vigilance, memory, and adaptive responses to stress.173-175 A wide array of stressful stimuli activate LC neurons, alter their electrophysiological activity, and induce norepinephrine release.176-178 Stimulation of the LC elicits several stressassociated responses including ACTH release,179 anxiogenic-like behaviors,180 and suppression of immune functions.181 In addition, there are interactions between CRF and NE neurons in the CNS. Central administration of CRF alters activity of LC neurons and NE catabolism in terminal regions.13,182 Finally, dysfunction of catecholamergic neurons in the LC has been implicated in the pathophysiology of affective and stress-related disorders.183,184

Conclusions Maintenance of homeostasis in the presence of real or perceived challenges requires activation of a complex range of responses involving the endocrine, nervous, and immune systems, collectively known as the stress response. Inappropriate regulation of the stress response has been linked to a wide array of pathologies including autoimmune disease, hypertension, affective disorders, and major depression. In this review we briefly discussed the major neuronal and endocrine systems that contribute to maintenance of homeostasis in the presence of stress. Clearly deciphering the role of each of these systems and their regulatory mechanisms may provide new therapeutic targets for treatment and prophylaxis of stress-related disorders including anxiety, feeding, addiction, and energy metabolism. ❏ This work is supported by NIDDK Program Project Grant DK26741 and by the Clayton Medical Research Foundation, Inc. Wylie Vale is a Senior Clayton Medical Research Foundation Investigator.

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Función del eje hipotálamo-hipofisis-suprarenal en las respuestas endocrinas al estrés

Rôle de l’axe hypothalamo-hypophysosurrénalien dans les réponses neuroendocriniennes au stress

Los animales responden al estrés, activando una amplia gama de respuestas comportamentales y fisiológicas que se conocen, de forma genérica, como respuesta al estrés. El factor liberador de corticotropina (CRF) desempeña una misión cardinal en la respuesta al estrés, al regular el eje hipotálamo-hipófisis-suprarrenal (HHS). En respuesta al estrés, el CRF inicia una cascada de acontecimientos que culminan con la liberación de glucocorticoides por la corteza suprarrenal. Como consecuencia del elevado número de efectos fisiológicos y conductuales inducidos por los glucocorticoides, han surgido varios mecanismos para controlar la activación del eje HHS e integrar la respuesta al estrés. La inhibición por retroalimentación de los glucocorticoides contribuye decisivamente a regular la magnitud y la duración de su liberación. Además de esta retroalimentación glucocorticoidea, el eje HHS está regulado en el hipotálamo por un grupo diverso de proyecciones aferente de los núcleos límbicos, mesencefálicos y del tronco cerebral. La respuesta al estrés está mediada también, en parte, por las neuronas noradrenérgicas del tronco cerebral, los circuitos adrenomedulares simpáticos y los sistemas parasimpáticos. En resumen, el objetivo de esta revisión es exponer la importancia del eje HHS en la integración de las respuestas adaptativas al estrés. Asimismo, se señalan y describen brevemente los principales sistemas neuronales y endocrinos que contribuyen a la regulación del eje HHS y al mantenimiento de la homeostasis frente a los estímulos adversos.

Les animaux répondent au stress en activant un large panel de réponses comportementales et physiologiques, collectivement considérés comme constituant la réponse au stress. Le facteur de libération de corticotrophine (CRF) joue un rôle central dans la réponse au stress en régulant l’axe hypothalamohypophyso-surrénalien (HPA). Dans la réponse au stress, le CRF déclenche une cascade d’événements qui aboutissent à la libération de glucocorticoïdes à partir du cortex surrénalien. Etant donné le grand nombre d’effets physiologiques et comportementaux produits par les glucocorticoïdes, plusieurs mécanismes se sont développés afin de contrôler l’activation de l’axe HPA et intégrer les réponses au stress. Le rétrocontrôle inhibiteur des glucocorticoïdes joue un rôle essentiel dans l’ampleur et la la durée de leur libération. En plus de ce rétrocontrôle, l’axe HPA est régulé au niveau hypothalamique par différentes projections afférentes provenant du système limbique, du mésencéphale et des noyaux du tronc cérébral. La réponse au stress est également transmise en partie par les neurones noradrénergiques du tronc cérébral, les circuits sympathiques adrénomédullaires et le système parasympathique. En résumé, cet article a pour but d’examiner le rôle de l’axe HPA dans l’intégration des réponses adaptatives au stress. Nous avons aussi identifié et brièvement décrit les principaux systèmes neuronaux et endocriniens qui participent à la régulation de l’axe HPA et au maintien de l’homéostasie face à des agressions.

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146.Herman JP, Cullinan WE, Morano MI, Akil H, Watson SJ. Contribution of the ventral subiculum to inhibitory regulation of the hypothalamo-pituitary-adrenocortical axis. J Neuroendocrinol. 1995;7:475-482. 147.Cullinan WE, Herman JP, Watson SJ. Ventral subicular interaction with the hypothalamic paraventricular nucleus: evidence for a relay in the bed nucleus of the stria terminalis. J Comp Neurol. 1993;332:1-20. 148.Kohler C. Subicular projections to the hypothalamus and brainstem: some novel aspects revealed in the rat by the anterograde Phaseolus vulgaris leukoagglutinin (PHA-L) tracing method. Prog Brain Res. 1990;83:5969. 149.Herman JP, Dolgas CM, Carlson SL. Ventral subiculum regulates hypothalamo-pituitary-adrenocortical and behavioural responses to cognitive stressors. Neuroscience. 1998;86:449-459. 150.Mueller NK, Dolgas CM, Herman JP. Stressor-selective role of the ventral subiculum in regulation of neuroendocrine stress responses. Endocrinology. 2004;145:3763-378. 151.Finlay JM, Zigmond MJ, Abercrombie ED. Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience. 1995;64:619-628. 152.Jedema HP, Sved AF, Zigmond MJ, Finlay JM. Sensitization of norepinephrine release in medial prefrontal cortex: effect of different chronic stress protocols. Brain Res. 1999;830:211-217. 153.Figueiredo HF, Bruestle A, Bodie B, Dolgas CM, Herman JP. The medial prefrontal cortex differentially regulates stress-induced c-fos expression in the forebrain depending on type of stressor. Eur J Neurosci. 2003;18:23572364. 154.Sesack SR, Deutch AY, Roth RH, Bunney BS. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol. 1989;290:213-242. 155.Hurley KM, Herbert H, Moga MM, Saper CB. Efferent projections of the infralimbic cortex of the rat. J Comp Neurol. 1991;308:249-276. 156.Ahima RS, Harlan RE. Charting of type II glucocorticoid receptor-like immunoreactivity in the rat central nervous system. Neuroscience. 1990;39:579-604. 157.Akana SF, Chu A, Soriano L, Dallman MF. Corticosterone exerts site-specific and state-dependent effects in prefrontal cortex and amygdala on regulation of adrenocorticotropic hormone, insulin and fat depots. J Neuroendocrinol. 2001;13:625-637. 158.Matheson GK, Branch BJ, Taylor AN. Effects of amygdaloid stimulation on pituitary-adrenal activity in conscious cats. Brain Res. 1971;32:151-167. 159.Van de Kar LD, Blair ML. Forebrain pathways mediating stress-induced hormone secretion. Front Neuroendocrinol. 1999;20:1-48. 160.Petrovich GD, Swanson LW. Projections from the lateral part of the central amygdalar nucleus to the postulated fear conditioning circuit. Brain Res. 1997;763:247-54. 161.Dong HW, Petrovich GD, Swanson LW. Topography of projections from amygdala to bed nuclei of the stria terminalis. Brain Res Brain Res Rev. 2001;38:192-246. 162.Cullinan WE, Herman JP, Battaglia DF, Akil H, Watson SJ. Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience. 1995;64:477-505. 163.Kollack-Walker S, Watson SJ, Akil H. Social stress in hamsters: defeat activates specific neurocircuits within the brain. J Neurosci. 1997;17:88428855. 164.Kollack-Walker S, Don C, Watson SJ, Akil H. Differential expression of c-fos mRNA within neurocircuits of male hamsters exposed to acute or chronic defeat. J Neuroendocrinol. 1999;11:547-559.

165.Figueiredo HF, Bodie BL, Tauchi M, Dolgas CM, Herman JP. Stress integration after acute and chronic predator stress: differential activation of central stress circuitry and sensitization of the hypothalamo-pituitaryadrenocortical axis. Endocrinology. 2003;144:5249-5258. 166.Sawchenko PE, Brown ER, Chan RK, et al. The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res. 1996;107:201-222. 167.Thrivikraman KV, Su Y, Plotsky PM. Patterns of fos-immunoreactivity in the CNS induced by repeated hemorrhage in conscious rats: correlations with pituitary-adrenal axis activity. Stress. 1997;2:145-158. 168.van der Kooy D, Koda LY, McGinty JF, Gerfen CR, Bloom FE. The organization of projections from the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat. J Comp Neurol. 1984;224:1-24. 169.Canteras NS, Simerly RB, Swanson LW. Organization of projections from the medial nucleus of the amygdala: a PHAL study in the rat. J Comp Neurol. 1995;360:213-245. 170.Dallman MF, Pecoraro N, Akana SF, et al. Chronic stress and obesity: a new view of comfort food ”. Proc Natl Acad Sci U S A. 2003;100:11696-11701. 171. Sved AF, Cano G, Passerin AM, Rabin BS. The locus coeruleus, Barrington’s nucleus, and neural circuits of stress. Physiol Behav. 2002;77:737-742. 172. Foote SL, Bloom FE, Aston-Jones G. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev. 1983;63:844-914. 173.Aston-Jones G, Ennis M, Pieribone VA, Nickell WT, Shipley MT. The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science. 1986;234:734-737. 174.Aston-Jones G, Shipley MT, Chouvet G, et al. Afferent regulation of locus coeruleus neurons: anatomy, physiology and pharmacology. Prog Brain Res. 1991;88:47-75. 175.Valentino RJ, Curtis AL, Page ME, Pavcovich LA, Florin-Lechner SM. Activation of the locus ceruleus brain noradrenergic system during stress: circuitry, consequences, and regulation. Adv Pharmacol. 1998;42:781-784. 176.Abercrombie ED, Jacobs BL. Single-unit response of noradrenergic neurons in the locus coeruleus of freely moving cats. II. Adaptation to chronically presented stressful stimuli. J Neurosci. 1987;7:2844-288. 177.Passerin AM, Cano G, Rabin BS, Delano BA, Napier JL, Sved AF. Role of locus coeruleus in foot shock-evoked Fos expression in rat brain. Neuroscience. 2000;101:1071-1082. 178.Dayas CV, Buller KM, Crane JW, Xu Y, Day TA. Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci. 2001;14:1143-1152. 179. Ward DG, Grizzle WE, Gann DS. Inhibitory and facilitatory areas of the rostral pons mediating ACTH release in the cat. Endocrinology. 1976;99:1220-1228. 180.Butler PD, Weiss JM, Stout JC, Nemeroff CB. Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus. J Neurosci. 1990;10:176-183. 181.Rassnick S, Sved AF, Rabin BS. Locus coeruleus stimulation by corticotropin-releasing hormone suppresses in vitro cellular immune responses. J Neurosci. 1994;14:6033-6040. 182.Lavicky J, Dunn AJ. Corticotropin-releasing factor stimulates catecholamine release in hypothalamus and prefrontal cortex in freely moving rats as assessed by microdialysis. J Neurochem. 1993;60:602-612. 183.Southwick SM, Bremner JD, Rasmusson A, Morgan CA III, Arnsten A, Charney DS. Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry. 1999;46:1192-1204. 184.Sullivan GM, Coplan JD, Kent JM, Gorman JM. The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias. Biol Psychiatry. 1999;46:1205-1218.

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Basic research Behavioral control, the medial prefrontal cortex, and resilience Steven F. Maier, PhD; Jose Amat, PhD; Michael V. Baratta, MA; Evan Paul, BA; Linda R. Watkins, PhD

T

he experience of traumatic life events is an important factor in the development of a number of clinical conditions, ranging from anxiety disorders such as post-traumatic stress disorder (PTSD) to drug addiction. However, not all individuals who encounter stressful life events develop these disorders, and so there is considerable interest in understanding what makes an individual vulnerable, and what makes an individual resilient to the deleterious effects of traumatic events.1 Genetic factors doubtlessly play a role, but aspects of the stress experience and complex cognitive factors regarding how the individual appraises or views that experience have been argued to be key. In humans, most studies of resilience have included the individual’s perceived self-efficacy,2 perceived ability to cope,3 or actual ability to exert control over the stressor4 as key variables. Furthermore, other factors, such as religious faith5 and sociopolitical effectiveness,3 have been argued to produce resilience because they induce a sense of control. It is difficult to study variables such as these in animals, yet it is in animals that detailed neurobiological mechanisms can be explored. The stressor controllability paradigm, however, is one of the few that allows isolation of this type of process. Here, animals that receive stressors that are physically identical are compared, with one group having behavioral control over an aspect of the stressor (its termination), and the other group having no control. In our version of this paradigm, rats are placed in small boxes with a wheel mounted on the front. The

The degree of control that an organism has over a stressor potently modulates the impact of the stressor, with uncontrollable stressors producing a constellation of outcomes that do not occur if the stressor is behaviorally controllable. It has generally been assumed that this occurs because uncontrollability actively potentiates the effects of stressors. Here it will be suggested that in addition, or instead, the presence of control actively inhibits the impact of stressors. At least in part, this occurs because (i) the presence of control is detected by regions of the ventral medial prefrontal cortex (mPFCv); and (ii) detection of control activates mPFCv output to stress-responsive brain stem and limbic structures that actively inhibit stressinduced activation of these structures. Furthermore, an initial experience with control over stress alters the mPFCv response to subsequent stressors so that mPFCv output is activated even if the subsequent stressor is uncontrollable, thereby making the organism resilient. The general implications of these results for understanding resilience in the face of adversity are discussed. © 2006, LLS SAS

Author affiliations: Department of Psychology and Center for Neuroscience, University of Colorado at Boulder, Colorado, USA


Keywords: stress; learned helplessness; serotonin; medial prefrontal cortex; resilience; anxiety


Address for correspondence: Steven F. Maier, University of Colorado, Department of Psychology, Campus Box 345, Boulder, CO 80309-0345, USA (e-mail: [email protected])

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Basic research Selected abbreviations and acronyms 5-HT CE CS DRN ES IS LC mPFCv mPFC PTSD US

serotonin central nucleus of amygdala conditioned stimulus dorsal raphe nucleus escapable shock inescapable shock locus coeruleus medial prefrontal cortex ventral medial prefrontal cortex post-traumatic stress disorder unconditioned stimulus

rat's tail extends from the rear of the box so that electrodes can be directly fixed to the tail. For one group of rats (“escape”) each of a series of tailshocks terminate when the rat turns the wheel with its paws. Thus, this group has behavioral control over the termination of each tailshock. Each member of a second group (“yoked”) is paired with one of the escape group and simply receives tailshocks of the same durations as determined by its partner; turning the wheel has no consequence. There are other stressors whose sequelae may well be due to the uncontrollability of the stressor (eg, social defeat), but since controllability cannot be readily manipulated in these paradigms, this cannot be determined. Indeed, this is why shock is used in our studies. We know of no other aversive event whose controllability can readily be manipulated in such a way that the subjects with and without control experience identical physical events. Research conducted by numerous laboratories has revealed a constellation of behavioral changes that follow uncontrollable, but not controllable, shocks. Thus, rats exposed to uncontrollable shock later fail to learn to escape shock in a different situation (the so-called “learned helplessness” effect), are inactive in the face of aversive events (so-called “behavioral depression”), become less aggressive and show reduced social dominance, behave anxiously in tests of “anxiety” such as the social interaction test, are neophobic, develop ulcers, respond in exaggerated fashion to drugs of abuse, etc.6 None of these outcomes follow if the organism is able to exert control over the stressor. Prior research has focused on the neural mechanism(s) by which uncontrollable stress (inescapable shock, IS) leads to the above behavioral outcomes. Indeed, this can be said of most stress research in animals, since the stres-

sors that are used (restraint, social defeat, cold water, etc) have almost always been uncontrollable. There has been very little work directed at understanding the mechanism(s) by which control confers protection from the effects of the stressor. Indeed, most experiments studying the neurobiology of stress do not even contain a group for whom the stressor is controllable—the typical comparison is between a group exposed to an uncontrollable stressor and a home cage control group. What is known is that uncontrollable stress produces sequelae that are not produced by physically identical controllable stress. It has been implicitly assumed that this difference occurs because the organism detects/learns/perceives that the uncontrollable stressor is uncontrollable, and that this sets in motion the neural cascade that mediates the behavioral outcomes. The unstated assumption has been that stress per se produces neural consequences that are then magnified by the detection/learning/perception of uncontrollability. That is, it has been assumed that uncontrollability is the “active ingredient.” From this point of view, controllable stressors fail to produce outcomes such as exaggerated anxiety simply because they lack the active uncontrollability element. However, it is also possible that instead the presence of control is the “active ingredient.” Here, the detection/learning/perception of control would inhibit neural responses to stressors. Of course, both could be true. As will become clear, this is not merely a semantic difference. The purposes of the present paper are to review recent work suggesting that the presence of control does actively inhibit limbic and brain stem reactions to a stressor, and the mechanisms whereby this inhibition is achieved. It will be argued that the research that will be described provides insights into mechanisms that produce resilience in the face of adversity.

Serotonin and the dorsal raphe nucleus As noted above, most of the research on stressor controllability has been directed at understanding how uncontrollable stress produces its behavioral outcomes, such as poor escape learning and exaggerated fear/anxiety. Different laboratories have focused on different brain regions and neurotransmitter systems. We have concentrated our efforts on the dorsal raphe nucleus (DRN). The DRN is the largest of the raphe nuclei and provides serotonergic (5-HT) innervation to much of the forebrain, as well as other structures. We originally stud-

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Control, medial prefrontal cortex, and resilience - Maier et al

ied the DRN as a potential critical mediator of the behavioral effects of IS because it projects to structures that are the proximate neural mediators of many of the behavioral sequelae of IS, and elevated 5-HT within these structures seemed to produce the appropriate behaviors. For example, the dorsal periaqueductal gray is a proximate mediator of escape behavior,7 and it is innervated by the DRN. Moreover, stimulation of the DRN interferes with escape.8 Analogous neural arrangements existed for many of the other behavioral consequences of IS, and so it seemed, a priori, as if the known behavioral consequences of IS would occur if IS were to differentially activate DRN 5-HT neurons. The DRN has proved to have a complex subnuclear organization, with different regions of the DRN receiving discrete sets of afferents and having different efferent projections.9 Our work has implicated mid and caudal regions of the DRN as being critical to IS effects. All that needs to be noted here is that this work, as well as recent research from other laboratories,10 has delineated a 5-HT system, projecting to a number of mesolimbic structures, that appears to be important in the mediation of anxiety-like behavior.11 We12 have argued that the changes produced by IS are much more related to anxiety than depression, and so the argument that what is involved is an exaggerated 5-HT response is not problematic. The most relevant findings are the following: (i) IS produces a much greater activation of 5-HT neurons in the mid and caudal DRN than do exactly equal amounts and distributions of escapable tailshock (ES). This has been assessed both by an examination of Fos in 5-HTlabeled cells13 as well as measurement of 5-HT efflux within the DRN14 and projection regions of the DRN15 with in vivo microdialysis; (ii) This intense activation of 5-HT neurons leads to the accumulation of high extracellular levels of 5-HT within the DRN. This high concentration of 5-HT desensitizes/downregulates inhibitory somatodendritic 5-HT1A receptors within the DRN for a number of days16; (iii) 5-HT1A desensitization/downregulation within the DRN sensitizes DRN 5HT neurons since this normal source of tonic inhibition is now reduced. Thus, for a number of days, stimuli that normally produce little or no 5-HT response now induce large 5-HT activation.15 Behavioral testing conditions such as escape training, fear conditioning, etc, now lead to exaggerated 5-HT release in projection regions of the DRN, the proximate cause of the behavioral outcomes. It is known that DRN 5-HT activity is a cause of the

behavioral outcomes of IS because lesion of the DRN17 and selective pharmacological inhibition of 5-HT DRN neurons at the time of behavioral testing18 completely block the behavioral effects of IS. In addition, pharmacological inhibition of DRN 5-HT activity at the time of IS prevents the usual behavioral outcomes of IS from occurring.18 Finally, simply activating DRN 5-HT neurons, in the absence of any IS, produces the same behavioral outcomes as does IS.19 This focus on the DRN is not meant to suggest that other structures are not involved. For example, the work of J. Weiss (eg, ref 20) clearly implicates the locus coeruleus (LC). However, the behavioral effects of IS and other uncontrollable stressors must be mediated by a complex neural circuit, and the DRN is likely but one, albeit critical, part of the circuit. We believe that the DRN is a key integrative site on the efferent end of the circuit and receives inputs from multiple key structures. The LC can be viewed as one of these inputs.21

The medial prefrontal cortex Although the work summarized above clearly implicates the DRN as a key site in the mediation of the behavioral effects of uncontrollable stress, the concept that it must be part of a more extended circuit naturally suggests the question of whether the DRN (or LC) could be the structure that detects/learns/perceives whether a stressor is, or is not, under behavioral control. The DRN is a small brain stem structure consisting of perhaps 30 000 neurons in the rat. Moreover, the DRN does not receive direct somatosensory input. Thus, it would appear to have neither the inputs required, nor the “processing power,” to compute whether a stressor is controllable or uncontrollable. The circuitry that performs this analysis must have available to it information concerning exactly when motor responses occur and when the stressor begins and ends. Further, it must be able to compute the correlation between the two. We thus determined inputs to the DRN that mediate the effects of uncontrollable stress, and uncovered several (locus coeruleus, lateral habenula, and likely the bed nucleus of the stria terminalis [BNST]). However, none were themselves sensitive to stressor controllability—they simply provided excitatory drive to the DRN whenever a stressor was present, controllable or uncontrollable.22 In any case, the detection/computation of degree of control would seem likely to be a cortical function, and so

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Basic research subjects turned the wheel and terminated the tailshocks, but did not benefit from the experience. This is in keeping with data indicating that the mPFC is not involved in the learning of habits or motor responses, but rather in more complex cognitive aspects of behavior. Thus, when the mPFCv was inactivated the animals learned to turn the wheel, but this now did not lead to inhibition of the DRN. The DRN acted as if the stressor was uncontrollable, even though the rats turned the wheel and escaped normally! The foregoing suggests that what is important is whether the mPFCv is activated during a stressor, not whether the stressor is actually controllable or not. To further test this idea, we directly activated the mPFCv during IS and ES. The mPFCv was activated by microinjection of the GABA antagonist picrotoxin, a procedure that has been shown to activate mPFCv output.30 Figure 1 shows the results of shuttlebox escape testing administered 24 hours after the ES and IS sessions, or home cage control treatment. Escape trials terminated automatically after 30 sec if the subject failed to escape on that trial, and so group means near 30 seconds indicate that most of the rats in the group completely failed to escape. In vehicle-injected subjects, IS interfered with later shuttlebox escape and ES did not, as is typical. Dramatically, IS produced no interference with escape at all if the mPFCv was activated during the IS with picrotoxin. These animals did not have a means to control shock during the initial stress

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it is of interest to inquire into which regions of cortex provide monosynaptic inputs to the DRN. Interestingly, the DRN receives all, or virtually all, of its cortical inputs from infralimbic (IL) and prelimbic (PL) regions of the medial prefrontal cortex (mPFC).23 The mPFC is involved with mediating “executive functions”24; functions that are consistent with behavioral control detection. Furthermore, the mPFC has been shown to be a key site in “contingency learning” as opposed to habit formation,25 a process very close to control learning. IL and PL regions, which comprise the ventral mPFC (mPFCv) send excitatory glutamatergic projections to the DRN.26 However, within the DRN these pyramidal glutamatergic projections synapse preferentially onto γaminobutyric acid (GABA)-ergic interneurons that inhibit the 5-HT cells.26 As would be expected from this anatomy, electrical stimulation of regions of the mPFCv that contain output neurons to the DRN leads to inhibition of 5-HT activity within the DRN.27,28 The fact that activation of mPFCv output to the DRN actively inhibits DRN 5-HT activity immediately suggests that if the mPFCv is indeed involved in control/lack of control detection, then perhaps it is really control that is the active ingredient, leading to mPFCv-mediated active inhibition of the DRN when it is present. Here the idea is that aversive stimulation per se drives the DRN, and when the presence of behavioral control is detected by the mPFCv, the DRN, and perhaps other stress-responsive limbic and brain stem structures (see below) are actively inhibited. In our first attempt to test the role of the mPFCv, we inactivated the mPFCv during exposure to IS and ES by microinjecting muscimol into the region.29 Muscimol is a GABA agonist, and so inhibits the activity of cells that express GABA receptors, such as the pyramidal output neurons. Inactivating the mPFCv did indeed eliminate the differential effects of controllability—that is, IS and ES now produced the same outcomes. However, mPFCv inactivation eliminated the IS-ES in a particular way. The presence of control was no longer protective, and now ES as well as IS produced later escape learning failure and exaggerated fear conditioning. Furthermore, ES now activated the DRN to the same degree as did IS. Inactivating the mPFCv did not make IS better or worse; it acted only in ES subjects to eliminate the protective effect of control. It is important to note that muscimol microinjection did not retard the learning of the wheel-turn escape response during ES by the ES subjects. That is, the ES

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Figure 1. Mean latency to escape across blocks of five shuttlebox trials 24 h after experimental treatment. Experimental treatments were escapable shock (ES), yoked inescapable (IS), or home cage control (HC). P, picrotoxin before experimental treatment; V, vehicle

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Behavioral immunization, resilience, and the mPFCv In both humans and animals, an individual’s early or initial experiences with stressors can determine how that individual reacts to subsequent stressful life experiences.31 Many years ago, it was reported that an initial experience with controllable shock blocks the typical behavioral effects of a later exposure to uncontrollable shock, even if the two experiences occur in very different environments.32,33 That is, an initial experience with control seemed to “immunize” the rat subjects. This immunization phenomenon is very different than the usual effects of control that have been studied. In the typical experiment, the presence of control blunts the impact of the stressor that is occurring at that time. However, in the immunization paradigm, an initial experience with control blunts the impact of an uncontrollable stressor occurring at a later period of time. This immunization phenomenon has not been studied at the neurobiological level. Clearly, the initial exposure to controllable stress would activate the mPFCv. It is our hypothesis that there is plasticity in this system so that mPFCv activity becomes associated with or “tied” to the stressor or some aspect of the stress experience such as fear/anxiety (see below). If this were so, then the mPFCv would become activated during the later uncontrollable stressor, thereby inhibiting the DRN and protecting the organism from outcomes that depend on DRN activation. During the past year we have begun to test this admittedly speculative hypothesis. Figure 2 shows the results of an experiment in which rats received either ES, IS, or HC treatment on Day 1, and IS in a different environment 7 days later. Shuttlebox escape testing occurred 24 hours after the Day 8 IS. Either intra-mPFCv muscimol or vehicle microinjection preceded the Day 1 treatment. As is evident, the experience of ES 7 days before IS completely blocked the behavioral effect of IS. That is, behavioral immunization occurred. However, mPFCv inactivation during ES blocked the ability of ES to produce immunization. In a separate experiment, the mPFCv was inactivated at the time of the Day 8 IS rather than during ES on Day 1. This manipulation also blocked immu-

nization (data not shown in the Figure). Thus, mPFCv activity is necessary for immunization, both at the time of the initial experience with control and the later exposure to the uncontrollable stressor for protection to occur. The hypothesis being considered suggests that, as above, it is not control per se that is critical, but rather whether the mPFCv is activated during the initial experience with the aversive event. Thus, we conducted an identical experiment to the one just described, but activated the mPFCv with picrotoxin during the Day 1 stress session. Figure 3 shows the shuttlebox escape latencies. ES, of course, produced immunization. Activating the mPFCv by itself, without the presence of a stressor (P-HC/IS) did not confer protection against the effects of IS. However, the combination of picrotoxin and IS produced immunization. That is, the experience of uncontrollable stress actually protected the organism if the mPFCv was activated during the experience. Finally, if it is true that after an initial experience with control now even IS would activate the mPFCv, then the DRN should be inhibited during IS. Figure 4 shows extracellular levels of 5-HT within the DRN during IS in animals that had received either IS, ES, or HC 7 days earlier. IS produced a large increase in 5-HT as usual, but this effect was virtually eliminated by prior ES. Here, the DRN acted as if the stressor were controllable. This result is analogous to an “illusion of control” at the neuro30 M-ES/IS

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experience, but simply activating the mPFC during the stressor protected them. Importantly, the DRN was now not activated—it responded as if the shock was controllable (these data are not shown).

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Figure 2. Mean latency to escape across blocks of five shuttlebox trials. Day 1 treatments were escapable shock (ES), yoked inescapable (IS), or home cage control (HC). All animals received inescapable shiock (IS) on Day 8. Escape testing occurred on Day 9. M, muscimol before day 1 treatment; V, vehicle

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Basic research chemical level. Clearly, an initial experience with control promotes resilience in the face of later aversive stimulation, and does so by activating the mPFCv.

Fear conditioning and the amygdala To this point we have focused on the interaction between the mPFCv and the DRN, with control leading to protection against the effects of aversive events by increasing mPFCv inhibition of the DRN. However, the mPFCv projects to other stress-responsive structures as well. The amygdala is of special interest in this regard. The amygdala is a key site in the mediation of fear and anxiety. Its role in fear conditioning is well known, and fear conditioning has been argued to be a key process in the development of a number of anxiety disorders.34 The work of numerous investigators has suggested the following scenario (see ref 35 for a review). Inputs from neutral stimuli (the conditioned stimulus [CS], eg, a tone) and aversive stimulation (the unconditioned stimulus [US], eg, a footshock) converge in the lateral amygdala (LA) where the association between the CS and US is formed by an N-methyl-D-aspartate (NMDA)/long-term potentiation (LTP)-dependent process. Expression of conditioned fear involves CS transmission to the LA, connections from the LA to the central nucleus of the amygdala (CE) either directly or indirectly via the basal nucleus, and then output connections from the CE to regions of the

brain that are the proximate mediators of the specific aspects of fear responses (autonomic, endocrine, and behavioral). This is an oversimplified scheme (eg, 36, 37), but it nevertheless captures a large amount of data. In the present context, it is interesting to note that the mPFCv projects to the amygdala,38 and stimulation of the mPFCv has been reported to inhibit the increase in electrical activity in the LA produced by an already conditioned fear stimulus, as well as the fear response to that stimulus, and to prevent the association between CS and US when they are paired.39 Similarly, Quirk et al40 found that mPFCv stimulation reduces output from the CE in response to electrical stimulation of input pathways to the CE, and Milad et al41 found mPFCv stimulation to reduce fear responses produced by a fear CS. Although the exact projections of the mPFCv to the amygdala responsible for the inhibition of fear conditioning and fear responses resulting from mPFCv stimulation are unclear, the mPFCv does project to the intercalated cell mass (ITM) within the amygdala. These cells are almost all GABAergic, and project to the CE, providing an obvious pathway by which mPFCv activation could inhibit the CE.42 Indeed, Berretta et al30 found that stimulation of the mPFCv with picrotoxin increases Fos expression in the GABAergic cells of the ITM. 300

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Figure 3. Mean latency to escape across blocks of five shuttlebox trials. Day 1 treatment s were escapable shock (ES), yoked inescapable (IS), or home cage control (HC). All animals received inescapable shock (IS) on Day 8. Escape testing occurred on Day 9. P, picrotoxin before experimental treatment; V, vehicle

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Figure 4. Extracellular levels of serotonin (5-HT) within the dorsal raphe nucleus (DRN), as a percentage of baseline, before, during, and after inescapable shock (IS). Separate groups received either escapable shock (ES), yoked inescapable (IS), or home cage control (HC) 7 days earlier.

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The foregoing suggests that any factor that increases mPFCv output to the amygdala should reduce fear. We have reviewed research that suggests that behavioral control increases mPFCv output to the DRN, thereby reducing DRN-driven behavioral changes. Perhaps this phenomenon is more general, and control also increases mPFCv output to the amygdala, thereby inhibiting CE function and fear. Consistent with this possibility, it is already known that ES leads to the conditioning of less fear to cues that are present than does IS. However, the possibility being considered here makes an even stronger prediction. Recall that an initial experience with ES protected the organism against the effects of subsequent IS, the argument having been that the original experience led the later IS to now activate the mPFCv. The idea was that the initial ES experience “tied” mPFCv activation to shock, or to something associated with or produced by shock. What if that “something” is fear? If this were so, then an initial experience with ES should actually interfere with fear conditioning conducted some time later in a different environment. To begin to explore these ideas, we first gave rats ES or yoked IS in wheel turn boxes, or HC treatment. Seven 1

Freezing

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days later the rats received fear conditioning in a standard gridbox chamber. A tone was paired with gridshock, and the level of conditioning to the tone and to the environmental context was measured 2 days later. Freezing to the context was used as the measure of conditioning to the context. The rats were simply placed in the fear conditioning chamber for 5 min and freezing assessed.To assess fear conditioned to the tone, the rats were placed in a novel chamber and freezing measured for 3 min.The tone was then sounded for 3 min. Figure 5 shows the results. First, it should be stated that there was virtually no freezing at all on the conditioning day before the first footshock.Thus, the freezing observed on the test day was the result of conditioning, not some aftereffect of the earlier IS or ES. The results for fear conditioned to the context are on the left. IS 7 days before fear conditioning exaggerated fear conditioning, a result that was already known.43 In contrast, prior ES retarded fear conditioning. The results for conditioning to the tone, shown on the right, were similar.These results are dramatic, as ES is itself quite “stressful” and is not somehow “negative stress.” Indeed, the ES conditions used here produce a hypothalamo-pituitary-adrenal response that is as large as that produced by IS.44,45 We know of no other position that would predict, or even explain, how exposure to a highly stressful event could retard the later development of fear. Clearly, much more work is needed, but it may be that experiences of control produce resilience in the face of circumstances that induce fear. The amygdala is importantly involved in fear-related processes that go beyond the conditioning of fear to anxiety more generally. It thus may be that experiences of control, and other circumstances that might activate the mPFCv, confer resistance to the development of anxiety.

0.25

Conclusions and clinical implications 50 Context

Pretone

Tone

Figure 5. Percentage of the observation intervals on which freezing occurred during testing for fear conditioning. Testing was 24 h after conditioning. Groups received either escapable shock (ES), yoked inescapable (IS), or home cage control (HC) 7 days before fear conditioning. Data on the left shows freezing in the context in which conditioning had occurred. Data on the right shows freezing before and during the tone that had been paired with shock, with testing occurring in a novel context.

The general conclusion to be reached is that control is not detected or computed by brain stem structures such as the DRN, but rather by circuitry within the mPFCv. Stress or aversive stimulation per se would seem to activate structures such as the DRN, with this activation then being inhibited by input from the mPFCv if behavioral control is present. This arrangement might make good evolutionary sense. Primitive organisms possess only a limited behavioral capacity to deal with threats, and in such species adaptations and responses to threats are largely physiological in nature. For these types of species

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Basic research behavioral control and other methods of psychological coping are largely irrelevant, and so it may make sense that more primitive parts of the brain that are involved in responding to threats are themselves insensitive to dimensions such as behavioral controllability. As organisms became more complex, behavioral methods of coping became possible. Under circumstances in which a threat can be dealt with behaviorally, it would be adaptive to inhibit or reduce the more physiological adaptive mechanisms since they can be costly in various ways.46 Of course, more recently evolved “higher” regions of the brain such as the mPFC would have taken this function. It is also possible that a lack of control might weaken the inhibitory control exerted by the mPFC. The experiments discussed above were not well suited to detecting effects in this direction given possible “ceiling effects.” Indeed, we have some evidence that uncontrollability might exert this sort of effect, but it is too preliminary to present. Although our evidence is limited, it further suggests that initial experiences with stressors can bias the system such that the mPFCv responds to later stressors as it did to earlier stressors. If this plasticity proves to be real, then this would constitute a mechanism of resilience. The fear conditioning data presented above suggests that this mechanism may generalize broadly, with control over tailshock generalizing to fear conditioning. Thus, experiences with control may be broadly protective. Of course, there is no reason to believe that behavioral con-

trol is unique, and there are likely other aspects of experience that would activate mPFCv inhibition of stressresponsive limbic and brain stem structures. The research and theorizing presented here articulates well with the recent clinical literature. Abnormalities in mPFC function have been detected in disorders ranging from depression47 to PTSD.48 Imaging studies of PTSD are especially illuminating in the present context, since they typically measure both amygdala and mPFC function. Not surprisingly, PTSD patients show substantial amygdala activation to stimuli related to the events that caused the disorder. Thus, combat veterans with PTSD show exaggerated amygdala activation to war scenes, relative to nonPTSD controls.48 Interestingly, they also show exaggerated amygdala activity to fear stimuli unrelated to combat, such as fearful faces.49 However, PTSD patients have reduced mPFC activity in response to these stimuli,48-50 and this often correlates with the degree of disorder. It is possible that there is exaggerated amygdala activation in PTSD because there has been a loss of mPFC inhibition of the amygdala. Many of the events that induce PTSD are ones over which the individual has little behavioral control. Not all of the individuals who experience these events develop PTSD, and it may be that earlier experiences with control or other forms of coping protect against the development of the disorder by biasing the mPFC to respond actively, thereby maintaining inhibition of the amygdala, and perhaps other stress-responsive structures. ❏

REFERENCES

9. Lowry CA. Functional subsets of serotonergic neurones: implications for control of the hypothalamic-pituitary-adrenal axis. J Neuroendocrinol. 2002;14:911-923. 10. Singewald N, Sharp T. Neuroanatomical targets of anxiogenic drugs in the hindbrain as revealed by Fos immunocytochemistry. Neuroscience. 2000;98:759-770. 11. Abrams JK, Johnson PL, Hay-Schmidt A, Mikkelsen JD, Shekhar A, Lowry CA. Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs. Neuroscience. 2005;133:983-997. 12. Maier SF, Watkins LR. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev. 2005;29:829-841. 13. Grahn RE, Will MJ, Hammack SE, et al. Activation of serotoninimmunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor. Brain Res. 1999;826:35-43. 14. Maswood S, Barter JE, Watkins LR, Maier SF. Exposure to inescapable but not escapable shock increases extracellular levels of 5-HT in the dorsal raphe nucleus of the rat. Brain Res. 1998;783:115-120. 15. Amat J, Matus-Amat P, Watkins LR, Maier SF. Escapable and inescapable stress differentially alter extracellular levels of 5-HT in the basolateral amygdala of the rat. Brain Res. 1998;812:113-120. 16. Greenwood BN, Foley TE, Day HE, et al. Freewheel running prevents learned helplessness/behavioral depression: role of dorsal raphe serotonergic neurons. J Neurosci. 2003;23:2889-2898.

1. Agaibi CE, Wilson JP. Trauma, PTSD, and resilience: a review of the literature. Trauma Violence Abuse. 2005;6:195-216. 2. Zimmerman MA, Ramirez-Valles J, Maton KI. Resilience among urban African American male adolescents: a study of the protective effects of sociopolitical control on their mental health. Am J Community Psychol. 1999;27:733-751. 3. Yi JP, Smith RE, Vitaliano PP. Stress-resilience, illness, and coping: a person-focused investigation of young women athletes. J Behav Med. 2005;28:257-265. 4. Chorpita BF, Barlow DH. The development of anxiety: the role of control in the early environment. Psychol Bull. 1998;124:3-21. 5. Kaplan Z, Matar MA, Kamin R, Sadan T, Cohen H. Stress-related responses after 3 years of exposure to terror in Israel: are ideological-religious factors associated with resilience? J Clin Psychiatry. 2005;66:1146-1154. 6. Maier SF, Watkins LR. Stressor controllability, anxiety, and serotonin. Cogn Ther Res. 1998;6:595-613. 7. Graeff FG, Viana MB, Mora PO. Dual role of 5-HT in defense and anxiety. Neurosci Biobehav Rev. 1997;21:791-799. 8. Schmitt P, Sandner G, Colpaert FC, De Witte P. Effects of dorsal raphe stimulation on escape induced by medial hypothalamic or central gray stimulation. Behav Brain Res. 1983;8:289-307.

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Control comportamental, corteza prefrontal medial y resiliencia

Contrôle comportemental, cortex médian préfrontal et résilience

El grado de control que ejerce un organismo sobre un factor estresante modula poderosamente la repercusión de éste; los elementos incontrolables generadores de estrés determinan una constelación de resultados que no se daría si esos factores pudieran controlarse comportamentalmente. En general, se ha admitido que esto ocurre porque la falta de control potencia de una manera activa los efectos de los elementos estresantes. Aquí se propone como tesis complementaria o alternativa que la presencia del control inhibe activamente la repercusión de estos elementos. Esto sucede, al menos en parte, porque i) las regiones de la corteza prefrontal ventromedial detectan el control e ii) la detección del control activa las eferencias de la corteza prefrontal ventromedial hacia el tronco encefálico y las estructuras límbicas, que responden al estrés lo que inhibe fuertamente la activación de estas estructuras inducida por el estrés. Es más, la experiencia inicial de control del estrés modifica la respuesta de la corteza prefrontal ventromedial a los factores estresantes subsiguientes, de manera que las eferencias de la corteza prefrontal ventromedial se activan, aun cuando el elemento estresante posterior resulte incontrolable, con lo que el organismo adquiere resiliencia. Se comentan las implicaciones generales de estos resultados para entender la resiliencia frente a la adversidad.

Le degré de contrôle qu’un organisme exerce sur un facteur de stress module fortement l’impact de ce dernier. Les facteurs de stress incontrôlables engendrent un cortège de comportements qui ne se produiraient pas si le facteur de stress pouvait être maîtrisé. L’absence de contrôle est connue pour potentialiser fortement les effets des facteurs de stress. A contrario, ainsi qu’il l’est suggéré dans cet article, la présence d’un contrôle inhibe de manière active l’impact des facteurs de stress. Ceci survient au moins du fait de deux facteurs 1) la présence du contrôle est détectée au niveau des régions du cortex préfrontal médioventral (mPFCv) ; et 2) cette détection active les efférences du mPFCv vers le tronc cérébral et les structures limbiques sensibles au stress inhibant fortement leur activation due au stress. De plus, une première expérience de stress contrôlé modifie la réponse du mPFCv face aux agressions ultérieures, si bien que l’efférence du mPFCv est activée même si le facteur de stress suivant reste incontrôlable, rendant de ce fait l’organisme résilient. Les implications générales de ces résultats pour comprendre la résilience face aux agressions vont être examinées dans cet article.

17. Maier SF, Grahn RE, Kalman BA, Sutton LC, Wiertelak EP, Watkins LR. The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock. Behav Neurosci. 1993;107:377-388. 18. Maier SF, Grahn RE, Watkins LR. 8-OH-DPAT microinjected in the region of the dorsal raphe nucleus blocks and reverses the enhancement of fear conditioning and interference with escape produced by exposure to inescapable shock. Behav Neurosci. 1995;109:404-412. 19. Maier SF, Busch CR, Maswood S, Grahn RE, Watkins LR. The dorsal raphe nucleus is a site of action mediating the behavioral effects of the benzodiazepine receptor inverse agonist DMCM. Behav Neurosci. 1995;109:759766. 20. Simson PG, Weiss JM, Ambrose MJ, Webster A. Infusion of a monoamine oxidase inhibitor into the locus coeruleus can prevent stressinduced behavioral depression. Biol Psychiatry. 1986;21:724-734. 21. Grahn RE, Hammack SE, Will MJ, et al. Blockade of alpha1 adrenoreceptors in the dorsal raphe nucleus prevents enhanced conditioned fear and impaired escape performance following uncontrollable stressor exposure in rats. Behav Brain Res. 2002;134:387-392. 22. Amat J, Sparks PD, Matus-Amat P, Griggs J, Watkins LR, Maier SF. The role of the habenular complex in the elevation of dorsal raphe nucleus serotonin and the changes in the behavioral responses produced by uncontrollable stress. Brain Res. 2001;917:118-126.

23. Gabbott PL, Warner TA, Jays PR, Salway P, Busby SJ. Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol. 2005;492:145-177. 24. Dalley JW, Cardinal RN, Robbins TW. Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev. 2004;28:771-784. 25. Ostlund SB, Balleine BW. Lesions of medial prefrontal cortex disrupt the acquisition but not the expression of goal-directed learning. J Neurosci. 2005;25:7763-7770. 26. Jankowski MP, Sesack SR. Prefrontal cortical projections to the rat dorsal raphe nucleus: ultrastructural features and associations with serotonin and gamma-aminobutyric acid neurons. J Comp Neurol. 2004;468: 518-529. 27. Hajos M, Richards CD, Szekely AD, Sharp T. An electrophysiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat. Neuroscience. 1998;87:95-108. 28. Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci. 2001;21:9917-9929. 29. Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8:365-371.

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Basic research 30. Berretta S, Pantazopoulos H, Caldera M, Pantazopoulos P, Pare D. Infralimbic cortex activation increases c-Fos expression in intercalated neurons of the amygdala. Neuroscience. 2005;132:943-953. 31. Gutman DA, Nemeroff CB. Persistent central nervous system effects of an adverse early environment: clinical and preclinical studies. Physiol Behav. 2003;79:471-478. 32. Williams JL, Maier SF. Transituational immunization and therapy of learned helplessness in the rat. J Experimental Psychol: Animal Behav Proc. 1977;3:240-253. 33. Moye TB, Hyson RL, Grau JV, Maier SF. Immunization of opioid analgesia: effects of prior escapable shock on subsequent shock-induced and morphine-induced antinociception. Learn Motiv. 1983;14:238-251. 34. Lissek S, Powers AS, McClure EB, et al. Classical fear conditioning in the anxiety disorders: a meta-analysis. Behav Res Ther. 2005;43:1391-1424. 35. Sotres-Bayon F, Bush DE, LeDoux JE. Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction. Learn Mem. 2004;11:525-535. 36. Maren S. Synaptic mechanisms of associative memory in the amygdala. Neuron. 2005;47:783-786. 37. Kim JJ, Jung MW. Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review. Neurosci Biobehav Rev. 2006;30:188-202. 38. McDonald AJ. Cortical pathways to the mammalian amygdala. Prog Neurobiol. 1998;55:257-332. 39. Rosenkranz JA, Moore H, Grace AA. The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. J Neurosci. 2003;23:11054-11064. 40. Quirk GJ, Likhtik E, Pelletier JG, Pare D. Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J Neurosci. 2003;23:8800-8807.

41. Milad MR, Vidal-Gonzalez I, Quirk GJ. Electrical stimulation of medial prefrontal cortex reduces conditioned fear in a temporally specific manner. Behav Neurosci. 2004;118:389-394. 42. Royer S, Martina M, Pare D. An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J Neurosci. 1999;19:10575-10583. 43. Rau V, DeCola JP, Fanselow MS. Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neurosci Biobehav Rev. 2005;29:1207-1223. 44. Maier SF, Ryan SM, Barksdale CM, Kalin NH. Stressor controllability and the pituitary-adrenal system. Behav Neurosci. 1986;100:669-674. 45. Helmreich DL, Watkins LR, Deak T, Maier SF, Akil H, Watson SJ. The effect of stressor controllability on stress-induced neuropeptide mRNA expression within the paraventricular nucleus of the hypothalamus. J Neuroendocrinol. 1999;11:121-128. 46. McEwen BS, Stellar E. Stress and the individual. Mechanisms leading to disease. Arch Intern Med. 1993;153:2093-2101. 47. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry. 2000;48:813-829. 48. Bremner JD, Staib LH, Kaloupek D, Southwick SM, Soufer R, Charney DS. Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study. Biol Psychiatry. 1999;45:806-816. 49. Shin LM, Wright CI, Cannistraro PA, et al. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry. 2005;62:273-281. 50. Phan KL, Britton JC, Taylor SF, Fig LM, Liberzon I. Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder. Arch Gen Psychiatry. 2006;63:184-192.

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Basic research Angst and the amygdala Jay Schulkin, PhD

F

ear, as the perception of danger, is an adaptive response, and fundamental in problem-solving and survival. In fact, fear is an emotion that likely evolved as part of problem-solving.1 Appraisal mechanisms which discern danger become overactive, leading to increased perception of fear, which then leads to anxious thought, and perhaps to endless gloom.2,3 In psychological terms, both anxious and depressive states have a common core of heightened negative affect,4 a product of overactivity of the neural systems that underlie fear3,5 and that contribute to a number of affective disorders.6 While fear is a central state of the brain, changes in heart rate, blood pressure, respiration, facial muscles, and catecholamines, both peripheral and central, all influence the state of fear.3,5 One should note at the outset that fear, of which there are several kinds (conditioned fear, fear of unfamiliar objects, fear to sensory stimuli, etc7), is more than amygdala function, and amygdala function is more than fear8,9; however, fear is one thing in which the amygdala participates, and exaggerated amygdala activation creates a vulnerability to affective disorders.6,10,11

Fear is an adaptation to danger, but excessive fear underlies diverse forms of mental anguish and pathology. One neural site linked to a sense of adversity is the amygdala, and one neuropeptide, corticotropin-releasing hormone (CRH), is localized within the central nucleus of the amygdala. Glucocorticoids enhance the production of CRH in this region of the brain, resulting in increased attention to external events and, when sustained for longer periods of time, perhaps contributing to anxious depression. © 2006, LLS SAS


Keywords: amygdala; fear; angst Author affiliations: Department of Physiology and Biophysics, Georgetown University, School of Medicine, Washington, DC, USA; Clinical Neuroendocrinology Branch, National Institute of Mental Health, Bethesda, Md, USA Address for correspondence: Dr J. Schulkin, Department of Research, American College of Obstetricians and Gynecologists, 409 12th St, SW Washington, DC 200024-2188, USA (e-mail: [email protected])


Anatomical considerations about the amygdala Regions of the amygdala receive and send information from both cortical and subcortical regions.12-14 More specifically, the basolateral complex is comprised of the lateral, basal, and accessory basal nuclei, which are richly innervated by neocortical and subcortical uni- and polymodal sensory regions,13-15 which then relay information to the central nucleus of the amygdala.16 Intra-amygdala connectivity is widespread.13,14

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Basic research Selected abbreviations and acronyms ACTH BNST CRH HPA PTSD PVN

adrenocorticotropic hormone bed nucleus of stria terminalis corticotropin-releasing hormone hypothalamic-pituitary-adrenal post-traumatic stress disorder paraventricular nucleus

The central nucleus projects to numerous nuclei in the midbrain and brain stem to orchestrate the rapid and primary behavioral, autonomic, and endocrine responses to threat and danger.3,5,17 The central nucleus also receives visceral information from brain stem sites that include the solitary and parabrachial nuclei18 and reciprocally projects to these brain stem regions (eg, ref 19). Regions of the amygdala directly project to the nucleus accumbens, which led investigators20,21,22 to suggest an anatomical route by which motivation and motor control action are linked in the organization of active behavior (see also refs 21-25). In addition to projections from the central nucleus of the amygdala to midbrain and brain stem targets important for mounting quick behavioral, autonomic, and endocrine responses to danger, the amygdala projections to the cortex and subcortical structures are also quite extensive.13,14 In rat, the sources are the lateral, basal, and accessory basal nuclei, and their projections are fairly restricted to the multisensory temporal lobe structures (perirhinal, pyriform, and entorhinal cortices) and prefrontal cortex.26 In primate brain, the primary visual cortex also receives input from the amygdala.12 These cortical structures also contribute the heaviest cortical input to the amygdala, suggesting that many of the connections between the amygdala and cortex are reciprocal. This is particularly the case with the amygdala and prefrontal cortex, both anatomically12,26 and functionally (for review see refs 27, 28). In addition to the basolateral nucleus of the amygdala, the central nucleus of the amygdala also plays a unique role in conditioned fear.3,5 The basolateral complex of the amygdala, with its rich afferents from the thalamus and cortical regions, is neuroanatomically situated to connect information about neutral stimuli with those that produce pain or are harmful. The central nucleus can orchestrate behavioral responses related to fear via its direct connections to numerous midbrain and brain stem regions and circuits instantiating various fear-related behaviors.17,29-31 Thus, the central

nucleus of the amygdala, via its projections to lower brain, orchestrates behavioral (freezing5,17), autonomic, and endocrine responses to fear, while efferents of the basal nucleus of the amygdala participate in active avoidance behaviors to fear,23,32,33 likely through basal ganglia. The bed nucleus of the stria terminalis (BNST) is anatomically linked to the central/medial amygdala34 and is also distinguished from the basolateral complex as being part of an autonomic brain system.25 Importantly, the central nucleus and the BNST are not only the major efferent sources of input to midbrain and brain stem targets controlling autonomic responses to fear, but are the main recipients of autonomic information from the nucleus of the solitary tract and parabrachial nucleus.13,19,35 Corticotropin-releasing hormone (CRH) is one of the cell groups (neuropeptides) richly expressed in the central nucleus of the amygdala and in the lateral BNST, and therefore is of special interest, as it is tied to all of these behavioral and autonomic events (see below). There are reasonable conceptual issues of what defines the amygdala,25,36 and the ultimate basis for deciding what is amygdala is still open to investigation (eg, the extent to which the amygdala is part of the striatum and/or the larger cortical areas, the link to the BNST). There is little doubt that the amygdala is importantly involved in diverse forms of motivated behaviors (eg, fear) and their aberration during pathological states.

Fear, uncertainty, unfamiliar objects, and the amygdala Humans with damage to the amygdala have impaired fearrelated behavior and autonomic responses to conditioned stimuli (eg, refs 37-41). Also, positron emission tomography (PET) imaging studies in normals have shown greater activation of the amygdala during fear and anxiety-provoking stimuli than during presentation of neutral stimuli.42 Such PET studies have revealed that the amygdala is activated when presented with fearful, unfamiliar, and uncertain faces.2,43,44 With the use of functional magnetic resonance imaging (fMRI), it has further been shown that the amygdala is activated and then habituates when subjects are shown fearful faces but not when they are shown neutral or happy faces45,46; however, the amygdala is also responsive to a variety of facial responses.47,48 A number of studies have also demonstrated that anxiety disorder patients have excessive activation in the amygdala when presented with stimuli that provoke anxiety attacks.6,10,27

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Angst and the amygdala - Schulkin

CRH expression and the brain One cell group within the amygdala (and the primary focus of this review) and elsewhere in the brain is CRH,24,49,50 which is well known to be both a peptide that regulates pituitary and adrenal function and an extrahypothalamic peptide hormone linked to a number of behaviors, including behavioral expressions of fear.51-53 CRH cell bodies are widely distributed in the brain.49,50 The majority of CRH neurons within the paraventricular nucleus (PVN) are clustered in the parvicellular division. Other regions with predominant CRH-containing neurons are the lateral BNST and the central division of the central nucleus of the amygdala.49,54 To a smaller degree, there are CRH cells in the lateral hypothalamus and the prefrontal and cingulate cortex. In brain stem regions, CRH cells are clustered near the locus coeruleus (Barrington’s nucleus), parabrachial region, and regions of the solitary nucleus.49,50,55,56 The CRH family has at least two receptors, CRH1 and CRH2, localized in rodent and primate brain (eg, refs 5760). Activation of both the CRH1 and CRH2 receptors is linked to a G protein, and activates adenylate cyclase cascade and an increase in intracellular cyclic adenosine monophosphate (cAMP) and calcium levels; CRH appears to bind primarily to CRH1 receptors.60,61 The distribution of CRH1 receptor sites includes regions of the hippocampus, septum, and amygdala (medial and lateral region) and neocortex, ventral thalamic, and medial hypothalamic sites; sparse receptors are located in the PVN and the pituitary gland. The distribution is widespread in cerebellum in addition to brain stem sites such as major sensory nerves and the solitary nucleus.62,63 The distribution of CRH2 receptors is more limited than that of CRH1 receptors and is found primarily in subcortical regions including the amygdala, septum, BNST, and PVN and ventral medial nucleus of the hypothalamus.63,64

Differential regulation of CRH by glucocorticoids Glucocorticoids are importantly involved in the restraint of CRH production in regions of the PVN.65,66 This negative feedback is a fundamental way in which the hypothalamic-pituitary-adrenal (HPA) axis is restrained during stress and activity.67 Glucocorticoids directly control neuronal excitability.68 Some of the glucocorticoid effects on

the brain are quite rapid, suggesting that corticosterone has nongenomic membrane effects via γ–aminobutyric acid(GABA)-ergic mechanisms.69 Neurons within the lateral BNST and within the PVN may activate or inhibit PVN function via GABAergic mechanisms.70,71 While the profound effect of inhibition is indisputable, there are neuronal populations within the PVN that project to the brain stem that are not inhibited by glucocorticoids, and the activity of which is actually enhanced.66,72 That is, CRH neurons en route to the pituitary are restrained by glucocorticoids, but CRH en route to other regions of the brain appears not to be restrained.66,73-75 Moreover, the activity of extrahypothalamic regions of the brain in which CRH is expressed (central nucleus of the amygdala or lateral BNST) is actually increased by glucocorticoid hormones.54,66,75,76

CRH, glucocorticoids, and fear-related behaviors Central CRH activation has been consistently linked to the induction of fear, uncertainty, unfamiliarity, and uncontrollability in animal studies.9, 52,53,77-79 Central infusions of CRH induce or potentiate a number of fearrelated behavioral responses,80 and infusion of CRH antagonists both within and outside the amygdala reduce fear-related responses.52,81 One study, for example, reported that injection of a CRH antagonist into the basolateral complex of the amygdala, one of the regions in the amygdala which contains glucocorticoid receptors,82 immediately following footshock diminished retention of aversive conditioning in an inhibitory avoidance task.32 It was also shown in this study that the expression of CRH in the central nucleus of the amygdala increased 30 minutes following footshock. The results indicated that, similar to glucocorticoids and norepinephrine magnifying memory,33 CRH in the amygdala modulated learning and memory for aversive events.83 While glucocorticoids are essential in the development of fear,84 perhaps by the induction of central CRH, glucocorticoids, and CRH both play a larger role in the organization of behavior.85-87 Nonetheless, glucocorticoids are secreted under a number of experimental conditions in which fear, anxiety, novelty, and uncertainty are experimental manipulations.9,78,88-90 In contexts where there is loss of control, or the perception of a loss of control (worry is associated with the loss of control), glucocorticoids are secreted. This holds across a number of

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Basic research species, including humans; perceived control reduces the levels of glucocorticoids.88 These findings are congruent with those of Curt Richter91 who observed an enlarged adrenal gland in stressed, fearful wild rats when compared with unstressed laboratory analogs. Glucocorticoids in the basolateral complex of the amygdala appear to be necessary for aversive and fear conditioning. For example, injection of the glucocorticoid receptor antagonist RU-486 into the basolateral complex of the amygdala will reduce the consolidation of aversive conditioning92 in addition to other forms of conditioning, including contextual fear.93 Other experiments have shown that glucocorticoid injections into the amygdala can facilitate aversive conditioning.33 Experiments like these, which use post-training injection procedures, demonstrate that glucocorticoids are necessary for consolidation of the memory of aversive conditioning and may facilitate the memory process.94,95 Glucocorticoid levels impact on learned fear.94-97 For example, in one study rats received conditioning trials in which the unconditioned stimulus (footshock) was presented concurrently with the conditioned stimulus (auditory tone). For several days after conditioning the rats were treated with corticosterone; conditioned fearinduced freezing was enhanced.96 Corticosterone, by the induction of central CRH expression, facilitates fear-related behavioral responses.76 Thus, in one study looking at contextual fear conditioning, groups of rats that were chronically treated with corticosterone displayed more fear conditioning than the vehicle-treated rats. Glucocorticoid antagonists disrupt contextual fear conditioning.94,95 Thus, the data suggest that repeated high levels of corticosterone can facilitate the retention of contextual fear conditioning, perhaps by the induction of CRH gene expression in critical regions of the brain such as the amygdala. Importantly, amygdala infusion of corticosterone aimed at the central nucleus also increases milder forms of anxiety as measured with rats in the elevated plus maze.98 Shepard et al have, furthermore, demonstrated that implants of corticosterone resulted in an increase in CRH expression in the central nucleus of the amygdala. In addition, the corticosterone implants to the central nucleus of the amygdala increased levels of CRH expression in the dorsal lateral BNST99 and administration of the type 1 CRH receptors decreased this fear-related response.100 In other tests, pretreatment with the type-l receptor CRH antagonist ameliorated fear-inducing events, or reactivity to the

events,100 (see also refs 101-103 for the role of the CRH type-1 receptor; and 104, 105 for the role of the type II receptor). Furthermore, Cook demonstrated that the CRH response in the amygdala of sheep to a natural (dog) and unnatural (footshock) adversity is regulated by glucocorticoids.106 Following acute exposure to the dog, for example, amygdala CRH had a large increase during exposure to the dog and a second peak corresponding to the increase in cortisol. Administration of a glucocorticoid receptor antagonist blocked the second CRH peak in the amygdala without affecting the first peak. There is a body of evidence suggesting that the BNST may be important for unconditioned fear107 and that perhaps CRH plays an important role.83 Lesions of the BNST do not interfere with conditioned fear-related responses, unlike lesions of regions of the amygdala which interfere with fear-potentiated startle or conditioned freezing.108,109 However, inactivation of the BNST can interfere with unconditioned startle responses109 and with longer-term CRH effects on behavior.109 High chronic plasma levels of corticosterone in adrenally intact rats facilitated CRH-induced startle responses.110 Perhaps what occurs normally is that the glucocorticoids, by increasing CRH gene expression, increase the likelihood that something will be perceived as a threat, which results in a startle response. Lesions of the BNST also interfere with unconditioned freezing of rats to a fox odor,111 while amygdala lesions do not.11,112 Corticosterone can potentiate freezing to predator odor,113 (Rosen et al, unpublished observations). Perhaps the BNST may be linked to CRH-facilitated unconditioned adaptive anxiety and to general anxiety associated with drug abuse and to symptoms associated with pathological generalized anxiety disorder.114-116

Depression, anxiety, CRH, cortisol, brain A genetic predisposition for a hyperactive amygdala has long been thought to result in a vulnerability to exaggerated fear and perhaps anxiety/depression.11,117 There is a substantial number of findings of increased activity in the amygdala of depressive patients.27,44,118 correlating with negative affect in other medication-free depressives119 and patients suffering from a number of anxiety disorders.2 In addition, a finding in depressive patients, particularly in those with comorbid anxiety, is hypercortisolemia.120-122 Interestingly, antiglucorticoids are, in a

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number of contexts, reported to ameliorate depressive symptoms,123,124 which perhaps results in a reduction in central CRH expression. Importantly, depressive patients tend to have higher levels of CRH in cerebrospinal fluid than normal controls.125-129 There is some evidence that TYPE 1 receptor regulation can impact on depression.130 One study has found a significant positive correlation between activity in the amygdala measured by PET and plasma cortisol levels in both unipolar and bipolar depressives.118 Interestingly, patients with major depression show exaggerated responses in the left amygdala to sad facial expressions.131,132 Acute infusions of cortisol in normal patients resulted in exaggerated amygdala responses to sad faces.46 This correlation may reflect either the effect of amygdala activity on CRH secretion or cortisol actions directly in amygdala. It is intriguing to speculate that the findings that patients with a first episode of depression have an enlarged amygdala133 may be due to increased chronic levels of glucocorticoids and blood flow in the amygdala.134 Interestingly, fearful anxious children in whom cortisol was elevated in development117,135 also display a hyperactive amygdala to social performance as adults.11 Importantly, there is evidence of increased dendritic hybridization in amygdala and decreased dendritic hybridization of the hippocampus in animals under duress.136 Glucocortiocoids are known to produce morphological changes in brain, typically decreases in hippocampal and prefrontal neurons’ dendritic trees.137,138 Moreover, studies have linked increased glucocorticoid production to changes in neuronal morphology in the basolateral complex of the amygdala following repeated stress136,139 and such changes in plasminogen activator in cell bodies within the amygdala promotes corticotropinreleasing factor (CRF) activity; the administration of antalarmin, a CRF TYPE 1 antagonist, does the converse.140 An fMRI study reported that, whereas the amygdala in both normals and depressives responded to aversive stimuli, the amygdala response of normals habituated quickly while the familial depressives’ amygdala remained active significantly longer.141 Whether CRH and cortisol are involved in the sensitized responses awaits further study. We do know that in animal studies, increased CRH increases the salience of familiar incentives9, 87,142 and perhaps glucocorticoids magnify the CRH effect.83,85,142

Data on anxiety also indicate that the amygdala and cortisol are interactive in several anxiety disorders and for which cortisol, and the return to normal function, may be therapeutic.143 Although the research has developed along two separate paths, activity in the amygdala in a number of different anxiety disorders has been shown to be highly reactive to triggers that evoke anxious reactions2,6 and the HPA axis is hyper-responsive in anxiety disorders, particularly post-traumatic stress disorder (PTSD).144-46 PTSD patients also have high norepinephrine/cortisol ratios144,147 In research on cortisol measures, PTSD patients have basal hypocortisolemia but increased reactivity of the HPA axis to cortisol, suggesting that CRH and adrenocorticotropic hormone (ACTH)-secreting cells are sensitized to cortisol in PTSD patients.145 Indeed, CRH has been found to be elevated in cerebrospinal fluid of PSTD patients.147,148 PTSD patients have normal resting (nonprovoked) levels of amygdala activity, but the amygdala is highly responsive to anxiety provocation.149-152 While most of these studies do not demonstrate an abnormal response of the amygdala per se, particularly because normal humans also demonstrate increased amygdala activity to fearful or aversive stimuli (however, they do suggest that the amygdala has a lower threshold for responding to fearful stimuli in anxiety disorder patients).153 While focus here has been on the amygdala and, to a lesser extent, on the BNST, a fundamental part of fear circuitry is the prefrontal cortex (eg, refs 27,154,155). The medial prefrontal cortex (mPFC), for example, plays a role in inhibition of fear responses and extinction.154,156 There is evidence that regions of the prefrontal cortex regulate glucocorticoid responses to duress.157-159 The prefrontal cortex has relatively dense expression of glucocorticoid receptors in most regions, including the infralimbic cortical areas and CRH neurons are also located in most regions of the prefrontal cortex,49,50 Rosen and Schulkin, unpublished data. Chronic glucocorticoid treatment has been shown to alter apical dendrites of medial prefrontal neurons.137

Conclusions Although the amygdala has been known to be involved in the emotion of fear since the seminal studies of Kluver and Bucy160 showed a taming effect of amygdala lesions in monkeys, research in the last two decades has produced great advances in determining the neuroanatomy of fear

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Basic research circuits. Not only has the amygdala been found to be critical for many types of fear, but fear circuits that connect the amygdala to many other brain regions have been described, which suggests that these circuits have evolved to function as neurobehavioral systems for particular kinds of cognitive and behavioral strategies. Understanding the neural circuitry that underlies fear/anxiety leads one to be in a better position for clinical judgment about treatment for states such anxious depression. Normal fear is an adaptation to danger; chronic anxiety and depression are the overexpression of the neural systems involved in adaptation to danger. Coping with anxious depression is metabolically expensive; expectations

of adversity predominate. Moreover, anxious depression is a condition in which there can be both high systemic cortisol and elevated CRH in the cerebrospinal fluid118,125,161,162 Anxious depressed patients also tend to have increased glucose metabolic rates in the amygdala.118,134 The cortisol that regulates CRH gene expression in the amygdala may underlie the fear and anxiety of the anxiously depressed person.3,85 The exaggerated amygdala response that can occur because of life events and genetic predisposition (eg, refs 11, 77, 90, 129) contributes to the anxious/depressed person’s altered perception and experience of the world, leading to a chronic sense of anticipatory angst. ❏

Angustia existencial y la amìgdala

Angoisse existentielle et amygdale

El miedo es una adaptación al peligro pero el miedo excesivo es la expresión de diversas formas de angustia y enfermedad mentales. Una localización neural relacionada con el sentido de la adversidad es la amígdala; el neuropéptido hormona liberadora de corticotropina (CRH), se localiza en el núcleo central del cuerpo amigdalino. Los glucocorticoides refuerzan la producción de CRH en esta región cerebral, con lo que aumenta la atención a los acontecimientos externos y, si se sostiene durante largos períodos, puede contribuir a la depresión ansiosa.

La peur est une adaptation au danger, mais une peur excessive est à l’origine de diverses formes d’angoisse et de pathologies. L’amygdale est un site cérébral traitant le concept d l’adversité. La CRH (corticotropin-releasing hormone) est un neuropeptide situé dans le noyau central de l’amygdale. Les glucocorticoïdes augmentent la sécrétion de CRH dans cette région du cerveau, conduisant ainsi à une attention accrue aux événements extérieurs. En se pérennisant sur de plus longues périodes, cette sécrétion pourrait contribuer au trouble anxio-dépressif.

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132. Surguladze S, Brammer MJ Keedwell P, et al. A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder. Biol Psychiatry. 2005;57:201-209. 133. Frodl T, Meisenzahl E, Zetzsche T, et al. Enlargement of the amygdala in patients with a first episode of major depression. Biol Psychiatry. 2002;51:708-714. 134. Drevets WC. Neuroimaging abnormalities in the amygdala in mood disorders. Ann NY Acad Sci. 2003;985:420-444. 135. Schmidt LA, Fox NA, Rubin KH, et al. Behavioral and neuroendocrine responses in shy children. Devel Psychobiol. 1997;30:127-140. 136. Vyas A, Mitra R, Shankaranarayana Rao B S, Chattarji S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002;22:6810-6818. 137. Wellman CL. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol. 2001;49:245-253. 138. Woolley CS, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 1990;531:225-231. 139. Mitra R, Jadhav S, McEwen BS, Vyas A, Chattarji S. Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc Natl Acad Sci U S A. 2005;102:9371-9376. 140. Matys T, Pawlak R, Matys E, Pavilides C, McEwen BS, Strickland S. Tissue plasminogen activator promotes the effects of corticotropin-releasing factor on the amygdala and anxiety-like behavior. Proc Nat Acad Sci U S A. 2004;101:1634516350. 141. Siegle GJ, Steinhauer SR, Thase ME, Stenger VA, Carter CS. Can't shake that feeling: event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals. Biol Psychiatry. 2002;51:693707. 142. Dallman MF, Pecoraro N, Akana SF, et al. Chronic stress and obesity: a new view of "comfort food". Proc Natl Acad Sci U S A. 2003;100: 11696-701. 143. Soravia LM, Heinrichs M Aerni A, et al. Glucocorticoids reduce phobic fear in humans. Proc Natl Acad Sci U S A. 2006;103:5585-5590. 144. Mason JW, Giller EL, Kosten TR, Harkness L. Elevation of urinary norepinephrine/cortisol ratio in posttraumatic stress disorder. J Nerv Ment Dis. 1988;176, 498-502. 145. Yehuda R. Current status of cortisol findings in post-traumatic stress disorder. Psych Clin N Am. 2002;25:341-368. 146. Yehuda R, Giller EL, Southwick SM, Lowy MT, Mason JW. Hypothalamic-pituitary-adrenal dysfunction in posttraumatic stress disorder. Biol Psychiatry. 1991;30:1031-1048. 147. Baker DG, Ekhator NN, Kasckow JW, et al. Plasma and cerebrospinal fluid interleukin-6 concentrations in post-traumatic stress disorder. Neuroimmunomodulation. 2001;9:209-217. 148. Bremner JD, Licinio J, Darnell A, et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry. 1997;154:624-629. 149. Birbaumer N, Grodd W, Diedrich O, et al. fMRI reveals amygdala activation to human faces in social phobics. Neuroreport. 1998;9:1223-1226. 150. Rauch SL, van der Kolk BA, Fisler RE, et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry. 1996;53:380-387. 151. Rauch SL, Whalen PJ, Shin LM, et al. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry. 2000;47:769-776. 152. Stein MB, Goldin PR, Sareen J, et al. Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry. 2002;59:1027-1034. 153. Schneider F, Weiss U, Kessler C, et al. Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia. Biol Psychiatry. 1999;45:863-871. 154. Quirk GJ, Russo GK, Barron JL, Lebron K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci. 2000;20:6225-6231. 155. Phelps EA, Delgado MR, Nearing KI, LeDoux JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron. 2004;43:897-405. 156.Morgan MA, LeDoux JE. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. Behav Neurosci. 1995;109:681-688.

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Basic research Experimental models of stress Vladimir K. Patchev, MD, PhD; Alexandre V. Patchev, MD

S

Illustrating the complexity of the stress response and its multifaceted manifestations is the leading idea of this overview of experimental paradigms used for stress induction in laboratory animals. The description of key features of models based on naturalistic stressors, pharmacological challenges, and genomic manipulations is complemented by comprehensive analysis of physiological, behavioral, neurochemical, and endocrine changes and their appropriateness as outcome readouts. Particular attention has been paid to the role of sex and age as determinants of the dynamics of the stress response. Possible translational applications of stress-inducing paradigms as models of disease are briefly sketched. © 2006, LLS SAS


Keywords: stress; animal model; behavior; neurochemistry; neuroendocrinology; translational medicine Author affiliations: Corporate Research, Bayer Schering Pharma, Berlin, Germany (Vladimir K. Patchev); Max Planck Institute of Psychiatry, Munich, Germany (Alexandre V. Patchev) Address for correspondence: Vladimir K. Patchev, TRG G&A, Bayer Schering Pharma, Müllerstr. 178, 13342 Berlin, Germany (e-mail:[email protected]) Copyright © 2006 LLS SAS. All rights reserved

tress comprises mobilization of basic physiological repertoires for coping with adversity and restoring homeostasis; inappropriate strain on this arsenal, with respect to either magnitude or duration of the response, precipitates measurable pathological aberrations in several systems of the organism.1-4 After more than six decades of research, virtually every aspect of the organism’s responses to stress has been addressed, and numerous end-point parameters have been proposed as descriptors of general and specific reactions to stressful stimuli. Stress-induced changes in perception, behavior, thermoregulation, social interactions, sleep, cognition, endocrine secretions, neurotransmission, reproductive competence, immune defense, cardiovascular and gastrointestinal function, metabolic outcome, and susceptibility to noxious impact have shown rather concurrent patterns across mammalian species and, therefore, have become reliable indices of both stress exposure and stress-coping ability. However, these universal responses to homeostatic disturbance are beset by certain “original sins”: (i) their activation results in overcorrection of vital parameters that may linger for some time before the status quo is reinstalled; (ii) mobilization of the “full standard repertoire” mostly exceeds the strict demand for the counterbalance of occasional or solitary shifts in homeostasis; (iii) the magnitude and dynamics of response depend not solely on the intensity of the stressful challenge, but also on numerous codeterminant variables, such as stimulus duration and context, sex, age, health condition, and previous experience of the individual, to name only a few. From the perspective of stress modeling, three important consequences of the temporal dimension should be taken into consideration: the time point of assessment of indicators of the stress, the duration of the stressful challenge, and the phenomenon of habituation. Systems involved in

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Basic research Selected abbreviations and acronyms ACTH AVP CRH DMH GABA GR LHPA POMC PVN

adrenocorticotropic hormone vasopressin corticotropin-releasing hormone dorsomedial hypothalamic nucleus 웂-aminobutyric acid glucocorticoid receptor limbic-hypothalamic-pituitary-adrenal pro-opiomelanocortin paraventricular nucleus

the organism’s response to stress have different activation latencies; accordingly, measurable end-point changes occur at different intervals upon the challenge. Further, these systems act within physiological limits (described by, eg, synthetic and secretory capacity, feedback regulation within the system, consistency with key vital functions, etc) and cannot indefinitely maintain a maximal level of performance. Thus, changes in measurable end points vary depending on the duration of the stimulus, its perceived homeostatic threat, and the efficacy of the individually selected coping strategy (see below), but also due to output readjustment or exhaustion of the involved system. Finally, repeated exposure to homotypic stressors has been shown to produce gradual decline in the magnitude of several, but not all, commonly used indices of physiological response to stress. The omnipresence of this phenomenon is debatable, though there may be controversy based on species and paradigm differences. Habituation to repeated homotypic stress has a plausible teleological explanation: it is supposed to ensure the ability of a system involved in stress response to discriminate and adequately meet novel incoming challenges. Here, another important feature of the stress response, referred to as cross-sensitization, should be mentioned. It has been recognized that, despite habituation to repeated homotypic challenge, stress-responsive systems retain and, more importantly, even augment, their ability to react to challenges of a different modality. Several substrates of this phenomenon have been identified,5 and its importance in the pathogenesis of stress-related disorders is generally recognized.1,2,4 Experimental modeling of stress requires clear definition of the research objectives, and consideration of numerous factors that may modify individual aspects of the stress response. Investigation of the magnitude and temporal course of a particular stress-responsive parameter to a single challenge of limited duration has substantial

diagnostic value in several medical disciplines. Ensuring truly “baseline” conditions for the variable of interest by minimization of confounding input from the environment and consideration of sex- and age-related response deviations are usually sufficient prerequisites for obtaining reliable results. However, tasks which aim at the examination of the resistance of a stress-responsive physiological system under the influence of long-term or superimposed challenges, pharmacological treatment, or coexisting pathology, are by far more demanding. In such cases, careful evaluation of the condition and response capacity of the targeted system, alterations in its basal function resulting from each individual influence, and the time course of response must be added to the former requirements.

End points for assessment of the response to stress Stress induces mobilization of a broad array of reactions which involve virtually every physiological system, albeit with different time courses. Accordingly, numerous parameters can be used for response monitoring in models of stress, under the provision that their temporal profiles and the changes possibly occurring in the course of habituation/sensitization are sufficiently defined. Behavioral end points The original description of the response to stress as a “fight-or-flight” reaction and evidence that arousal activation is invariably associated with this response implies that observation of general behavior can reliably disclose symptoms of stress. Assessment of the explorative activity by means of well-established quantifiable parameters is a frequently used behavioral descriptor of the response to stress in laboratory rodents.6 As in most species exposure to novelty is a stressor per se, monitoring of stressinduced effects in this experimental condition should be preceded by careful baseline definition. Although outcome may vary depending on the characteristics and duration of the challenge, decreased exploratory activity is considered to be a reliable behavioral consequence of stress exposure. In its extreme expression, this response is described as “freezing,” a period of time during which locomotion and exploration are completely abolished. The freezing response is reproducibly evoked in several stress paradigms, and protocols for its quantification have

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been developed.7 Behavioral deficits known as acquired immobility, behavioral despair, and learned helplessness can be viewed as alterations specifically associated with severe stress; however, a learning component has a leading role in the manifestation of these phenomena. Behavioral responses to stress are frequently linked with anxiety, and there is a substantial overlap of neurochemical mechanisms activated by stressful challenges and those involved in the control of anxiety. Evaluation of anxiety belongs to the standard arsenal for the assessment of behavioral effects of stress, and offers a direct possibility to disclose stress-associated neuropathological consequences. Since habituation may rapidly occur in some experimental paradigms used for evaluation of anxiety,6 caution applies to their repeated use for the examination of long-term effects. Elicitation of defensive behavior is a core component of the stress response, and can be perceived as a continuum of altered anxiety. Assessment of manifestation of aggression and changes in its prestress degree of expression (especially within an established group hierarchy) is a recommended approach for the monitoring of stress effects,8 and substantial correlation between behavioral and neurochemical end points has been established. Analysis of audible and, especially, ultrasonic vocalization is a well-established method for the assessment of stress in pain- and fear-based paradigms,9 especially in infant rats whose endocrine responses are subject to developmental inconsistency (see below). In juvenile animals, ultrasonic vocalization reliably indicates anxiety, but can be specifically modulated by maternal contact or predator cues.10 Stress exerts profound effects on the acquisition, retention, and retrieval of new behavioral repertoire. As this process is an integral part of the formation of strategies for coping with stress and correlations with morphological and neurochemical measures have been established, assessment of learning and memory can be used for the evaluation of transient and persistent consequences of stress. The emphasis, however, should be put on “persistent,” as behavioral acquisition is associated with the mobilization of several stress-responsive neurochemical mechanisms, and the outcome depends on their “reverberation,” especially considering factors such as stress duration, crosstalk between neurochemical systems, and the organism’s adequate coping with the challenge. Several publications on this subject note dichotomous effects: short and controllable stress facilitates acquisition, whereas severe chronic stress interferes with mem-

ory consolidation and retrieval. Activation of monoaminergic transmission and arousal is a plausible explanation of the former phenomenon, while biphasic effects of glucocorticoids, also in conjunction with their secondary influence on neurotransmission, have been implicated in the interpretation of shifts in learning and memory performance under stressful conditions.11 To make this issue even more complicated, significant contribution of sex and age to this outcome should be noted. The concise message in the context of this review is that the impairment of acquisition, consolidation, and retrieval can serve as descriptors of detrimental consequences of poorly controlled chronic stress. Physiological end points Cardiovascular responses, such as changes in heart rate and arterial blood pressure, were recognized early as essential components of the response to stress, and are causally associated with the activation of the autonomic nervous system. With the increasing popularity of telemetric recording equipment, monitoring of cardiovascular end points has become a useful research tool in stress models.12 The capacity of stress to trigger pain suppression has been known for a long time, and the involved neurochemical mechanisms have been comprehensively elucidated.13 Measurement of stress-induced analgesia belongs to the standard repertoire of methods for monitoring of stress and pharmacological assessment of involved neurotransmitter and neuromodulator systems. Transient increase in body core temperature is a wellestablished physiological correlate of stress. Although the proper nature of stress-induced hyperthermia is still a matter of debate, its time course and several contributing neuropharmacological mechanisms have been extensively studied, and the reliability of the method confirmed in various experimental settings.14 Several stressful challenges significantly influence feeding behavior, and investigations of the underlying neurochemical mechanisms have revealed the involvement of some stress-responsive systems in this phenomenon. Changes in the amount and pattern of food intake have been sporadically used for stress monitoring per se, whereas exposure to stress has advanced to a modeling approach of eating disorders.15 Stress-induced changes in sleep architecture in experimental animals have been comprehensively described16

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Basic research and used for monitoring in different models; invasive interventions and sophisticated equipment have limited their widespread application. Metabolic end points Stress triggers distinct metabolic alterations, most of which are readily discernible. The “prototypic” metabolic response to acute stress consists of rapid and strong elevation of plasma concentrations of glucose, insulin, glycerol, and ketone bodies. The latter effects probably reflect the stimulation of adipose tissue lipase by circulating catecholamines. Activation of the autonomic nervous system has been also associated with stress-induced stimulation of glucagon secretion. Changes associated with repeated stress are also of catabolic nature, but less dramatic and, in some aspects (insulin) inconsistent. Both acute and chronic stress regimens decrease triacylglycerol levels, whereas reports on changes in cholesterol fractions are controversial.17 Neurochemical end points Increased sympathoadrenal outflow in the periphery and activation of monoaminergic neurotransmission in the brain were among the first described neurochemical correlates of the stress response, and their importance for the elicitation of several allostatic reactions in the organism is beyond doubt. Measurement of circulating levels of catecholamines and/or their metabolites, as well as their content, release, and biosynthesis in discrete brain regions18 have become standard approaches for stress response monitoring. Continuous microdialysis of discrete projection areas, in combination with morphological and histochemical techniques, has provided comprehensive description of the neuronal populations and pathways affected by stress, as well as of their distinct responsiveness to specific stressors.3 Meticulous studies on the role of catecholamines in stress have shown that the morphofunctional heterogeneity of peripheral and central monoaminergic systems ensures discriminative responses to individual stress modalities. Early experimental evidence for stress-induced changes in serotonergic neurotransmission has been extensively corroborated in subsequent pharmacological studies.19 Monitoring of serotonin synthesis, release, and receptor expression have provided valuable insight into the role of this transmitter in certain aspects of the behavioral

and neuroendocrine response to stress and the pathogenesis of stress-related disorders. Evidence for global activation of dopaminergic neurotransmission under stressful conditions and links to stress-related pathology suggests possible use of changes in this system for stress monitoring. These include morphological and functional heterogeneity of dopaminergic pathways, intricate involvement of dopaminergic transmission in selective information transfer, and motivation, integration, and adjustment of central nervous system (CNS) responses to novelty and aversion20; however, the appropriateness of dopamine-related end points in stress research requires careful evaluation. It should be noted that individual dopaminergic projections display differential degree of activation following stress, with the mesoprefrontal pathway being particularly vulnerable,21 and the character of changes in dopaminergic transmission might heavily depend on the context of stress and cross-modulation by multiple convergent neurotransmitter input and endocrine variables. Stressinduced changes in reward-mediating neurotransmitters and their interaction with other neurohumoral constituents of the stress response entail the possibility of using liability to addiction as a measure for the assessment of behavioral impact of stress. Activation of cerebral cholinergic transmission by stress has been documented, and its established roles in arousal, motivation, and cognition are suggestive of an involvement in the processing of stressful stimuli. Probably due to differential regional and temporal release patterns, as well as discordant observations on their coincidence with other physiological end points,22 changes in acetylcholine release are less frequently used as end points for stress evaluation. Dramatic stress-induced increase in extracellular levels of glutamate, the major excitatory amino acid transmitter, have been reported in numerous brain regions. Glutamate efflux in the prefrontal cortex has been implicated in the modulation of the dopamine response to stress, and an array of potential pathological consequences was outlined.23 Interactions between adrenocortical secretions and glutamate signaling in the hippocampus have prompted strong interest in the role of this neurotransmitter in long-term consequences of stress and their projections to various aspects of neuro- and psychopathology, as well as therapeutic strategies.24 Measurements of the synthesis and release of γ-aminobutyric acid (GABA) in the course of stress response have

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a long history; however, results are burdened by controversy, and the relevance of this end point in stress monitoring has been questioned.25 On the other hand, pharmacological modification of GABA-ergic transmission and measurement of changes in GABA receptor properties convincingly demonstrate a substantial involvement of GABA in the control of the stress response. The importance of GABA has been increasingly associated with anxiety and related defensive responses, as well as regulation of stress-specific neuroendocrine circuits.26 It is pertinent to note that several aspects of GABA-ergic neurotransmission can be obscured by endogenous steroid hormone derivatives, which act as allosteric ligands of the GABA-A receptor, and whose synthesis is increased following stress. These compounds have been shown to influence several aspects of the behavioral and neuroendocrine response to stress. Antinociceptive effects of endocannabinoids, evidence for stress-related changes in their release in discrete brain areas, and localization of cannabinoid receptors in neuronal populations that participate in the behavioral and endocrine response to stress have stimulated the interest in monitoring the activity of this system. Although the current prevailing view is that endocannabinoids play a pivotal role in the modulation of the stress response and neuroprotection, several contentious issues on the dynamics of these modulatory effects remain to be resolved.27 The causal involvement of endogenous opioids in stressinduced analgesia has been the starting point for extensive research on the global role of opioidergic transmission in stress. Ample evidence supports the view that opioidergic systems are profoundly affected by stress, and their secretory products participate in several aspects of the organism’s response. Alterations in the endogenous opioid tone are implicated in stress-related endocrine and autonomic responses.28 Anatomical and neurochemical heterogeneity of endogenous opioidergic systems, however, has made pharmacological paradigms a preferential approach for the investigation of stress-related changes in opioid neurotransmission. Observations of rapid induction of proto-oncogenes in distinct brain regions by various stress modalities led to the adoption of c-fos expression as a firm morpho-functional marker of stress exposure. Monitoring of c-fos induction is a reliable tool for the identification of neuronal populations affected by stress,29 and has significantly contributed to the delineation of neural pathways

involved in the stress response.3 The applicability of this method is, however, restricted to post-mortem examination; it should be also noted that signs of habituation of this response have been described, and controversy exists as to whether its magnitude reflects the stressfulness and intensity of the challenge. Nonetheless, monitoring of proto-oncogene induction may become an essential approach to the elucidation of spatiotemporal patterns in novel and less familiar models of stress. It should be mentioned that several neuropeptide systems in the brain are substantially affected by stress30 and, upon characterization of their distinct expression patterns in the selected paradigm, might eventually enrich the palette of neurochemical indicators. Endocrine end points Activation of the limbic-hypothalamo-pituitary-adrenal (LHPA) neuroendocrine axis is not only a “constant companion” of the stress response, but also provides the most reliable neurohumoral substrate for the assessment of its magnitude, dynamics and, ultimately, the capacity of the organism to overcome the present and meet subsequent challenges. As comprehensive work of reference has addressed the structural and functional organization and the regulation of the LHPA axis under stressful conditions,31 here we will focus on the conclusiveness of individual measures of its activity in models of stress. Input from stress-responsive neural circuits onto the hypothalamic paraventricular nucleus (PVN) induces the release of neuropeptide secretagogues of adrenocorticotropin (ACTH). Although stress-related fluctuations in corticotropin-releasing hormone (CRH) blood levels have been reported, its measurement in the systemic circulation has not attained widespread appreciation in laboratory animals. Monitoring of CRH concentrations in hypophyseal portal blood and, especially, perfusates and dialysates from defined brain regions is considered more reliable, and enables the distinction of CRH release from individual neuronal populations.3 The most popular approach, however, is the direct assessment of CRH neurons by either the “output” of the hypophyseotropic population to the median eminence or the “steady state” of the CRH gene expression. The latter gained importance also in view of evidence for multiple neurotropic effects of intracerebral projections of CRH neurons, beyond those involved in the neuroendocrine response to stress.32 CRH-coding transcripts in the parvocellular compart-

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Basic research Systemic glucocorticoid levels under quiescent conditions (eg, at the nadir and zenith of circadian activity), the amplitude of the acute stress-induced increase (albeit influenced by sex, age and diurnal time point of examination), and the sensitivity of the hypothalamopituitary unit for glucocorticoids (as defined by the swiftness of reinstatement of basal secretions after stress cessation or the capacity of exogenously administered glucocorticoids to subdue the diurnal secretory peak) comprehensively characterize the status of the LHPA axis (Figure 1). Stress profoundly affects reproductive function and gonadal secretions; however, changes in sex hormone levels following acute stress are not among the widely used monitoring end points. While there is unambiguous evidence that stress exposure impairs gonadal function and reproductive activity, the reserved use of measurements of gonadal secretions for the assessment of acute stress consequences is based on the complexity of neural mechanisms which control the key variable, the pulsatile discharge of gonadotropin-releasing hormone (GnRH)-producing neurons.38 On the other hand, decreased gonadotropin levels, suppressed secretion of gonadal steroids, disruption of the ovarian cycle, and inhibition of sexual behavior are consistent outcomes of chronic and

15’ Peak response

Serum corticosterone level

ment of the PVN are a good descriptor of LHPA axis activity under basal and stress-related conditions. Measurements of circulating vasopressin (AVP) levels have been used for assessment of stress responses; however, caution applies to their interpretation, due to the heterogeneity of the neuronal populations that produce AVP found in the circulation.33 Peripheral AVP originates mainly from the posterior pituitary terminals of magnocellular neurons of the supraoptic and the posterior-lateral portion of the paraventricular nucleus, and the involvement of these neuronal populations in the control of the LHPA axis is ambivalent.34 Thus, quantification of AVP expression in anatomically defined neuronal clusters, which make up the adenohypophyseal projection of the PVN, appears to be the method of choice for assessment of the contribution of vasopressin to the endocrine response to stress. Extensive research in the past has shown that stress-associated changes in CRH and AVP expression in the PVN follow distinct temporal patterns, with AVP “coming into action” with certain delay or in the course of chronic stress load.35 Oxytocin and angiotensin also deserve mention as auxiliary peptidergic ACTH secretagogues. Like AVP, oxytocin is produced in heterogeneous neuronal populations, and is released in response to various stressors in the systemic and adenohypophyseal portal circulation. Induction of oxytocin synthesis and secretion have been documented in various stress paradigms, and its role seems to extend beyond that of mere “booster” of CRH and AVP. However, while oxytocin is clearly a stress-responsive hormone, the interpretation of its “net” effect compels consideration of dissociated secretory activity of hypophyseotropic and intracerebral projections, subject’s sex and physiological condition, stress modality, and other interacting factors.36 Changes in angiotensin secretion represent an established component of the neuroendocrine response to stress, with multiple involvements in several aspects of allostasis.37 Increased concentrations of ACTH in the systemic circulation and its precursor peptide pro-opiomelanocortin (POMC) in the anterior pituitary are a typical consequence of stress exposure. While in acute stress ACTH responses fairly reflect the activity level of CRH neurons, chronic stress and continuous CRH hypersecretion result in desensitization of pituitary CRH receptors and blunted ACTH release. This dissociation between CRH hyperactivity and refractory corticotrophin responsiveness is a pathognomonic feature of stress-associated neuroendocrine dysregulation.

120’ Shut-off Diurnal zenith

Suppression of diurnal peak Dexamethasone injection

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Diurnal nadir + acute stress 0600 1200 Clock time

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Figure 1. Algorithm for the assessment of basal and stressinduced LHPA activity and its sensitivity to glucocorticoid negative feedback in the rat. The curve depicts the course of changes in serum corticosterone levels. Shaded areas indicate diurnal dark phases; bold and light symbols denote time points of blood sample collection and experimental interventions, respectively. LHPA, limbichypothalamic-pituitary-adrenal

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insuperable stress.39 Circulating prolactin levels promptly increase with acute stress40 and are a reliable endocrine end point, even if one abstains from reflective elaboration on the multiplicity of pathophysiological projections of stress-related hyperprolactinemia. Growth hormone secretion is altered by stress40; however, the pattern of changes may vary depending on the stress modality and require sophisticated evaluation. Alterations in thyroid axis function and hormone secretion following stress exposure have been described in various experimental settings. The reported consequences of acute stress are somewhat contradictory, as both activation and inhibition have been described. Suppression by chronic or uncontrollable stress41 is in line with the prevailing view of thyroid axis hypofunction in stress-related disorders; however, conflicting data exist also on this aspect. Immunological end points The immune system is unequivocally influenced by stress, and changes in various aspects of the inflammatory/ immune response have been extensively documented. Exposure to infectious agents or antigenic challenge are stressful stimuli per se, and trigger a cascade of reactions within an intricate network which encompasses several components of the humoral stress response. The changes in immunological parameters following nonimmune stressful stimuli, however, are mostly considered consequences of the activation of two fast-acting stress-responsive systems, the sympatho-adrenomedullary and the hypothalamo-pituitary-adrenocortical.42,43 In general, immunosuppression is an obvious and understandable effect of acute stress, whereas persistent activation of the LHPA axis under the condition of chronic stress is accompanied with substantial shift in the quality of the immune response.

Experimental approach to stress induction Physiological responses directed to restoration of the homeostasis and encompassing changes in several of the above-listed end points can be elicited by a myriad of environmental challenges and perturbations of the milieu intérieur. For the purpose of modeling, however, it is essential to demonstrate that a given challenge engenders traceable changes in (preferably, more than one) end points indicative of the occurrence of an allostatic response.

The most widely used classification of stress-inducing paradigms operates with two principal categories: systemic (physical) and neurogenic (psychoemotional), with conscious processing of the stimulus being the leading separation criterion.31 While adhering to this taxonomy, we will take the liberty to introduce, for didactic reasons, subcategories based upon the procedural features of the stress model. Naturalistic models of survival threat Deprivation paradigms Food deprivation (not to be confused with caloric restriction) produces alterations in numerous descriptors of the humoral and behavioral response to stress. While demonstration of rapid-onset responses requires consideration of species-specific circadian activity patterns, prolonged food deprivation produces long-term consequences which are compatible with those seen in chronic exposure to stress.44 Water deprivation and ensuing dehydration has been shown to elicit humoral changes suggestive of stressinduced LHPA axis activation.45 Similar effects can be rapidly triggered by osmotic challenge using intraperitoneal injections of hypertonic saline. Osmotic challenge is a reliable paradigm of stress induction, and repeated application is reportedly not accompanied by signs of response desensitization. Since dehydration selectively activates neuronal populations with a primary role in osmoregulation and only auxiliary contributions to the LHPA axis stimulation, explanation of mechanisms involved in the hormonal response suffers from a certain inconsistency. Deprivation of rapid eye movement (REM) sleep by different procedures is a recognized method of stress induction.There is firm evidence that prolonged sleep deprivation affects several physiological parameters in a fashion indicative of severe stress.46 In this paradigm initial responses can be largely ascribed to the encounter with a highly adverse and novel environment, whereas changes seen in the course of long-term exposure also reflect progressive exhaustion of adaptation-relevant systems. Restriction of the freedom of locomotion and exploration, better known and referred to as restraint or immobilization, is probably the most widespread method of stress induction (as judged by its reported use in more than 2000 publications). In any mode of application (single short-term, intermittent, chronic), restraint is per-

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Basic research ceived as a severe stressor, and robustly induces the entire spectrum of known allostatic responses.47 Exposure to adverse environmental stimuli Cold exposure (also cold-water swimming) causes noticeable activation of several stress-responsive systems.48 The magnitude of some changes suggests that cold environment is not a powerful stressor in adult rats, but is a reliable method of stress induction in neonates. Cold stress is consistently associated with activation of the thyroid axis, which probably serves thermogenesis. Significant neurochemical and endocrine responses have been documented in laboratory rodents following exposure to a hot environment.49 While the magnitude of changes seems to correlate with the abruptness of transition and the ambient temperature, their temporal dynamics is rather sluggish. Acute hemorrhage is a powerful signal for the activation of allostatic mechanisms. Induction of neurohumoral and endocrine responses by this systemic stressor has been extensively documented,50 whereas behavioral and metabolic alterations have not been systematically examined. Even if not associated with specific adverse stimuli, exposure to novel environment is a well-recognized naturalistic stressor, and changes in brain catecholamines and pituitary and adrenal secretions have been demonstrated. Less congruous are data concerning the dynamics of the hormonal response following repeated exposure and the direction of changes in hypothalamic peptide stimulators of ACTH release.51,52 Several environmental signals acting through different sensory modalities (auditory, visual, tactile) have been shown to elicit stress responses. Audiogenic stress (noise exposure) is a well-characterized paradigm, with response profiles of individual parameters having been thoroughly examined.53 Exposure to bright light or abrupt alteration of illumination rhythms are naturalistic stressors in laboratory rodents, and endocrine responses have been documented,54 though some mechanisms require elucidation. Responses induced by modification of the illumination regimen may be obscured by interference with established circadian and ultradian activity patterns of the involved physiological systems. The capacity of olfactory stimuli to elicit pronounced stress reactions is best exemplified by studies employing the paradigm of exposure to odors originating from either a predator or a stressed cospecific individual.

Odor-induced stress responses do not completely overlap with those seen after realistic encounter with a predator.55 The importance of olfactory stressors in experimental routine should be taken into consideration: whenever animals are sequentially stressed, the odor of the “predecessor” must be eliminated after completion of the test. Pain paradigms Nociceptive stimuli are among the most powerful inducers of stress responses. Although concerns of animal welfare have gradually diminished the use of pain-based paradigms, painful manipulations, such as electric footshock, tail pinch, and pharmacologically-induced hyperalgesia (formalin, carrageenan), have served for decades as fundamental approaches for stress induction and dependable manifestation of most of the known stress-associated reactions of the organism. Chronic pain of inflammatory or neuropathic origin produces consequences that show extensive similarities and share several mediators with chronic stress.56 Fear-and anxiety-based paradigms Exposure to a predator is a prototypic example for fearmediated stress induction, and the response profiles of several systems have been comprehensively elucidated.55 Intriguingly, repeated predator stress appears to promote a homotypic sensitization of neuroendocrine response mechanisms, with little evidence for a primary involvement of hypothalamic corticotropin secretagogue-producing neuronal populations.57 Albeit with certain exaggeration, the generic term neophobia summarizes the anxiogenic potential of a host of stimuli emerging from either the natural environment or the laboratory setting58 and their capacity to evoke measurable behavioral, neurochemical, endocrine, and metabolic stress responses. This intrinsic conflict between the drive for exploration of a novel environment and the assessment of the threatening potential of nonfamiliar stimuli is exploited for the generation of standard methods of fear- and anxiety-based stress induction.59 Conditioned anticipation of fearful experience is also a powerful tool for the induction of stress responses, and there is substantial overlapping of the anatomical substrates involved in unconditioned and conditioned fear. However, quantitative and, to a lesser degree, qualitative

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differences in the activation of distinct neural populations have been revealed,60 and the LHPA axis appears to have a crucial role in the emergence of conditioned fear. It should be mentioned that the degree of stress response resulting from the first (and, sometimes, also subsequent) exposure to experimental devices and procedures must be meticulously characterized and, if possible, minimized by handling, in order to avoid bias while measuring the "proper" outcome of a stress model. Models of social conflict and disruption Interactions within a cospecific group (population) are probably the most persistent source of stressful stimuli; however, in a colony of highly domesticated laboratory animals their impact often remains unaccounted, especially when using them as subjects in stress experiments. The baseline characteristics and the response profiles of end points used for stress assessment may critically depend on the individual's status within the rapidly formed social group hierarchy and/or his or her previous experience in this environment. Models based on social conflicts exploit either the aggravation of existing, or the de novo creation of, stressful interactions in the course of establishing and maintaining of hierarchic relationships of dominance or subordination. Specific conflict-producing experimental settings, such as territory defense (resident-intruder paradigm, colony overcrowding), hierarchy formation (social defeat, visible burrow system), offspring protection, and social instability are comprehensively reviewed.61 These paradigms produce strong alterations in several indicators of the stress response and, upon chronic application, the outcome may mimic the features of human pathological conditions. In rats there are pronounced sex differences in the liability to social stress, with females being generally refractory to paradigms of hierarchy formation, but responsive to conditions of social instability.62 Social isolation (solitary housing) has been considered an appropriate method for stress induction63; however, some caveats of this model merit consideration. Social isolation implies long-term deprivation of the familiar environment and, accordingly, immediate effects of separation can be ascribed to novelty and experimental procedures (eg, handling, restraint). Most consequences of social isolation become manifest after longer exposure periods. Finally, alterations in stress-related end points may be indicative of increased sensitivity to superim-

posed challenges rather than persistent activation of stress-responsive systems. Disruption of social contacts during early ontogeny, mostly referred to as maternal separation/deprivation, is a powerful stressor in several species. The reputation of this paradigm is based on its capacity to evoke long-lasting alterations in the function of several adaptation-relevant systems and their susceptibility to stress.64 A few marginal notes appear appropriate with regard to the practical use of this model. While immediate behavioral correlates (eg, vocalization) have been routinely used for monitoring the effects of maternal separation, the time course of endocrine responses to this stressor indicates that significant changes become apparent only after 2 to 4 hours of exposure, and their amplitude may vary depending on the age of the animals.65 Thus, although maternal deprivation is a recognized stressor, caution applies to the selection of parameters and timepoints for the assessment of its early consequences. Pharmacological models Accumulation of knowledge on neurohumoral systems, which participate in the processing of stressful stimuli and induction of related physiological reactions, enables the use of appropriate pharmacological agents to modify the activity of individual response cascade fragments and bring about changes in end-point indicators even in the absence of a prototypic stressor. Conceivably, druginduced alterations in the initial "links" of stress-reactive chains would result in a broader spectrum of "downstream" responses; however, as systems of allostatic regulation operate through closed-loop mechanisms, pharmacological modifications that interfere with feedback circuits are also capable of changing the activity level of several interconnected response cascades. Several pharmacological challenges are able to activate individual stress-responsive systems (eg, the LHPA axis). However, since stress is a complex and multipronged response, the list of pharmacological agents that can simultaneously influence several systems is rather short. The concomitant occurrence of pharmacologically induced responses in multiple systems involved in adaptation is exemplified by the effects of ether inhalation. This stressor produces behavioral agitation (before anesthesia takes place) and affects brain monoamine metabolism, and CRH and AVP biosynthesis and release. Likewise, glucoprivation induced by either insulin or 2-deoxyglucose

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Basic research administration results in distinct stress-like behavioral, neurochemical, and neuroendocrine alterations. Abundant experimental evidence shows that pharmacological modulation of the major neurotransmitter systems that inaugurate the response to stressful stimuli can mimic several behavioral and endocrine responses to stress. Approaches aiming at the activation of distinct aspects of monoaminergic neurotransmission have been impressively summarized66 and their efficacy convincingly demonstrated. The established role of GABA-ergic signaling as a major tonic inhibitor of stress responses provides plausible explanation for the capacity of GABA/benzodiazepine antagonists to induce several behavioral and endocrine correlates of stress or augment the responsiveness to systemic and emotional challenges.67 Although endogenous opioids definitely contribute to several aspects of the response to stress, divergent effects of opioid administration on neuroendocrine parameters, also due to intricate interactions with other neurotransmitter systems, appear to be somewhat at odds with the reigning opinion that opioids tonically suppress the LHPA axis.68 It is thus helpful to consider that the issue discussed herein concerns pharmacological effects with abrupt onset, which are not expected to produce immediately dramatic shifts in what is called “opioidergic tone.” An abridged statement in the context of this paper summarizes that (i) acute administration of morphine or receptor-selective opioid agonists results in distinct stresslike changes of neuroendocrine end points and (ii) similar phenomena occur after spontaneous or antagonistprecipitated withdrawal from chronic opioid treatment. As with several other opioid-sensitive systems, development of tolerance is accompanied by attenuated responsiveness of the LHPA axis to subsequent opioid administration. The effects of psychomotor stimulants, as exemplified by cocaine69 and amphetamine,70 include stress-like symptoms of behavioral disruption and defensive withdrawal and stimulation of hypothalamo-pituitary-adrenal secretions. Most of these effects and the stress-contrasting suppression of prolactin release are ascribed to their agonistic influence on central monoaminergic transmission. Elevation of circulating ACTH and glucocorticoid concentrations has been demonstrated following intracerebral cannabinoid treatment; however, the involvement of drug-specific signaling mechanisms remains unclear, as specific cannabinoid receptor antagonists have produced biphasic effects.

Alcohol administration powerfully stimulates the LHPA axis71 and potentiates defensive responses. As with opioids, endocrine changes in the course of chronic treatment are suggestive of the development of selective tolerance. In view of its essential role in the initiation and integration of behavioral, autonomic, and endocrine responses to stress, exogenous CRH dependably mimics several consequences of stressful stimuli. It should be added, however, that the stressogenic action of CRH is warranted following intracerebral administration, while some divergence (eg, in cardiovascular effects) may occur following systemic application.72 Despite compelling evidence for the involvement of vasopressin in several aspects of the stress response,73 administration of exogenous vasopressin has produced, at best, modest stress-like symptoms. Concerning the endocrine response, these observations are in agreement with the auxiliary role of vasopressin in the control of the LHPA axis. Continuing interest in the involvement of neuropeptides other than ACTH secretagogues in stress and emerging availability of selective analogues suggests novel possibilities for the use of such agents in pharmacological stress modeling.30,74 Persistent hypercorticalism has been shown to result in deterioration of neuroendocrine circuits that control the basal activity of the LHPA axis and its responsiveness to stressful challenges.4 This outcome can be brought about pharmacologically by long-term administration of supraphysiological doses of glucocorticoids. Although this approach is confined to the LHPA axis and manifestation of stress-related symptoms in other systems has not been meticulously examined, distinct signs of basal hyperactivity and exaggerated endocrine responses to stress persist in this model for several weeks upon cessation of the glucocorticoid treatment.75 A typical example of pharmacologically induced activation of several stress-reactive systems is represented by peptide mediators/integrators of the inflammatory and immune responses. The most frequently used agents are tumor necrosis factor α, interleukin-1 and interleukin6, or their sequential releaser, bacterial lipopolysaccharide (LPS). Endotoxin- or cytokine-induced effects involve a complex of typical defensive behavioral responses, referred to as “sickness behavior,” with vagal afferentation playing an essential role.76 Alterations in central and peripheral neurotransmission largely resemble those evoked by physical and neurogenic stress modalities,77 and activation of the LHPA axis is a firmly

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established consequence.78 Suppression of reproductive functions as part of the “sickness behavior,” and in terms of endocrine secretions79 has been demonstrated; it seems that cytokine-mediated disruption of the gonadal axis employs mechanisms which are independent of those involved in the general stress response. The reports on changes in growth hormone and prolactin secretion upon cytokine challenge are ambivalent. The list of drugs with stressogenic properties becomes considerably longer if LHPA axis activation is considered a solitary symptom of stress. Association of thyreotoxicosis with symptoms of hypercorticalism has prompted experimental studies showing that chronic administration of thyroid hormones leads to activation of the LHPA axis.80 Increased secretion of ACTH and glucocorticoids has been also seen following treatment with cholinomimetics, adenosine and histamine agonists, phosphodiesterase inhibitors, free fatty acids, and a high-fat diet. However, convincing evidence is still lacking that these agents are able to elicit a full-scale stress response. Genetic models Since stress is a transient condition, and its enduring presence is incompatible with survival, the following subject should be understood as models of increased stress responsiveness resulting from genetic manipulations or selective breeding. Breeding strategies aiming at the consolidation of behavioral traits suggestive of increased vulnerability to stress have yielded interesting models; however, concordant changes in multiple end points were not always observable. Thus, several rat strains which are typified by enhanced anxiety and dysproportionate behavioral responsiveness to stress displayed inconsistent signs of increased (Fawn-Hooded, Maudsley reactive, Roman high avoidance) or, even, paradoxically subdued (Syracuse low avoidance) LHPA axis activity. The behavioral repertoire of the Flinders Sensitive line reveals several symptoms of aberrant responsiveness, but abnormal hormonal reactions could be evoked only by specific pharmacological challenges. Similarly, animals selected for their predisposition to learned helplessness upon stress exposure are fulfilling several behavioral and neurochemical criteria,81 but establishment of endocrine correlates seems to depend on additional challenges during early ontogeny. Recent reports indicate that selective breeding based on the manifestation of enhanced anxi-

ety produces a phenotype that is characterized by dominance of defensive responses to novelty, increased ultrasonic vocalization, and amplified endocrine reactivity. In this rat line, increased activity of the LHPA axis appears to result from vasopressin overexpression and hypersecretion, and the phenotype apparently correlates with distinct signs of polymorphism in the vasopressin gene promoter.82 The most advanced approach to stress liability modeling is the targeted modifications of the expression of genes encoding individual components of stress-responsive cascades. Overexpression of monoamine-synthesizing enzymes, even in brain regions of specific importance, was not associated with a stress-prone phenotype.83 More successful were genetic modifications of mechanisms involved in the control of endogenous catecholamine release and metabolism. Genomic disruption of α2adrenoceptors resulted in behavioral and neurochemical phenotypes that resemble those seen following stress exposure or pharmacological interventions,84 but copresent endocrine alterations have not been reported. Similarly, increased behavioral responsiveness to stressful stimulin animals deficient for monoamine oxidase A85 and catechol-o-methyltransferase86 is not accompanied by corresponding changes in endocrine end points. Overexpression of inflammatory cytokines (interleukin6, leukemia inhibitory factor) and growth hormone has resulted in distinct symptoms of LHPA axis activitation which, however, have been ascribed to either altered adrenocortical sensitivity or improper pituitary development. The most compelling data have been obtained in studies with transgenics overexpressing CRH. The phenotype of these animals recapitulates most of the effects seen following CRH administration, such as increased anxiety and defensive behavior, impaired autonomic functions, immunosuppression, reproductive impairment, and LHPA axis hyperactivity under basal and post-challenge conditions.87 Genetic elimination of the CRH-binding protein resulted in behavioral symptoms compatible with increased CRH bioavailability, but failed to alter pituitary-adrenal secretions under basal and stress-related conditions.88 The crucial role of glucocorticoid receptor (GR) signaling in the tonic restraint and dynamic feedback control of the magnitude and duration of the neuroendocrine stress response, as well as its involvement in virtually every aspect of allostasis and adaptation,43 has prompted

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Basic research numerous investigations on the outcome of GR genetic modifications. The results have produced more questions than answers, thus illustrating the intricacy of neuroendocrine control of stress responsiveness. Partial or complete disruption of GR expression in the brain has consistently led to increased LHPA axis output; however, surprisingly, this was not accompanied by behavioral alterations (as disclosed by measures of anxiety)89; some signs of coincident behavioral and neuroendocrine impairment following targeted GR disruption were reported only recently.90 Brain-specific overexpression of GR had anxiogenic effects, but failed to alter the activity of the LHPA axis under both basal and stressful conditions.91 An elegant explanation of these confounding observations suggests that proper GR signaling in the brain not only controls the expression of stressogenic neuropeptides, but also ensures the correct detection of stress-induced adrenocortical output and its translation into defensive behavioral responses.92

The importance of sex and age Sex-related dichotomy has been recognized and extensively studied with regard to virtually every aspect of the stress response. Sympathoadrenal responses to stress93 and basal or stress-induced LHPA axis activity are higher in females, as long as physiological gonadal secretions are maintained (for review see ref 94). The neurobiological foundations for this dichotomy appear to be laid down during early ontogeny under the organizing influence of perinatal sex hormone levels.95 Glucocorticoid-sensing mechanisms in the female brain operate at lower discrimination thresholds, and female sex steroids seem to deflect the loss of sensitivity induced by autologous downregulation.94 Most of the listed differences are abolished by gonadectomy and reinstalled by hormone replacement, thus underlining the role of activating effects of physiological gonadal secretions.94,96 Interestingly, sex-specific differences in the magnitude of neurochemical and neuroendocrine responses do not correlate with the expression of defensive behavior. Several studies using various experimental paradigms indicate that stress-induced behavioral suppression and anxiety are rather a “male privilege.” Experimental data on sex differences in stress-related analgesia reveal that this phenomenon is predominantly expressed in males, and generally matches gender differences seen in the responsiveness to analgesic drugs. The abovementioned

sex differences in neuroendocrine responses to stress are not necessarily in accordance with observations in humans. Data from clinical studies are suggestive of stronger responsiveness in males,97 and these sex-specific profiles persisted under the condition of simulated hypogonadism.98 The robust female-specific response to stress in laboratory rodents is significantly attenuated during pregnancy, parturition, and lactation. Extensive research in the past has elucidated the joint causal contribution of various neurochemical and neuroendocrine mechanisms to this stress-protective phenomenon.99 During a defined phase of early ontogeny (between postnatal days 3 and 14) rats and mice display blunted pituitary-adrenal responsiveness to several stressors that are perfectly effective in adult animals. The mechanisms underlining this stress-hyporesponsive period have been exhaustively elucidated. Briefly, subdued hormonal secretions following stress are believed to reflect the immaturity of pituitary corticotropin synthesis,100 sluggish mobilization of adrenocortical steroidogenesis, and tight, pituitary-focused glucocorticoid-mediated control of the LHPA axis.101 Stress hyporesponsiveness during early ontogeny is not absolute, as it can be breached by cytokine, endotoxin, and pharmacological challenges or pre-exposure to maternal separation. There are changes in proto-oncogene expression in relevant areas, and the neonatal brain reacts to several stressful stimuli,102 but neuronal activation is apparently not translated into commensurate endocrine responses. The behavioral repertoire in infant animals is relatively poor, and does not provide many end point choices for the assessment of the stress response. Nonetheless, ultrasonic vocalization, a reliable sign of behavioral distress, is manifest also during the stress-hyporesponsive period. The LHPA axis function in senescent animals displays aberrations that are attributed to dwindling efficacy of GR-mediated feedback control. While age-dependent differences in the magnitude of the stress-induced secretory response occasionally become apparent after a single challenge, deficits in its termination can be readily disclosed in both acute and chronic paradigms. Impaired signal discrimination in glucocorticoid-sensing mechanisms is considered the principal cause for protracted duration of the secretory response to stress in aged animals. A few debatable issues affecting the use of aged subjects in models of stress should be mentioned. Data on LHPA function under basal conditions are contradic-

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tory,103,104 and there is little evidence that disinhibition of this endocrine axis becomes apparent during its circadian acrophase. Age-associated changes in the adrenocortical sensitivity and expression/secretion of CRH and AVP are also arguable. Although some discordance exists as to the response profiles of the sympatho-adrenomedullary system and brain monoamines in aged animals, the majority of published data suggests exaggerated and, in some cases, protracted increases, with possible aberrations depending on the stressor modality.105 Observations of reduced neophobia and anxiety (but also locomotion and exploration) in aged rodents106 is a further illustration of the difficulties on the way to an all-embracing view of age-associated control of stress responsiveness.

Translational aspects: models of stress as models of disease Assessment of individual aspects of the response to acute stress provides valuable information on the integrity of the major systems of vital importance for adaptation, as well as on the perception of a stimulus as a homeostatic threat. Usually, response deficiency is interpreted as a clue for the search of organic damage in the challenged system or, alternatively, a sign of negligible aversive property/hazard potential of the stressful stimulus. Rather than by its magnitude, the physiological dimension of a response to stress is defined by the organism's ability to terminate it upon cessation of the stimulus or by the implementation of adequate means to control it or avoid repeated exposure. Elimination of the latter prerequisites is readily achieved in stress paradigms employing enduring, variable, and nonpredictable challenges, whose common outcome is persistent activation and, ultimately, insuperable allostatic load. Rheostasis (set-point shifting) may postpone, but not prevent, exhaustion of adaptive capacity, and is probably the best indicator of the transition from norm to pathology. Achievement of persistent shift in set points of signal reading and thresholds of response initiation, and the resulting formation of self-potentiating vicious circuits describes the objectives of the generation of stress-based models of disease. These objectives can be achieved in several paradigms under the conditions of chronic, unpredictable, and uncontrollable exposure, but also by exploiting sex- and age-dependent set-point differences or their pharmacological or genetic modification.

The list of stress-related models that have been successfully used to establish approximate correlates of human disease is long and steadily growing. Evidence for the role of stress as (at the minimum) precipitating factor in depression and has encouraged the extensive transfer of stress paradigms into models of this disease. Posttraumatic stress disorder is another major area for the translational application of experimental stress models. Stress-based paradigms have a firm place in the arsenal of methods for realistic modeling of alcohol and drug addiction, withdrawal, and relapse. Knowledge accumulated in stress research has been implicated in models of eating disorders, aggression, and self-destructive behavior. Increasing understanding of specific stress-related consequences in vital physiological systems has opened new possibilities for the modeling of cardiovascular, gastrointestinal, and, more recently, metabolic conditions. The profound projections of stress to the regulation of the immune responsiveness and reproduction form a solid rationale for the use of stress paradigms in investigations of the pathogenesis of inflammatory/immune disorders and reproductive disturbance.

Conclusions: the perfect model Under laboratory conditions, stress can be readily emulated through numerous modalities. Nevertheless, stress modeling is associated with considerable problems casting doubts on the quality of results and the validity of conclusions. Several essential features of allostatic responses, such as variable amplitude, sensitization, and habituation, and complex interactions between their mechanisms preclude the existence of perfect models. Besides adherence to general precautions that guarantee the reproducibility of experimental data (eg, animal strain, sex, age, source, ambient conditions, staff skills, etc), preemptive consideration of certain issues may improve the design and performance of animal models of stress.What is the temporal profile of the selected outcome? Is the stressor capable of eliciting coincident changes in several systems? Are there confounding interactions between simultaneously activated responses? Can effects be obscured by physiological oscillations of the baseline of the selected parameter? Are the responses of interest subject to rapidly evolving habituation or cross-sensitization? What are the physiological limits of the system used for response monitoring? This catalogue can be extended depending on the experimental objective and investigator’s concerns.

429

Basic research Research areas with a long and successful history, such as the biology of stress, persuade scientists to rely unreservedly on the validity and reliability of frequently used "hallmark" techniques and experimental models. One of our intentions was to underline that the complexity of the stress response may produce variable outcomes, even in models that have been established for decades. Thus, adherence to the rule Sapiens nihil affirmat quod non

probat may prove more useful than recommendations in favor of, or dissuasion from, the use of specific models and end points. ❏ Please note that the reference list below is an abridged list; a full list of the references used for this article can be obtained by contacting the author: [email protected]

Modelos experimentales de estrés

Modèles expérimentaux du stress

La complejidad de la respuesta al estrés y sus manifestaciones polifacéticas son la linea conductora de esta revisión de paradigmas experimentales empleados para inducir estrés en animales de laboratorio. La descripción de las características fundamentales de los modelos, que están basados en los elementos estresantes naturales, provocaciones farmacológicas y manipulaciones genómicas se completa con un análisis extenso de los cambios fisiológicos, de comportamento, neuroquímicos y endocrinos y su idoneidad como criterios de evaluación. Se ha prestado especial atención a la importancia del sexo y la edad como determinantes de la dinámica de la respuesta al estrés. Se esbozan de forma sucinta las posibles aplicaciones translacionales de los paradigmas inductores del estrés como modelos de enfermedad.

Cette vue d’ensemble des paradigmes expérimentaux utilisés pour l’induction du stress chez les animaux de laboratoire a pour but d’illustrer la complexité de la réponse au stress et la multiplicité de ses manifestations. La description des caractéristiques clés concernant les différents modèles sont décrits, basés sur des stresseurs nature, sur des tests pharmacologiques ou sur des manipulations du génome, et sont complétés par une analyse détaillée des variations physiologiques, comportementales, neurochimiques et endocriniennes et de leur intérêt pour les résultats qui en découlent. Le rôle du sexe et de l’âge, en tant que déterminants de la dynamique de la réponse au stress, a été particulièrement étudié. La possibilité d’appliquer ces paradigmes d’induction du stress aux modèles pathologiques est brièvement évoquée.

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Clinical research Genetics of stress response and stress-related disorders Marcus Ising, PhD; Florian Holsboer, MD, PhD

R

ecent advances in molecular genetics have stimulated basic and clinical research, and opened up access to hypothesis-driven and unbiased genetic approaches.With knowledge of the genes involved in complex basic functions like the stress response, and of multifactorial diseases like stress-related disorders, we can improve our understanding of the mechanisms and moderators involved in the biology of normal and altered stress response, which in turn will help to identify new drug targets and interventions for stress-related disorders.

Stress response and stress-related disorders Though there is no generally accepted definition, stress is usually defined as a state of disturbed homeostasis evoking a multiplicity of somatic and mental adaptive reactions, which are summarized as stress response aimThe major findings regarding the genetics of stress response and stress-related disorders are: (i) variations in genes involved in the sympathetic system or in the hypothalamic-pituitary-adrenocortical axis are associated with altered stress responses; (ii) genes related to the renin-angiotensin-aldosterone system or inflammation/immune response show associations with cardiovascular disorders; (iii) genes involved in monoaminergic neurotransmitter systems are associated with bipolar disorder and unipolar depression. The vast majority of these association studies followed a conventional hypothesis-driven approach, restricting the gene selection to established candidates. This very conservative approach retarded our understanding of the complex interplay between genetic factors, stress response, and stress-related disorders. Chip-based whole-genome technologies will open up access to new unbiased and statistically efficient approaches that will help to identify new candidate genes, which should be thoroughly validated in clinical and preclinical confirmatory studies. This, together with the use of new text- and information-mining tools, will bring us closer to integrating all the findings into sophisticated models delineating the pathways from genes to stress response and stress-related disorders. © 2006, LLS SAS


Keywords: stress; cardiovascular disorder; bipolar disorder; unipolar depression; genetics; sympathetic system; hypothalamic-pituitary-adrenocortical axis; reninangiotensin-aldosterone system

Address for correspondence: Marcus Ising, PhD, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, D-80804 Munich, Germany (e-mail: [email protected])

Author affiliations: Max Planck Institute of Psychiatry, Munich, Germany Copyright © 2006 LLS SAS. All rights reserved

433


Clinical research Selected abbreviations and acronyms ACTH AVP CRH DEX GR HPA MR RAAS TSST

adrenocorticotropic hormone, corticotropin (arginin)-vasopressin corticotropin-releasing hormone dexamethasone glucocorticoid receptor hypothalamic-pituitary-adrenocortical mineral corticoid receptor renin-angiotensin-aldosterone system Trier Social Stress Test

ing to reconstitute the initial homeostasis or allostasis,1 ie, a new level of homeostasis after successful adaptation.2 The pioneer of stress research, Hans Selye, claimed a stimulus-independent nonspecificity of the stress response3,4 which has been criticized by others.1,5,6 Nevertheless, different kinds of stressors, physical and psychosocial, lead equivocally to a rapid activation of the sympathetic nervous system followed by a stimulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Successful coping with stress implies an appropriate regulation of the stress response and an effective termination when the stress is over or the individual has adapted to the new conditions.

The perception of a stressful situation activates a large number of neuronal circuits in the prefrontal cortex and limbic system, including the hypothalamus, where the sympathetic nervous system is activated; this in turn leads to a widespread release of noradrenalin from the postganglionic fibers and to the release of adrenalin (and noradrenalin) from the adrenal medulla. Additionally, the parvocellular neurons of the hypothalamus are stimulated to secrete the neuropeptides corticotropin-releasing hormone (CRH) and vasopressin (AVP) into the portal vessel system to activate the synthesis and release of corticotropin (ACTH) from the anterior pituitary. ACTH, in turn, stimulates the adrenal cortex to synthesize and release glucocorticoids, in particular cortisol (in humans). These hormones have a multiplicity of functions, which are necessary for the adaptation to acute stress, but can be pathogenic when the organism is persistently exposed. Therefore, a fine-tuned regulation of the sympathetic system and of the HPA axis is essential to avoid the development of a pathological dysregulation that can progress to stress-related disorders, which can be defined as illnesses whose causation, onset, or development is substantially influenced by stress and its neurobiological correlates. Among others, cardiovascular dis-

Normal regulation

Dysregulation = Glucocorticoid receptor = Minereralocorticoid receptor

+

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Figure 1. Model for normal and impaired regulation of the HPA axis. HPA, hypothalamic-pituitary-adrenocortical; CRH, corticotropin-releasing hormone; AVP, arginin-vasopressin; POMC, pro-opiomelanocortin; ACTH, adrenocorticotropic hormone

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Genetics of stress - Ising and Holsboer

orders such as hypertension and coronary artery disease, as well as psychiatric diseases such as bipolar disorder and unipolar depression, are examples of stress-related disorders that will be discussed in this review. The main central structure for the regulation of the autonomic nervous system is the hypothalamus, which receives input from cortical and subcortical structures, as well as from peripheral receptors and organs. The primary regulatory elements of the HPA axis are the corticosteroid receptors, glucocorticoid receptors (GR), and mineral corticoid receptors7 (for details see ref 8). As indicated in the left panel of Figure 1, activation of the HPA axis leads to the secretion of cortisol (in humans), which induces a negative feedback inhibition to CRH and AVP (at the level of the hypothalamus) and to ACTH (at the level of the anterior pituitary). Impaired corticosteroid signaling results in an attenuation of the negative feedback inhibition, which could result in the failure to sufficiently suppress CRH and AVP release from the hypothalamus and ACTH from the anterior pituitary, which in turn leads to chronically elevated levels of cortisol (Figure 1, right panel). The attenuated negative feedback inhibition can be most sensitively diagnosed with a neuroendocrine challenge test of the HPA axis, the combined dexamethasone (dex)/CRH test.9 In this test, the stimulating effects of 100 µg intravenous human CRH upon ACTH and cortisol are examined under the suppressive action of 1.5 mg of dexamethasone.10,11 This test is sensitive to impaired GR signaling at

Cortisol (ng/mL)

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40 Recurrent depression (N=209) Single episode (N=77) Chronic depression (N=37) Controls (N=81)

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16.00

16.15

Time Figure 2. Cortisol response to the combined dex/CRH test is elevated in depression (AUC, P<.001) suggesting dysregulation of the HPA axis due to impaired glucocorticoid signaling. Dex, dexamethasone; CRH, corticotropin-releasing hormone; HPA, hypothalamic-pituitary-adrenocortical; AUC, area under the curve

the pituitary level, as well as to the effects of increased secretion of the hypothalamic neuropeptides CRH and AVP, which is a consequence of impaired central GR signaling.8,12,13 Impaired HPA axis regulation during an acute episode is the most consistent laboratory finding in depression and bipolar disorder (see refs 13 to 15 for reviews), which corresponds to the concept of stress-related disorders. Accordingly, the majority of depressed patients exhibit an exaggerated ACTH and cortisol response to the combined dex/CRH test (Figure 2). These alterations were shown to normalize after successful antidepressant treatment,11,16-18 suggesting that altered HPA axis regulation and its normalization is involved in the pathogenesis of and recovery from depression, respectively.

Genetics of stress response Evidence for heritability is a prerequisite for the involvement of genetic factors. The most efficient way for evaluating heritability is twin studies comparing phenotypical similarity between monozygotic and dizygotic twins. Twin data are available for the Trier Social Stress Test (TSST),19 which is a standardized procedure for the assessment of the psychosocial stress response. Briefly, this test comprises a public speaking task involving a mock job interview and a mental arithmetic task. Subjects are asked to prepare a presentation for promoting their candidacy for a position that is tailored to their education. After the preparation time, subjects give their presentation in front of a panel of judges who are evaluating the talk. After 5 minutes, subjects are requested to perform an unexpected mental arithmetic task for a further 5 minutes. HPA axis activity (plasma ACTH and cortisol and/or salivary cortisol) is evaluated before and after the tasks as well as during recovery. Federenko and coworkers20 reported a heritability estimate (h2) of 0.32 for the plasma cortisol response to the TSST in 33 monozygotic and 25 dizygotic twin pairs, suggesting moderate heritability, but this increased up to 0.98 in two repetitions of the test. Heritability estimates for ACTH and salivary cortisol were distinctly smaller in the first test session, but increased markedly in the repeated test sessions. A previous study by Kirschbaum and coworkers21 with 13 monozygotic and 11 dizygotic twin pairs also reported only marginal heritability for the salivary cortisol response to a single administration of the

435

Clinical research TSST. High heritability was observed for salivary cortisol after stimulation with 100 µg human CRH (without dex suppression) and no heritability was found for the salivary cortisol response to strenuous physical exercise (ergometer activity).21 200 Depression Unaffected HRP Unaffected HRP 4 years later Healthy controls

Cortisol (nmol/L)

160

120

100 µg hCRH

80

40

0 14.30

14.45

15.00

15.15

15.30

15.45

16.00

16.15

16.30

Time Figure 3. Cortisol response to the combined dex/CRH test is moderately elevated in high risk probands for affective disorders (AUC, P<.05), which was stable over time at the group level (AUC, P=.758) as well as at the individual level (Pearson correlation, r=.51, P<.05) in a follow-up investigation 4 years later. Dex, dexamethasone; CRH, corticotropin-releasing hormone; AUC, area under the curve Genes Psychosocial stress response Glucocorticoid receptor (GR, NR3C1)

GABA(A) α6 receptor subunit (GABRA6) Opioid receptor µ1 (OPRM1)

Chromosomal position 5q31.3

5q34 6q24-q25

Endocrine HPA challenge tests Glucocorticoid receptor (GR, NR3C1)

5q31.3

Angiotensin-converting enzyme (ACE)

17q23.3

Brain-derived neurotrophic factor (BDNF)

11p13

No heritability data are available for the combined dex/CRH test. However, in the Munich Vulnerability Study,22,23 the combined dex/CRH test was conducted in healthy first-degree relatives of patients with a major depressive disorder, who are assumed to carry a genetic vulnerability for affective disorders. These so-called high-risk probands (HRPs) are characterized by a moderately elevated hormonal response to the combined dex/CRH test, which was significantly higher compared with controls without a personal or familial history of psychiatric disorders, but less pronounced compared with the response in acutely depressed patients. Modell and coworkers24 replicated these findings in still unaffected HRPs who were re-examined in a follow-up investigation about 4 years later (Figure 3), suggesting that this trait-like impaired regulation of the HPA system could reflect the genetic vulnerability for affective disorders in these subjects. Despite the statistical evidence for a considerable heritability of the stress response, the number of significant genetic findings is small, and the conclusiveness rather limited. The findings are summarized in Table I. Due to the importance of the HPA system for the stress response, which is primarily regulated by GR, the GR gene has been proposed as the primary candidate for the

Results

Combined BclI and N363S polymorphisms associated with salivary cortisol response to psychosocial stress (Trier Social Stress Test, TSST) in male mono- and dizygotic twins25; replicated in male unrelated subjects but not in female subjects (Kumsta and Wüst, 2006; personal communication) T1521C polymorphism associated with ACTH, cortisol, and blood pressure response to psychosocial stress (TSST) in healthy subject26 A118G polymorphism associated with cortisol response to psychosocial stress (modified TSST) in healthy subjects27 BclI and N363S polymorphisms associated with ACTH and cortisol suppression after oral low-dose dexamethasone (dexamethasone suppression test) in elderly subjects28,29 Insertion/deletion polymorphism associated with hormonal response to the combined dexamethasone suppression/CRH stimulation test in acute major depression30,31 Val66Met polymorphism associated with ACTH and cortisol response to the combined dexamethasone suppression/CRH stimulation test in acute depression23

Table I. Genetic associations with stress response in human paradigms. GABA, γ-aminobutyric acid; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; HPA, hypothalamic-pituitary-adrenal

436



genetic association studies. Significant associations between GR and psychosocial stress response were reported, but only when a haplotype approach is applied25 or when male subjects are separately analyzed (Kumsta and Wust, 2006; personal communication). Further genetic associations, not yet replicated, are reported for the γ-aminobutyric acid (GABA) A 6 receptor subunit gene26 and for an nonsynonymous exon single-nucleotide polymorphism (SNP) of the micro-opioid receptor 1 (MOR) gene.27 Additional evidence for an involvement of the GR gene in the genetics of the stress response has been provided by two other studies (Table I) employing a low-dose dex suppression test in elderly subjects.28,29 In this test, plasma cortisol levels after oral administration of dex are interpreted as an indicator for GR sensitivity, which is the major regulator of the stress hormone activity at the pituitary level. Two other studies in patients suffering from major depression30,31 reported associations between the angiotensin-converting enzyme (ACE) gene and the hormonal response to the combined dex suppression/CRH stimulation test, which is the most sensitive challenge test for evaluating stress hormone regulation. ACE is involved in the so-called reninangiotensin cascade of water regulation, which in turn affects blood volume and blood pressure. A recent study observed an association between the combined dex/CRH test and brain-derived neurotrophic factor (BDNF) in depressed patients, which has been interpreted as evidence for an involvement of a reduced neuroplasticity in the development of disturbed HPA axis regulation.23 Taken together, there are only a limited number of studies examining the association between candidate genes and the stress response. Besides genes involved in the sympathetic (ACE) or HPA axis-mediated (GR) stress response, further genes constituting different biological systems implicated in emotional regulation26 and neuroplasticity (BDNF) have been examined. However, the results show only moderate effect sizes, although heritability estimates suggest a strong involvement of genetic factors. Further evidence for genes involved in the regulation of the stress response could be provided by clinical studies investigating genetic vulnerability factors for stress-related disorders. These genetic risk factors are assumed to be responsible for an inappropriate response to repeated and/or continuous stress and thus for mediating the vulnerability for stress-related disorders.

Genetics of stress-related disorders A large number of diseases can be understood as stressrelated disorders, and most of them are characterized by an at least moderate heritability. In this review, we focus on the most prevalent stress-related disorders, hypertension and coronary artery disease, as examples of cardiovascular disorders, and on bipolar disorder and unipolar depression as examples of psychiatric disorders. Cardiovascular disorders are the leading cause of mortality in the Western world, and are projected to become the leading cause of disease burden worldwide in 2020.32 Essential hypertension is the most common cardiovascular disorder, with a lifetime prevalence of above 50% in most western communities, affecting approximately 1 billion individuals worldwide33; heritability estimates around 30% have been reported.34 Myocardial infarction is a serious outcome of coronary artery disease. Twin studies suggest that the risk for myocardial infarction is fairly heritable, with a heredity estimate of 60% in females and 26% in males.35 A large number of case-control association studies in essential hypertension are available (Table IIa) focussing on a number of candidate gene systems. The majority of findings have been obtained with candidates from the sympathetic system, including adrenergic genes, genes of the renin-angiotensin-aldosterone system (RAAS), and genes involved in vascular regulation. Despite the large number of studies, only a few associations can be regarded as convincing, including the associations with the angiotensinogen (AGT), aldosterone synthase (CYP11B2), and with the renin (REN) gene, all involved in the RAAS. Several studies report gene x gene interaction effects, eg, between the endothelin 1 (EDN1) and serotonin receptor 2a (5HTR2A) genes,69 and between the ACE, aldosterone synthase (CYP11B2), and α adductin (ADD1) genes.42 Several candidate genes from other biological systems (eg, DRD2, GNB3, ACSM3) have been proposed, but no unambiguous conclusion can yet be drawn from the findings from these studies. As for hypertension, a large number of genetic association studies have also been conducted for coronary artery disease. However, the results are more difficult to interpret than in hypertension, since different clinical conditions, including myocardial infarction and arteriosclerosis/stenosis, are integrated as coronary artery disease. Most candidate genes showing replicable associations

437

Clinical research have been derived from the concept of inflammation as a major risk factor for coronary heart disease. Convincing evidence for genetic associations has been reported for genes involved in innate immunity or genes moderating the inflammatory reaction, such as leukotrienes and lymphotoxins (Table IIb). The number of positive results outweighs the negative findings, and most effect sizes were in an at least moderate range. Nevertheless, not all candidate genes derived from potent endophenotypes show convincing associations. One example of this divergence is lipoprotein A, which has been identified as a potent vulnerability factor for coronary artery disease,98 even though there is only a little evidence for a genetic association of the lipoprotein A (LPA) gene. Further gene candidates have been derived from studies in mendelian disorders involving premature coronary artery diseases such as familial hypercholesterolemia, familial defective apolipoprotein B (APOB), sitosterolemia, and Tangier disease. An overview of these findings is provided by Watkins and Genes

Chromosomal position

Adrenergic system β2-adrenoceptor (ADRB2)

5q31-q32

β3-adrenoceptor (ADRB3)

8p12-p11.2

Renin-angiotensin-aldosterone system Angiotensin-converting enzyme (ACE) Angiotensinogen (AGT) Aldosterone synthase (CYP11B2) Angiotensin (AT1) receptor (AGTR1) α Adductin (ADD1) Atrial natriuretic peptide (NPPA, NPPB) Renin (REN) 11β-hydroxisteroid dehydrogenase 2 (HSD11B2) Vascular system Endothelin 1 (EDN1)

17q23.3 1q42-q43 8q21-q22 3q21-q25 4p16.3 1p36.2 1q32 16q22 6p24.1

Nitric oxide synthase (NOS3) Other genes D2 receptor (DRD2)

7q36 11q23

G protein β3 subunit (GNB3) SAH (ACSM3)

12p13 16p13.11

Farrall.99 However, the translation of these findings to multifactorial cardiovascular disorders is limited. Besides cardiovascular diseases, bipolar disorder and unipolar depression are further examples of burdensome stress-related disorders with a distinct heritability and a high prevalence in the general population, especially unipolar depression, which is projected to become the second leading cause for disease burden in 2020.32 Lifetime prevalence of bipolar disorder is around 1% according to population-based epidemiological studies in Europe100 as well as in the US,101 while lifetime prevalence of unipolar depression is distinctly higher, with a similar rate of 17% in Europe and in the USA. Twin studies suggest a high heritability for bipolar disorder, with heritability estimates, h2, ranging between 80% and 90%, and a moderate heritability for unipolar depression with h2 between 33% and 42%.102 Most candidate genes for association studies with bipolar disorder and unipolar depression have been derived from neurotransmitter systems involved in antidepres-

Results

Significant associations reported in Caucasian36,37 and Asian populations,38 but also several negative findings39 Significant associations reported in Caucasian population40 and in male type 2 diabetics41 Significant small to moderate effects,42-45 but also several negative reports40,46-48 Largest number of positive studies,47,49,50 but also some negative findings51 More positive52-56 than negative57 reports Mixed results, positive findings49 as well as negative reports44 Mixed results, positive findings58 as well as negative reports51 Less positive findings59 than negative reports60,61 Predominance of positive findings62-64 Weak positive effects are reported65,66 Significant association with blood pressure in obese subjects;67,68 some evidence for association with hypertension69; in interaction with 5-HTR2A Less positive findings70 than negative reports71,72 Associated with hypertension73 and with elevated blood pressure in personality disorder74 Less positive findings75 than negative reports51,54,76 Mixed results, positive findings77 as well as negative reports78

Table IIa. Replicated findings of genetic associations with hypertension. 5-HT, serotonin; SAH, SA hypertension-associated homolog

438



sant drug action. Only some of the findings could be consistently replicated, including associations between the monoaminoxidase A (MAOA)103 and catechol-o-methyltransferase (COMT) gene and bipolar disorder and tryptophan hydroxilase 2 (TPH2) gene and unipolar depresGenes Innate immunity CD14 molecule (CD14) Toll-like receptor 4 (TLR4)

Chromosomal position 5q31.1 9q32-q33

Leukotrienes Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) Leukotriene A4 hydrolase (LTA4H)

12q22

Other genes Lymphotoxine α (LTA)

6p21.3

Galectin 2 (LGALS2)

22q13.1

13q12

sion (Table III). Further conclusive evidence exists for an involvement of the D-aminoacidoxidase activator DAOA (G72)/G30 locus in the susceptibility for bipolar disorder, but also for schizophrenia. A large number of studies have examined the genetic associations between

Results

Significant associations with myocardial infarction,79-81 but also negative reports82,83 Significant associations reported for acute coronary events84 and myocardial infarction85,86 but not with coronary stenosis87 Evidence for an association with myocardial infarction88,89 and arteriosclerosis90 Significant association with ethnicity-specific risk for myocardial infarction in different ethnic samples91 Significant association with myocardial infarction in Japanese populations92,93 as well with arteriosclerosis in Caucasians,94 but also negative reports95,96 Associated with myocardial infarction97; protein interacts with LTA

Table IIb. Replicated findings of genetic associations with coronary artery disease. Genes Bipolar disorder Monoaminoxidase A (MAOA) Catechol-o-methyltransferase (COMT) 5-HT transporter (SLC6A4) D-aminoacidoxidase activator DAOA (G72) / G30

Chromosomal position 5q31.3 22q11.21 17q11.1-q12 13q33-q34

Brain-derived neurotrophic factor (BDNF)

11p13

P2X ligand-gated ion channel 7 (P2RX7) Unipolar depression Tryptophan hydroxilase 2 (TPH2) 5-HT transporter (SLC6A4)

12q24 12q21.1 17q11.1-q12

Glucocorticoid receptor (NR3C1)

5q31.3

P2X ligand-gated ion channel 7 (P2RX7)

12q24

Results

Significant associations with a modest effect size confirmed by metaanalyses103,104 suggesting greatest effects in female patients Meta-analysis revealed a modest effect size105,106 and has been suggested as a common susceptibility gene for bipolar disorder and schizophrenia107 A number of positive studies108-111 confirmed in meta-analyses,112,113 but also negative studies for 5-HTTLPR,114 one negative meta-analysis105 Several positive reports with polymorphisms in the proximity of these nested genes,7,115-117 but also with schizophrenia, suggesting a common susceptibility locus118 Family-based association studies showed significant effects119,120 but most replication studies were negative121-124; one study suggested association with a subgroup of patients displaying rapid cycling124 Significant associations reported125,126 Significant associations with major depression127,128 and suicide129 More depressive symptoms in carriers of the short 5-HTTLPR allele,130,131 but also negative reports114,132 BclI and ER22/23EK polymorphisms associated with susceptibility to recurrent unipolar depression133 Significant associations with unipolar depression reported134,135

Table III. Replicated findings of genetic associations with bipolar disorder and unipolar depression. 5-HT, serotonin

439

Clinical research polymorphisms in the serotonin (5-HT) transporter (SLC6A4) gene and bipolar disorder and unipolar depression. Most attention focused on a functional insertion/deletion polymorphism in the promoter region to SLC6A4, known as 5HTTLPR. Despite several positive results, the number of negative replications is increasing, and the relevance of this polymorphism for the susceptibility to bipolar disorder or unipolar depression is meanwhile being challenged. Besides SLC6A4, P2X ligand-gated ion channel 7125 is the only gene showing replicated effects for susceptibility to both bipolar disorder and unipolar depression. This gene codes for a cation-selective ion channel expressed in central glial cells as well as in neurons, and is assumed to regulate immune function and neurotransmitter release.136,137 In summary, genetic association studies in stress-related disorders have provided evidence for an involvement of several other genes not identified by basic genetic studies on stress response. Since an inappropriate response to repeated and/or continuous stress mediates the susceptibility to stress-related disorders, these genes are also assumed to moderate the stress response. We have reviewed genetic association studies in hypertension, coronary artery disease, bipolar disorder, and unipolar depression. Due to the large and rapidly increasing number of publications, it is impossible to provide a complete overview. However, we have tried to summarize the most consistent and most frequently discussed findings. It is important to note that different classes of candidate genes have been investigated in the four diagnostic groups reported in this review, despite their common relationship to stress and inappropriate stress response. While candidate genes in hypertension and coronary artery disease are primarily related to the RAAS and to inflammation/immune response, respectively, the majority of candidate genes in bipolar disorder and unipolar depression are derived from monoaminergic neurotransmitter systems. This makes it clear that our actual knowledge of the complex interplay between genetic fac-

tors, altered stress response, and stress-related disorders is still limited, and that further research and new approaches are required to improve our understanding of these complex functions.

REFERENCES

4. Selye H. Stress and the general adaptation syndrome. BMJ. 1950;4667:1383-1392. 5. Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA. 1992;267:1244-1252. 6. Mason JW. A re-evaluation of the concept of “non-specificity” in stress theory. J Psychiatr Res. 1971;8:323-333. 7. Schumacher J, Jamra RA, Freudenberg J, et al. Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. Mol Psychiatry. 2004;9:203-207.

1. Pacak K, Palkovits M. Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev. 2001;22:502148. 2. McEwen BS. Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology. 2000;22:108-124. 3. Selye H. A syndrome produced by diverse nocuous agents. Nature. 1936;138:32.

Conclusion and outlook The summarized findings do not provide an exhaustive and satisfying answer about the genetics of stress response and stress-related disorders. Many single findings are still unconnected, and the restriction of the gene selection to established candidates has retarded our understanding of the complex interplay between genetic factors, stress response, and stress-related disorders. Sophisticated models, especially those aiming to integrate the findings from basic and clinical research as well as from the different types of stress-related disorders, are required to close the gap in our knowledge. The new chip-based whole-genome technologies, Affymetrix GeneChip and Illumina Genotyping BeadChip, are powerful tools for this endeavor. With this technology, the advantages of an unbiased approach as provided by linkage analysis, and the statistical power of association studies are combined to identify new candidate genes. However, results from unbiased approaches are always preliminary, and require validation in confirmatory studies. This means that independent replication studies are needed, but also clinical studies taking gene x gene and gene x environment interactions into account. For causal inferences, preclinical experiments are required, including (conditional) genetic modification and the development of specific compounds as research tools for the protein targets. Finally, text- and information-mining tools, which are already available but have to be further developed, will be very helpful to integrate all findings into sophisticated models delineating the pathways from genes to stress response and stress-related disorders. There is still a long way to go—but the prerequisites for success are more present than ever. ❏

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Genetica de la respuesta al estrés y de los trastornos relacionados con el estrés

Génétique de la réponse au stress et des troubles liés au stress

Los descubrimentos principales en la genética de y de los trastornos relacionados con el estrés son: i) las variaciones de los genes implicados en el sistema simpático o en el eje hipotálamo-hipófisis-corteza suprarrenal están asociadas con respuestas alteradas al estrés; ii) los genes relacionados con el sistema renina-angiotensina-aldosterona o la respuesta inflamatoria/inmunitaria están asociados a los trastornos cardiovasculares; iii) los genes implicados en los sistemas neurotransmisores monoaminérgicos están asociados al trastorno bipolar y a la depresión unipolar. La inmensa mayoría de estos estudios de asociación siguieron un enfoque convencional, impulsado por hipótesis, lo que restringe la selección de genes candidatos conocidos. Este método tan conservador ha retrasado el conocimiento de la interrelación compleja entre los factores genéticos, la respuesta al estrés y los trastornos relacionados con éste. Las tecnologías de chip para el estudio de todo el genoma abrirán las puertas a métodos nuevos, objectivos y eficaces, lo que estadísticamente permitirá identificar nuevos genes candidatos que serán validados minuciosamente en estudios confirmatorios clínicos y preclínicos. Todo ello, sumado al uso de nuevos instrumentos para la explotación de texto e información, nos ayudará a integrar todos los datos dentro de modelos complejos que delimiten las vías desde los genes hasta la respuesta al estrés y los trastornos relacionados con el estrés.

Voici les principaux résultats sur la génétique de la réponse au stress et des troubles liés au stress: 1) les variations des gènes impliqués dans le système sympathique ou l’axe hypothalamo-hypophyso-surrénalien sont associées à des anomalies de la réponse au stress ; 2) les gènes liés au système rénine-angiotensine-aldostérone ou à une la réponse inflammatoire/immune sont associés avec des maladies cardiovasculaires ; 3) les gènes impliqués dans les systèmes de neurotransmission monoaminergiques sont associés aux troubles bipolaires et à la dépression unipolaire. La grande majorité de ces études d’association a suivi une approche conventionnelle hypothético-déductive, limitant donc la sélection des gènes aux candidats établis. Cette approche très conservatrice a retardé notre compréhension des interactions complexes entre les facteurs génétiques, la réponse au stress et les troubles liés au stress. Les technologies de puce à ADN sur le génome entier ouvriront la voie à de nouvelles approches non biaisées et statistiquement efficaces qui permettront d’identifier de nouveaux gènes candidats. Ces derniers devront être minutieusement validés dans des études cliniques et précliniques de confirmation. Ces technologies, associées à de nouveaux outils d’analyse des textes et des informations, nous permettront d’intégrer plus facilement tous les résultats dans des modèles sophistiqués précisant les voies qui vont des gènes à la réponse au stress et aux troubles liés au stress.

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82. Nauck M, Winkelmann BR, Hoffmann MM, Bohm BO, Wieland H, Marz W. C(-260)T polymorphism in the promoter of the CD14 gene is not associated with coronary artery disease and myocardial infarction in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Am J Cardiol. 2002;90:1249-1252. 83. Koch W, Kastrati A, Mehilli J, von BN, Schomig A. CD14 gene -159C/T polymorphism is not associated with coronary artery disease and myocardial infarction. Am Heart J. 2002;143:971-976. 84. Ameziane N, Beillat T, Verpillat P, et al. Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arterioscler Thromb Vasc Biol. 2003;23:E61-E64. 85. Edfeldt K, Bennet AM, Eriksson P, et al. Association of hyporesponsive toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J. 2004;25:1447-1453. 86. Pasterkamp G, Van Keulen JK, De Kleijn DP. Role of Toll-like receptor 4 in the ini-tiation and progression of atherosclerotic disease. Eur J Clin Invest. 2004;34:328-334. 87. Yang IA, Holloway JW, Ye S. TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis. Atherosclerosis. 2003;170:187-190. 88. Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thor-steinsdottir U, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. 2004 36:233-239. 89. Helgadottir A, Gretarsdottir S, St Clair D, et al. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet. 2005;76:505-509. 90. Dwyer JH, Allayee H, Dwyer KM, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350:29-37. 91. Helgadottir A, Manolescu A, Helgason A, et al. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet. 2006;38:68-74. 92. Ozaki K, Ohnishi Y, Iida A, et al. Functional SNPs in the lymphotoxinalpha gene that are associated with susceptibility to myocardial infarction. Nat Genet. 2002;32:650-654. 93. Iwanaga Y, Ono K, Takagi S, et al. Association analysis between polymorphisms of the lymphotoxin-alpha gene and myocardial infarction in a Japanese population. Atherosclerosis. 2004;172:197-198. 94. Laxton R, Pearce E, Kyriakou T, Ye S. Association of the lymphotoxinalpha gene Thr26Asn polymorphism with severity of coronary atherosclerosis. Genes Immun. 2005;6:539-541. 95. Clarke R, Xu P, Bennett D, Lewington S, et al. Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study. PLoS Genet. 2006;2:E107. 96. Yamada A, Ichihara S, Murase Y, et al. Lack of association of polymorphisms of the lymphotoxin alpha gene with myocardial infarction in Japanese. J Mol Med. 2004;82:477-483. 97. Ozaki K, Inoue K, Sato H, et al. Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro. Nature. 2004;429:72-75. 98. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation. 2000;102:1082-1085. 99. Watkins H, Farrall M. Genetic susceptibility to coronary artery disease: from promise to progress. Nat Rev Genet. 2006;7:163-173. 100.Jacobi F, Wittchen HU, Holting C, et al. Prevalence, co-morbidity and correlates of mental disorders in the general population: results from the German Health Interview and Examination Survey (GHS). Psychol Med. 2004;34:597-611. 101.Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19. 102.Craddock N, Forty L. Genetics of affective (mood) disorders. Eur J Hum Genet. 2006;14:660-668. 103.Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC. Analysis of the monoamine oxidase A (MAOA) gene in bipolar affective disorder by association studies, meta-analyses, and sequencing of the promoter. Am J Med Genet. 1999;88:398-406. 104.Preisig M, Bellivier F, Fenton BT, et al. Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study. Am J Psychiatry. 2000;157:948-955.

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Clinical research Traumatic stress: effects on the brain J. Douglas Bremner, MD

Effects of traumatic stress

T

raumatic stressors such as early trauma can lead to post-traumatic stress disorder (PTSD), which affects about 8% of Americans at some time in their lives,1 as well as depression,2,3 substance abuse,1,4 dissociation,5 personality disorders,6,7 and health problems.8 For many trauma victims, PTSD can be a lifelong problem.9 The President’s New Freedom Commission Report highlights the importance of providing services for mental disorders related to early trauma.10-12 However, the development of effective treatments is limited by gaps in knowledge about the underlying neurobiological mechanisms that mediate symptoms of trauma-related disorders like PTSD. This paper reviews preclinical and clinical studies on the effects of traumatic stress on the brain.

Brain areas implicated in the stress response include the amygdala, hippocampus, and prefrontal cortex. Traumatic stress can be associated with lasting changes in these brain areas. Traumatic stress is associated with increased cortisol and norepinephrine responses to subsequent stressors. Antidepressants have effects on the hippocampus that counteract the effects of stress. Findings from animal studies have been extended to patients with post-traumatic stress disorder (PTSD) showing smaller hippocampal and anterior cingulate volumes, increased amygdala function, and decreased medial prefrontal/anterior cingulate function. In addition, patients with PTSD show increased cortisol and norepinephrine responses to stress. Treatments that are efficacious for PTSD show a promotion of neurogenesis in animal studies, as well as promotion of memory and increased hippocampal volume in PTSD. © 2006, LLS SAS

Normal development of the brain across the lifespan


Keywords: positron emission tomography; depression; stress; post-traumatic stress disorder Author affiliations: Departments of Psychiatry and Behavioral Sciences and Radiology, and the Emory Center for Positron Emission Tomography, Emory University School of Medicine, Atlanta, Ga, and the Atlanta VAMC, Decatur, Ga, USA Address for correspondence: J Douglas Bremner, MD, Emory University, 1256 Briarcliff Rd, Room 308e, Atlanta, GA 30306, USA (e-mail: [email protected]) Copyright © 2006 LLS SAS. All rights reserved

To understand how traumatic stress occurring at different stages of the life cycle interacts with the developing brain, it is useful to review normal brain development. The normal human brain undergoes changes in structure and function across the lifespan from early childhood to late life. Understanding these normal developmental changes is critical for determining the difference between normal development and pathology, and how normal development and pathology interact. Although the bulk of brain development occurs in utero, the brain continues to develop after birth. In the first 5 years of life there is an overall expansion of brain volume related to development of both gray matter and white

445


Clinical research Selected abbreviations and acronyms ACTH BDNF BPD CRF CS FDG HPA MRI mRNA NAA PET PTSD US

have included increased ventricular volume and reduction in gray matter, temporal lobe, and cerebellum volumes with normal aging, that begins before the age of 70.25,27,31-33 Therefore, trauma at different stages in life will presumably have different effects on brain development. The few studies that have looked at this issue do suggest that there are differences in the effects of trauma on neurobiology, depending on the stage of development at which the trauma occurs. Studies in this area, however, have been limited.

adrenocorticotropic hormone brain-derived neurotropic factor bipolar disorder corticotropin-releasing factor conditioned stimulus fluorodeoxyglucose hypothalamic-pituitary-adrenal magnetic resonance imaging messenger ribonucleic acid N-acetyl aspartate positron emission tomography post-traumatic stress disorder unconditioned stimulus

Neurobiology of PTSD

matter structures; however, from 7 to 17 years of age there is a progressive increase in white matter (felt to be related to ongoing myelination) and decrease in gray matter (felt to be related to neuronal pruning) while overall brain size stays the same.13-16 Gray matter areas that undergo the greatest increases throughout this latter developmental epoch include frontal cortex and parietal cortex.17,18 Basal ganglia decrease in size, while corpus callosum,19,20 hippocampus, and amygdala21-23 appear to increase in size during childhood, although there may be developmental sex-laterality effects for some of these structures.24 Overall brain size is 10% larger in boys than girls during childhood.24 During the middle part of life (from age 20 to 70) there is a gradual decrease in caudate,25 diencephalon,25 and gray matter,25,26 which is most pronounced in the temporal27 and frontal cortex,26 with enlargement of the ventricles26,27 and no change in white matter.25,26 Studies have not been able to document changes in hippocampal volume in normal populations during this period.27 After menopause in women at about the age of 50, however, there are changes in reproductive hormones, such as decreased levels of estrogen. Since estrogen promotes neuronal branching in brain areas such as the hippocampus,28 a loss of estrogen may lead to changes in neuronal structure. Although the effects of menopause on the brain have not been well studied, it is known that sex hormones also affect brain function and circuitry29; therefore, the changes in sex hormones with menopause will presumably affect brain function, as well as possibly structure. There is some evidence in super-elderly individuals (age >70) for modest reductions in hippocampal volume with late stages of aging.27,30 More robust findings

PTSD is characterized by specific symptoms, including intrusive thoughts, hyperarousal, flashbacks, nightmares, and sleep disturbances, changes in memory and concentration, and startle responses. Symptoms of PTSD are hypothesized to represent the behavioral manifestation of stress-induced changes in brain structure and function. Stress results in acute and chronic changes in neurochemical systems and specific brain regions, which result in long-term changes in brain “circuits,” involved in the stress response.34-37 Brain regions that are felt to play an important role in PTSD include hippocampus, amygdala, and medial prefrontal cortex. Cortisol and norepinephrine are two neurochemical systems that are critical in the stress response (Figure 1). The corticotropin-releasing factor (CRF)/hypothalamicpituitary-adrenal (HPA) axis system plays an important role in the stress response. CRF is released from the hypothalamus, with stimulation of adrenocorticotropic hormone (ACTH) release from the pituitary, resulting in glucocorticoid (cortisol in man) release from the adrenal, which in turn has a negative feedback effect on the axis at the level of the pituitary, as well as central brain sites including hypothalamus and hippocampus. Cortisol has a number of effects which facilitate survival. In addition to its role in triggering the HPA axis, CRF acts centrally to mediate fear-related behaviors,38 and triggers other neurochemical responses to stress, such as the noradrenergic system via the brain stem locus coeruleus.39 Noradrenergic neurons release transmitter throughout the brain; this is associated with an increase in alerting and vigilance behaviors, critical for coping with acute threat.40-42 Studies in animals showed that early stress has lasting effects on the HPA axis and norepinephrine. A variety of early stressors resulted in increased glucocorticoid

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Traumatic stress and the brain - Bremner

response to subsequent stressors.43-45 Maternally deprived rats had decreased numbers of glucocorticoid receptors in the hippocampus, hypothalamus, and frontal cortex.46 Stressed animals demonstrated an inability to terminate the glucocorticoid response to stress,47,48 as well as deficits in fast-feedback of glucocorticoids on the HPA axis, which could be related to decreased glucocorticoid receptor binding in the hippocampus.49 Early postnatal adverse experiences increase hypothalamic CRF messenger ribonucleic acid (mRNA), median eminence CRF content, and stress-induced glucocorticoid50 and ACTH release.46 These effects could be mediated by an increase in synthesis of CRH mRNA following stress.51 In nonhuman primates, adverse early experiences resulted in long-term effects on behaviors, as well as elevated levels of CRF in the cerebrospinal fluid.52 Exposure to chronic stress results in potentiation of noradrenergic responsiveness to subsequent stressors

and increased release of norepinephrine in the hippocampus and other brain regions.42 Preclinical and clinical studies have shown alterations in memory function following traumatic stress,53 as well as changes in a circuit of brain areas, including hippocampus, amygdala, and medial prefrontal cortex, that mediate alterations in memory.54 The hippocampus, a brain area involved in verbal declarative memory, is very sensitive to the effects of stress. Stress in animals is associated with damage to neurons in the CA3 region of the hippocampus (which may be mediated by hypercortisolemia, decreased brain-derived neurotrophic factor (BDNF), and/or elevated glutamate levels) and inhibition of neurogenesis.55-60 High levels of glucocorticoids seen with stress were also associated with deficits in new learning.61,62 Antidepressant treatments have been shown to block the effects of stress and/or promote neurogenesis.58,63-66 Animal studies have demonstrated several agents with

Stress

Cerebral cortex Long-term storage of traumatic memories

Amygdala Conditioned fear DA,

Hippocampus

BZ

Medial & orbitoand orbitoprefrontal cortex Extinction to fear through amygdala inhibition

CRF Hypothalamus Pituitary

GC receptors declarative memory

Cortisol induces atrophy

Increased opiate release

NE ACTH Locus coeruleus

Output to cardiovascular system HR and BP

Adrenal Long-term cortisol

Figure 1. Lasting effects of trauma on the brain, showing long-term dysregulation of norepinephrine and cortisol systems, and vulnerable areas of hippocampus, amygdala, and medial prefrontal cortex that are affected by trauma. GC, glucocorticoid; CRF, corticotropin-releasing factor; ACTH, adrenocorticotropin hormone; NE, norepinephrine; HR, heart rate; BP, blood pressure; DA, dopamine; BZ, benzodiazapine; GC, glucocorticoid

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Clinical research potentially beneficial effects on stress-induced hippocampal damage. It has been found that phenytoin blocks the effects of stress on the hippocampus, probably through modulation of excitatory amino acid-induced neurotoxicity.67 Other agents, including tianeptine, dihydroepiandosterone (DHEA), and fluoxetine have similar effects.63,64,66,68-73 These medications may share a common mechanism of action through upregulation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) that may lead to regulation of expression of specific target genes involved in structural modeling of the hippocampus. Such treatment effects on BDNF and trkB messenger ribonucleic acid (mRNA), can have long-term effects on brain structure and function. There is new evidence that neurogenesis is necessary for the behavioral effects of antidepressants,74,75 although this continues to be a source of debate.72,76 The hippocampus demonstrates an unusual capacity for neuronal plasticity and regeneration. In addition to findings noted above related to the negative effects of stress on neurogenesis, it has recently been demonstrated that changes in the environment, eg, social enrichment or learning, can modulate neurogenesis in the dentate gyrus of the hippocampus, and slow the normal age-related decline in neurogenesis.77,78 Rat pups that are handled frequently within the first few weeks of life (picking them up and then returning them to their mother) had increased type II glucocorticoid receptor binding which persisted throughout life, with increased feedback sensitivity to glucocorticoids, and reduced glucocorticoid-mediated hippocampal damage in later life.79 These effects appear to be due to a type of “stress inoculation” from the mothers' repeated licking of the handled pups.80 Considered together, these findings suggest that early in the postnatal period there is a naturally occurring brain plasticity in key neural systems that may “program” an organism’s biological response to stressful stimuli.These findings may have implications for victims of childhood abuse. Long-term dysregulation of the HPA axis is associated with PTSD, with low levels of cortisol found in chronic PTSD in many studies81-86 and elevations in CRF.82,87 Not all studies, however, have found lower cortisol levels in PTSD.88-91 Exposure to a traumatic reminder appears to be associated with a potentiated release of cortisol in PTSD.92 The few studies of the effects of early stress on neurobiology conducted in clinical populations of traumatized children have generally been consistent with findings from animal studies. Research in traumatized children

has been complicated by issues related to psychiatric diagnosis and assessment of trauma.93 Some studies have not specifically examined psychiatric diagnosis, while others have focused on children with trauma and depression, and others on children with trauma and PTSD. Sexually abused girls (in which effects of specific psychiatric diagnosis were not examined) had normal baseline cortisol and blunted ACTH response to CRF,94 while women with childhood abuse-related PTSD had hypercortisolemia.95 Another study of traumatized children in which the diagnosis of PTSD was established showed increased levels of cortisol measured in 24-hour urines.96 Emotionally neglected children from a Romanian orphanage had elevated cortisol levels over a diurnal period compared with controls.97 Maltreated school-aged children with clinicallevel internalizing problems had elevated cortisol compared with controls.98 Depressed preschool children showed increased cortisol response to separation stress.99 Adult women with a history of childhood abuse showed increased suppression of cortisol with low-dose (0.5 mg) dexamethasone.100 Women with PTSD related to early childhood sexual abuse showed decreased baseline cortisol based on 24-hour diurnal assessments of plasma, and exaggerated cortisol response to stressors (traumatic stressors101 more than neutral cognitive stressors).102 We also found that patients with PTSD had less of an inhibition of memory function with synthetic cortisol (dexamethasone) than normal subjects.103 Adult women with depression and a history of early childhood abuse had an increased cortisol response to a stressful cognitive challenge relative to controls,104 and a blunted ACTH response to CRF challenge.105 These findings show longterm changes in stress responsive systems. Early in development, stress is associated with increased cortisol and norepinephrine responsiveness, whereas with adulthood, resting cortisol may be normal or low, but there continues to be increased cortisol and norepinephrine responsiveness to stressors. In addition, early stress is associated with alterations in hippocampal morphology which may not manifest until adulthood, as well as increased amygdala function and decreased medial prefrontal function.

Cognitive function and brain structure in PTSD Studies in PTSD are consistent with changes in cognition and brain structure. Multiple studies have demonstrated verbal declarative memory deficits in PTSD.53,106-108

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Patients with PTSD secondary to combat109-113 and childhood abuse114,115 were found to have deficits in verbal declarative memory function based on neuropsychological testing. Studies, using a variety of measures (including the Wechsler Memory Scale, the visual and verbal components of the Selective Reminding Test, the Auditory Verbal Learning Test, Paired Associate Recall, the California Verbal New Learning Test, and the Rivermead Behavioral Memory Test), found specific deficits in verbal declarative memory function, with a relative sparing of visual memory and IQ.109-113,115-124 These studies have been conducted in both patients with PTSD related to Vietnam combat,109-113,116,119-121,123 rape,117 the Holocaust,124-126 adults with early childhood abuse,115 and traumatized children.118 One study in adult rape survivors showed that verbal declarative memory deficits are specifically associated with PTSD, and are not a nonspecific effect of trauma exposure.117 Another study of women with early childhood sexual abuse in which some, but not all, of the patients had PTSD, showed no difference between abused and nonabused women,127 while another study was not able to show a difference between Vietnam veterans with and without PTSD.128 Other types of memory disturbances studied in PTSD include gaps in memory for everyday events (dissociative amnesia),129 deficits in autobiographical memory,130 an attentional bias for trauma-related material,131-140 and frontal lobe-related impairments.141 These studies suggest that traumas such as early abuse with associated PTSD result in deficits in verbal declarative memory. It is not clear if cognitive deficits in early abuse survivors are specific to PTSD and are not related to the nonspecific effects of abuse. These effects were specific to verbal (not visual) memory, and were significant after controlling for IQ. Some of these studies used neuropsychological tests of declarative memory, such as the Wechsler Memory Scale (WMS) and Selective Reminding Test (SRT), that have been validated as sensitive to loss of neurons in the CA3 region of the hippocampus in epileptics who underwent hippocampal resection.142,143 Vietnam veterans with PTSD were originally shown by us to have 8% smaller right hippocampal volume based on magnetic resonance imaging (MRI) relative to controls matched for a variety of factors such as alcohol abuse and education (P<0.05); smaller volume was correlated with deficits in verbal declarative memory function as measured with the Wechsler Memory Scale.144 A second study from our group showed a 12% reduction in left hippocampal volume in 17 patients with childhood abuse-

related PTSD compared with 17 case-matched controls, that was significant after controlling for confounding factors.145 Smaller hippocampal volume was shown to be specific to PTSD within the anxiety disorders, and was not seen in panic disorder.146 Gurvits et al147 showed bilateral hippocampal volume reductions in combat-related PTSD compared with combat veterans without PTSD and normal controls. Combat severity was correlated with volume reduction. Stein et al148 found a 5% reduction in left hippocampal volume. Other studies in PTSD have found smaller hippocampal volume and/or reductions in N-acetyl aspartate (NAA), a marker of neuronal integrity.149-153 Studies in childhood154-156 and new-onset157,158 PTSD did not find hippocampal volume reduction, although reduced NAA (indicating loss of neuronal integrity) was found in medial prefrontal cortex in childhood PTSD.159 In a recent meta-analysis we pooled data from all of the published studies and found smaller hippocampal volume for both the left and the right sides, equally in adult men and women with chronic PTSD, and no change in children.160 More recent studies of holocaust survivors with PTSD did not find a reduction in hippocampal volume, although PTSD patients who developed PTSD in response to an initial trauma had smaller hippocampal volume compared with those who developed PTSD after repeated trauma, suggesting a possible vulnerability of smaller hippocampal volume.161 Two independent studies have shown that PTSD patients have deficits in hippocampal activation while performing a verbal declarative memory task,149,162 although it is unclear if this is a deficit in activation or higher hippocampal blood flow at baseline. Both hippocampal atrophy and hippocampal-based memory deficits reversed with treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine, which has been shown to promote neurogenesis (the growth of neurons) in the hippocampus in preclinical studies.163 In addition, treatment with the anticonvulsant phenytoin led to an improvement in PTSD symptoms164 and an increase in right hippocampal and right cerebral volume.165 We hypothesize that stress-induced hippocampal dysfunction may mediate many of the symptoms of PTSD which are related to memory dysregulation, including both explicit memory deficits as well as fragmentation of memory in abuse survivors. It is unclear at the current time whether these changes are specific to PTSD, whether certain common environmental events (eg, stress) in different disorders lead to similar brain changes, or whether common genetic traits lead to similar outcomes.

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Clinical research The meaning of findings related to deficits in memory and the hippocampus in PTSD, and questions related to the relative contribution of genetic and environmental factors, has become an important topic in the field of PTSD and stress research. There are three possible models, taking into account genetic or environmental factors, which have been proposed to explain smaller hippocampal volume in PTSD: Model A (Environment), Model B (Environment and Genetic), and Model C (Genetic).166-169 In Model C (Genetic), smaller hippocampal volume represents a premorbid risk factor for PTSD. In support of this model Pitman and colleagues170 have demonstrated that lower premilitary IQ is associated with combat-related PTSD, as well as finding a correlation between PTSD symptoms and hippocampal volume in twin brothers.151 Model A (Environment) states that stress leads to damage or inhibition of neurogenesis via hypercortisolemia, decreased BDNF, or increased glutamate. Model B (Environment/Genetic) states that a combination of environmental and genetic factors leads to deficits in hippocampal function and structure. Showing that an intervention like medication changes hippocampal volume and cognition would provide support for at least a partial contribution of the environment to the outcomes of interest. In addition to the hippocampus, other brain structures have been implicated in a neural circuitry of stress, including the amygdala and prefrontal cortex. The amygdala is involved in memory for the emotional valence of events, and plays a critical role in the acquisition of fear responses. The medial prefrontal cortex includes the anterior cingulate gyrus (Brodmann’s area [BA] 32) and subcallosal gyrus (area 25) as well as orbitofrontal cortex. Lesion studies demonstrated that the medial prefrontal cortex modulates emotional responsiveness through inhibition of amygdala function. Conditioned fear responses are extinguished following repeated exposure to the conditioned stimulus in the absence of the unconditioned (aversive, eg, electric shock) stimulus. This inhibition appears to be mediated by medial prefrontal cortical inhibition of amygdala responsiveness. Animal studies also show that early stress is associated with a decrease in branching of neurons in the medial prefrontal cortex.171 Rauch and colleagues found smaller volume of the anterior cingulate based on MRI measurements in PTSD172; we have replicated these findings in women with abuse and PTSD.160 An important question is whether these effects are reversible with treatment.

Neural circuits in PTSD Brain imaging studies have shown alterations in a circuit including medial prefrontal cortex (including anterior cingulate), hippocampus, and amygdala in PTSD. Many of these studies have used different methods to trigger PTSD symptoms (eg, using traumatic cues) and then look at brain function. Stimulation of the noradrenergic system with yohimbine resulted in a failure of activation in dorsolateral prefrontal, temporal, parietal, and orbitofrontal cortex, and decreased function in the hippocampus.173 Exposure to traumatic reminders in the form of traumatic slides and/or sounds or traumatic scripts was associated with an increase in PTSD symptoms, decreased blood flow, and/or failure of activation in the medial prefrontal cortex/anterior cingulate, including Brodmann’s area 25, or subcallosal gyrus, area 32 and 24, as measured with positron emission tomography (PET) or functional MRI (fMRI).174-183 Other findings in studies of traumatic reminder exposure include decreased function in hippocampus,176 visual association cortex,176,180 parietal cortex,176,179,180,184 and inferior frontal gyrus,176,179,180,184 and increased function in amygdala,181,184 posterior cingulate,174,176,177,180 and parahippocampal gyrus.174,176,178 Shin and colleagues found a correlation between increased amygdala function and decreased medial prefrontal function with traumatic reminders,181 indicating a failure of inhibition of the amygdala by the medial prefrontal cortex that could account for increased PTSD symptoms with traumatic reminders. Other studies found increased amygdala and parahippocampal function and decreased medial prefrontal function during performance of an attention task,182 increased posterior cingulate and parahippocampal gyrus and decreased medial prefrontal and dorsolateral prefrontal function during an emotional Stroop paradigm,185 and increased amygdala function with exposure to masked fearful faces.186 Retrieval of emotionally valenced words187 (eg “rape-mutilate”) in women with PTSD from early abuse resulted in decreases in blood flow in an extensive area which included orbitofrontal cortex, anterior cingulate, and medial prefrontal cortex (BA 25, 32, and 9), left hippocampus, and fusiform gyrus/inferior temporal gyrus, with increased activation in posterior cingulate, left inferior parietal cortex, left middle frontal gyrus, and visual association and motor cortex.188 Another study found a failure of medial prefrontal cortical/anterior cingulate activation, and decreased visual association and parietal

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cortex function, in women with abuse and PTSD relative to women with abuse without PTSD, during performance of the emotional Stroop task (ie, naming the color of a word such as “rape”).189 We recently found increased amygdala activation with classical fear conditioning (pairing a shock and a visual stimulus), and decreased medial prefrontal cortex function with extinction, in abuse-related PTSD.190 The findings described above point to a network of related regions mediating symptoms of PTSD, including medial prefrontal cortex, anterior cingulate, hippocampus, amygdala, posterior cingulate, parietal, visual association, and dorsolateral prefrontal cortex.191 Fewer brain imaging studies have been performed in children with PTSD. Several studies have shown alterations in electroencephalogram (EEG) measures of brain activity in children with a variety of traumas who were not selected for diagnosis compared with healthy children. About half of the children in these studies had a psychiatric diagnosis. Abnormalities were located in the anterior frontal cortex and temporal lobe and were localized to the left hemisphere.192,193 Two studies have found reductions in brain volume in children with trauma and PTSD symptoms.154,155 One group did not find reductions in hippocampal volume, either at baseline or over a longitudinal period,154,156 while another group found an 8.5% reduction in hippocampal volume that was not significant after controlling for smaller brain volumes in the PTSD group.155 One study used single-voxel proton magnetic resonance spectroscopy (proton MRS) to measure relative concentration of NAA and creatinine (a marker of neuronal viability) in the anterior cingulate of 11 children with maltreatment-related PTSD and 11 controls. The authors found a reduction in the ratio of NAA to creatinine in PTSD relative to controls.159 Studies have also found smaller size of the corpus callosum in children with abuse and PTSD relative to controls.154 as well as larger volume of the superior temporal gyrus.194 In a study of abused children in whom diagnosis was not specified, there was an increase in T2 relaxation time in the cerebellar vermis, suggesting dysfunction in this brain region.195 The reason for differences in findings between adults and children are not clear; however, factors such as chronicity of illness or interaction between trauma and development may explain findings to date. In summary, dysfunction of a circuit involving the medial prefrontal cortex, dorsolateral prefrontal cortex, and possibly hippocampus and amygdala during exposure to

traumatic reminders may underlie symptoms of PTSD. These studies have primarily assessed neural correlates of traumatic remembrance, while little has been done in the way of utilizing cognitive tasks as probes of specific regions, such as memory tasks as probes of hippocampal function.

MRI assessment of brain abnormalities in PTSD and trauma spectrum disorders Findings of smaller hippocampal volume appear to be associated with a range of trauma related psychiatric disorders, as long as there is the presence of psychological trauma. We have used MRI to show smaller hippocampal volume in PTSD,144,145,149,196 depression,197 depression with early abuse,198 borderline personality disorder (BPD) with early abuse,199 and Dissociative Identity Disorder (DID) with early abuse.200 The greatest magnitude of difference was seen in the DID patients, who had unusually severe early childhood sexual abuse histories. We did not find changes in hippocampal volume in patients with panic disorder without a history of abuse (suggesting that findings are not generalized to other anxiety disorders).201 We found smaller amygdala volume in BPD with early abuse199 and increased amygdala volume in depression.197,202 Patients with depression had smaller orbitofrontal cortex volume with no changes in anterior cingulate (BA 32) or medial prefrontal cortex (BA 25).203 More recently, we found smaller anterior cingulate volume in women with abuse and PTSD relative to controls.204

Neural circuits in women with abuse and PTSD We have used PET to study neural circuits of traumarelated disorders in women with early abuse and a variety of trauma spectrum mental disorders. Initially we studied women with abuse and PTSD.54,205-208 We initially measured brain activation with a paragraph-encoding task in conjunction with PET O-15 water measurement of brain blood flow. Women with abuse and PTSD showed a failure of hippocampal activation during the memory task relative to controls.149 Women with abuse and PTSD in this study also had smaller hippocampal volume measured with MRI relative to both women with abuse without PTSD and nonabused non-PTSD women. The failure of hippocampal activation was significant

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Clinical research after controlling differences in hippocampal volume as well as accuracy of encoding. In another study we measured neural correlates of exposure to a personalized script of childhood sexual abuse. Women with abuse and PTSD showed a failure of medial prefrontal and hippocampal activation relative to abused women without PTSD.176 Women with abuse and PTSD also showed a failure of medial prefrontal and hippocampal function during recall of paired word associates with traumaticemotional content (eg, “rape-mutilate”),188 and decreased medial prefrontal function during an emotional Stroop task with trauma-content words.209 Other studies showed a failure of medial prefrontal activation in women with BPD and early abuse during an abandonment script.210 Women with BPD and abuse had increased psychophysiological responses to abandonment scripts relative to trauma scripts, while women with PTSD and abuse had the opposite pattern,211 indicating differential responding in those two disorders in spite of the common exposure to early abuse. In another project we studied 19 physically healthy women including women with a history of severe childhood sexual abuse and the diagnosis of current PTSD (N=8) and women without childhood abuse or PTSD (N=11).212 All subjects underwent PET measurement of cerebral blood flow and psychophysiology measurement of heart rate and skin conductance during habituation, acquisition, and extinction conditions, on a single day, with scanning during a control condition on another day separated by 1 week from the active condition. Subjects were randomly assigned to undergo either the active condition or the control condition first (ie, active-control or control-active). Subjects were told at the beginning of the study that they would be exposed to electric shocks and viewing images on a screen during collection of PET and psychophysiology data. During habituation subjects were exposed to a blue square on a screen (conditioned stimulus [CS]), 4 seconds in duration, followed by 6 seconds of a blank screen. CS exposure was repeated eight times at regular intervals over 80 seconds in two separate blocks separated by 8 minutes. One PET image of brain blood flow was obtained starting from the beginning of each of the blocks. During active fear acquisition exposure to the blue square (CS) was paired with an electric shock to the forearm (unconditioned stimulus [UCS]). Subjects had 8 paired CS-UCS presentations at 10-second intervals for each of two blocks. With extinction subjects were again exposed to the blue squares (CS) with-

out shock (“active” extinction). On a second day subjects went through the same procedure with electric shocks delivered randomly when the blue square was not present (unpaired CS-UCS) (an equal number as on day 1) during scans 3 and 4, which served as a control for active fear acquisition. PTSD subjects had increased symptoms of anxiety, fear, dissociation, distress, substance use disorders (SUDs), and PTSD at all time points during both study days relative to non-PTSD. Acquisition of fear was associated with increased skin conductance (SC) responses to CS exposure during the active versus the control conditions in all subjects. There was increased SC for PTSD during the first CS-UCS presentation. Extinction of fear was associated with increased skin conductance (SC) responses to CS exposure during the active versus the control conditions in all subjects. When PTSD and nonPTSD subjects were examined separately, SC levels were significantly elevated in non-PTSD subjects undergoing extinction following the active compared with the control condition during session one. PTSD subjects showed activation of the bilateral amygdala during fear acquisition compared with the control condition. Non-PTSD subjects showed an area of activation in the region of the left amygdala. When PTSD subjects and control subjects were directly compared, PTSD subjects showed greater activation of the left amygdala during the fear conditioning condition (pairing of US and CS) relative to the random shock control than healthy women. Other areas that showed increased activation with fear acquisition in PTSD included bilateral superior temporal gyrus (BA 22), cerebellum, bilateral inferior frontal gyrus (BA 44, 45), and posterior cingulate (BA 24). Fear acquisition was associated with decreased function in medial prefrontal cortex, visual association cortex, and medial temporal cortex, inferior parietal lobule function, and other areas. Extinction of fear responses was associated with decreased function in the orbitofrontal and medial prefrontal cortex (including subcallosal gyrus, BA 25, and anterior cingulate BA 32), visual association cortex, and other areas, in the PTSD subjects, but not in the controls. Amygdala blood flow with fear acquisition was negatively correlated with medial prefrontal blood flow with fear extinction (increased blood flow in amygdala correlated with decreased blood flow in medial prefrontal cortex) in all subjects (r=-0.48; P<0.05). Increased amygdala blood flow with fear acquisition was positively correlated with PTSD (r=0.45), anxiety (r=0.44) and disso-

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ciative (r=0.80) symptom levels in PTSD (but not nonPTSD) subjects.There was a negative correlation between medial prefrontal blood flow during extinction and anxiety as measured with the Panic Attack Symptom Scale (PASS) during extinction in the PTSD group only, which was significant after correction for multiple comparisons (r=-0.90; P=0.006).190 This study was consistent with increased amygdala function with fear acquisition, and decreased medial prefrontal (anterior cingulate) function during extinction in PTSD. This is consistent with the model of an overactive amygdala and a failure of medial prefrontal cortex to extinguish, or shut off, the amygdala, when the acute threat is no longer present.

Treatment of PTSD Intervening soon after the trauma is critical for long-term outcomes, since with time traumatic memories become indelible and resistant to treatment.213 Early treatments are not necessarily effective. For instance, studies have shown that Critical Incident Stress Debriefing (CISD) can be associated with a worsening of outcome relative to no treatment at all.214 Pharmacological treatment of chronic PTSD has shown efficacy originally for imipramine,215 amitriptyline,216 and phenalzine,215 and later for brofaramine,217 paroxetine,218,219 and sertraline.220 Selective serotonin reuptake inhibitors (SSRIs) and tianeptine are now recommended as first-line treatment for PTSD.221-226 The utility of early treatment is also demonstrated by animal studies showing that pretreatment before stress with antidepressants reduces chronic behavioral deficits related to stress.227,228 Antidepressants, including both norepinephrine and serotonin reuptake inhibitors, as well as gabapentine and phenytoin, promote nerve growth (neurogenesis) in the hippocampus, while stress inhibits neurogenesis.63,64,66,69,71,75,229 This is important because hippocampal neurogenesis has been shown to be required for antidepressant response.74 Few studies have examined the effects of pharmacological treatment on brain structure and function in patients with trauma-related mental disorders. We studied a group of patients with depression and found no effect of fluoxetine on hippocampal volume, although there were increases in memory function230 and hippocampal activation measured with PET during a memory encoding task. Depressed patients with a history of childhood trauma were excluded, and we subsequently have found hippocampal volume reductions at baseline in women with early abuse and

depression but not in women with depression without early abuse;198 this suggests that the study design of excluding patients with early trauma may account for the negative result. Other studies in depression showed that smaller hippocampal volume was a predictor of resistance to antidepressant treatment.231 Smaller orbitofrontal cortex volume is associated with depression; one study in geriatric depression found smaller orbitofrontal cortex volume, while length of antidepressant exposure was correlated with larger orbitofrontal volume.232 Several studies have looked at functional brain imaging response to antidepressants in depression. Single photonemission computed tomography (SPECT) blood flow studies in depression showed that antidepressants increased anterior cingulate, right putamen, and right thalamus function.233 SPECT Xenon-133 studies showed reduced prefrontal function at baseline in depression, with treatment responders showing reduced perfusion in prefrontal cortex compared with nonresponders after treatment.234 In a fluorodeoxyglucose (FDG) PET study of brain function patients with depression treated with fluoxetine who had a positive response to treatment had limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate) in function. Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes.235 Sertraline resulted in an increase in middle frontal gyrus activity in depression measured with PET FDG, as well as increased function in right parietal lobe and visual association cortex.236 Successful paroxetine therapy of depression was associated with increased glucose metabolism measured with PET in dorsolateral, ventrolateral, and medial aspects of the prefrontal cortex, parietal cortex, and dorsal anterior cingulate.Areas of decreased metabolism were noted in both anterior and posterior insular regions (left) as well as right hippocampal and parahippocampal regions.237 In another PET FDG study, at baseline, subjects with depression had higher normalized metabolism than controls in the prefrontal cortex (and caudate and thalamus), and lower metabolism in the temporal lobe. With treatment with paroxetine, subjects with depression had metabolic changes in the direction of normalization in these regions.238 A PET FDG study of patients with depression and controls showed that at baseline, the mean metabolism was increased in the left and right lateral orbital cortex/ventrolateral prefrontal cortex (PFC), left amygdala,

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Clinical research and posterior cingulate cortex, and decreased in the subgenual anterior cingulate cortex (ACC) and dorsal medial/dorsal anterolateral PFC in depressives relative to controls. Following treatment with antidepressants, metabolism significantly decreased in the left amygdala and left subgenual ACC.The metabolic reduction in the amygdala and right subgenual ACC appeared largely limited to those subjects who both responded to treatment and remained well at 6 months’ follow-up.239 Another study showed that antidepressant treatment of depression resulted in a decrease in amygdala activation with emotional faces as measured with fMRI.240 In summary, studies show changes in limbic and prefrontal cortical regions with successful antidepressant treatment of depression. Fewer studies have looked at the effects of pharmacological treatment on the brain in anxiety disorders. One PET FDG study showed that caudate function decreased with treatment of obsessive compulsive disorder with antidepressants.241 Paroxetine resulted in a decrease in glutamate/glutamine measured with magnetic resonance spectroscopy (MRS) in children with obsessive-compulsive disorder (OCD).242 Patients with PTSD were shown to have an increase in hippocampal volume and memory function with paroxetine,163 and increased right hippocampal and right cerebral volume with phenytoin.165 No published studies have looked at the effects of pharIncreased blood flow with fear acquisition versus control in abuse-related PTSD Orbitofrontal cortex Superior temporal gyrus

Left amygdala Yellow areas represent areas of relatively greater increase in blood flow with paired vs unpaired US-CS in PTSD woman alone, z>3.09, P<0.001

Figure 2. Neural correlates of fear conditioning in women with abuse and PTSD. There was increased amygdala activation with fear acquisition using a classical conditioning paradigm relative to nonPTSD abused women. PTSD, post-traumatic stress disorder

macological treatment on brain function in PTSD, or on sensitive markers of brain chemistry like NAA. Brain biomarkers like NAA represent an objective marker of neural plasticity. To date psychiatry has relied on subjective reports as the gold standard. However, this is limited by self-reporting and the subjective interpretations of symptoms and response to treatment. Brain markers of antidepressant response may provide a complementary approach to assessing response to treatment, as well as providing insight into the mechanisms of treatment response. Our group is trying to look at mechanisms in the brain underlying treatment response in PTSD.

Effects of pharmacotherapy on brain function and structure in PTSD We have begun to assess the effects of pharmacotherapy on brain structure and function in PTSD.243 We recently assessed the effects of phenytoin on brain structure and function. Studies in animals show that phenytoin, which is used in the treatment of epilepsy and is known to modulate glutamatergic function, blocks the effects of stress on the hippocampus.67 We studied nine patients with PTSD in an open-label function before and after treatment with phenytoin. Phenytoin resulted in a significant improvement in PTSD symptoms.164 Phenytoin also resulted in increases in both right hippocampal volume and right hemisphere volume.165 These findings indicate that phenytoin has an effects on PTSD symptoms as well as brain structure in PTSD patients. We have assessed the effects of open-label paroxetine on memory and the hippocampus in PTSD. Male and female patients with symptoms of PTSD were medication-free for at least 4 weeks before participation in the study. Twenty-eight patients were found to be eligible and started the medication phase. Of the total patient sample five patients did not finish due to noncompliance; 23 patients completed the study. Before patients started the medication phase, neuropsychological tests were administered, including the Wechsler Adult Intelligence Scale – Revised, WAIS-R (arithmetic, vocabulary, picture arrangement, and block design test), two subtests of the Wechsler Memory ScaleRevised, WMS-R, including logical memory (free recall of two story narratives, which represents verbal memory) and figural memory (which represents visual memory and involved reproduction of designs after a 6-second presentation); and the verbal and visual components of

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the Selective Reminding Test, SRT. Paroxetine was prescribed in the first visit after the pre-treatment assessments.All patients started open-label with a dose of 10 mg daily and were titrated up to 20 mg in 4 days. Paroxetine treatment resulted in a mean 54% reduction in PTSD symptoms as measured with mean changes from baseline on the CAPS total score (P<0.005) among study completers. Improvement was equally strong on all symptom cluster scores (Re-experiencing,Avoidance/Numbing, Hyperarousal). Treatment also resulted in significant improvements in verbal declarative memory as measured with the WMS-R paragraph recall for delayed recall (P<0.005) and percent retention (80.2 to 91.1; P=0.003), but not immediate recall. Improvements were significant on all subscales of the Verbal Component of the SRT; including long-term recall and delayed recall. Repeated measures ANOVA with side as the repeated measure showed a main effect for treatment related to a 4.6% increase in mean hippocampal volume (1857.3 mm3 [SD 225.6] to 1906.2 mm3, [SD 243.2]) with treatment (F=8.775 df=1. 36; P=0.005). Increased hippocampal volume was seen for both left (5.6%) (1807.6 mm3 [SD 255.5] to 1909.3 mm3 [SD 236.9]) and right (3.7%) (1906.9 mm3 [SD 195.8] to 1976.7 mm3 (SD 249.6]) hippocampus.There was no change in whole brain volume with treatment. Increase in hippocampal volume was significant after adding whole brain volume before and after treatment to the model.

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Discussion Traumatic stress has a broad range of effects on brain function and structure, as well as on neuropsychological components of memory. Brain areas implicated in the stress response include the amygdala, hippocampus, and prefrontal cortex. Neurochemical systems, including cortisol and norepinephrine, play a critical role in the stress response. These brain areas play an important role in the stress response. They also play a critical role in memory, highlighting the important interplay between memory and the traumatic stress response. Preclinical studies show that stress affects these brain areas. Furthermore, antidepressants have effects on the hippocampus that counteract the effects of stress. In fact, promotion of nerve growth (neurogenesis) in the hippocampus may be central to the efficacy of the antidepressants. Studies in patients with PTSD show alterations in brain areas implicated in animal studies, including the amygdala, hippocampus, and prefrontal cortex, as well as in neurochemical stress response systems, including cortisol and norepinephrine. Treatments that are efficacious for PTSD show a promotion of neurogenesis in animal studies, as well as promotion of memory and increased hippocampal volume in PTSD. Future studies are needed to assess neural mechanisms in treatment response in PTSD. ❏

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Clinical research Estrés traumático: efectos en la cerebro

Effets du stress traumatique sur le cerveau

El estrés traumático surte efectos muy diversos sobre la función y la estructura cerebrales. Las regiones cerebrales implicadas en la respuesta al estrés son la amígdala (núcleo amigdalino), el hipocampo y la corteza prefrontal. Los sistemas neuroquímicos, como el cortisol y la noradrenalina, desempeñan una misión crítica en la respuesta al estrés. Estas regiones cerebrales influyen sobre la respuesta al estrés y sobre la memoria, lo que subraya la interrelación entre la memoria y la respuesta al estrés traumático. Los antidepresivos actúan sobre el hipocampo y contrarrestan el efecto del estrés. Los estudios sobre pacientes con trastorno por estrés postraumático (TEPT) revelan alteraciones en las regiones cerebrales implicadas en los estudios con animales como la amígdala, el hipocampo y la corteza prefrontal, así como en los sistemas neuroquímicos de respuesta al estrés, entre ellos el cortisol y la noradrenalina. Los tratamientos con eficacia frente al TEPT promueven la neurogénesis en los estudios con animales y también aumentan la memoria, y el volumen hipocámpico en el TEPT. Se requieren nuevos estudios para evaluar los mecanismos neurales de la respuesta terapéutica en el TEPT.

Le stress traumatique exerce une grande variété d’effets sur la fonction et la structure cérébrales. Les aires cérébrales impliquées dans la réponse au stress comprennent l’amygdale, l’hippocampe et le cortex préfrontal. Les systèmes neurochimiques, incluant le cortisol et la norépinéphrine, jouent un rôle critique dans la réponse au stress. Ces aires cérébrales influent sur la mémoire et sur la réponse au stress traumatique, soulignant ainsi les interactions existant entre les deux. Les effets des antidépresseurs sur l’hippocampe compensent les effets du stress. Les études chez les patients atteints de trouble stress post-traumatique (ESPT) montrent des modifications des aires cérébrales impliquées au cours des études animales, telles l’amygdale, l’hippocampe et le cortex préfrontal, ainsi que des modifications des systèmes neurochimiques de réponse au stress comme le cortisol et la noradrénaline. Les traitements efficaces dans l’ESPT entraînent une activation de la neurogenèse chez l’animal de même qu’une amélioration de la mémoire et une augmentation du volume de l’hippocampe dans l’ESPT. Il faudra d’autres études pour évaluer les mécanismes neuronaux dans la réponse thérapeutique au cours de l’ESPT.

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Clinical research Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior A. Leslie Morrow, PhD; Patrizia Porcu, PhD; Kevin N. Boyd, BS; Kathleen A. Grant, PhD

N

euroactive steroids are endogenous neuromodulators that can be synthesized de novo in the brain as well as in the adrenal glands, ovaries, and testes (for review see ref 1).The biosynthetic pathway for these steroids is shown in Figure 1. Among these compounds, the metabolites of deoxycorticosterone (DOC) and progesterone, 3α,21-dihydroxy-5α-pregnan-20-one (3α,5α-THDOC or allotetrahydrodeoxycorticosterone) and 3α-hydroxy-5α-pregnan20-one (3α,5α-THP or allopregnanolone) are the most potent positive modulators of γ-aminobutyric acid type A (GABAA) receptors.2,3 Systemic administration of 3α,5α-THDOC and 3α,5αTHP induces anxiolytic, anticonvulsant, and sedative-hypnotic effects, similar to those induced by other GABAA Activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to elevations in 웂-aminobutyric acid (GABA)-ergic neuroactive steroids that enhance GABA neurotransmission and restore homeostasis following stress. This regulation of the HPA axis maintains healthy brain function and protects against neuropsychiatric disease. Ethanol sensitivity is influenced by elevations in neuroactive steroids that enhance the GABAergic effects of ethanol, and may prevent excessive drinking in rodents and humans. Low ethanol sensitivity is associated with greater alcohol consumption and increased risk of alcoholism. Indeed, ethanol-dependent rats show blunted neurosteroid responses to ethanol administration that may contribute to ethanol tolerance and the propensity to drink greater amounts of ethanol. The review presents evidence to support the hypothesis that neurosteroids contribute to ethanol actions and prevent excessive drinking, while the lack of neurosteroid responses to ethanol may underlie innate or chronic tolerance and increased risk of excessive drinking. Neurosteroids may have therapeutic use in alcohol withdrawal or for relapse prevention. © 2006, LLS SAS


Keywords: hypothalamic-pituitary-adrenal axis, ethanol, neuroactive steroid, rat, monkey, human Author affiliations: Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA (A. Leslie Morrow, Patrizia Porcu, Kevin N. Boyd); Curriculum in Toxicology, University of North Carolina School of Medicine, Chapel Hill, NC, USA (A. Leslie Morrow, Kevin N. Boyd); Copyright © 2006 LLS SAS. All rights reserved

Department of Behavioral Neurosciences & the Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA (Kathleen A. Grant) Address for correspondence: A. Leslie Morrow, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, 3027 Thurston-Bowles Building, CB #7178, Chapel Hill, NC 27599-7178, USA (email: [email protected])

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Clinical research Selected abbreviations and acronyms 3움-HSD 3움,5움-THDOC 3움,5움-THP ACTH CRF DOC GABA HPA PMDD

3움 hydroxysteroid dehydrogenase 3움,21-dihydroxy-5움-pregnan-20-one 3움-hydroxy-5움-pregnan-20-one adrenocorticotropic hormone corticotropin-releasing factor deoxycorticosterone 웂-aminobutyric acid hypothalamic-pituitary-adrenal premenstrual dysphoric disorder

receptor positive modulators and ethanol (for review see ref 4). Neuroactive steroids interact with GABAA receptors via specific binding sites on α subunits5 that allosterically modulate binding to GABA and benzodiazepine recognition sites.6 In addition, neuroactive steroids compete for [35S] t-butylbicyclophosphorothionate (TBPS) binding sites.6 These steroids alter GABAA receptor func-

tion by enhancing GABA-mediated Cl- conductance and directly stimulating Cl- conductance in voltage clamp studies and [36Cl-] flux studies.2,3,7 Neuroactive steroids appear to interact with multiple neurosteroid recognition sites,8,9 and these sites may differentiate direct gating of Cl- vs allosteric modulation of GABA-mediated conductance9 or represent different properties of recognition sites on distinct GABAA receptor subtypes.10,11 Studies of the structural requirements for neurosteroid activity at GABAA receptors include 3α reduction and 5α/5β reduction of the A ring, as well as hydroxylation of C21.12 The 5β-reduced metabolites of DOC and progesterone, 3α,5β-THDOC and 3α,5β-THP are equipotent modulators of GABAergic transmission.8,13,14 Humans synthesize these 5β-reduced neuroactive steroids; moreover, the concentrations of 3α,5β-THP are physiologically relevant and comparable to those of 3α,5α-THP in human plasma and cerebrospinal fluid.15,16 In addition, 3α,5α- and 3α,5β-reduced

CHOLESTEROL

DHEA Sulfate Sulfotransferase

Pregnenolone sulfate

Sulfatase

CYP11A

DHEA 17웁-HSD

Sulfotransferase CYP17

Androstenediol

PREGNENOLONE

17-OH Pregnenolone 3웁-HSD

3움-HSD 3웁-HSD

3웁-HSD

Sulfatase

CYP17

Androstenedione 5웁-reductase

CYP17

Testosterone

5α-dihydro5움-reductase progesterone (DHP)

CYP19

17웁-HSD

3움-HSD

5움-reductase

Deoxycorticosterone (DOC)

11-Deoxycortisol

Estradiol Estrone

CYP11B1

CYP11B1

Corticosterone

Cortisol Dihydrotestosterone 3움-HSD

3α,5α-THP (Allopregnanolone)

CYP21

CYP21

CYP19

3움-HSD

Progesterone

17-OH Progesterone

17웁HSD

5움-reductase

3α,5β-THP (Pregnanolone)

5β-dihydroprogesterone (DHP)

3웁-HSD

5α-dihydroDOC

3α,5α-THDOC (AllotetrahydroDOC)

5웁-reductase 3움-HSD

5β-dihydroDOC

CYP11B2

11웁-HSD

18-hydroxylation

Cortisone

18-OH Corticosterone CYP11B2

Androstanediol

5움/5웁-reductase and 3움-HSD

3α,5α-reduced cortisol

18-oxidation

Aldosterone

3α,5β-reduced cortisol

Figure 1. Biosynthetic pathway for neuroactive steroids. DHEA, dehydroepiandrosterone; DOC, deoxycorticosterone

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3α,5β-THDOC (TetrahydroDOC)


Ethanol, HPA axis, and neuroactive steroids - Morrow et al

cortisol have antagonist properties at both GABA and neurosteroid recognition sites of GABAA receptors, and these compounds are the most abundant metabolites of cortisol in human urine.17 However, to our knowledge, there is no data in the literature on the presence of these metabolites in human brain.

Stress increases plasma and brain levels of GABAergic neuroactive steroids

exhibit no circulating concentrations of 3α,5α-THP and 3α,5α-THDOC, but brain levels are still detectable,18 suggesting that brain synthesis plays an important role in neurosteroid actions. Indeed, brain synthesis of 3α,5α-THP can be increased by ethanol in adrenalectomized immature animals allowed sufficient time for adaptation,32 suggesting that brain synthesis of neurosteroids may exhibit plasticity in response to physiological challenges.

Neuroactive steroids and the HPA axis

Progesterone

DOC

3α,5α-THDOC

↓

↓

↓

↓

↓

NA

NA -- / ↓

NA NA

--

NA NA

/ -- / ↓

NA

NA NA

↓

↓

/ ↓

↓

↓

↓

↓ ↓ ↓

-/ --

3α,5α-THP

↓

Pregnenolone

↓

↓ ↓

Rats Acute ethanol Acute stress Monkeys Acute ethanol Acute stress/HPA axis Humans Acute ethanol Acute stress/HPA axis

The activation of the HPA axis in response to acute stress increases the release of CRF from the hypothalamus, which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary; this, in turn, stimulates the adrenal cortex to release glucocorticoids, neuroactive steroid precursors, and GABAergic neuroactive steroids. Glucocorticoids, mainly cortisol in humans and nonhuman primates, and corticosterone in rodents, provide negative feedback on the hypothalamus and pituitary. Likewise, GABAergic neuroactive steroids inhibit CRF production and release,ACTH release, and subsequent corticosterone levels in rodents.33-35 The ability of neuroactive steroids to reduce HPA axis activation may play an important role in returning the animal to homeostasis following stressful events. This physiological coping response appears to be critical for mental health, since it is dysregulated in various mood disorders, including depression, post-traumatic stress disorder, and premenstrual dysphoric disorder (PMDD). Neuroactive steroid concentrations are altered in various pathophysiological conditions that involve dysfunction of

↓

The brain and plasma concentrations of GABA agonistlike neuroactive steroids are increased by acute stress and ethanol administration in rodents.18-21 The increase in 3α,5α-THP reaches pharmacologically significant concentrations in brain between 50 and 100 nM that is sufficient to enhance GABAA receptor activity and produce behavioral effects. Similarly, both stress and acute ethanol administration elevate levels of 3α,5α-THP in human plasma,22-25 although effects of ethanol in humans are controversial.26,27 In addition, corticotropin-releasing factor (CRF) infusion increases 3α,5α-THP levels in human plasma.28 The levels detected in human plasma are lower than rodent plasma and brain. However, 3α,5α-THP levels in post-mortem human brain are similar to rat brain and sufficient to have GABAergic activity.29 Table I summarizes the effects of acute stress on neuroactive steroid levels in rodents, monkeys, and humans. The increase in neuroactive steroid levels elicited by stressful stimuli, including ethanol administration, appears to be mediated by activation of the hypothalamic-pituitaryadrenal (HPA) axis, since it is no longer apparent in adrenalectomized animals.18,30,31 Adrenalectomized animals

Table I. Summary of the changes in neuroactive steroids and their precursors in rats, monkeys, and healthy human subjects induced by acute ethanol administration or by acute stress or HPA stimulation. These effects are described and referenced in the text. = increase; ↓ = decrease; -- = unchanged; na = not assayed; HPA axis: activation by naloxone, CRF, or ACTH; 3α,5α-THDOC, 3α,21-dihydroxy-5α-pregnan-20-one; 3α,5αTHP, 3α-hydroxy-5α-pregnan-20-one; DOC, deoxycorticosterone; HPA, hypothalamic-pituitary-adrenal; CRF, corticotropin-releasing factor; ACTH, adrenocorticotropic hormone ↓

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Clinical research the HPA axis.The HPA axis plays an important role in the pathophysiology of depression: patients with major depression have elevated cortisol levels, a consequence of hypersecretion of CRF due to lowered feedback mechanisms,36 which also contributes to a blunted dexamethasone response.37 Some neuroactive steroid concentrations are decreased in patients with major depression as well as in animal models of depression,15,16,38,39 and administration of antidepressant drugs increases these neuroactive steroids in patients and in rodent brain and plasma.40-44 This decrease in neuroactive steroids might play a role in the hyperactivity of CRF, since neurosteroids negatively regulate CRF expression and release from the hypothalamus. This increase might be mediated by the HPA axis via an increased serotonin neurotransmission that stimulates the release of CRF (for review see ref 45). While acute fluoxetine administration increases brain levels of 3α,5α-THP, chronic administration of fluoxetine decreases 3α,5α-THP and 3α,5α-THDOC in rat brain and plasma,43 probably as a consequence of a reduced basal HPA axis activity induced by antidepressant treatments.36 Neuroactive steroids are also altered in PMDD, although the literature is controversial, reporting either decrease, no change, or increase in 3α,5α-THP plasma levels.22,46-53 Differences in analytic methods, diagnostic criteria, or presence of other comorbid psychiatric disorders might account for these discrepancies. Furthermore, PMDD patients had a blunted 3α,5α-THP response to stress22 and to HPA axis challenges.53 Women with a history of depression, regardless of PMDD symptoms, also had a blunted 3α,5α-THP response to stress.54 An altered neuroactive steroid response to stress and acute ethanol administration has been shown in socially isolated animals,38,55 and this is accompanied by altered HPA axis responsiveness.56 All this experimental evidence emphasizes the important link between HPA axis function and neuroactive steroid levels in the maintenance of homeostasis and healthy brain function.

Neuroactive steroids have ethanol-like discriminative stimulus properties in rodents and nonhuman primates The discriminative stimulus paradigm can be used as an in vivo assay of receptor-mediated activity, and may help define the neurotransmitter systems that underlie the behavioral effects of a given dose and class of drug.57 In addition, drug discrimination can be used as an assay of

subjective effects for cross-species comparisons.58 The relation between subjective effects of a drug and its reinforcing effects is largely asymmetrical: reinforcing effects are discriminable, but not all discriminable effects are reinforcing.58 For example, ethanol can make a person feel simultaneously drowsy, euphoric, and calm, but only some of these subjective effects will be associated with increased drinking of ethanol. Neurosteroids such as 3α,5α-THP, 3α,5β-THP, 3β,5β THP, and 3α,5α-THDOC have been characterized in drug discrimination procedures as similar to other GABAA receptor positive modulators, including benzodiazepines, barbiturates, and ethanol in rats and mice (reviewed in ref 59). Further, neurosteroids that are negative modulators of GABAA receptor function, such as pregnenolone sulfate and dehydroepiandrosterone sulfate, do not substitute for the discriminative stimulus effects of ethanol.60 However, in male rats, the basis for the 3α,5β-THP discrimination also appears to be composed of N-methyl-D-aspartate (NMDA) receptor antagonism and serotonin-3 (5-HT3) receptor agonist activity,61 an effect not found in mice.59 These results suggest a species difference in the neurotransmitter systems underlying the 3α,5β-THP stimulus cues. In the macaque monkey, 3α,5α-THP produces a discriminative stimulus effect that is similar to that of ethanol, and sensitivity to these effects is dependent upon the phase of the menstrual cycle, with higher circulating progesterone in the menstrual cycle producing increased sensitivity to ethanol.62 Furthermore, in male and female monkeys, 3α,5α-THP can produce stimulus effects similar to both a relatively low (1.0 g/kg) and higher (2.0 g/kg) dose of ethanol.63 The common element in all three species tested (mice, rats, and monkeys) appears to be positive GABAA receptor modulation. The neurosteroid 3α,5β-THP substitution for ethanol shows wide individual differences in rats, mice, and monkeys.59,60,62 This is an unusual finding, because there is extensive training involved in establishing the discrimination, and such overtraining dampens variance across individuals. It has been speculated that the source of such individual variance in sensitivity to neurosteroids is due to the additive effect of experimenter-administered neurosteroids with circulating levels in neurosteroids that differ due to individual variations of HPA axis function.60 Monkeys also show a wide individual variation in the amount of ethanol they will self-administer, from an average of 1 to 2 drinks/day to an average of over 12

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drinks/day.The relationship between sensitivity to ethanollike effects of neurosteroids and propensity to self-administer ethanol has not been directly tested. However, the suggestion from data showing lower sensitivity to the discriminative stimulus effects of ethanol in the follicular phase of the menstrual cycle (when progesterone and DOC levels are low) and increased alcohol consumption in women during the follicular phase is intriguing.64 In addition, it has been documented in women who drink heavily and monkeys who self-administer high daily doses of ethanol that their menstrual cycles are disrupted and progesterone levels are very low.65,66 It will be of interest to first determine sensitivity to the discriminative stimulus effects of ethanol and then allow monkeys to self-administer ethanol to more directly correlate aspects of discriminative stimuli (subjective effects) with risk for heavy drinking.

Neuroactive steroids mediate specific ethanol actions following acute administration in rodents Systemic administration of moderate doses (1 to 2.5 g/kg) of ethanol increases both plasma and brain levels of 3α,5α-THP and 3α,5α-THDOC.19,21,31,67,68 Ethanol-induced elevations in neuroactive steroids reach physiologically relevant concentrations that are capable of enhancing GABAergic transmission. The effect of ethanol on neuroactive steroid levels is dose- and time-dependent, and correlates with the time course of some, but not all, effects of ethanol. For example, the motor incoordinating effects of ethanol appear prior to elevations in neuroactive steroids,69 whereas the anticonvulsant effects of ethanol appear in congruence with elevations of these steroids.68 A large body of evidence from multiple laboratories suggests that ethanol-induced elevations of GABAergic neuroactive steroids contribute to many behavioral effects of ethanol in rodents. Neuroactive steroids have been shown to modulate ethanol’s anticonvulsant effects,68 sedation,30 impairment of spatial memory,4,70 anxiolytic-like,71 and antidepressant-like72 actions. Each of these behavioral responses is prevented by pretreatment with the biosynthesis inhibitor finasteride and/or by prior adrenalectomy. The hypnotic effect of ethanol is partially blocked by adrenalectomy. Importantly, administration of the immediate precursor of 3α,5α-THP restores effects of ethanol in adrenalectomized animals, showing that brain synthesis of neu-

roactive steroids modulates effects of ethanol.30 However, neuroactive steroids do not appear to influence the motor incoordinating effects of ethanol, since neither finasteride administration or adrenalectomy diminish these actions.69 Taken together, these studies suggest that elevations in neuroactive steroids influence many of the GABAergic effects of ethanol in vivo and the effects of neuroactive steroids may determine sensitivity to many behavioral effects of ethanol.

Neuroactive steroid precursors are increased by acute ethanol administration in rodents While several studies have demonstrated that acute ethanol challenges can result in significant increases in neuroactive steroids in plasma and brain, fewer studies have examined in detail the importance of ethanol’s effect on their precursors. As early as the 1940s, it was found that DOC acetate and progesterone induced anesthetic effects in rats73 and both DOC and progesterone had antiseizure effects,74 probably due to their 3αreduced metabolites.75,76 DOC, the precursor of 3α,5αTHDOC, and progesterone, the precursor of 3α,5α-THP, can readily cross the blood-brain barrier and distribute throughout the brain. These precursors of GABAergic neuroactive steroids are synthesized in the adrenals, beginning with cholesterol’s metabolism to pregnenolone (Figure 1). While small amounts of these steroids may be formed de novo in the brain, ethanol-induced increases in neuroactive steroids are predominantly formed from adrenal precursors.77 Plasma and brain concentrations of pregnenolone and progesterone are increased more rapidly than 3α,5α-THP after acute ethanol administration.31,78 Other studies have also shown increases in both plasma and brain DOC after acute ethanol administration. DOC levels were increased in cerebral cortex, cerebellum, hippocampus, hypothalamus, and olfactory bulb and tubercle, ranging from 28-fold increases in the cerebellum to 38-fold increases in the hypothalamus.79 A significant increase in DOC levels across many brain regions has also been reported by Kraulis et al following intravenous injections of [1,2-3H]-DOC.80 A strong correlation exists between plasma and brain levels of DOC. The temporal and regional associations found in these studies suggest that the steroids originate in the adrenals and are transported to the brain. Upon entering the brain the steroids are metabolized by 5α-reductase and 3αdehydrogenase enzymes. These enzymes display brain

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Clinical research region and cell specific expression81 that may be responsible for the regional distribution of steroid levels following acute ethanol administration. Furthermore, DOC levels measured in the Khisti et al study are comparable to 3α,5α-THDOC levels measured in plasma and brain,21 suggesting that DOC formed after acute ethanol administration may be largely converted to the GABAergic neurosteroid 3α,5α-THDOC. Studies of ethanol’s effects on neurosteroid precursors are important not only to determine the sources and synthesis of potent metabolites, but also to establish their role in physiological functions.

enhanced responses following 3α,5α-THP administration produces the opposite effect of other GABAA receptor agonists, such as muscimol and barbiturates,85 suggesting a unique role for GABAA receptor neurosteroid binding sites in regulating ethanol consumption. Interestingly, ethanol-dependent rats develop tolerance to ethanolinduced increases in neurosteroid levels,4,79 which may influence the excessive drinking that is observed in ethanol-dependent rats.86 Together, these data suggest a strong relationship between neurosteroid levels and ethanol consumption that may involve both genetic and environmental factors.

Effects of neuroactive steroids on drinking behavior in rodents

Mechanisms of ethanol-induced elevations of neuroactive steroids in plasma and brain

The GABAergic system is important in regulating ethanol consumption, and neurosteroids can also alter drinking behavior through their actions on GABAA receptors. 3α,5α-THP dose-dependently increased ethanol self-administration in nondependent ethanolpreferring P rats, while decreasing ethanol administration in ethanol-dependent P rats.4 This suggests a complex relationship whereby neurosteroids may promote drinking in nondependent animals consuming small amounts of ethanol, while protecting against excessive drinking in dependent animals. This possibility is supported by data in male C57BL/6J mice where 3α,5α-THP dose-dependently modulated ethanol intake in a 2-hour session, with low doses (3.2 mg/kg) increasing ethanol consumption and high doses (24 mg/kg) decreasing ethanol consumption.82 In addition, at doses of 10 and 17 mg/kg, 3α,5αTHP has been shown to have rewarding properties in mice.83 However, other studies in nondependent rats have shown that pretreatment with a 3 mg/kg dose of 3α,5αTHP, but not a 1- or 10-mg/kg dose, increases oral selfadministration of ethanol.84 This result suggests that 3α,5α-THP dose-dependently mediates some of the reinforcing effects of ethanol, and its concentration in brain may have an important influence on drinking behavior. Indeed, Sardinian alcohol-preferring rats have larger 3α,5α-THP and 3α,5α-THDOC elevations after ethanol administration than their non-alcohol-preferring counterparts.21 Other studies have shown that increased ethanol intake after 3α,5α-THP administration is selective for ethanol-reinforced responding, and cannot be attributed to palatability or increased motor activity during the experimental sessions.85 Furthermore, the ethanol

Ethanol-induced elevations in neuroactive steroids appear to involve activation of the HPA axis to increase circulating levels of neuroactive steroids and their precursors, as well as direct effects of ethanol on brain synthesis. Adrenalectomy completely blocks the effects of ethanol on cerebral cortical 3α,5α-THP concentrations; however, the effect of ethanol on cerebral cortical levels of 3α,5α-THP can be restored by administration of its precursor, 5α-dihydroprogesterone (5α-DHP), to adrenalectomized rats.30 Since the steroid biosynthetic enzymes are present across brain,87 it is likely that ethanol-induced increases in brain levels of neuroactive steroids involve brain synthesis that may contribute to effects of ethanol. The first step in steroid synthesis is the translocation of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, where P450scc converts it to pregnenolone. This step is mediated by steroidogenic acute regulatory protein (StAR) and/or the peripheral benzodiazepine receptor. Ethanol rapidly increases the synthesis and translocation of StAR protein from the cytosol to the mitochondria in the adrenal gland.30 Hence, it is likely that increases in GABAergic neuroactive steroids in adrenals are secondary to ethanol-induced increases in all steroid synthesis initiated by StAR activity. To determine if ethanol could alter other steroidogenic enzyme activity in rat brain and adrenal minces, Morrow and colleagues investigated the effects of ethanol on 5αreductase and 3α-hydroxysteroid dehydrogenase (3αHSD) enzyme activity (unpublished data). Ethanol (10 to 100 mM) did not alter 5α-reductase activity, measured by the conversion of [14C]progesterone to [14C]5α-DHP in tis-

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sue minces. In contrast, ethanol (30 to 100 mM) increased the conversion of [14C]5α-DHP to [14C]3α,5α-THP by a maximum of 30 ± 3.6% in the olfactory bulb and tubercle, but had no effect in the adrenal gland. Ethanol did not alter nicotinamide adenine dinucleotide phosphate (NADPH) effects on enzyme activity. Fluoxetine was tested as a positive control since previous studies showed that fluoxetine decreased the Km of a recombinant 3αHSD enzyme.88 Fluoxetine increased the activity of 3αHSD enzyme in the olfactory bulb and tubercle and adrenal gland and this effect was blocked by the 3α-HSD inhibitor indomethacin. Since the 3α-HSD enzyme possesses bidirectional activity, the effect of ethanol on the oxidative activity of 3α-HSD was determined. Ethanol did not alter the conversion of [3H]3α,5α-THP to [3H]5α-DHP in rat olfactory bulb and tubercle or adrenal gland. An increase in the reductive activity of the 3α-HSD with no change in the oxidative direction would cause a greater conversion of 5α-DHP to 3α,5α-THP. This effect could contribute to ethanol-induced increases in brain 3α,5αTHP levels. Indeed, the increased reductive activity of 3αHSD would be predicted to increase brain levels of both 3α,5α-THP and other 3α,5α-reduced neuroactive steroids such as 3α,5α-THDOC.

Suppression of neuroactive steroid responses following chronic ethanol exposure in rats It is well known that chronic stress results in adaptation of the HPA axis, leading to decreased levels of corticosterone in rats.89 Repeated exposure to alcohol also blunts the response of the HPA axis to a second ethanol challenge.90 This blunting of the HPA axis is associated with reduction in CRF and ACTH elevations following ethanol challenge.91 In line with these observations, chronic ethanol consumption in rats results in blunted elevation of cerebral cortical 3α,5α-THP4 and plasma and brain DOC levels following acute ethanol challenge,79 compared with pair-fed control rats. These findings suggest that there is tolerance to ethanol-induced increases in neuroactive steroid levels. Since decreases in brain neurosteroid levels were concomitant with decreases in plasma neurosteroid levels, it is likely that the observed decreases in 3α,5α-THP and DOC levels were dependent on blunted HPA axis activity. Thus, adaptations of the HPA axis may contribute to tolerance to effects of ethanol that are mediated by the GABAergic neuroactive steroids.

Chronic ethanol administration to rodents and humans produces tolerance to ethanol and cross-tolerance to benzodiazepines and barbiturates. In contrast, ethanoldependent rats are sensitized to the anticonvulsant effects of both 3α,5α-THP and 3α,5α-THDOC.92-94 These studies also show that GABAA receptor sensitivity to 3α,5α-THP and 3α,5α-THDOC is enhanced in ethanoldependent rats, likely due to the reduction of ethanolinduced levels in these animals described above. Since ethanol-dependent rats are sensitized to anticonvulsant actions of neuroactive steroids, this class of compounds may be therapeutic during ethanol withdrawal. Indeed, neurosteroid therapy may have advantages over benzodiazepine therapy since benzodiazepines exhibit crosstolerance with ethanol. Further studies are needed to explore this possibility.

Effects of ethanol on neuroactive steroids in humans The potential role of neuroactive steroids in alcohol action in humans is relatively unexplored and inconsistent. Recent human studies show that male and female adolescents seen in the emergency room for alcohol intoxication had elevated plasma levels of the neuroactive steroid 3α,5α-THP.24,25 Furthermore, various subjective effects of ethanol during the rising phase of the blood alcohol curve are diminished by prior administration of the neurosteroid biosynthesis inhibitor finasteride.95 Finasteride reduces the formation of both 3α,5αTHP and 3α,5α-THDOC by inhibiting the reduction of progesterone and DOC to intermediate precursors. Indeed, finasteride pretreatment blocked subjective effects of alcohol using three different scales to measure the activating, sedating, anesthetic, and peripheral dynamic aspects of alcohol actions. The ability of finasteride to reduce the subjective effects of alcohol was not observed in individuals carrying the GABAA α2 subunit polymorphism associated with alcoholism, suggesting that individuals carrying this polymorphism have reduced sensitivity to both alcohol and finasteride.95 Other studies show that 3α,5α-THP levels are decreased during the peak of alcohol withdrawal and return to normal levels upon recovery.96,97 Likewise, abstinent alcoholics exhibit diminished progesterone levels as well as a lowered ratio of progesterone to pregnenolone.98 In contrast, laboratory administration of low or moderate doses of ethanol appears to have no effect on plasma 3α,5α-THP levels26

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Clinical research or to decrease 3α,5α-THP levels.27,99 The basis of these conflicting results is unknown, but may involve pharmacologically different ethanol doses, different analytic methods to measure neurosteroids, or environmental factors that influence neurosteroid synthesis in humans. Alternatively, different neuroactive steroids may be elevated in humans vs rodents, or the effects of ethanol on neuroactive steroid levels in humans may be restricted to brain. Table I summarizes the different effects of ethanol on neuroactive steroid levels in rodents, monkeys, and humans. Humans, but not rodents, synthesize multiple 5β-reduced neuroactive steroids including 3α,5β-THP and 3α,5βTHDOC. 3α,5β-THP levels are comparable to those of 3α,5α-THP in human plasma and cerebrospinal fluid.15,16 These neuroactive steroids also modulate GABAergic transmission,8,13,14 but have not been measured in humans after ethanol administration. Additionally, the primary stress steroids in humans are cortisol and 11-deoxycortisol, while progesterone and corticosterone are the primary stress steroids in rodents. 3α,5β-reduced cortisol is a negative modulator of GABAA receptors,17 and could contribute to the subjective effects of ethanol in humans.Thus, the combined effects of 3α,5α- and 3α,5β-reduced neuroactive steroids may contribute to the effects of ethanol in humans and nonhuman primates. These steroids have never been measured following ethanol, stress, or HPA axis activation in humans or nonhuman primates. Comprehensive studies of neuroactive steroid levels in humans are needed. While 3α,5α-THP and 3α,5αTHDOC are the primary neuroactive steroids in rodents, other neuroactive steroids may be more relevant in humans. For example, plasma progesterone of adrenal origin is present at much higher levels in rodents than humans, suggesting an explanation for higher levels of plasma 3α,5α-THP in rodents vs humans. Other GABAergic 3α,5α- and 3α,5β-reduced neuroactive steroids, derived from DOC, dehydroepiandrosterone (DHEA), and testosterone, are known GABAergic modulators100-102 that may be elevated by HPA axis activation in humans. Unfortunately, simple inexpensive analytic methods to measure these steroids are not available. The ability of finasteride to block the subjective effects of ethanol in humans may be due to its ability to prevent the formation of any or all of these neuroactive steroids. Indeed, the combined effects of all steroids regulated by acute or chronic ethanol exposure may contribute to its actions in all species.

Effects of ethanol on neuroactive steroid precursors in nonhuman primates and humans We have recently shown that acute ethanol challenges in cynomolgus monkeys do not change plasma pregnenolone and DOC levels. Two doses of ethanol, 1.0 and 1.5 g/kg, were tested via intragastric administration, and neither was able to increase neuroactive steroid precursors or circulating cortisol levels despite an average blood ethanol level of 147 mg/dL.103,104 In contrast, acute ethanol administration increases pregnenolone, progesterone, DOC, and their neuroactive metabolites in rat brain and plasma,4,31,79,105 and this increase is also prevented by adrenalectomy/orchiectomy, consistent with ethanol activation of the HPA axis.31,105 These results suggest that higher doses of ethanol might be necessary to stimulate the HPA axis and thus increase pregnenolone and DOC levels in nonhuman primates. Indeed, Williams and collaborators106 have shown that intravenous administration of ethanol up to 1.9 g/kg failed to increase plasma ACTH levels in rhesus monkeys. Other studies using 2.0 g/kg ethanol have reported increased cortisol levels in monkeys under conditions where monkeys were restrained on a flat surface while receiving ethanol, which may contribute to HPA axis activation.107 The possibility that pregnenolone, DOC, and their neuroactive metabolites might be differentially regulated in nonhuman primates compared with rodents cannot be ruled out; future studies will be necessary to further address this question. The effects of ethanol on neuroactive steroid precursors in humans are inconsistent to date. Laboratory administration of moderate doses of ethanol (0.7 to 0.8 g/kg) has recently been reported to increase pregnenolone and DHEA levels and to decrease progesterone levels in healthy human subjects.27 In contrast, Holdstock et al26 reported that ethanol administration to healthy volunteers increased progesterone levels in women during the luteal phase, but had no effect during the follicular phase or in men. Low alcohol consumption in premenopausal women was associated with increased estradiol, androstenedione, and testosterone levels throughout the menstrual cycle, while progesterone levels were increased only in the luteal phase.108 Moreover, abstinent alcoholic women had diminished progesterone levels and a lower progesterone to pregnenolone ratio during the luteal phase.98 In contrast, others reported that chronic male alcoholics had higher basal progesterone compared with healthy controls.109

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These variable data suggest that genetic and/or environmental factors may influence effects of ethanol on steroid precursors.

HPA axis modulation in alcohol-dependent humans Among the neuropsychiatric disorders that show alterations in HPA axis responsiveness is alcoholism. ACTH and cortisol secretion is increased during ethanol intoxication and acute alcohol withdrawal.110-117 In contrast, an attenuated responsiveness of the HPA axis has been found in both drinking and abstinent alcohol-dependent patients. Alcohol-dependent patients have low cortisol and 11deoxycortisol basal levels, show a greater suppression in cortisol and ACTH concentrations following dexamethasone test, and have a reduced cortisol response to exogenous ACTH administered after dexamethasone.118 Moreover, they have attenuated ACTH and cortisol responses after pituitary stimulation by ovine or human CRF119-122 and an altered ACTH response to naloxone.123 An altered cortisol and ACTH response to ovine CRF and naloxone have also been found in sons of alcoholics.124-126 These data are consistent with the idea that HPA axis dysregulation may contribute to altered neurosteroid responses in human alcoholism, though studies showing this consequence of alcoholism are not available to date.

HPA axis modulation of DOC and pregnenolone in cynomolgus monkeys While stimulation of the HPA axis by acute stress or ethanol administration plays a pivotal role in increasing GABAergic neuroactive steroids and their precursors in rodent brain and plasma, few data are available for nonhuman primates. We have recently demonstrated that plasma DOC and pregnenolone levels in ethanol-naïve cynomolgus monkeys are differentially regulated by various challenges to the HPA axis.103,104 Plasma DOC levels are sensitive to hypothalamic and pituitary activation of the axis and to negative feedback mechanisms assessed by the dexamethasone test.Thus, administration of naloxone at the doses of 125 and 375 µg/kg increased plasma DOC levels up to 86% and 97%, respectively. This is consistent with data showing an activation of the HPA axis and increased cortisol and ACTH levels in humans and nonhuman primates.125,127,128 CRF (1 µg/kg) increased plasma DOC levels up to 111%, and this increase was positively

correlated with the increase in cortisol levels in the same subject, dexamethasone (130 µg/kg) decreased DOC levels by 42%, in agreement with a suppression of HPA axis activity. In contrast, administration of ACTH (10 ng/kg) 46 hours after 0.5 mg/kg dexamethasone had no effect on plasma DOC levels, suggesting that DOC synthesis is independent of ACTH stimulation of the adrenals. Furthermore, changes in DOC levels were correlated with changes in cortisol levels only for some of these challenges, suggesting that other neuroendocrine factors could regulate DOC synthesis in nonhuman primates.103 Pregnenolone levels in the same cynomolgus monkey subjects were differentially regulated from DOC. Naloxone administration (125 and 375 µg/kg) increased plasma pregnenolone up to 222 and 216%, respectively. In contrast, CRF (1 µg/kg) and dexamethasone (130 µg/kg) had no effect on pregnenolone levels, while ACTH (10 ng/kg), 4 to 6 hours after 0.5 mg/kg dexamethasone, decreased plasma pregnenolone levels by 43%. CRF and ACTH administration decreased the ratio of plasma pregnenolone:DOC, suggesting increased metabolism of pregnenolone into DOC or other steroids.104 Thus, circulating pregnenolone levels are subject to complex regulation involving factors other than direct HPA axis modulation. Naloxone could increase pregnenolone levels through mechanisms independent of HPA axis activation, given that exogenous CRF and ACTH had no effect on pregnenolone levels. Opioid receptors are present in peripheral tissue including the adrenals,129 and a direct action of naloxone on these receptors cannot be ruled out. Opioidergic neurons regulate gonadotropin-releasing hormone (GnRH) secretion,130 and it is possible that the increase in plasma pregnenolone levels induced by naloxone is due to increased gonadal steroidogenesis via opioid inhibition of GnRH. Furthermore, naloxone could have a direct action on the enzymes involved in steroid biosynthesis. Further studies are needed to investigate these possibilities.

Are neuroactive steroid responses to HPA axis stimulation linked to alcohol drinking? Neuroactive steroid responses to HPA axis challenges in ethanol-naïve animals may predict future alcohol consumption. Studies have so far focused on nonhuman primates. Dexamethasone suppresses DOC levels in monkey plasma and the degree of dexamethasone suppression measured in ethanol-naïve monkeys was predictive of sub-

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Clinical research sequent alcohol drinking in these monkeys. That is, the highest alcohol drinking was found in the monkeys that showed the lowest suppression of DOC levels in response to dexamethasone.103 In this study, the monkeys with the lowest response to dexamethasone also developed a pattern of chronic binge drinking, drinking the equivalent of 16 or more drinks in 22 h in approximately 20% of their drinking sessions (Grant et al, submitted). This binge drinking pattern of high quantity of alcohol intake in short time periods persisted throughout 1 year of ethanol self administration (Grant et al, unpublished). In contrast, no other DOC responses to HPA axis stimulation in ethanolnaïve monkeys were predictive of subsequent voluntary drinking or binge drinking. The effect of dexamethasone on plasma DOC levels in monkeys appears to be a trait marker of risk for high alcohol consumption. This trait marker also correlated with alcohol intakes in a small group (n=4) of rhesus monkeys (unpublished data collected in collaboration with David P. Friedman at Wake Forest University).These findings need to be replicated in other primate studies of ethanol self-administration,

including cohorts of humans that have not yet started drinking. This adaptation in precursor responses suggests there will also be adaptations in GABAergic neuroactive steroids derived from DOC.

Potential role of neuroactive steroids in ethanol sensitivity and risk for alcoholism: a hypothesis While the physiological significance is unknown, dysregulation of the HPA axis is associated with ethanol dependence in humans.118,122 HPA axis suppression in alcohol dependence results in diminished elevations of GABAergic neuroactive steroids in rodents as described above. Diminished elevations of GABAergic neuroactive steroids following ethanol exposure would result in reduced sensitivity to the anxiolytic, sedative, anticonvulsant, cognition-impairing, and discriminative stimulus properties of ethanol. Reduced sensitivity to ethanol is associated with greater risk for the development of alcoholism in individuals with alcoholism in their family.131,132

Hypothetical role of neuroactive steroids in alcoholism

Acute ethanol consumption

Innate alcohol tolerance

Chronic ethanol consumption

Increased GABAergic neuroactive steroids

Blunted effect of ethanol on neuroactive steroids

Increased sensitivity to neuroactive steroids

Increased ethanol sensitivity

Blunted ethanol sensitivity

Reduced risk of excessive drinking

Increased risk of excessive drinking

Neuroactive steroids may be therapeutic during withdrawal or for relapse prevention

Alcohol use disorders

Figure 2. Schematic representation of the hypothetical role of neuroactive steroids in ethanol sensitivity and risk for alcoholism. GABA, γ-aminobutyric acid

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Moreover, individuals with the GABAA receptor α2 subunit polymorphism that is associated with alcohol dependence exhibit substantially reduced sensitivity to the subjective effects of ethanol compared with individuals that lack this polymorphism.95 Likewise, rats and mice with low sensitivity to various behavioral effects of alcohol tend to self-administer greater amounts of ethanol in laboratory settings. The BXD recombinant inbred strains of mice, PKCγ and PKCε knockout mice, alcohol-preferring P rats, and high-alcohol-drinking (HAD) rats are but a few examples.Taken together, these observations suggest that ethanol-induced elevations of GABAergic neuroactive steroids in brain may underlie important aspects of ethanol sensitivity that may serve to prevent excessive alcohol consumption (Figure 2). The loss of these responses may promote excessive alcohol consumption to achieve the desired effects of ethanol.A deficiency in neurosteroid responses to ethanol intake could result from suppression of the HPA axis or other genetic/environmental factors that inhibit neurosteroid synthesis in brain. Hence, the lack of neurosteroid elevations in response to ethanol could underlie innate ethanol tolerance or ethanol tolerance induced by long-term ethanol use. Indeed, the observation that finasteride did not alter the subjective effects of ethanol in subjects with the GABAA receptor α2 subunit polymorphism associated with alcohol dependence95 is consistent with the idea that neurosteroid responses contribute to ethanol sensitivity and risk for alcoholism. Both forms of tolerance may promote excessive alcohol consumption. Excessive alcohol consumption, particularly binge drinking, is a significant risk factor for all alcohol use disorders, including alcohol dependence and alcoholism. The restoration of ethanol sensitivity in ethanol-dependent patients may therefore have thera-

peutic utility. However, it is unclear at this time whether neuroactive steroid supplementation would reduce excessive alcohol consumption in humans. Indeed, as mentioned above, low doses of neuroactive steroids increased operant ethanol self-administration under some conditions,84 while neuroactive steroids reduce ethanol consumption at high doses82 or in ethanol-dependent rats.4 The relationship between HPA axis response, GABAergic neuroactive steroids, and alcohol drinking deserves further studies in nonhuman primates and humans.

REFERENCES

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Summary and conclusions The effects of acute ethanol administration on neuroactive steroid levels found in rodents have not been found in monkeys or humans. Does this mean that neuroactive steroids do not have an important role in ethanol action in these species? We doubt this conclusion, since monkeys exhibit discriminative stimulus properties of ethanol and neuroactive steroids that are indistinguishable.62 Furthermore, the steroid biosynthesis inhibitor finasteride blocks the subjective effects of ethanol in humans.95 Primates may synthesize different GABAergic neuroactive steroids in response to ethanol challenge. These steroids may include 3α,5α- and 3α,5β-reduced derivatives of progesterone, DOC, and testosterone, all of which have potent GABAergic activity. Further studies are needed to translate a large body of rodent research on GABAergic neuroactive steroids to better understand the role of endocrine factors in alcohol sensitivity and risk for alcoholism. ❏ This work was supported by NIH grants R37 AA10564 (ALM) and UO1 AA13515 (ALM) and UO1 AA13510 (KAG).

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Clinical research La modulación de los esteroides neuroactivos por el eje hipotálamo-hipofisissuprarenal, influye en la sensibilidad al etanol y en la conducta frente a la bebida

Le comportement alcoolique la sensibilité à l’éthanol dépendent de la modulation des stéroïdes neuroactifs GABAergiques au niveau de l’axe hypothalamo-hypophysosurrénalien

La activación del eje hipotálamo-hipófisis-suprarrenal (HHS) determina una elevación de los esteroides neuroactivos GABA (ácido Á-aminobutírico)érgicos que refuerzan la neurotransmisión de GABA y restablecen la homeostasia después del estrés. Esta regulación del eje HHS mantiene sana la función cerebral y la protege frente a las enfermedades neuropsiquiátricas. La sensibilidad al etanol depende de las elevaciones de esteroides neuroactivos que potencian los efectos GABAérgicos del etanol y pueden impidiran el consumo excesivo de alcohol por los roedores y seres humanos. La sensibilidad baja al alcohol se asocia a un mayor consumo de éste, con el riesgo consiguiente de etilismo. De hecho, las ratas dependientes del etanol muestran una respuesta neuroesteroidea a la administración de etanol muy reducida, lo que puede contribuir a la tolerancia etanólica y a la propensión a beber mayores cantidades de alcohol. En esta revisión se ofrecen pruebas que respaldan la hipótesis de que los neuroesteroides contribuyen a las acciones del etanol e impiden un consumo excesivo, mientras que la falta de respuesta neuroesteroidea al etanol podría explicar la tolerancia innata o crónica y el mayor riesgo de excesos en la bebida. Los neuroesteroides podrían tener una utilidad terapéutica en la abstinencia del alcohol o en la evitación de las recaídas.

L’activation de l’axe hypothalamo-hypophyso-surrénalien (HHS) entraine une élévation de la sécrétion des stéroïdes neuroactifs GABA-ergiques (acide 웂aminobutirique) qui stimulent la neurotransmission GABA et restaurent l’homéostasie après le stress. Cette régulation de l’axe HHS maintient une fonction cérébrale saine et protège des maladies neuropsychiatriques. Les élévations des stéroïdes neuroactifs influent sur la sensibilité à l’éthanol en augmentant ses effets GABAergiques et peuvent ainsi prévenir les consommations alcooliques excessifs chez les rongeurs et chez l’homme. Une faible sensibilité à l’éthanol est associée à une plus grande consommation d’alcool et à un risque d’alcoolisme plus important. Les réponses neurostéroïdes à l’administration d’éthanol chez des rats rendus alcoolodépendants sont donc diminuées, ce qui peut contribuer à une tolérance à l’éthanol et à une propension à en boire de plus grandes quantités. Cette revue de la littérature fournit des arguments en faveur de l’hypothèse d’une contribution des neurostéroïdes aux effets de l’éthanol et à la prévention de sa consommation excessive alors qu’un déficit des réponses neurostéroïdes peut être à la base d’une tolérance innée ou invétérée chronique et d’un risque augmenté de consommation excessive d’alcool. Les neurostéroïdes peuvent avoir une utilité thérapeutique dans le sevrage alcoolique ou dans la prévention d’une rechute.

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110.Mendelson JH, Ogata M, Mello NK. Adrenal function and alcoholism I. Serum cortisol. Psychosom Med. 1971;33:145-157. 111.Iranmanesh A, Veldhuis JD, Johnson ML, Lizarralde G. 24-hour pulsatile and circadian patterns of cortisol secretion in alcoholic men. J Androl. 1989;10:54-63. 112.Adinoff B, Martin PR, Bone GH, et al. Hypothalamic-pituitary-adrenal axis functioning and cerebrospinal fluid corticotropin releasing hormone and corticotropin levels in alcoholics after recent and long-term abstinence. Arch Gen Psychiatry. 1990;47:325-330. 113.Adinoff B, Risher-Flowers D, De Jong J, et al. Disturbances of hypothalamic-pituitary-adrenal axis functioning during ethanol withdrawal in six men. Am J Psychiatry. 1991;148:1023-1025. 114.Adinoff B, Ruether K, Krebaum S, Iranmanesh A, Williams MJ. Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men. Alcohol Clin Exp Res. 2003;27:1420-1427. 115.Inder WJ, Joyce PR, Wells JE, et al. The acute effects of oral ethanol on the hypothalamic-pituitary-adrenal axis in normal human subjects. Clin Endocrinol (Oxf). 1995;42:65-71. 116.Waltman C, Blevins LSJ, Boyd G, Wand GS. The effects of mild ethanol intoxication on the hypothalamic-pituitary-adrenal axis in non-alcoholic men. J Clin Endocrinol Metab. 1993;77:518-522. 117.Hundt W, Zimmermann U, Pottig M, Spring K, Holsboer F. The combined dexamethasone-suppression/CRH-stimulation test in alcoholics during and after acute withdrawal. Alcohol Clin Exp Res. 2001;25:687691. 118.Adinoff B, Krebaum SR, Chandler PA, Ye W, Brown MB, Williams MJ. Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-monthabstinent alcohol-dependent men, part 1: adrenocortical and pituitary glucocorticoid responsiveness. Alcohol Clin Exp Res. 2005;29:517-527. 119.Wand GS, Dobs AS. Alterations in the hypothalamic-pituitary-adrenal axis in actively drinking alcoholics. J Clin Endocrinol Metab. 1991;72:12901295. 120.Costa A, Bono G, Martignoni E, Merlo P, Sances G, Nappi G. An assessment of hypothalamo-pituitary-adrenal axis functioning in non-depressed, early abstinent alcoholics. Psychoneuroendocrinology. 1996;21:263-275.

121.Ehrenreich H, Schuck J, Stender N, et al. Endocrine and hemodynamic effects of stress versus systemic CRF in alcoholics during early and medium term abstinence. Alcohol Clin Exp Res. 1997;21:1285-1293. 122.Adinoff B, Krebaum SR, Chandler PA, Ye W, Brown MB, Williams MJ. Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-monthabstinent alcohol-dependent men, part 2: response to ovine corticotropinreleasing factor and naloxone. Alcohol Clin Exp Res. 2005;29:528-537. 123. Inder WJ, Joyce PR, Ellis MJ, Evans MJ, Livesey JH, Donald RA. The effects of alcoholism on the hypothalamic-pituitary-adrenal axis: interaction with endogenous opioid peptides. Clin Endocrinol (Oxf). 1995;43:283-290. 124.Waltman C, McCaul ME, Wand GS. Adrenocorticotropin responses following administration of ethanol and ovine corticotropin-releasing hormone in the sons of alcoholics and control subjects. Alcohol Clin Exp Res. 1994;18:826-830. 125.Wand GS, Mangold D, El Deiry S, McCaul ME, Hoover D. Family history of alcoholism and hypothalamic opiodergic activity. Arch Gen Psychiatry. 1998;55:1114-1119. 126.Hernandez-Avila CA, Oncken C, Van Kirk J, Wand GS, Kranzler HR. Adrenocorticotropin and cortisol responses to a naloxone challenge and risk for alcoholism. Biol Psychiatry. 2002;51:652-658. 127.Jackson RV, Grice JE, Hockings GI, Torpy DJ. Naloxone-induced ACTH release: mechanism of action in humans. J Pharmacol Exp Ther. 1995;285:518526. 128.Williams KL, Ko MC, Rice KC, Woods JH. Effect of opioid receptor antagonists on hypothalamic-pituitary-adrenal activity in rhesus monkeys. Psychoneuroendocrinology. 2003;28:513-528. 129.Witter G, Hope P, Pyle D. Tissue distribution of opioid receptor gene expression in the rat. Biochem Biophys Res Commun. 1996;218:877-881. 130.Kalra SP, Hovarth T, Naftolin F, Xu B, Pu S, Kalra PS. The interactive language of the hypothalamus for the gonadotropin releasing hormone (GnRH) system. J Neuroendocrinol. 1997;9:569-576. 131.Schuckit MA. Low level of response to alcohol as a predictor of future alcoholism. Am J Psychiatry. 1994;151:184-189. 132.Schuckit MA, Smith TL. An 8-year follow-up of 450 sons of alcoholic and control subjects. Arch Gen Psychiatry. 1996;53:202-210.

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Poster Estrogen enhances stress-induced prefrontal cortex dysfunction: relevance to Major Depressive Disorder in women It is well documented that exposure to stress can precipitate or exacerbate many mental illnesses,1,2 including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Women are twice as likely as men to develop these disorders,3,4 as well as most anxiety disorders and phobias,5 but the biological causes of this discrepancy are poorly understood. Interestingly, there is evidence that the increased prevalence of MDD in women occurs primarily during the childbearing years, when circulating estrogen is present.6,7 These observations raise questions as to whether men and women have distinct neurobiological responses to stress, and if so, how might estrogen mediate these differences? Attempts to answer these questions in animal models have generated a growing body of literature demonstrating that estrogen can, indeed, modulate the effects of stress in the brain. Moreover, these effects are demonstrable in brain regions relevant to MDD, and are consistent with the idea that estrogen might enhance the stress response, promoting a greater vulnerability to mental illness. The medial prefrontal cortex (PFC) is widely recognized as a site of dysfunction in patients with stress-related disorders,8 particularly MDD. Post-mortem studies of suicide victims’ brains reveal marked morphological changes—most notably, reduced glia and neuron number in the ventromedial PFC.9 Similarly, magnetic resonance imaging (MRI) studies demonstrate reduced volume of this area in depressed patients,10 as well as abnormal activity.11 The PFC integrates information from multiple brain areas to regulate behavior, thought, and affect12— functions that are often compromised in MDD patients.13 In animal models, the integrity of the PFC is most commonly tested using working memory tasks, which require animals to keep information “online” in the absence of external cues, continually update information, and inhibit inappropriate responses. Exposure to stress has consistently been shown to impair performance on such tasks in nonhuman primates and male rodents,14 but until recently, neither sex differences nor estrogen effects on this phenomenon had been explored. Copyright © 2006 LLS SAS. All rights reserved

The first studies to examine sex differences in the effects of stress on PFC function elicited the stress response in young adult male and female rats with injections of varying doses of the benzodiazepine inverse agonist FG7142. FG7142 is a well-documented anxiogenic drug that is frequently used as a model for stress, given its reliability in producing the biochemical and physiological effects of stress: increased corticosterone release, increased catecholamine turnover, elevated heart rate, and increased blood pressure.15 Moreover, animals that have been administered FG7142 exhibit classic stress-related behaviors, including defecating, urinating, freezing, and ultrasonic vocalizations.16 Following FG7142 administration, animals were tested on a classic measure of working memory—delayed alternation in the T-maze. At high doses of FG7142, all animals displayed impairment on the T-maze. At lower doses, however, only females showed impairment, suggesting that they were more sensitive to the detrimental effects of stress on mPFC function (Figure 1a). To test

478

Poster by: Rebecca M. Shansky, PhD; Amy F. T. Arnsten, PhD Mount Sinai School of Medicine, New York, NY, USA (Rebecca M. Shansky); Yale University School of Medicine, New Haven, Conn, USA (Amy F. T. Arnsten) (e-mail: [email protected])

whether fluctuating hormones produced this sex effect, the experiment was repeated while female rats’ estrus phase was monitored. It was found that these rats only displayed sensitivity to FG7142 during proestrus, when estrogen levels are highest. Animals in estrus, characterized by low estrogen levels, responded to the low dose of FG7142 in a manner comparable to that of males—that is, showing no impairment at all17 (Figure 1b). This effect was further replicated using a more conventional stress paradigm, restraint. While 2 hours of restraint stress produced working memory impairments in all groups, only females in proestrus were impaired by 1 hour of restraint as well (Figure 1c).18 Taken together, these studies suggest that fluctuating hormones can interact with stress systems to modulate PFC function during stress. This idea was explored further by ovariectomizing a new group of female rats, and implanting a time-release capsule containing either estrogen (OVX + E) or cholesterol

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(OVX) as a control. These rats were then treated with the same low dose of FG7142 that impaired proestrus females, but not estrus females or males, and then tested on the T-maze task. Strikingly similar results were found—like females in proestrus, the estrogen-treated animals were impaired by this low dose, while OVX animals, like estrus females or males, were unaffected. Collectively, this and the above studies provide compelling evidence that high levels of estrogen, whether occurring naturally or experimentally, can produce a sensitivity to the detrimental effects of stress in the PFC (Figure 1b). The possible mechanisms by which estrogen confers this sensitivity have only just begun to be illuminated. The PFC receives sizeable afferents from midbrain catecholaminergic nuclei locus coeruleus (LC),19 the primary source of norepinephrine (NE), and ventral tegmental area (VTA), the primary source of dopamine (DA). The influence of these projections on PFC functioning has been extensively studied, and it is widely accepted that the relationship between catecholamine levels in the PFC and working memory performance is manifest in an “inverted U” curve.20 Specifically, experimental or agerelated catecholamine depletion produces PFC-mediated Figure 1. Sex differences and estrogen effects on stress-induced working memory impairment. a) Dose-response curve for male and female animals’ performance on working memory task delayed alternation after administration of pharmacological stressor FG7142. Mean scores after 0, 0.5, 2, 5, 10, and 15 mg/kg respectively were, for males, 76+/-2.7, 79+/-7.5, 76+/-4.6, 55+/-9, 50+/-7.5, and 48+/-4.2; for females, 69.7+/-3.4, 66+/-8.4, 51.67+/-10, 50+/-8, 50+/-6.1, and 37+/-8. Repeated measures ANOVA revealed a significant sex x drug interaction F(5,40)=2.4, P=0.05). Post-hoc analysis (test of effects) showed the 2 mg/kg dose to have the most prominent sex difference, where the females were impaired, but the males were not F(1,8)=6.2, P<.04. b) Working memory performance after 2 mg/kg FG7142 varied according to estrogen levels. Scores after vehicle or 2 mg/kg FG7142, respectively were, for intact females in proestrus, 75+/-6 and 57.7+/-2.3; for intact females in estrus, 74+/-6 and 81+/-4.5; for ovariectomized (OVX) females, 79+/-6.5 and 73+/-6.7; for OVX females with estrogen replacement (OVX + E), 79+/-5.5 and 65+/-4.5. In both experiments, animals with high estrogen levels (proestrus and OVX + E) were significantly impaired by FG7142 (P<.0002 and P<.03, respectively). c) Working memory performance after restraint stress varied according to estrogen levels. Scores after 0, 1, or 2 h restraint stress, respectively were, for males: 73.3+/-2.3, 76+/-4.5, and 58+/-7.42; females in estrus, 72.3+/-2.1, 75+/- 3.6, and 62.8+/-6.55; for females in proestrus, 69.3+/-2, 50+/-3.7, and 60+/-5.7. Only females in proestrus were significantly impaired by 1 h restraint (P<.0005). * = significantly different from self in control conditions, † = significantly different from self in estrus.

479


Poster cognitive deficits in monkeys and rodents21 that can be reversed with administration of DA or NE receptor agonists.22,23 However, extreme increases in mPFC catecholamine levels can also have a detrimental effect on PFC function (Figure 2), exerting their actions through the very receptors that restore performance in animals whose catecholamine systems have been compromised. Such increases in catecholamine release are seen with stress,24 and it has been shown in male rats that stressinduced PFC dysfunction is due in part to binding of the DA D1 receptor, and the subsequent activation of the protein kinase A (PKA) intracellular signaling pathway.25, 26 Conversely, stress-induced impairments can be reversed through stimulation of the NE α-2 receptor,27 whose activation leads to an inhibition of PKA activity. To examine whether estrogen’s enhancement of stressinduced PFC dysfunction was due to actions at the NE α-2 receptor, OVX and OVX + E animals were coadministered an impairing dose of FG7142 and a dose of

the α-2 agonist guanfacine (GFC) known to restore stress-related performance deficits in males, and then tested on the delayed alternation task. Although OVX animals required almost three times as much FG7142 as OVX + E in order to show impairment, OVX showed complete reversal of the impairment with GFC, while OVX + E showed no improvement (Figure 3). These results suggest that estrogen might cause sensitivity to stress-induced PFC dysfunction through suppression of an animal’s responsiveness to NE α-2 stimulation. Western Blot analysis showed no difference in PFC NE α-2 protein levels between OVX and OVX + E (Figure 4), indicating that this effect is not due to changes in protein expression, but likely to actions downstream of the receptor. The exact mechanism by which estrogen elicits this effect has yet to be identified. However, estrogen treatment has been shown in hypothalamus to uncouple the NE α-2 receptor from its G-protein,28 thus rendering it ineffective. If this likewise occurs in the PFC, GFC’s inability to rescue working memory function in stressed OVX + E animals could thus be explained.

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Figure 2. The correlation between accuracy of delayed alternation performance in the rat and the ratio of DOPAC to dopamine in the prefrontal cortex. Rats were given vehicle or FG7142 (20 mg/kg) before being tested on delayed alternation, and were sacrificed immediately after testing. Increased dopamine turnover in the prefrontal cortex significantly correlated with impaired performance on the delayed alternation task (r=0.627, P<0.01). DOPAC, 3,4dihydrophenylacetic acid; DA, dopamine Reproduced from reference 24: Murphy BL, Arnsten AFT, Goldman-Rakic PS, Roth RH. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci U S A. 1996;93:1325-1329. Copyright © National Academy of Sciences 1996.


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Figure 3. Estrogen suppresses norepinephrine (NE) 움-2 receptor-mediated rescue of working memory function during stress. a) OVX and OVX + E were administered increasing doses of FG7142 in order to find the lowest impairing dose for each animal. b) Despite receiving higher doses of FG7142 (10+/-3.7 mg/kg vs 3.5+/-1.2 mg/kg), OVX showed full rescue of PFC function with coadministration of NE α2 agonist guanfacine (GFC), while OVX + E showed no improvement (scores of 74.3+/-3.9 vs 47.5+/-5.5, P<.0007). *, significantly different from self in control conditions, †, significantly different from OVX in same condition. PFC, prefrontal cortex

480

REFERENCES 1. Turner RJ, Lloyd DA. Stress burden and the lifetime incidence of psychiatric disorder in young adults: racial and ethnic contrasts. Arch Gen Psychiatry. 2004;61:481-488. 2. Lechin F, Van der Dijs B, Benaim M. Stress versus depression. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20:899-950. 3. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA. 1996;276:293-299. 4. Breslau N, Chilcoat HD, Kessler RC, Peterson EL, Lucia, V. C. Vulnerability to assaultive violence: further specification of the sex difference in posttraumatic stress disorder. Psychol Med. 1999;29:813-821. 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 6. Bebbington P, Dunn G, Jenkins R, et al. The influence of age and sex on the prevalence of depressive conditions: report from the National Survey of Psychiatric Morbidity. Int Rev Psychiatry 2003;15:74-83. 7. Sloan DM, Kornstein SG. Gender differences in depression and response to antidepressant treatment. Psychiatr Clin North Am. 2003;26:581-594. 8. Liberzon I, Phan KL. Brain-imaging studies of posttraumatic stress disorder. CNS Spectr. 2003;8:641-650. 9. Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45:1085-1098. 10.Botteron KN, Raichle ME, Drevets WC, Heath AC, Todd RD. Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biol Psychiatry. 2002;51:342-344. 11.Drevets WC, Price JL, Simpson JR Jr, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature.1997;386:824-827. 12.Arnsten AFT. The biology of feeling frazzled. Science. 1998; 280:17111712. 13.Schatzberg AF, Posener JA, De Battista C, Kalehzan BM, Rothschild AJ, Shear PK. Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness. Am J Psychiatry. 2000;157:1095-1100. 14.Arnsten AFT. Stress impairs PFC function in rats and monkeys: role of dopamine D1 and norepinephrine alpha-1 receptor mechanisms. Prog Brain Res. 2000;126:183-192. 15.Dorow R, Horowski R, Pashelke G, Amin M, Braestrup C. Severe anxiety induced by FG7142, a B-carboline ligand for benzodiazepine receptors. Lancet. 1983;2:98-99.

Pb o +

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The work described here demonstrates that female rats are more sensitive to stress-induced PFC dysfunction, especially under conditions of high estrogen levels. While this heightened stress response may confer survival value during danger, it may also increase susceptibility for stress-related disorders such as depression. That estrogen also mediated distinct responses to actions at NE α-2 receptors suggests that a more thorough investigation of hormone-intracellular signaling cascade interactions may yield useful information regarding the potential prevention and treatment of stress-induced disorders in women. A better understanding of the neurobiology underlying sex differences in the cognitive response to stress is imperative in forwarding the development of more appropriate therapeutic targets and methods. ❏

Pb o

Poster by: Rebecca M. Shansky, PhD; Amy F. T. Arnsten, PhD

Coomassie

OVX + Est

OVX + Pbo

Figure 4. Estrogen does not affect norepinephrine 움-2 receptor expression in the PFC. As assessed by Western Blot, OVX and OVX + E did not differ in their levels of NE α-2 protein. PFC, prefrontal cortex

16.Ninan PT, Insel TM, Cohen RM, Cook JM, Skolnick P, Maul SM. Benzodiazepine receptor-mediated experimental anxiety in primates. Science. 1982;218:1332-1334. 17.Shansky RM, Glavis-Bloom C, Lerman D, et al. Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction. Mol Psychiatry. 2004;9:531-538. 18.Shansky RM, Rubinow K, Brennan A, Arnsten AF. The effects of sex and hormonal status on restraint-stress-induced working memory impairment. Behav Brain Funct. 2006;2:8. 19.Lewis DA, Morrison JH. Noradrenergic innervationof monkey prefrontal cortex: a dopamine-beta-hydroxylase immunohistochemical study. J Comp Neurol. 1989;282:317-330. 20.Arnsten AFT. Catecholamine modulation of prefrontal cortical cognitive function. Trends Cogn Sci. 1998;2:436-447. 21.Arnsten AFT, ed. Age-Related Cognitive Deficits and Neurotransmitters: the Role Of Catecholamine Mechanisms in Prefrontal Cortical Cognitive Decline. New York, NY: Plenum Press; 1999. 22.Arnsten AFT, Cai JX, Steere JC, Goldman-Rakic PS. Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: The effects of quinpirole on memory and motor performance in monkeys. J Neurosci. 1995;15: 3429-3439. 23.Arnsten AFT, Contant TA. Alpha-2 adrenergic agonists decrease distractability in aged monkeys performing a delayed response task. Psychopharmacology. 1992;108:159-169. 24.Murphy BL, Arnsten AFT, Goldman-Rakic PS, Roth RH. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Nat Acad Sci U S A. 1996;93:13251329. 25.Murphy BL, Arnsten AFT, Jentsch JD, Roth RH. Dopamine and spatial working memory in rats and monkeys: pharmacological reversal of stressinduced impairment. J Neurosci. 1996;16:7768-7775. 26.Taylor JR, Birnbaum SG, Ubriani R, Arnsten AFT. Activation of protein kinase A in prefrontal cortex impairs working memory performance. J Neurosci. 1999;19:RC23. 27.Birnbaum SG, Podell DM, Arnsten AFT. Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats. Pharmacol Biochem Behav. 2000;67:397-403. 28.Ansonoff MA, Etgen AM. Receptor phosphorylation mediates estradiol reduction of alpha2-adrenoceptor coupling to G protein in the hypothalamus of female rats. Endocrine. 2001;14:165-174.

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Article in a supplement: 2. Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson’s disease: genes, environment and mitochondria. Parkinsonism Relat Disord. 2003;9(suppl 2):S59-S64.

Chapter in a book: 3. Carpenter WT Jr, Buchanan RW. Domains of psychopathology relevant to the study of etiology and treatment in schizophrenia. In: Schulz SC, Tamminga CA, eds. Schizophrenia: Scientific Progress. New York, NY: Oxford University Press; 1989:13-22.

4. Peripheral and Central Nervous System Advisory Committee. Meeting Documents. Available at: http://www.fda.gov/ohrms/dockets/ac/cder01.htm. Rockville, Md: Food and Drug Administration. Accessed October 21, 2004. 5. McGlashan TH, Zipursky RB, Perkins DO, et al. Olanzapine versus placebo for the schizophrenic prodrome: 1-year results. Paper presented at: 156th Annual Meeting of the American Psychiatric Association; May 17-22, 2003; San Francisco, Calif.

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NIH Public Access Author Manuscript Psychol Bull. Author manuscript; available in PMC 2006 February 7.

NIH-PA Author Manuscript

Published in final edited form as: Psychol Bull. 2004 July ; 130(4): 601–630.

Psychological Stress and the Human Immune System: A MetaAnalytic Study of 30 Years of Inquiry Suzanne C. Segerstrom and University of Kentucky Gregory E. Miller University of British Columbia

Abstract


The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.


Since the dawn of time, organisms have been subject to evolutionary pressure from the environment. The ability to respond to environmental threats or stressors such as predation or natural disaster enhanced survival and therefore reproductive capacity, and physiological responses that supported such responses could be selected for. In mammals, these responses include changes that increase the delivery of oxygen and glucose to the heart and the large skeletal muscles. The result is physiological support for adaptive behaviors such as “fight or flight.” Immune responses to stressful situations may be part of these adaptive responses because, in addition to the risk inherent in the situation (e.g., a predator), fighting and fleeing carries the risk of injury and subsequent entry of infectious agents into the bloodstream or skin. Any wound in the skin is likely to contain pathogens that could multiply and cause infection (Williams & Leaper, 1998). Stress-induced changes in the immune system that could accelerate wound repair and help prevent infections from taking hold would therefore be adaptive and selected along with other physiological changes that increased evolutionary fitness. Modern humans rarely encounter many of the stimuli that commonly evoked fight-or-flight responses for their ancestors, such as predation or inclement weather without protection. However, human physiological response continues to reflect the demands of earlier environments. Threats that do not require a physical response (e.g., academic exams) may therefore have physical consequences, including changes in the immune system. Indeed, over the past 30 years, more than 300 studies have been done on stress and immunity in humans, and together they have shown that psychological challenges are capable of modifying various features of the immune response. In this article we attempt to consolidate empirical knowledge about psychological stress and the human immune system through meta-analysis. Both the construct of stress and the human immune system are complex, and both could consume book-

Correspondence concerning this article should be addressed to Suzanne C. Segerstrom, Department of Psychology, University of Kentucky, 115 Kastle Hall, Lexington, KY 40506-0044, or Gregory E. Miller, Department of Psychology, University of British Columbia, 2136 West Mall, Vancou-ver, British Columbia V6T IZ4, Canada. E-mail: [email protected] or [email protected].

Segerstrom and Miller

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length reviews. Our review, therefore, focuses on those aspects that are most often represented in the stress and immunity literature and therefore directly relevant to the meta-analysis.


Conceptualizing Stress


Despite nearly a century of research on various aspects of stress, investigators still find it difficult to achieve consensus on a satisfactory definition of this concept. Most of the studies contributing to this review simply define stress as circumstances that most people would find stressful, that is, stressors. We adopted Elliot and Eisdorfer’s (1982) taxonomy to characterize these stressors. This taxonomy has the advantage of distinguishing among stressors on two important dimensions: duration and course (e.g., discrete vs. continuous). The taxonomy includes five categories of stressors. Acute time-limited stressors involve laboratory challenges such as public speaking or mental arithmetic. Brief naturalistic stressors, such as academic examinations, involve a person confronting a real-life short-term challenge. In stressful event sequences, a focal event, such as the loss of a spouse or a major natural disaster, gives rise to a series of related challenges. Although affected individuals usually do not know exactly when these challenges will subside, they have a clear sense that at some point in the future they will. Chronic stressors, unlike the other demands we have described, usually pervade a person’s life, forcing him or her to restructure his or her identity or social roles. Another feature of chronic stressors is their stability—the person either does not know whether or when the challenge will end or can be certain that it will never end. Examples of chronic stressors include suffering a traumatic injury that leads to physical disability, providing care for a spouse with severe dementia, or being a refugee forced out of one’s native country by war. Distant stressors are traumatic experiences that occurred in the distant past yet have the potential to continue modifying immune system function because of their long-lasting cognitive and emotional sequelae (Baum, Cohen, & Hall, 1993). Examples of distant stressors include having been sexually assaulted as a child, having witnessed the death of a fellow soldier during combat, and having been a prisoner of war. In addition to the presence of difficult circumstances, investigators also use life-event interviews and life-event checklists to capture the total number of different stressors encountered over a specified time frame. Depending on the instrument, the focus of these assessments can be either major life events (e.g., getting divorced, going bankrupt) or minor daily hassles (e.g., getting a speeding ticket, having to clean up a mess in the house). With the more sophisticated instruments, judges then code stressor severity according to how the average person in similar biographical circumstances would respond (e.g., S. Cohen et al., 1998; Evans et al., 1995).


A smaller number of studies enrolled large populations of adults who were not experiencing any specific difficulty and examined whether their immune responses varied according to their reports of perceived stress, intrusive thoughts, or both. Other studies have examined stressed populations, in which a larger range of subjective responses may be detected. This work grows out of the view that people’s biological responses to stressful circumstances are heavily dependent on their appraisals of the situation and cognitive and emotional responses to it (Baum et al., 1993; Frankenhauser, 1975; Tomaka, Blascovich, Kibler, & Ernst, 1997).

Overview of the Immune System As many behavioral scientists are unfamiliar with the details of the immune system, we provide a brief overview. For a more complete treatment, the reader is directed to the sources for the information presented here (Benjamini, Coico, & Sunshine, 2000; Janeway & Travers, 1997; Rabin, 1999). Critical characteristics of various immune components and assays are also listed in Table 1.

Psychol Bull. Author manuscript; available in PMC 2006 February 7.


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Components of the Immune System


There are several useful ways of dividing elements of the immune response. For the purposes of understanding the relationship of psychosocial stressors to the immune system, it is useful to distinguish between natural and specific immunity. Natural immunity is an immune response that is characteristic not only of mammals but also lower order organisms such as sponges. Cells involved in natural immunity do not provide defense against any particular pathogen; rather, they are all-purpose cells that can attack a number of different pathogens1 and do so in a relatively short time frame (minutes to hours) when challenged. The largest group of cells involved in natural immunity is the granulocytes. These cells include the neutrophil and the macrophage, phagocytic cells that, as their name implies, eat their targets. The generalized response mounted by these cells is inflammation, in which neutrophils and macrophages congregate at the site of injury or infection, release toxic substances such as oxygen radicals that damage invaders, and phagocytose both invaders and damaged tissue. Macrophages in particular also release communication molecules, or cytokines, that have broad effects on the organism, including fever and inflammation, and also promote wound healing. These proinflammatory cytokines include interleukin(IL)-1, IL-6, and tumor necrosis factor alpha (TNFα). Other granulocytes include the mast cell and the eosinophil, which are involved in parasitic defense and allergy.


Another cell involved in natural immunity is the natural killer cell. Natural killer cells recognize the lack of a self-tissue molecule on the surface of cells (characteristic of many kinds of virally infected and some cancerous cells) and lyse those cells by releasing toxic substances on them. Natural killer cells are thought to be important in limiting the early phases of viral infections, before specific immunity becomes effective, and in attacking self-cells that have become malignant. Finally, complement is a family of proteins involved in natural immunity. Complement protein bound to microorganisms can up-regulate phagocytosis and inflammation. Complement can also aid in antibody-mediated immunity (discussed below as part of the specific immune response).


Specific immunity is characterized by greater specificity and less speed than the natural immune response. Lymphocytes have receptor sites on their cell surfaces. The receptor on each cell fits with one and only one small molecular shape, or antigen, on a given invader and therefore responds to one and only one kind of invader. When activated, these antigen-specific cells divide to create a population of cells with the same antigen specificity in a process called clonal proliferation, or the proliferative response. Although this process is efficient in terms of the number of cells that have to be supported on a day-to-day basis, it creates a delay of up to several days before a full defense is mounted, and the body must rely on natural immunity to contain the infection during this time. There are three types of lymphocytes that mediate specific immunity: T-helper cells, Tcytotoxic cells, and B cells. The main function of T-helper cells is to produce cytokines that direct and amplify the rest of the immune response. T-cytotoxic cells recognize antigen expressed by cells that are infected with viruses or otherwise compromised (e.g., cancer cells) and lyse those cells. B cells produce soluble proteins called antibody that can perform a number of functions, including neutralizing bacterial toxins, binding to free virus to prevent its entry into cells, and opsonization, in which a coating of antibody increases the effectiveness of natural

1The term pathogen is used here to refer to microorganisms that can cause disease. This term is most appropriate in the evolutionary context we proposed in the article’s introduction because it focuses on susceptibility to infection. However, the reader should be aware that pathogens are only a subset of antigens, that is, all substances that evoke an immune response. Other antigenic substances include, for example, transformed self-cells (i.e., cancer cells), transplanted tissue, and allergens (i.e., antigens that evoke an allergic response). Psychol Bull. Author manuscript; available in PMC 2006 February 7.


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immunity. There are five kinds of antibody: Immunoglobulin (Ig) A is found in secretions, IgE binds to mast cells and is involved in allergy, IgM is a large molecule that clears antigen from the bloodstream, IgG is a smaller antibody that diffuses into tissue and crosses the placenta, and IgD is of unknown significance but may be produced by immature B cells. An important immunological development is the recognition that specific immunity in humans is composed of cellular and humoral responses. Cellular immune responses are mounted against intracellular pathogens like viruses and are coordinated by a subset of T-helper lymphocytes called Th1 cells. In the Th1 response, the T-helper cell produces cytokines, including IL-2 and interferon gamma (IFNγ). These cytokines selectively activate T-cytotoxic cells as well as natural killer cells. Humoral immune responses are mounted against extracellular pathogens such as parasites and bacteria; they are coordinated by a subset of Thelper lymphocytes called Th2 cells. In the Th2 response, the T-helper cell produces different cytokines, including IL-4 and IL-10, which selectively activate B cells and mast cells to combat extracellular pathogens. Immune Assays


Immune assays can quantify cells, proteins, or functions. The most basic parameter is a simple count of the number of cells of different subtypes (e.g., neutrophils, macrophages), typically from peripheral blood. It is important to have an adequate number of different types of immune cells in the correct proportions. However, the normal range for these enumerative parameters is quite large, so that “correct” numbers and proportions can cover a wide range, and small changes are unlikely to have any clinical significance in healthy humans.


Protein production—either of antibody or cytokines—can be measured in vitro by stimulating cells and measuring protein in the supernatant or in vivo by measuring protein in peripheral blood. For both antibody and cytokine, higher protein production may represent a more robust immune response that can confer protection against disease. Two exceptions are levels of proinflammatory cytokines (IL-1, IL-6, and TNFα) and antibody against latent virus. Proinflammatory cytokines are increased with systemic inflammation, a risk factor for poorer health resulting from cardiac disease, diabetes mellitus, or osteoporosis (Ershler & Keller, 2000; Luster, 1998; Papanicoloaou, Wilder, Manolagas, & Chrousos, 1998). Antibody production against latent virus occurs when viral replication triggers the immune system to produce antibodies in an effort to contain the infection. Most people become infected with latent viruses such as Epstein-Barr virus during adolescence and remain asymptomatically infected for the rest of their lives. Various processes can activate these latent viruses, however, so that they begin actively replicating. These processes may include a breakdown in cellular immune response (Jenkins & Baum, 1995). Higher antibody against latent viruses, therefore, may indicate poorer immune control over the virus. Functional assays, which are performed in vitro, measure the ability of cells to perform specific activities. In each case, higher values may represent more effective immune function. Neutrophils’ function can be quantified by their ability to migrate in a laboratory assay and their ability to release oxygen radicals. The natural killer cytotoxicity assay measures the ability of natural killer cells to lyse a sensitive target cell line. Lymphocyte proliferation can be stimulated with mitogens that bypass antigen specificity to activate cells or by stimulating the T cell receptor.

Pathways Between Stress and the Immune System How could stress “get inside the body” to affect the immune response? First, sympathetic fibers descend from the brain into both primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid tissues (Felten & Felten, 1994). These fibers can release a wide variety of substances that influence immune responses by binding to receptors on white blood



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cells (Ader, Cohen, & Felten, 1995; Felten & Felten, 1994; Kemeny, Solomon, Morley, & Herbert, 1992; Rabin, 1999). Though all lymphocytes have adrenergic receptors, differential density and sensitivity of adrenergic receptors on lymphocytes may affect responsiveness to stress among cell subsets. For example, natural killer cells have both high-density and highaffinity β2-adrenergic receptors, B cells have high density but lower affinity, and T cells have the lowest density (Anstead, Hunt, Carlson, & Burki, 1998; Landmann, 1992; Maisel, Fowler, Rearden, Motulsky, & Michel, 1989). Second, the hypothalamic–pituitary–adrenal axis, the sympathetic–adrenal–medullary axis, and the hypothalamic–pituitary–ovarian axis secrete the adrenal hormones epinephrine, norepinephrine, and cortisol; the pituitary hormones prolactin and growth hormone; and the brain peptides melatonin, β-endorphin, and enkephalin. These substances bind to specific receptors on white blood cells and have diverse regulatory effects on their distribution and function (Ader, Felten, & Cohen, 2001). Third, people’s efforts to manage the demands of stressful experience sometimes lead them to engage in behaviors— such as alcohol use or changes in sleeping patterns—that also could modify immune system processes (Kiecolt-Glaser & Glaser, 1988). Thus, behavior represents a potentially important pathway linking stress with the immune system.


Maier and Watkins (1998) proposed an even closer relationship between stress and immune function: that the immunological changes associated with stress were adapted from the immunological changes in response to infection. Immunological activation in mammals results in a syndrome called sickness behavior, which consists of behavioral changes such as reduction in activity, social interaction, and sexual activity, as well as increased responsiveness to pain, anorexia, and depressed mood. This syndrome is probably adaptive in that it results in energy conservation at a time when such energy is best directed toward fighting infection. Maier and Watkins drew parallels between the behavioral, neuroendo-crine, and thermoregulatory responses to sickness and stress. The common thread between the two is the energy mobilization and redirection that is necessary to fight attackers both within and without.

Models of Stress, the Immune System, and Health


Conceptualizations of the nature of the relationship between stress and the immune system have changed over time. Selye’s (1975) finding of thymic involution led to an initial model in which stress is broadly immunosuppressive. Early human studies supported this model, reporting that chronic forms of stress were accompanied by reduced natural killer cell cytotoxicity, suppressed lymphocyte proliferative responses, and blunted humoral responses to immunization (see S. Cohen, Miller, & Rabin, 2001; Herbert & Cohen, 1993;Kiecolt-Glaser, Glaser, Gravenstein, Malarkey, & Sheridan, 1996, for reviews). Diminished immune responses of this nature were assumed to be responsible for the heightened incidence of infectious and neoplastic diseases found among chronically stressed individuals (Andersen, Kiecolt-Glaser, & Glaser, 1994; S. Cohen & Williamson, 1991). Although the global immunosuppression model enjoyed long popularity and continues to be influential, the broad decreases in immune function it predicts would not have been evolutionarily adaptive in life-threatening circumstances. Dhabhar and McEwen (1997, 2001) proposed that acute fight-or-flight stressors should instead cause redistribution of immune cells into the compartments in which they can act the most quickly and efficiently against invaders. In a series of experiments with mice, they found that during acute stress, T cells selectively redistributed into the skin, where they contributed to enhancement of the immune response. In contrast, during chronic stress, T cells were shunted away from the skin, and the immune response to skin test challenge was diminished (Dhabhar & McEwen, 1997). On the basis of these findings they proposed a biphasic model in which acute stress enhances, and chronic stress suppresses, the immune response.



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A modification of this model posits that short-term changes in all components of the immune system (natural and specific) are unlikely to occur because they would expend too much energy to be adaptive in life-threatening circumstances. Instead, stress should shift the balance of the immune response toward activating natural processes and diminishing specific processes. The premise underlying this model is that natural immune responses are better suited to managing the potential complications of life-threatening situations than specific immune responses because they can unfold much more rapidly, are subject to fewer inhibitory constraints, and require less energy to be diverted from other bodily systems that support the fight-or-flight response (Dopp, Miller, Myers, & Fahey, 2000; Sapolsky, 1998).


Even with this modification of the biphasic model, neither it nor the global immunosuppression model sufficiently explains findings that link chronic stress with both disease outcomes associated with inadequate immunity (infectious and neoplastic disease) and disease outcomes associated with excessive immune activity (allergic and autoimmune disease). To resolve this paradox, some researchers have chosen to focus on how chronic stress might shift the balance of the immune response. The most well-known of these models hypothesizes that chronic stress elicits simultaneous enhancement and suppression of the immune response by altering patterns of cytokine secretion (Marshall et al., 1998). Th1 cytokines, which activate cellular immunity to provide defense against many kinds of infection and some kinds of neoplastic disease, are suppressed. This suppression has permissive effects on production of Th2 cytokines, which activate humoral immunity and exacerbate allergy and many kinds of autoimmune disease. This shift can occur via the effects of stress hormones such as cortisol (Chiappelli, Manfrini, Franceschi, Cossarizza, & Black, 1994). Th1-to-Th2 shift changes the balance of the immune response without necessarily changing the overall level of activation or function within the system. Because a diminished Th1-mediated cellular immune response could increase vulnerability to infectious and neoplastic disease, and an enhanced Th-2 mediated humoral immune response could increase vulnerability to autoimmune and allergic diseases, this cytokine shift model also is able to reconcile patterns of stress-related immune change with patterns of stress-related disease outcomes (Marshall et al., 1998).

Who Is Vulnerable to Stress-Induced Immune Changes?


If the stress response in the immune system evolved, a healthy organism should not be adversely affected by activation of this response because such an effect would likely have been selected against. Although there is direct evidence that stress-related immunosuppression can increase vulnerability to disease in animals (e.g., Ben Eliyahu, Shakhar, Page, Stefanski, & Shakhar, 2000; Quan et al., 2001; Shavit et al., 1985; Sheridan et al., 1998), there is little or no evidence linking stress-related immune change in healthy humans to disease vulnerability. Even large stress-induced immune changes can have small clinical consequences because of the redundancy of the immune system’s components or because they do not persist for a sufficient duration to enhance disease susceptibility. In short, the immune system is remarkably flexible and capable of substantial change without compromising an otherwise healthy host. However, the flexibility of the immune system can be compromised by age and disease. As humans age, the immune system becomes senescent (Boucher et al., 1998; Wikby, Johansson, Ferguson, & Olsson, 1994). As a consequence, older adults are less able to respond to vaccines and mount cellular immune responses, which in turn may contribute to early mortality (Ferguson, Wikby, Maxson, Olsson, & Johansson, 1995; Wayne, Rhyne, Garry, & Goodwin, 1990). The decreased ability of the immune system to respond to stimulation is one indicator of its loss of flexibility. Loss of self-regulation is also characteristic of disease states. In autoimmune disease, for example, the immune system treats self-tissue as an invader, attacking it and causing pathology



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such as multiple sclerosis, rheumatoid arthritis, Crohn’s disease, and lupus. Immune reactions can also be exaggerated and pathological, as in asthma, and suggest loss of self-regulation. Finally, infection with HIV progressively incapacitates T-helper cells, leading to loss of the regulation usually provided by these cells. Although each of these diseases has distinct clinical consequences, the change in the immune system from flexible and balanced to inflexible and unbalanced suggests increased vulnerability to stress-related immune dysregulation; furthermore, dysregulation in the presence of disease may have clinical consequences (e.g., Bower, Kemeny, Taylor, & Fahey, 1998).

The Present Analysis We performed a meta-analysis of published results linking stress and the immune system. We feel that this area is in particular need of a quantitative review because of the methodological nature of most studies in this area. For practical and economic reasons, many psychoneuroimmunology studies have a relatively small sample size, creating the possibility of Type II error. Furthermore, many studies examine a broad range of immunological parameters, creating the possibility of Type I error. A quantitative review, of which metaanalysis is the best example, can better distinguish reliable effects from those arising from both Type I and Type II error than can a qualitative review.


We combined studies in such a way as to test the models of stress and immune change reviewed above. First, we examined each stressor type separately, yielding separate effects for stressors of different duration and trajectory. Second, we examined both healthy and medical populations, allowing comparison of the effects of stress on resilient and vulnerable populations; along the same lines, we also examined the effects of age. Finally, we examined all immune parameters separately so that patterns of response (e.g., global immunosuppression vs. cytokine shift) would be clearer.

Method Article Identification


Articles for the meta-analysis were identified through computerized literature searches and searches of reference lists. MEDLINE and PsycINFO were searched for the years 1960 –2001. Following the example of Herbert and Cohen (1993), we used the terms stress, hassles, and life events in combination with the term immune to search both databases. The reference lists of 11 review articles on stress and the immune system (Benschop, Geenen, et al., 1998; Biondi, 2001; Cacioppo, 1994; S. Cohen & Herbert, 1996; S. Cohen et al., 2001; Herbert & Cohen, 1993; Kiecolt-Glaser, Cacioppo, Malarkey, & Glaser, 1992; Kiecolt-Glaser, McGuire, Robles, & Glaser, 2002; Maier, Watkins, & Fleshner, 1994; O’Leary, 1990; Zorrilla et al., 2001) were then searched to identify additional articles. We selected only articles that met a number of inclusion criteria. The first criterion was that the work had to include a measure of stress. This criterion could be met if a sample experiencing a stressor was compared with an unstressed control group, if a sample experiencing a stressor was compared with itself at a baseline that could reasonably be considered low stress, or if differing degrees of stress in a sample were assessed with an explicit measure of stress. This criterion was not met if, for example, anxiety—an affective state—was used as a proxy for stress, or it seemed likely that a “baseline” assessment occurred during periods of significant stress. The second criterion was that the stressor had to be psychosocial. Stressors that included a significant physical element such as pain, cold, or physical exhaustion were eliminated (e.g., Antarctic isolation, space flight, military training). The third criterion was that the work had to include a measure of the immune system. This criterion was met by any enumerative or functional in vitro or in vivo immune assay. However, clinical disease outcomes such as HIV Psychol Bull. Author manuscript; available in PMC 2006 February 7.


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progression or rhinovirus infection did not meet this criterion. Finally, we eliminated articles from which a meaningful effect size could not be abstracted. For example, when between- and within-subjects observations were treated as independent, the reported effect was likely to be inflated. In a few cases, effects of stress and clinical status were confounded—that is, a stressed clinical group was compared with an unstressed healthy group—and hence these studies were excluded from the meta-analysis. Stressor Classification We coded stressors in the articles into five classes: acute time-limited, brief naturalistic, event sequence, chronic, and distant. The most difficult distinctions among event sequence, chronic, and distant stressors were based on temporal and qualitative considerations. Event sequences included discrete stressors occurring 1 year or less before immune assessment and could be of any severity. These were most often normative stressors such as bereavement. Chronic stressors were ongoing stressors such as caregiving and disability. Distant stressors were severe, traumatic events that could meet the stressor criterion for posttraumatic stress disorder (American Psychiatric Association, 1994), such as combat exposure or abuse, and had happened more than 1 year before immune assessment. Most stressors in this category occurred 5 to 10 years before immune assessment. Disagreements in stressor classification were resolved by consensus. Subgroups for moderator analyses were similarly decided.


The Meta-Analysis Overview of procedures—Meta-analysis is a tool for synthesizing research findings. It proceeds in two phases. In the first, effect sizes are computed for each study. An effect size represents the magnitude of the relationship between two variables, independent of sample size. In this context it can be viewed as a measure of how much two groups, one experiencing a stressor and the other not, differ on a specific immune outcome. In the second phase, effect sizes from individual studies are combined to arrive at an aggregate effect size for each immune outcome of interest.


We used Pearson’s r as the effect size metric in this meta-analysis. Effect sizes for individual studies were computed using descriptive statistics presented in the original published reports. When these statistics were not available, we requested them from authors. This strategy was successful in most circumstances. To compute Pearson’s r from descriptive statistics in between-subjects designs, we subtracted the control group mean from the stressed group mean and divided this value by the pooled sample standard deviation. The value that emerged from this computation, known as Cohen’s d, was then converted into a Pearson’s r by taking the square root of the quantity d2/(d2 + 4). (See Rosenthal, 1994.) To compute Pearson’s r from descriptive statistics in within-subjects designs, we subtracted the group mean at baseline from the group mean during stress and divided this quantity by the sample standard deviation at baseline. This d value was converted into a Pearson’s r by taking the square root of the quantity d2/(d2 + 4). In cases in which descriptive statistics were not available, Pearson’s r was computed from inferential statistics using standard formulae (Rosenthal, 1994). These formulae had to be modified slightly for studies that used within-subjects designs because effect sizes are systematically overestimated when they are calculated from repeated measures test statistics (Dunlap, Cortina, Vaslow, & Burke, 1996). In these situations we derived effect size estimates using the formula d = tc[2 (1 − r)]1/2, where tc corresponds to the value of the t statistic for correlated measures, and r corresponds to the value of the correlation between outcome measures at pretest and posttest (Dunlap et al., 1996). Because very few studies reported the value of r, we used a value of .60 to compute effect sizes in this meta-analysis. This represents the average correlation between pre-stress and poststress measures of immune function in a series of studies performed in our laboratories. To ensure that the meta-analytic findings were robust to variations in r, we conducted follow-up analyses using r values ranging from .45 to .



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75. Very similar findings emerged from these analyses, suggesting that the values we present below are reliable estimates of effect size. If anything, they are probably conservative estimates, because the pre–post correlation between immune measures often is substantially lower than . 60. The effect size estimates from individual studies were subsequently aggregated using randomeffects models with the software program Comprehensive Meta-Analysis (Borenstein & Rothstein, 1999). The random-effects model views each study in a meta-analysis as a random observation drawn from a universe of potential investigations. As such, it assumes that the magnitude of the relationship between stress and the immune system differs across studies as a result of random variance associated with sampling error and differences across individuals in the processes of interest. Because of these assumptions, random-effects models not only permit one to draw inferences about studies that have been done but also to generalize to studies that might be done in the future (Raudenbush, 1994; Shadish & Haddock, 1994). It also bears noting that in the population of studies on stress and immunity there is likely to be a fair amount of nonrandom variance, as researchers who examine ostensibly similar phenomena may still differ in terms of the samples they recruit, the operational definition of stress they use, and the laboratory methods they utilize to assess a specific immune process.


Separate random-effects models were computed for each immune outcome included in the meta-analysis. Prior to computing the random-effects model, r values derived from each study were z-transformed by the software program, as recommended by Shadish and Haddock (1994), to stabilize variance. The z values were later back-transformed into r values to facilitate interpretation of the meta-analytic findings. In the end, each random-effects model yielded an aggregate weighted effect size r, which can be interpreted the same way as a correlation coefficient, ranging in value from −1.00 to 1.00. Each r statistic was weighted before aggregation by multiplying its value by the inverse of its variance; this procedure enabled larger studies to contribute to effect size estimates to a greater extent than smaller ones. Weighting effect sizes is important because larger studies provide more accurate estimates of true population parameters (Shadish & Haddock, 1994). After each aggregate effect size had been derived, we computed 95% confidence intervals around it, assessed whether it was statistically significant, and computed a heterogeneity coefficient to determine whether the studies contributing to it had yielded consistent findings. Following convention, aggregate effect sizes were considered statistically different from zero when (a) their corresponding z value was greater than 1.96 and (b) the 95% confidence intervals around them did not include the value zero (Rosenthal, 1991; Shadish & Haddock, 1994).


To determine whether the studies contributing to each aggregate effect size shared a common population value, we computed the heterogeneity statistic Q (Shadish & Haddock, 1994). This statistic is chi-square distributed with k – 1 degrees of freedom, where k represents the number of independent effect sizes included. When a statistically significant heterogeneity test emerged, we searched for moderators (characteristics of the participants, stressful experience, or measurement strategy) that could explain the variability across studies. The first step in this process involved estimating correlations between participant characteristics (e.g., mean age, percentage female) and immune effects to examine whether the strength of effects varied according to demographics. When it was possible to do so, we then stratified the studies according to characteristics of the stressful experience (e.g., duration, quality) or the measurement strategy (e.g., interview, checklist), and computed separate random-effects analyses for each subgroup. Handling missing data—Occasionally authors of studies failed to report the descriptive or inferential statistics needed to compute an effect size. In some of these cases, the authors noted that there was a significant difference between a stressed and control group. When this



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occurred, we computed effect sizes assuming that p values were equivalent to .05. This represents a conservative approach because the actual p values were probably smaller. In other cases, the authors noted that a stressed and control group did not differ with respect to an immune outcome, but failed to provide any further statistical information. When this occurred, we computed effect sizes assuming that there was no difference at all between the groups (r = .00). Because there is seldom no difference at all between two groups, this also represents a conservative strategy. Imputation was used in less than 7% of cases.


Handling dependent data—The validity of a meta-analysis rests on the assumption that each value contributing an aggregate effect size is statistically independent of the others (Rosenthal, 1991). We devised a number of strategies to avoid violating this independence assumption. First, in studies that assessed stimulated-lymphocyte proliferation at multiple mitogen dosages, we computed the average effect size across mitogen dosages, and we used this value to derive aggregate indices. We used an analogous strategy for studies that assessed natural killer cell cytotoxicity at multiple effector:target cell ratios. Second, in studies that utilized designs in which multiple laboratory stressors were compared with a control condition, the average effect size across stressor conditions was computed and later used to derive aggregate indices. Because this averaging procedure in most cases yielded an effect size that was smaller than that of the most potent stressor, we also computed meta-analyses using the larger of the effect sizes from each study rather than the average. Doing so did not alter any of the substantive findings we report. Third, in studies in which immune outcomes were assessed on multiple occasions during a stressful experience, the average effect size across occasions was used to derive aggregate indices. Note that we did not conduct meta-analyses of recovery effects, that is, immune values after a stressor had ended. Although such an analysis would answer interesting questions about the stress-recovery process, there were not enough studies that included similar immune outcomes assessed at similar time points after stress to permit a complete analysis. Fourth, because some data were published in more than one outlet, we contacted authors of multiple publications to determine sample independence or dependence.

Results Preliminary Findings


The meta-analysis is based on effect sizes derived from 293 independent studies. These studies were reported in 319 separate articles in peer-reviewed scientific journals (see Table 2). A total of 18,941 individuals participated in these studies. Their mean age was 34.8 years (SD = 15.9). Although the studies collectively included a broad range of age groups (range = 5–78 years), most focused heavily on younger adults. More than half of the studies (51.3%) had a mean age under 30.0 years, and more than four fifths (84.8%) had a mean age under 55.0 years. Slightly more than two thirds of the studies (68.5%) included women; in the average study almost half (42.8%) of the participants were female. The vast majority of studies (84.8%) focused on medically healthy adults.2 Of those that included medical populations, most focused on HIV/ AIDS (k = 18; 38.3%), arthritis (k = 6; 12.8%), cancer (k = 5; 10.6%), or asthma (k = 4; 8.5%). With respect to the kinds of stressors examined by studies in the meta-analysis, the most commonly utilized models were acute laboratory challenges (k = 85; 29.0%) and brief naturalistic stressors (k = 63; 21.5%). Stressful event sequences (k = 30; 10.2%), chronic

2The proportion of student samples varied across stressor categories. Nearly all of the studies of brief naturalistic stressors used student samples (k = 60; 95.2%) because these stressors were predominantly examinations. Student samples were also used in a large minority of acute time-limited stressor studies (k = 31; 40.5%) but constituted a small minority of samples used in studies of life-event checklists (k = 8; 14.0%) and studies of event sequences (k = 2; 6.6%), and student samples were not used in studies of chronic stressors or stress appraisals and intrusions. These are rough estimates, as some studies did not specify whether young adult samples were drawn from a student population. Psychol Bull. Author manuscript; available in PMC 2006 February 7.


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stressors (k = 23; 7.8%), and distant traumatic experiences (k = 9; 3.1%) were explored less frequently. More than a quarter of the studies in the meta-analysis modeled the stress process by administering nonspecific life-event checklists (k = 53; 18.1%) and/or global perceived stress measures (k = 21; 7.1%) to participants. A small minority of studies examined whether reports of perceived stress or intrusive memories were associated with the extent of immune dysregulation within populations who had suffered a specific traumatic experience (k = 9; 3.1%). The studies in the meta-analysis examined 292 distinct immune system outcomes. A minority of these outcomes were assessed in three or more studies (k = 87; 30.0%), and as such, they are the focus of the meta-analyses we present in the rest of this article (see Table 1). The most commonly assessed enumerative outcomes were counts of T-helper lymphocytes (k = 90; 30.7%), T-cytotoxic lymphocytes (k = 81; 27.6%), natural killer cells (k = 67; 22.9%), and total lymphocytes (k = 52; 17.7%). The most commonly assessed functional outcomes were natural killer cell cytotoxicity (k = 94; 32.1%) and lymphocyte proliferation stimulated by the mitogens phytohemagglutinin (PHA; k = 65; 22.2%), concanavalin A (ConA; k = 39; 13.3%), and pokeweed mitogen (PWM; k = 26; 8.9%). Interpreting the Meta-Analytic Findings


Table 1 lists the immune parameters analyzed with the arm of the immune system to which they belong (natural or specific) and, briefly, their function. Where relevant, cell surface markers used to identify classes of immunocytes in flow cytometry are given. For example, the cell surface marker CD19 is used to identify B lymphocytes. Recall that different models of stress and the immune system posit differential effects of stress on subsets of the immune system—for example, natural versus specific immunity or cellular (Th1) versus humoral (Th2) immunity. Table 1 acts as a guide for interpreting the pattern of results in light of these models.


In the following sections we describe the meta-analytic results for each stressor category. A useful rule of thumb for judging effect sizes is to consider values of .10, .30, and .50 as corresponding to small, medium, and large effects, respectively (J. Cohen & Cohen, 1983); more generally, the aggregate effect size r can be interpreted in the same fashion as a correlation, with values ranging from −1.00 to 1.00. Positive values indicate that the presence of a stressor increases a particular immune parameter relative to some baseline (or control) condition. We should caution the reader that in some analyses, our statistics are derived from as few as three independent studies. Although meta-analyses of small numbers of studies do not pose any major statistical problems, it is important to remember that they have limited power to detect statistically significant effect sizes. What a meta-analysis can accurately provide in these instances, however, is an estimate of how much and what direction a given stressor’s presence influences a specific immune outcome (i.e., an effect size estimate). Meta-Analytic Results for the Effects of Stressors Acute time-limited stressors—Acute time-limited stressors included primarily experimental manipulations of stressful experiences, such as public speaking and mental arithmetic, that lasted between 5 and 100 min. Reliable effects on the immune system included increases in immune parameters, especially natural immunity. The most robust effect of this kind of experience was a marked increase in the number of natural killer cells (r =.43) and large granular lymphocytes (r =.53) in peripheral blood (see Table 3). This effect is consistent with the view that acute stressors cause immune cells to redistribute into the compartments in which they will be most effective (Dhabhar & McEwen, 1997). However, other types of lymphocytes did not show robust redistribution effects: B cells and T-helper cells showed very little change (rs = −.07 and .01, respectively), and this change was not statistically significant across studies. T-cytotoxic lymphocytes did tend to increase reliably in peripheral blood,



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though to a lesser degree than their natural immunity counterparts (r =.20); this increase drove a reliable decline in the T-helper:T-cytotoxic ratio (r = −.23). However, natural killer cells as well as T-cytotoxic cells can express CD8, the marker most often used to define the latter population. Because some studies did not use the T cell receptor (CD3) to differentiate between CD3–CD8+ natural killer cells and CD3+CD8+ T-cytotoxic cells, it is possible that the effect for “T-cytotoxic cells” is actually being driven by natural killer cells (Benschop, RodriguezFeuerhahn, & Schedlowski, 1996). The results for cell percentages roughly parallel those for number. However, the percentage data are harder to interpret because any given parameter is linearly dependent on the other parameters: For example, the enumerative data suggest that the decrease in percentage T-helper cells (r = −.24) is probably an artifact of the increases in percentage natural killer cells (r = . 24) and percentage T-cytotoxic cells (r = .09).


Another effect that may be considered a redistribution effect is the significant increase in secretory IgA in saliva (r = .22). The time frame of these acute stressors is too short for the synthesis of a significant amount of new antibody; therefore, this increase is probably due to release of already-synthesized antibody from plasma cells and increased translocation of antibody across the epithelium and into saliva (Bosch, Ring, de Geus, Veerman, & Amerongen, 2002). This effect therefore represents relocation, albeit of an immune protein rather than an immune cell. There were also a number of functional effects. First, natural killer cell cytotoxicity significantly increased with acute stressors (r = .30), but only when the concomitant increase in proportion of natural killer cells in the effector mix was not removed statistically. When examined on a per-cell basis, cytotoxicity did not significantly increase (r = .12). One could, therefore, consider the increase in cytotoxicity a methodological artifact of the definition of effector in effector:target ratios. However, to the degree that one is interested in the general cytotoxic potential of the contents of peripheral blood rather than that of a specific natural killer cell, the uncorrected value is more illustrative. Second, mitogen-stimulated proliferative responses decreased significantly. Again, this could be a methodological artifact of the mix of cells in the assay. However, the proportion of total T and B cells, which are responsible for the proliferative response to PWM and ConA, did not decrease as reliably or as much as did the proliferative response (rs = −.05 to −.11 vs. −.10 to −.17), suggesting that acute stressors do decrease this function of specific immunity. Finally, the production of two cytokines, IL-6 and IFNγ, was increased significantly following acute stress (rs = .28 and .21, respectively).


The data for acute stressors, therefore, support an upregulation of natural immunity, as reflected by increased number of natural killer cells in peripheral blood, and potential downregulation of specific immunity, as reflected by decreased proliferative responses. Other indicators of upregulated natural immunity include increased neutrophil numbers in peripheral blood (r = . 30), increased production of a proinflammatory cytokine (IL-6), and increased production of a cytokine that potently stimulates macrophages and natural killer cells as well as T cells (IFNγ). The only exception to this pattern was the increased secretion of IgA antibody, which is a product of the specific immune response. An interesting question for future research is whether this effect is part of a larger nonspecific protein release in the oral cavity in response to acute stress (cf. Bosch et al., 2002). It bears noting that a number of the findings presented in Table 3 are accompanied by significant heterogeneity statistics. To identify moderating variables that might explain some of this heterogeneity, we examined whether effect sizes varied according to demographic characteristics of the sample (mean age and percentage female) or features of the acute challenge (its duration and nature). Neither of the demographic characteristics showed a



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consistent relationship with immune outcomes. Although these findings suggest that acute time-limited stressors elicit a similar pattern of immune response for men and women across the life span, this conclusion needs to be viewed somewhat cautiously given the narrow range of ages found in these studies. We also did not find a consistent pattern of relationships between features of the acute challenge and immune outcomes. Acute stressors elicited similar patterns of immune change across a wide spectrum of durations ranging from 5 though 100 min and irrespective of whether they involved social (e.g., public speaking), cognitive (e.g., mental arithmetic), or experiential (e.g., parachute jumping) forms of stressful experience.


Brief naturalistic stressors—Table 4 presents the meta-analysis of brief naturalistic stressors for medically healthy adults. The vast majority of these stressors (k = 60; 95.2%) involved students facing academic examinations. In contrast to the acute time-limited stressors, examination stress did not markedly affect the number or percentage of cells in peripheral blood. Instead, the largest effects were on functional parameters, particularly changes in cytokine production that indicate a shift away from cellular immunity (Th1) and toward humoral immunity (Th2). Brief stressors reliably changed the profile of cytokine production via a decrease in a Th1-type cytokine, IFNγ (r = −.30), which stimulates natural and cellular immune functions, and increases in the Th2-type cytokines IL-6 (r = .26), which stimulates natural and humoral immune functions, and IL-10 (r = .41), which inhibits Th1 cytokine production. Note that IFNγ and IL-6 share the property of stimulating natural immunity but differentially stimulate cytotoxic versus inflammatory effector mechanisms. Their dissociation after brief naturalistic stress indicates differential effects between Th1 and Th2 responses rather than natural and specific responses. The functional assay data are consistent with this suggestion of suppression of cellular immunity via decreased Th1 cytokine production: The T cell proliferative response significantly decreased with brief stressors (r = −.19 to −.32), as did natural killer cell cytotoxicity (r = −.11). Increased antibody production to latent virus, particularly Epstein-Barr virus (r = .20), is also consistent with suppression of cellular immunity, enhancement of humoral immunity, or both.


There was also evidence that age contributed to vulnerability to stress-related immune change during brief naturalistic stressors, even within a limited range of relatively young ages. When we examined whether effect sizes varied according to demographic characteristics of the sample, sex ratio did not show a consistent pattern of relations with immune processes. However, the mean age of the sample was strongly related to study effect size. To the extent that a study enrolled participants of older ages, it was likely to observe more pronounced decreases in natural killer cell cytotoxicity (r = −.58, p = .04; k = 14), T lymphocyte proliferation to the mitogens PHA (r = −.58, p = .04; k = 13) and ConA (r = −.31, p = .38; k = 9), and production of the cytokine IFNγ (r = −.63, p = .09; k = 8) in response to brief naturalistic stress. The strength of these findings is particularly surprising given the narrow range of ages found in studies of brief natural stress; the mean participant age in this literature ranged from 15.7 to 35.0 years. We also calculated effect sizes for three studies examining the effects of examination stress on individuals with asthma (see Table 5). These three studies, all emanating from a team of investigators at the University of Wisconsin—Madison, found that stress reliably increased superoxide release (r = .20 to .37) and decreased natural killer cell cytotoxicity (r = − .33). Because natural killer cells are stimulated by Th1 cytokines, this change is consistent with a Th1-to-Th2 shift. However, stress also reliably increased T cell proliferation to PHA (r = .32), which is not consistent with such a shift. The generally larger effect sizes are consistent with the idea that individuals with immunologically mediated disease are more susceptible to stressrelated immune dysregulation, but the reversed sign for T cell proliferation also indicates that



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that pattern of dysregulation may also be more disorganized. That is, the organized pattern of suppression of Th1 but not Th2 immune responses in healthy individuals undergoing brief stressors may reflect regulation in the healthy immune system. In contrast, the lack of regulation in a diseased immune system may lead to more chaotic changes during stressors.


Stressful event sequences—The meta-analysis of stressful event sequences is presented in Table 6. With the exception of significant increases in the number of circulating natural killer cells and the number of antibodies to the latent Epstein-Barr virus, the findings indicate that stressful event sequences are not associated with reliable immune changes. For many immune outcomes, however, significant heterogeneity statistics are evident. Studies of healthy adults generally fell into two categories that yielded disparate patterns of immune findings. The largest group of studies focused on the death of a spouse as a stressor and, as such, used samples consisting primarily of older women. Collectively, these studies found that losing a spouse was associated with a reliable decline in natural killer cell cytotoxicity (r = − .23, p = . 01; k = 6) but not with alterations in stimulated-lymphocyte proliferation by the mitogens ConA (r = − .04, p = .45; k = 4), PHA (r = −.01, p = .93; k = 7), or PWM (r = −.08, p = .76; k = 3) or with changes in the number of T-helper lymphocytes (r = .07, p = .52; k = 6) or T-cytotoxic lymphocytes (r = −.13, p = .45; k = 5) in peripheral blood. The next largest group of studies in this area examined immune responses to disasters, which may have different neuroendocrine consequences than loss; whereas loss is generally associated with increases in cortisol, trauma may be associated with decreases in cortisol (Yehuda, 2001;Yehuda, McFarlane, & Shalev, 1998). Natural disaster samples tended to focus on middle-aged adults of both sexes who were direct victims of the disaster, rescue workers at the scene, or personnel at nearby medical centers. There were medium-size effects suggesting increases in natural killer cell cytotoxicity (r = .25, p = .53; k = 4) and stimulated-lymphocyte proliferation by the mitogen PHA (r = .26, p = .33; k = 2), as well as decreases in the number of T-helper lymphocytes (r = −.20, p = .43; k = 2) and T-cytotoxic lymphocytes (r = −.23, p = .55; k = 2) in the circulation. However, none of them was statistically significant because of the small number of studies involved, and therefore these effects should be considered suggestive but not reliable. An additional group of studies in this area examined immune responses to a positive initial biopsy for breast cancer in primarily middle-aged female participants before and after the procedure. The three studies of this nature did not yield a consistent pattern of relations with any of the immune outcomes.


In summary, stressful event sequences did not elicit a robust pattern of immune changes when considered as a whole. When these sequences are broken down into categories reflecting the stressor’s nature, the meta-analysis yields evidence of declines in natural immune response following the loss of a spouse, nonsignificant increases in natural and specific immune responses following exposure to natural disaster, and no immune alterations with breast biopsy. Unfortunately, we cannot determine whether these disparate patterns of immune response are attributable to features of the stressors, demographic or medical characteristics of the participants, or some interaction between these factors. Chronic stressors—Chronic stressors included dementia caregiving, living with a handicap, and unemployment. Like other nonacute stressors, they did not have any systematic relationship with enumerative measures of the immune system. They did, however, have negative effects on almost all functional measures of the immune system (see Table 7). Both natural and specific immunity were negatively affected, as were Th1 (e.g., T cell proliferative responses) and Th2 (e.g., antibody to influenza vaccine) parameters. The only nonsignificant change was for antibody to latent virus; this effect size was substantial (r = .44), but there was also substantial heterogeneity. Further analyses showed that demographics did not moderate



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this effect: Immune responses to chronic stressors were equally strong across the age spectrum as well as across sex.


Distant stressors—Distant stressors were traumatic events such as combat exposure or abuse occurring years prior to immune assessment. The meta-analytic results for distant stressors appear in Table 8. The only immune outcome that has been examined regularly in this literature is natural killer cell cytotoxicity, and it is not reliably altered in persons who report a distant traumatic experience. Meta-Analytic Results for the Effects of Checklists and Ratings


Nonspecific life events—Most of the studies in this area examined whether immune responses varied as a function of the number of life events a person endorsed on a standard checklist, a person’s rating of the impact of those events, or both. As Table 9 illustrates, this methodology yielded little in the way of significant outcomes in healthy participants. To determine whether vulnerability to life events might vary across the life span, we divided studies into two categories on the basis of a natural break in the age distribution. These analyses provided evidence that older adults are especially vulnerable to life-event–induced immune change. In studies that used samples of adults who had a mean age above 55, life events were associated with reliable declines in lymphocyte-proliferative responses to PHA (r = −.40, p = . 05; k = 2) and natural killer cell cytotoxicity (r = −.59, p = .001; k = 2). These effects were much weaker in studies with a mean age below 55: Life events were not associated with proliferative responses to PHA (r = −.22, p = .24; k = 2), and showed a reliable but modest relationship with natural killer cell cytotoxicity (r = −.10, p = .03; k = 8). The differences in effect size between older and younger adults were statistically significant for natural killer cell cytotoxicity ( p < .001) but not PHA-induced proliferation ( p <.15). None of the other moderators we examined—sex ratio, kind of life event assessed (daily hassle vs. major event), or the method used to do so (checklist vs. interview)—was related to immune outcomes. Table 10 presents the relationship between life events and immune parameters in participants with HIV/AIDS. The presence of life events was associated with a significant reduction in the number of natural killer cells and a marginal reduction in the number of T-cytotoxic lymphocytes. It is unrelated to the number of T-helper lymphocytes, the percentage of Tcytotoxic lymphocytes, and the T-helper:T-cytotoxic ratio, all of which are recognized indicators of disease progression for patients with HIV/AIDS.


We have already proposed that immunological disease diminishes the resilience and selfregulation of the immune system, making it more vulnerable to stress-related disruption, and this may be the case in HIV-infected versus healthy populations. However, studies of HIVinfected populations also utilized more refined measures of life events (interviews that factor in biographical context) than did studies of healthy populations (typically, checklist measures). Unfortunately, we cannot differentiate between these explanations on the basis of the available data. Global stress appraisals and intrusive thoughts—The meta-analysis of stress appraisals and intrusive thoughts is displayed in Table 11. These studies generally enrolled large populations of adults who were not experiencing any specific form of stress and examined whether their immune responses varied according to stress appraisals and/or intrusive thoughts. This methodology was unsuccessful at documenting immune changes related to stress. Because of the small number of studies in this category, moderator analyses could not be performed. The meta-analysis results shown in Table 12 address a similar question with regard to persons who are in the midst of a specific event sequence or a chronic stressor. To the extent that they appraise their lives as stressful or report the occurrence of intrusive thoughts, these individuals Psychol Bull. Author manuscript; available in PMC 2006 February 7.


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exhibit a significant reduction in natural killer cell cytotoxicity. Although this effect does not extend to the number of T-helper and T-cytotoxic lymphocytes in the circulation, it suggests that a person’s subjective representation of a stressor may be a determinant of its impact on the immune response. Evidence Regarding Type I Error and Publication Bias The large number of effect sizes generated by the meta-analysis raises the possibility of Type I error. One strategy for evaluating this concern involves dividing the number of significant findings in a meta-analysis by the total number of analyses conducted. When we performed this calculation, a value of 25.6% emerged, suggesting that more than one fourth of the analyses yielded reliable findings. This exceeds the 5% value at which investigators typically become concerned about Type I error rates and gives us confidence that the meta-analytic findings presented here are robust.


A second concern arises from the publication bias toward positive findings, which could skew meta-analytic results toward larger effect sizes. Fortunately, recent advances in meta-analysis enable one to evaluate the extent of this publication bias by using graphical techniques. A funnel plot can be drawn in which effect sizes are plotted against sample sizes for any group of studies. Because most studies in any given area have small sample sizes and therefore tend to yield more variable findings, the plot should end up looking like a funnel, with a narrow top and a wide bottom. If there is a bias against negative findings in an area, the plot is shifted toward positive values or a chunk of it will be missing entirely. We drew funnel plots for all of the immune outcomes in the meta-analysis for which there were a sufficient number of observations. Although not all of them yielded perfect funnels, there was no systematic evidence of publication bias. Space limitations prevent us from including all plots; however, Figure 1 displays three plots that are prototypical of those we drew. As is evident from the data in the figure, psychoneuroimmunology researchers seem to be reporting positive and negative findings—and not hiding unfavorable outcomes when they do emerge. Thus, we do not have any major concerns about publication bias leading this meta-analysis to dramatically overestimate effect sizes.

Discussion


The immune system, once thought to be autonomous, is now known to respond to signals from many other systems in the body, particularly the nervous system and the endocrine system. As a consequence, environmental events to which the nervous system and endocrine system respond can also elicit responses from the immune system. The results of meta-analysis of the hundreds of research reports generated by this hypothesis indicate that stressful events reliably associate with changes in the immune system and that characteristics of those events are important in determining the kind of change that occurs. Models of Stress and the Immune System Selye’s (1975) seminal findings suggested that stress globally suppressed the immune system and provided the first model for how stress and immunity are related. This model has recently been challenged by views that relations between stress and the immune system should be adaptive, at least within the context of fight-or-flight stressors, and an even newer focus on the balance between cellular and humoral immunity. The present meta-analytic results support three of these models. Depending on the time frame, stressors triggered adaptive upregulation of natural immunity and suppression of specific immunity (acute time-limited), cytokine shift (brief naturalistic), or global immunosuppression (chronic).



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NIH-PA Author Manuscript NIH-PA Author Manuscript

When stressors were acute and time-limited—that is, they generally followed the temporal parameters of fight-or-flight stressors—there was evidence for adaptive redistribution of cells and preparation of the natural immune system for possible infection, injury, or both. In evolution, stressor-related changes in the immune system that prepared the organisms for infections resulting from bites, puncture wounds, scrapes, or other challenges to the integrity of the skin and blood could be selected for. This process would be most adaptive when it was also efficient and did not divert excess energy from fight-or-flight behavior. Indeed, changes in the immune system following acute stress conformed to this pattern of efficiency and energy conservation. Acute stress upregu-lated parameters of natural immunity, the branch of the immune system in which most changes occurred, which requires only minimal time and energy investment to act against invaders and is also subject to the fewest inhibitory constraints on acting quickly (Dopp et al., 2000; Sapolsky, 1998). In contrast, energy may actually be directed away from the specific immune response, as indexed by the decrease in the proliferative response. The specific immune response in general and proliferation in particular demand time and energy; therefore, this decrease might indicate a redirection away from this function. Similar redirection occurs during fight-or-flight stressors with regard to other nonessential, future-oriented processes such as digestion and reproduction. As stressors became more chronic, the potential adaptiveness of the immune changes decreased. The effect of brief stressors such as examinations was to change the potency of different arms of specific immunity —specifically, to switch away from cellular (Th1) immunity and toward humoral (Th2) immunity. The stressful event sequences tended to fall into two substantive groups: bereavement and trauma. Bereavement was associated with decreased natural killer cell cytotoxicity. Trauma was associated with nonsignificantly increased cytotoxicity and increased proliferation but decreased numbers of T cells in peripheral blood. The different results for loss and trauma mirror neuroendocrine effects of these two types of adverse events. Loss—maternal separation in nonhuman animals and bereavement in humans—is commonly associated with increased cortisol production (Irwin, Daniels, Risch, Bloom, & Weiner, 1988; Laudenslager, 1988; McCleery, Bhagwagar, Smith, Goodwin, & Cowen, 2000). In contrast, trauma and posttraumatic stress disorder are commonly associated with decreased cortisol production (see Yehuda, 2001; Yehuda et al., 1998, for reviews). To the degree that cortisol suppresses immune function such as natural killer cell cytotoxicity, these results have the potential to explain the different effects of loss and trauma event sequences.


The most chronic stressors were associated with the most global immunosuppression, as they were associated with reliable decreases in almost all functional immune measures examined. Increasing stressor duration, therefore, resulted in a shift from potentially adaptive changes to potentially detrimental changes, initially in cellular immunity and then in immune function more broadly. It is important to recognize that although the effects of chronic stressors may be due to their duration, the most chronic stressors were associated with changes in identity or social roles (e.g., acquiring the role of caregiver or refugee or losing the role of employee). These chronic stressors may also be more persistent, that is, constantly rather than intermittently present. Finally, chronic stressors may be less controllable and afford less hope for control in the future. These qualities could contribute to the severity of the stressor in terms of both its psychological and physiological impact. Increasing stressor chronicity also impacted the type of parameter in which changes were seen. Compared with the natural immune system, the specific immune system is time and energy intensive and as such is expected to be invoked only when circumstances (either a stressor or an infection; cf. Maier & Watkins, 1998) persist for a longer period of time. Affected immune domains—natural versus specific—were consistent with the duration of the stressors—acute versus chronic. Furthermore, changing immune responses via redistribution of cells can happen



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much faster than changes via the function of cells. The time frames of the stressor and the immune domain were also consistent; acute stress affected primarily enumerative measures, whereas stressors of longer duration affected primarily functional measures. The results of these analyses suggest that the dichotomization of the immune system into natural and specific categories and, within specific immunity, into cellular and humoral measures, is a useful starting point with regard to understanding the effects of stressors. Categorizing an immune response is a difficult process, as each immune response is highly redundant and includes natural, specific, cellular, and humoral immune responses acting together. Given this redundancy, the differential results within these theoretical divisions were remarkably, albeit not totally, consistent. As further immunological research defines these divisions more subtly, the results with regard to stressors may become even clearer. However, the present results suggest that the categories used here are meaningful.


The results of this meta-analysis reflect the theoretical and empirical progress of this literature over the past 4 decades. Increased differentiation in the quality of stressors and the immunological parameters investigated have allowed complex models to be tested. In contrast, previous meta-analyses were bound by a small number of more homogenous studies. Herbert and Cohen (1993) reported on 36 studies published between 1977 and 1991, finding broadly immunosuppressive effects of stress. Zorrilla et al. (2001) reported on 82 studies published between 1980 and 1996, finding potentially adaptive effects of acute stressors in addition to evidence for immunosuppression with longer stressors. It is important to note that metaanalytic findings are bound by the models tested in the literature. As more complex models are tested, more complex relationships emerge in meta-analysis. We next consider some such areas of complexity that should be considered in future psychoneuroimmunology research. Individual Differences and Immune Change Under Stress


The meta-analytic results indicate that organismic variables such as age and disease status moderate vulnerability to stress-related decreases in functional immune measures. Both aging and HIV are associated with immune senescence and loss of responsiveness (Effros et al., 1994; Effros & Pawelec, 1997), and both are also associated with disruption of neuroendocrine inputs to the immune system (Kumar et al., 2002; Madden, Thyagarajan, & Felten, 1998). The loss of self-regulation in disease and aging likely makes affected people more susceptible to negative immunological effects of stress. Finally, the meta-analysis did not reveal effects of sex on immune responses to stressors. However, these comparisons simply correlated the sex ratio of the studies with effect sizes. Grouping data by sex would afford a more powerful comparison, but few studies organized their data that way. Gender may moderate the effects of stress on immunity by virtue of the effects of sex hormones on immunity; generally, men are considered to be more biologically vulnerable (Maes, 1999), and they may be more psychosocially vulnerable (e.g.,Scanlan, Vitaliano, Ochs, Savage, & Borson, 1998). It seems likely to us that individual differences in subjective experience also make a substantive contribution to explaining this phenomenon. Studies have convincingly demonstrated that people’s cardiovascular and neuroendocrine responses to stressful experience are dependent on their appraisals of the situation and the presence of intrusive thoughts about it (Baum et al., 1993; Frankenhauser, 1975; Tomaka et al., 1997). Although the same logic should apply to people’s immune responses to stressful experience, few of the studies in this area have included measures of subjective experience, and those reports were limited by methodological issues such as aggregation across heterogeneous stressors. As a consequence, measures of subjective experience were not significantly associated with immune parameters in healthy research participants, with the exception of a modest (r = −.10) relationship between intrusive thoughts and natural killer cell cytotoxicity. Psychological variables such as personality and emotion can give rise to individual differences in psychological and concomitant immunological Psychol Bull. Author manuscript; available in PMC 2006 February 7.


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responses to stress. Optimism and coping, for example, moderated immunological responses to stressors in several studies (e.g., Barger et al., 2000; Bosch et al., 2001; Cruess et al., 2000; Segerstrom, 2001; Stowell, Kiecolt-Glaser, & Glaser, 2001). Mechanisms of Stress Effects on the Immune System Virtually nothing is known about the psychological pathways linking stressors with the immune system. Many theorists have argued that affect is a final common pathway for stressors (e.g., S. Cohen, Kessler, & Underwood, 1995; Miller & Cohen, 2001), yet studies have enjoyed limited success in attempting to explain people’s immune responses to life experiences on the basis of their emotional states alone (Bower et al., 1998; Cole, Kemeny, Taylor, Visscher, & Fahey, 1996; Miller, Dopp, Myers, Stevens, & Fahey, 1999; Segerstrom, Taylor, Kemeny, & Fahey, 1998). Furthermore, many studies have focused on the immune effects of emotional valence (e.g., unhappy vs. happy; Futterman, Kemeny, Shapiro, & Fahey, 1994), but the immune system may be even more closely linked to emotional arousal (e.g., stimulated vs. still), especially during acute stressors (S. Cohen et al., 2000). Finally, it is possible that emotion will prove to be relatively unimportant and that other mental processes such as motivational states or cognitive appraisals will prove to be the critical psychological mechanisms linking stress and the immune system (cf. Maier, Waldstein, & Synowski, 2003).


In terms of biological mechanisms, the field is further along, but much remains to be learned. A series of studies in the mid-1990s was able to show via beta-adrenergic blockade that activation of the sympathetic nervous system was responsible for the immune system effects of acute stressors (Bachen et al., 1995; Benschop, Nieuwenhuis, et al., 1994). Apart from these findings, however, little is known about biological mechanisms, especially with regard to more enduring stressors that occur in the real world. Studies that have attempted to identify hormonal pathways linking stressors and the immune system have enjoyed limited success, perhaps because they have utilized snapshot assessments of hormones circulating in blood. Future studies can maximize their chances of identifying relevant mediators by utilizing more integrated measures of hormonal output, such as 24-hr urine collections or diurnal profiles generated through saliva collections spaced throughout the day (Baum & Grunberg, 1995; Stone et al., 2001).


Future studies could also benefit from a greater emphasis on behavior as a potential mechanism. This strategy has proven useful in studies of clinically depressed patients, in which decreased physical activity and psychomotor retardation (Cover & Irwin, 1994; Miller, Cohen, & Herbert, 1999), increased body mass (Miller, Stetler, Carney, Freedland, & Banks, 2002), disturbed sleep (Cover & Irwin, 1994; Irwin, Smith, & Gillin, 1992), and cigarette smoking (Jung & Irwin, 1999) have been shown to explain some of the immune dysregulation evident in this population. There is already preliminary evidence, for instance, that sleep loss might be responsible for some of the immune system changes that accompany stressors (Hall et al., 1998; Ironson et al., 1997). Stress, the Immune System, and Disease The most pressing question that future research needs to address is the extent to which stressorinduced changes in the immune system have meaningful implications for disease susceptibility in otherwise healthy humans. In the 30 years since work in the field of psychoneuroimmunology began, studies have convincingly established that stressful experiences alter features of the immune response as well as confer vulnerability to adverse medical outcomes that are either mediated by or resisted by the immune system. However, with the exception of recent work on upper respiratory infection (S. Cohen, Doyle, & Skoner, 1999), studies have not yet tied these disparate strands of work together nor determined whether immune system changes are the mechanism through which stressors increase susceptibility to



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disease onset. In contrast, studies of vulnerable populations such as people with HIV have shown changes in immunity to predict disease progression (Bower et al., 1998).


To test an effect of this nature, researchers need to build clinical outcome assessments into study designs where appropriate. For example, chronic stressors reliably diminish the immune system’s capacity to produce antibodies following routine influenza vaccinations (see Table 7). Yet as far as we are aware, none of these studies has tracked illness to explore whether stress-related disparities in vaccine response might be sufficient to heighten susceptibility to clinical infection with influenza. Cytokine expression represents a relatively new and promising example of an avenue for research linking stress, immune change, and disease. For example, chronic stress may elicit prolonged secretion of cortisol, to which white blood cells mount a counterregulatory response by downregulating their cortisol receptors. This downregulation, in turn, reduces the cells’ capacity to respond to anti-inflammatory signals and allows cytokine-mediated inflammatory processes to flourish (Miller, Cohen, & Ritchey, 2002). Stress therefore might contribute to the course of diseases involving excessive nonspecific inflammation (e.g., multiple sclerosis, rheumatoid arthritis, coronary heart disease) and thereby increase risk for excess morbidity and mortality (Ershler & Keller, 2000;Papanicoloaou et al., 1998;Rozanski, Blumenthal, & Kaplan, 1999). Another example of the importance of cytokines to clinical pathology is in asthma and allergy, in which emerging evidence implicates excess Th2 cytokine secretion in the exacerbation of these diseases (Busse & Lemanske, 2001;Luster, 1998). Conclusion Sapolsky (1998) wrote, Stress-related disease emerges, predominantly, out of the fact that we so often activate a physiological system that has evolved for responding to acute physical emergencies, but we turn it on for months on end, worrying about mortgages, relationships, and promotions. (p. 7) The results of this meta-analysis support this assertion in one sense: Stressors with the temporal parameters of the fight-or-flight situations faced by humans’ evolutionary ancestors elicited potentially beneficial changes in the immune system. The more a stres-sor deviated from those parameters by becoming more chronic, however, the more components of the immune system were affected in a potentially detrimental way.


Further research is needed to support two other ideas elicited by this quote: the idea that subjective experience such as worry is more likely to result in stress-related immune change than objective experience and the idea that stress-related immune change results in stressrelated disease. Though the results of the meta-analysis were not encouraging on the first point, many of these studies suffered from methodological limitations. We hope that these results will inform investigations that go beyond the relationship between a stressful event and an immune parameter to investigate the psychological phenomena that mediate that relationship. Finally, these results can also inform investigations into stress, immunity, and disease process. Whether the disease is characterized by natural or specific immunity, its cytokine profile, and its regulation by anti-inflammatory agents such as cortisol, may determine the disparate effects of different kinds of stressors. Acknowledgements Preparation of this work was supported by American Heart Association Grant 0160367Z, the National Alliance for Research on Schizophrenia and Depression, National Institute of Mental Health Grant 61531, and Michael Smith Foundation for Health Research Grant CI-SCH-58. We thank Edith Chen for her helpful comments on an earlier version of the article and Jennifer Snedeker for assistance with manuscript preparation.



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Figure 1.

Funnel plots depicting relationship between effect size and sample size. PHA = phytohemagglutinin.



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Table 1

Immune Parameters Reported and Critical Characteristics Parameter

Arm of immune system


Cell Leukocytes Granulocytes Neutrophils Eosinophils Monocytes/macrophages Lymphocytes T lymphocytes T-helper lymphocytes

Natural Natural Natural Natural Natural Specific Specific Specific

Function


T-cytotoxic lymphocytes B lymphocytes Activated B lymphocytes Natural killer cells Immunoglobulin IgA, IgG, IgM Anti-EBV IgG Anti-HSV IgG Anti-influenza IgG postimmunization Cytokine Interleukin-1β Interleukin-2 Interleukin-4

Specific Specific Specific Natural

All white cells Inflammation Inflammation, phagocytosis Inflammation Inflammation, phagocytosis All lymphocytes Cellular immunity Cellular (Th1) or humoral (Th2) immunity Cellular (Th1) immunity Humoral (Th2) immunity Humoral (Th2) immunity Cellular (Th1) immunity

Specific Specific Specific Specific

Humoral (Th2) immunity Index of EBV replication/activation Index of HSV replication/activation Humoral (Th2) immunity

Natural Specific Specific

Interleukin-6 Interleukin-10 Interferon-γ

Natural Specific Natural and specific

Tumor necrosis factor-α Complement

Natural Natural

Inflammation, T cell activation T cell activation (Th1) B cell activation, antibody production (Th2) Inflammation Inhibits T cell activation (Th2) Macrophage, natural killer cell, and T cell activation (Th1) Inflammation Increases effectiveness of natural immunity

Functional assay Neutrophil superoxide release Natural killer cell cytotoxicity Proliferation to ConA

Natural Natural Specific

Proliferation to PHA

Specific

Proliferation to PWM

Specific

Cell surface marker

CD2 CD3, CD45RA (naive) CD4 CD8 CD19, CD20 CD23, CD30 CD16, CD56, CD57

C3

Inflammation Cellular (Th1) immunity Cellular (Th1) immunity (T cell proliferation) Cellular (Th1) immunity (T cell proliferation) Cellular (Th1) and humoral (Th2) immunity (T and B cell proliferation)

Note. Th1 = cells that direct a response to intracellular pathogens; Th2 = cells that direct a response to extracellular pathogens; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; EBV = Epstein-Barr virus; HSV = herpes simplex virus; ConA = concanavalin A; PHA = phytohemagglutinin; PWM = pokeweed mitogen.

NIH-PA Author Manuscript Psychol Bull. Author manuscript; available in PMC 2006 February 7.

NIH-PA Author Manuscript Bisselli et al., 1993 Borella et al., 1999 Bosch et al., 1996 Boyce et al., 1993, 1995 Davidson et al., 1999 Deinzer & Schüller, 1998 Deinzer et al., 2000 Dobbin et al., 1991 Fittschen et al., 1990

Aloe et al., 1994

Arber et al., 1992

Bachen et al., 1992, 1995

Barger et al., 2000

Beck et al., 2000

Benschop, Brosschot, et al., 1994

Benschop et al., 1995

Benschop, Jacobs, et al., 1996

Benschop, Nieuwenhuis, et al., 1994 Bongartz et al., 1987

Glaser, Kiecolt-Glaser, Stout, et al., 1985 Glaser et al., 1986, 1987, 1990, 1991, 1993, 1994, 1996, 1999 Gruzelier et al., 2001 Guidi et al., 1999 Halvorsen & Vassend, 1987 Jemmott & Magloire, 1988 Jemmott et al., 1983 Kamei et al., 1997, 1998 Kang et al., 1996, 1997, 1998 Kiecolt-Glaser et al., 1986, 1993, 1994, 1997, 2001 Kugler et al., 1996 Lacey et al., 2000

Breznitz et al., 1998

Brosschot et al., 1991, 1992, 1994

Burleson et al., 1998

Cacioppo et al., 1995, 1998

Caggiula et al., 1995

Caudell & Gallucci, 1995

Chi et al., 1993

S. Cohen et al., 2000

Cruse et al., 1993

Delahanty et al., 1996, 1998, 2000

Dopp et al., 2000

Bristow et al., 1997

Glaser, Kiecolt-Glaser, Speicher, & Holliday, 1985

Bosch et al., 2001

Gilbert et al., 1996

Baker et al., 1984, 1985

Brief naturalistic

Ackerman et al., 1996, 1998

Acute time-limited

Psychol Bull. Author manuscript; available in PMC 2006 February 7. Weiss et al., 1996

Spratt & Denney, 1991 Udelman, 1982

Solomon et al., 1997

Lutgendorf et al., 1997, 2001 McClelland et al., 1991 Nagabhushan et al., 2001 Pettingale et al., 1994

Kiecolt-Glaser et al., 1988 Lane et al., 1983

Irwin, Daniels, & Weiner, 1987 Kiecolt-Glaser, Fisher, et al., 1987

Irwin, Daniels, Smith, et al., 1987

Ironson et al., 1990, 1997 Irwin et al., 1986, 1988

Goodkin et al., 1996

Dworsky et al., 1989

Delahanty et al., 1997

Cruess et al., 2000

Beem et al., 1999

Bartrop et al., 1977

Arnetz et al., 1991

Aragona et al., 1996

Antoni et al., 1990

Event sequence

McKinnon et al., 1989 Mills et al., 1997, 1999 Nakano et al., 1998 Pariante et al., 1997 Sabioncello et al., 2000 Scanlan et al., 1998 Schlesinger & Yodfat, 1988 Stowell et al., 2001 Vedhara et al., 1999 Vitaliano et al., 1998

Lutgendorf et al., 1999

Dekaris et al., 1993 Dimsdale et al., 1994 Drummond & Hewson-Bower 1997 Esterling et al., 1994, 1996 Gennaro, Fehder, Cnaan, et al., 1997 Gennaro, Fehder, Nuamah, et al., 1997 Glaser & KiecoltGlaser, 1997 Glaser et al., 1998, 2000, 2001 Irwin et al., 1991, 1997 Kiecolt-Glaser et al., 1991, 1995, 1996 Kiecolt-Glaser, Glaser, et al., 1987 Lauc et al., 1998

Bauer et al., 2000

Chronic

NIH-PA Author Manuscript Table 2

Wilson et al., 1999

Spivak et al., 1997 Watson et al., 1983

Boscarino & Chang, 1999 Inoue-Sakurai et al., 2000 Laudenslager et al., 1998 Mosnaim et al., 1993

Distant

M. W. Linn et al., 1983, 1984

B. S. Linn et al., 1988

Liang et al., 1997

Levy et al., 1989

Leserman et al., 1997

Kubitz et al., 1986

Kessler et al., 1991

Jabaaij et al., 1993, 1996 Kemeny et al., 1989

Irwin et al., 1990

Irwin, Daniels, Bloom, et al., 1987

Howland et al., 2000

Graham et al., 1988

González-Quijano et al., 1998 Goodkin, Blaney, et al., 1992 Goodkin, Fuchs, et al., 1992

Gomez et al., 1994

Evans et al., 1995

F. Cohen et al., 1999

Byrnes et al., 1998

Birmaher et al., 1994

Benschop, Jabaaij, et al., 1998 Biondo et al., 1994

Abdeljaber et al., 1994

Life event

Wilcox et al., 2000

Vitaliano et al., 1998

Værnes et al., 1991

Tjemsland et al., 1997

Theorell et al., 1990

Song et al., 1999

Schaubroeck et al., 2001 Söderfeldt et al., 2000

Scanlan et al., 1998

Nakata et al., 2000

Nakamura et al., 1999

McDade, 2001

McClelland et al., 1982

Marsland et al., 2001

Maes et al., 1999

Lerman et al., 1999

Kusaka et al., 1992

Kawamura et al., 2001

Kawakami et al., 1997

Ironson et al., 1997

Hall et al., 1998

Halim et al., 2000

de Gucht et al., 1999

Andersen et al., 1998

Stress appraisal


Studies Used in the Meta-Analysis by Type of Stressor Segerstrom and Miller Page 42

NIH-PA Author Manuscript Lowe et al., 2000 Maes et al., 1997, 1998, 1999 Marchesi et al., 1989 Marshall et al., 1998 Marucha et al., 1998 McClelland et al., 1985 Ockenfels et al., 1994 Paik et al., 2000 Segerstrom, 2001 Segerstrom et al., 1998 Song et al., 1999 Uchakin et al., 2001 Van Rood et al., 1995 Vassend & Halvorsen, 1987 Vedhara & Nott, 1996 Wadee et al., 2001 Whitehouse et al., 1996 Wolf et al., 1994 Workman & La Via, 1987

Dugué et al., 1993 Endresen et al., 1991 Geenen et al., 1998 Gerits & DeBrabander, 1999 Gerritsen et al., 1996

Goebel & Mills, 2000 Goebel et al., 2000 Herbert et al., 1994 Jacobs et al., 2001 Jern et al., 1989 Johnson et al., 1996 Kamei et al., 1998 Kang & Fox, 2000 Landmann et al., 1984 Larson et al., 2001

Manuck et al., 1991 Marsland et al., 1995, 1997, 2001 Matthews et al., 1995 McDonald & Yagi, 1960 Miller, Dopp, et al., 1999 Mills & Dimsdale, 1996 Mills, Berry, et al., 1995 Mills et al., 1996, 1998 Mills, Haeri, & Dimsdale, 1995 Mills, Ziegler, et al., 1995 Moyna et al., 1999 Naliboff et al., 1991 Naliboff, Solomon, Gilmore, Benton, et al., 1995 Naliboff, Solomon, Gilmore, Fahey, et al., 1995 Neumann & Chi, 1999 Neumann et al., 1998, 2000 Ohira et al., 1999 Olff et al., 1995 Pawlak et al., 1999, 2000 Pehlivanođlu et al., 2001 Peters et al., 1999 Pike et al., 1997 Redwine et al., 2001 Ring et al., 2000 Rohleder et al., 2001 Sauer et al., 1995 Schedlowski, Jacobs, Alker, et al., 1993 Schedlowski, Jacobs, & Stratmann, et al., 1993 Schmid-Ott et al., 1998, 2001 Sgoutas-Emch et al., 1994 Sieber et al., 1992 Spangler, 1997 Stone et al., 1993 Tsopanakis & Tsopanakis, 1998 Uchino et al., 1995

Zisook et al., 1994

Event sequence

Chronic

NIH-PA Author Manuscript Brief naturalistic

Distant Martin & Dobbin 1988 McClelland et al., 1980 McDade et al., 2000 McIntosh et al., 1993 McNaughton et al., 1990 Miletic et al., 1996 H. Moss et al., 1998 R. B. Moss et al., 1989 Mulder et al., 1995 Patterson et al., 1995 Perry et al., 1992 Petrey et al., 1991 Rabkin et al., 1991 Ravindran et al., 1996 Schlesinger & Yodfat, 1991 Shea et al., 1991 Thomason et al., 1996 Thornton et al., 2000 Vialettes et al., 1989 Zautra et al., 1989

Life event

Stress appraisal


Acute time-limited

Segerstrom and Miller Page 43



Van der Pompe et al., 1997, 1998 Van der Voort et al., 2000 Wang et al., 1998 Weisse et al., 1990 Willemsen et al., 1998 Winzer et al., 1999 Zakowski, 1995 Zakowski et al., 1992, 1994 Zeier et al., 1996

Event sequence

Chronic

NIH-PA Author Manuscript Brief naturalistic

Distant

Life event

Stress appraisal


Acute time-limited

Segerstrom and Miller Page 44



Page 45

Table 3

Meta-Analysis of Immune Responses to Acute Time-Limited Stress in Healthy Participants Immune marker


Leukocyte subset count Leukocytes Granulocytes Neutrophils Eosinophils Monocytes Lymphocytes T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes T-helper:T-cytotoxic ratio Naive T lymphocytes B lymphocytes Activated B lymphocytes Natural killer cells Large granular lymphocytes Leukocyte subset percentage Granulocytes Neutrophils Monocytes Lymphocytes T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes B lymphocytes Natural killer cells Total immunoglobulins Serum IgA Serum IgM Secretory IgA secretion rate Secretory IgA concentration Basal cytokine levels Interleukin-1β Natural killer cell function Natural killer cell cytotoxicity Per-cell cytotoxicity Lymphocyte proliferation Proliferation to ConA Proliferation to PHA Proliferation to PWM Cytokine production Interleukin-1β Interleukin-4 Interleukin-6 Interferon-γ

k

N

r

SEr

95% CI

p

Q

25 12 3 3 15 24 33 42 42 19 3 18 4 41 8

1,129 397 86 81 590 828 1,452 1,678 1,678 920 241 739 60 1,635 362

.17 .08 .30 −.10 .04 .18 .07 .01 .20 −.23 −.09 −.07 −.15 .43 .53

.04 .06 .12 .16 .05 .05 .03 .03 .03 .10 .11 .04 .14 .06 .30

.10, .25 minus;.04, .19 .08, .50 −.39, .21 −.05, .13 .09, .26 .01, .12 −.05, .05 .15, .25 −.40, −.04 −.29, .12 −.14, .01 −.40, .14 .33, .51 .00, .83

.001 .18 .009 .53 .43 .001 .01 .86 .001 .02 .41 .08 .31 .001 .05

34.61 31.77 2.13 2.99 15.43 31.77 25.48 23.72 34.05 17.98 2.46 16.23 0.48 172.75*** 165.64***

5 5 7 7 10 14 15 5 15

295 217 277 350 497 642 692 248 693

−.13 .04 .06 .06 −.05 −.24 .09 −.11 .24

.10 .07 .09 .06 .09 .04 .04 .07 .11

−.31, .07 −.10, .18 −.12, .23 −.05, .16 −.22, .13 −.31, −.16 .01, .16 −.24, .02 .03, .42

.20 .56 .55 .30 .62 .001 .03 .09 .02

7.24 3.75 10.82 1.34 28.05*** 13.61 9.28 1.46 90.19***

4 3 6 8

91 67 293 337

.12 .14 .22 .22

.11 .13 .08 .09

−.10, .33 −.12, .37 .06, .37 .05, .38

.30 .30 .008 .01

0.95 0.61 6.92 13.05

4

89

−.01

.11

−.23, .21

.91

0.25

37 8

1,398 287

.30 .12

.05 .11

.20, .39 −.09, .32

.001 .26

108.85*** 18.12*

17 26 10

706 1,120 480

−.17 −.17 −.10

.04 .04 −.05

−.24, −.09 −.23, −.10 −.19, −.01

.001 .001 .03

14.12 35.36 5.84

3 3 3 3

78 136 143 96

.01 −.19 .28 .21

.12 .11 .09 .11

−.23, .23 −.39, .03 .13, .44 .01, .40

.98 .08 .001 .05

5.78 2.38 12.84** 0.24

Note. CI = confidence interval; IgA = immunoglobulin A; IgM = immunoglobulin M; ConA = concanavalin A; PHA = phytohemagglutinin; PWM = pokeweed mitogen. *


p < .05.

**

p < .01.

***

p < .001.



Page 46

Table 4

Meta-Analysis of Immune Responses to Brief Naturalistic Stress in Healthy Participants Immune marker


Leukocyte subset count Leukocytes Granulocytes Neutrophils Monocytes Lymphocytes T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes T-helper:T-cytotoxic ratio B lymphocytes Natural killer cells Leukocyte subset percentage Monocytes Lymphocytes T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes B lymphocytes Natural killer cells Total immunoglobulins Serum IgA Serum IgG Serum IgM Secretory IgA rate Secretory IgA concentration Specific immunoglobulin Epstein-Barr virus Herpes simplex virus Complement molecule C3 Natural killer cell function Natural killer cell cytotoxicity Lymphocyte proliferation Proliferation to ConA Proliferation to PHA Proliferation to PWM Cytokine production Interleukin-1β Interleukin-2 Interleukin-4 Interleukin-6 Interleukin-10 Interferon-γ Tumor necrosis factor-α

k

N

r

SEr

95% CI

p

Q

9 3 5 6 9 5 7 6 12 5 5

249 56 103 120 236 110 197 185 351 126 103

.20 .01 .11 .06 .06 .03 .06 .05 .01 .48 −.15

.07 .15 .11 .10 .08 .10 .08 .08 .07 .56 .11

.07, .32 −.27, .29 −.07, .34 −.13, .25 −.10, .23 −.18, .22 −.09, .21 −.10, .20 −.11, .14 −.51, .92 −.35, .06

.002 .93 .18 .52 .46 .81 .43 .50 .84 .35 .16

12.95 0.01 2.33 3.90 10.46 0.05 1.08 1.74 13.68 99.48***

4 3 5 11 12 3 5

98 97 160 350 362 121 163

.11 −.13 −.16 −.11 −.03 .07 −.02

.11 .11 .18 .10 .06 .53 .19

−.10, .32 −.33, .08 −.47, .19 −.29, .09 −.14, .08 −.74, .80 −.38, .35

.30 .23 .36 .28 .60 .89 .93

2.33 2.05 13.67** 26.56** 8.84 42.48*** 18.20**

6 7 7 4 9

243 290 290 139 350

.11 .06 .02 .09 .19

.07 .06 .10 .33 .18

−.02, .24 −.06, .17 −.17, .21 −.50, .63 −.20, .46

.10 .37 .83 .78 .40

1.28 2.54 13.41* 31.31*** 66.97***

7 4

359 225

.20 .18

.04 .08

.10, .30 −.02, .34

.001 .08

6.56 4.97

3

116

−.16

.10

−.34, .03

.09

1.77

14

468

−.11

.05

−.21, −.01

.04

14.55

9 14 3

220 443 106

−.32 −.19 −.17

.15 .09 .15

−.56, −.03 −.35, −.02 −.43, .12

.03 .03 .24

27.08*** 33.38*** 4.75

6 4 3 3 3 8 3

149 107 81 100 95 314 100

.11 −.17 −.10 .26 .41 −.30 .18

.08 .36 .12 .11 .11 .13 .19

−.05, .27 −.71, .49 −.32, .13 .06, .44 .21, .57 −.51, .05 −.19, .51

.17 .63 .39 .01 .001 .02 .34

15.07*** 27.34*** 0.69 0.79 1.65 28.76*** 5.10

2.06

Note. CI = confidence interval; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; ConA = concanavalin A; PHA = phytohemagglutinin; PWM = pokeweed mitogen.


*

p < .05.

**

p <.01.

***

p <.001.



Page 47

Table 5

Meta-Analysis of Immune Responses to Brief Naturalistic Stress in Participants With Asthma Immune marker


Neutrophil function Superoxide release with FMLP Superoxide release with PHA Natural killer cell function Natural killer cell cytotoxicity Lymphocyte proliferation Proliferation to PHA

k

N

r

SEr

3

216

.20

.07

3

216

.37

3

216

3

216

95% CI

p

Q

.06, .32

.004

0.39

.07

.24, .49

.001

0.68

−.33

.07

−.45, −.21

.001

0.50

.32

.07

.19, .43

.001

0.35

Note. CI = confidence interval; FMLP = N-formyl-met-leu-phe; PHA = phytohemagglutinin.

NIH-PA Author Manuscript NIH-PA Author Manuscript Psychol Bull. Author manuscript; available in PMC 2006 February 7.


Page 48

Table 6

Meta-Analysis of Immune Responses to Stressful Event Sequences in Healthy Participants Immune marker


Leukocyte subset count Monocytes Lymphocytes T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes T-helper:T-cytotoxic ratio B lymphocytes Natural killer cells Leukocyte subset percentage T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes B lymphocytes Specific immunoglobulin Epstein-Barr virus Natural killer cell function Natural killer cell cytotoxicity Lymphocyte proliferation Proliferation to ConA Proliferation to PHA Proliferation to PWM

k

N

r

SEr

95% CI

p

Q

3 5 5 9 8 6 5 4

113 223 213 566 544 296 185 370

−.02 .05 −.02 .03 −.14 .06 .02 .17

.10 .07 .07 .11 .15 .08 .08 .09

−.21, .17 −.09, .18 −.16, .12 −.19, .25 −.41, .15 −.09, .21 −.13, .17 .00, .34

.87 .49 .82 .81 .35 .44 .76 .05

0.39 2.65 0.37 39.29*** 58.22***

3 5 5 3

129 279 279 129

.02 .00 −.05 −.04

.09 .06 .06 .09

−.16, .19 −.12, .12 −.17, .07 −.22, .14

.85 .94 .43 .67

0.11 0.00 3.65 0.57

3

198

.21

.07

.07, .34

.003

1.18

13

698

−.03

.17

−.29, .34

.87

164.40***

6 11 7

297 675 284

−.04 .10 .12

.06 .10 .16

−.15, .08 −.09, .28 −.19, .40

.53 .32 .45

2.53 42.25*** 28.72***


Note. CI = confidence interval; ConA = concanavalin A; PHA = phytohemagglutinin; PWM = pokeweed mitogen. ***

p < .001.


7.54 0.35 5.06


Page 49

Table 7

Meta-Analysis of Immune Responses to Chronic Stress in Healthy Participants Immune marker


Leukocyte subset count Leukocytes Neutrophils Eosinophils Monocytes Lymphocytes T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes T-helper:T-cytotoxic ratio Activated B lymphocytes Natural killer cells Leukocyte subset percentage Monocytes T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes Natural killer cells Specific immunoglobulin Antibody to herpes simplex virus 1 Antibody to influenza after vaccination Natural killer cell function Natural killer cell cytotoxicity Lymphocyte proliferation Proliferation to ConA Proliferation to PHA Cytokine production Interleukin-2

k

N

r

SEr

95% CI

p

Q

4 3 3 4 4 5 10 10 6 3 4

240 124 124 240 240 470 786 786 528 138 158

.07 .36 −.07 −.04 −.06 −.03 −.05 −.08 −.11 −.02 −.14

.07 .36 .22 .17 .10 .05 .04 .08 .08 .09 .32

−.06, .19 −.33, .79 −.47, .35 −.36, .29 −.25, .13 −.12, .06 −.12, .03 −.23, .08 −.29, .08 −.19, .15 −.65, .45

.32 .31 .75 .83 .54 .55 .22 .34 .26 .82 .65

2.12 20.45*** 8.07* 14.33** 5.24 2.75 8.54 33.44*** 17.47**

3 5 10 10 6

224 522 860 860 246

.08 −.03 −.07 .02 .04

.10 .05 .06 .05 .09

−.11, .26 −.13, .07 −.18, .03 −.08, .11 −.13, .21

.42 .59 .19 .75 .64

3.18 4.93 19.45* 13.72* 7.85

3

185

.44

.34

−.19, .81

.17

20.78***

3

304

−.22

.05

−.33, −.11

.001

0.38

8

563

−.12

.05

−.20, −.01

.04

11.58

4 6

486 636

−.13 −.16

.06 .06

−.24, −.02 −.27, −.05

.02 .004

4.06 8.75

3

355

−.21

.05

−.31, −.11

.001

1.50

Note. CI = confidence interval; ConA = concanavalin A; PHA = phytohemagglutinin. *

p < .05.

**

p < .01.

***

p < .001.


0.03 33.61***


Page 50

Table 8

Meta-Analysis of Immune Responses to Distant Stressors and Posttraumatic Stress Disorder in Healthy Participants


Immune marker Natural killer cell cytotoxicity

k

N

r

SEr

95% CI

p

Q

3

94

−.05

.25

−.49, .41

.84

7.67*

Note. CI = confidence interval. *

p < .05.



Page 51

Table 9

Meta-Analysis of Immune Responses to Major and Minor Life Events of Unknown Duration in Healthy Participants


Immune marker


Leukocyte subset count Lymphocytes T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes T-helper:T-cytotoxic ratio Natural killer cells Leukocyte subset percentage T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes Natural killer cells Total immunoglobulins Serum IgA Serum IgG Serum IgM Secretory IgA rate Secretory IgA concentration Specific immunoglobulin Epstein-Barr virus Natural killer cell function Natural killer cell cytotoxicity Lymphocyte proliferation Proliferation to ConA Proliferation to PHA

k

N

r

SEr

95% CI

p

Q

5 4 5 5 3 4

537 237 227 227 70 194

−.18 .00 .00 .05 .14 −.08

.17 .07 .07 .07 .38 .07

−.47, .14 −.13, .13 −.13, .13 −.09, .18 −.54, .71 −.22, .07

.27 .99 .99 .48 .71 .28

20.28*** 0.00 0.00 3.02 12.11** 2.72

3 7 6 5

151 285 205 261

.20 .01 −.01 .00

.21 .06 .07 .06

−.21, .55 −.11, .13 −.15, .14 −.12, .12

.34 .83 .92 .99

7.61* 0.54 0.07 0.00

3 3 3 3 4

124 124 124 276 101

−.07 −.06 .03 −.08 −.16

.10 .10 .09 .10 .14

−.26, .14 −.24, .13 −.15, .21 −.26, .11 −.42, .12

.52 .54 .72 .43 .25

2.19 2.06 0.72 3.97 4.34

3

317

−.02

.11

−.23, .19

.86

5.65

12

672

−.07

.07

−.20, .07

.35

29.39***

3 4

72 131

−.13 −.26

.15 .15

−.35, .16 −.50, .03

.38 .08

2.49 6.11

Note. CI = confidence interval; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglob-ulin M; ConA = concanavalin A; PHA = phytohemagglutinin. *

p < .05.

**

p < .01.

***

p < .001.



Page 52

Table 10

Meta-Analysis of Immune Responses to Major and Minor Life Events of Unknown Duration in Participants With HIV/AIDS


Immune marker Leukocyte subset count T-helper lymphocytes T-cytotoxic lymphocytes T-helper:T-cytotoxic ratio Natural killer cells Leukocyte subset percentage T-helper lymphocytes T-cytotoxic lymphocytes

k

N

r

SEr

95% CI

Q

11 6 3 3

998 669 356 261

−.01 −.14 −.02 −.27

.03 .08 .05 .06

−.08, .05 −.29, .01 −.13, .09 −.38, −.15

.70 .08 .70 .001

7.70 17.92** 0.09 0.30

4 3

1,026 223

−.02 .00

.06 .07

−.15, .10 −.13, .13

.73 .99

7.58 0.00

Note. CI = confidence interval. **

p

p < .01.



Page 53

Table 11

Meta-Analysis of Immune Responses to Global Stress Appraisals in Healthy Participants Immune marker


Leukocyte subset count T lymphocytes T-helper lymphocytes T-cytotoxic lymphocytes Naive T lymphocytes Natural killer cells Leukocyte subset percentage T-helper lymphocytes T-cytotoxic lymphocytes Total immunoglobulin Serum IgG Natural killer cell function Natural killer cell cytotoxicity

k

N

r

SEr

95% CI

p

Q

3 3 4 3 3

241 241 279 241 205

−.15 −.14 −.02 −.09 −.20

.09 .10 .09 .11 .13

−.31, .03 −.32, .06 −.19, .15 −.29, .12 −.42, .04

.10 .18 .80 .41 .10

3.15 3.80 5.09 4.29 4.28

3 3

143 143

−.02 −.03

.09 .09

−.19, .15 −.23, .11

.79 .48

0.08 0.60

4

332

.02

.10

−.18, .20

.87

7.51

4

151

−.11

.09

−.27, .06

.21

1.85

Note. CI = confidence interval; IgG = immunoglobulin G.



Page 54

Table 12

Meta-Analysis of Immune Responses to Stress Appraisals and Intrusive Thoughts Within Healthy Stressed Populations


Immune marker Leukocyte subset count T-helper lymphocytes T-cytotoxic lymphocytes Natural killer cell function Natural killer cell cytotoxicity

k

N

r

SEr

95% CI

p

Q

3 3

462 462

−.10 −.26

.11 .32

−.31, .11 −.71, .34

.35 .40

7.52* 57.99***

3

566

−.15

.06

−.27, −.02

.02

7.97

Note. CI = confidence interval. *

p < .05.

***

p < .001.


Psychological Bulletin 2007, Vol. 133, No. 1, 25– 45

Copyright 2007 by the American Psychological Association 0033-2909/07/$12.00 DOI: 10.1037/0033-2909.133.1.25

If It Goes Up, Must It Come Down? Chronic Stress and the HypothalamicPituitary-Adrenocortical Axis in Humans Gregory E. Miller, Edith Chen, and Eric S. Zhou University of British Columbia The notion that chronic stress fosters disease by activating the hypothalamic-pituitary-adrenocortical (HPA) axis is featured prominently in many theories. The research linking chronic stress and HPA function is contradictory, however, with some studies reporting increased activation, and others reporting the opposite. This meta-analysis showed that much of the variability is attributable to stressor and person features. Timing is an especially critical element, as hormonal activity is elevated at stressor onset but reduces as time passes. Stressors that threaten physical integrity, involve trauma, and are uncontrollable elicit a high, flat diurnal profile of cortisol secretion. Finally, HPA activity is shaped by a person’s response to the situation; it increases with subjective distress but is lower in persons with posttraumatic stress disorder. Keywords: stress, trauma, cortisol, HPA axis

pituitary-adrenocortical (HPA) axis. This hormonal response system is present in organisms ranging from birds to humans and can be activated by a broad array of mental and physical stressors (McEwen, 1998; McEwen & Stellar, 1993; Weiner, 1992). Activation occurs when neurons in the paraventricular nucleus of the hypothalamus secrete corticotropin-releasing hormone (CRH). This molecule travels through the hypophyseal portal circulation to the anterior pituitary gland, which responds to its presence by secreting a pulse of adrenocorticotropin hormone (ACTH). The ACTH signal is carried through the peripheral circulation to the adrenal glands, which synthesize and release cortisol in a tissue layer called the zona fasciculata. Of the hormones released as part of this cascade, cortisol has been the subject of the most research attention, probably because of its widespread regulatory influences. Cortisol plays a key role in the central nervous system, where it is involved in learning, memory, and emotion; in the metabolic system, where it regulates glucose storage and utilization; and in the immune system, where it regulates the magnitude and duration of the inflammatory responses and the maturation of lymphocytes (Sapolsky, Romero, & Munck, 2000). Moreover, these are just the most prominent examples of cortisol’s actions; its influence also extends to multiple other systems in the body (Weiner, 1992). These observations have prompted scientists to advance numerous theories over the past 50 years linking stressors, cortisol, and disease. Common to each of these models is the notion that cortisol is a critical biological intermediary; it is seen as a primary mechanism through which chronic stressors get inside the body to bring about disease. Models of this type have been articulated for psychiatric disorders such as depression and schizophrenia (McEwen, 2000; E. F. Walker & Diforio, 1997); medical conditions such as cancer, arthritis, and diabetes (Bjorntorp & Rosmond, 1999; Sephton & Speigel, 2003; Heijnen & Kavelaars, 2005); and lifestyle problems such as obesity (Epel et al., 2000) and fatigue (Bower, Ganz, & Aziz, 2005). Cortisol has also been implicated as a primary suspect in more general models of stress and disease (S.

Exposure to chronic stress markedly increases vulnerability to adverse medical outcomes. This holds true across a wide variety of mental and physical conditions. For example, persons facing chronic stress are more likely to develop an episode of clinical depression, experience symptoms of an upper respiratory infection following viral exposure, suffer from a flare up of an existing allergic or autoimmune condition, and show accelerated progression of chronic diseases such as acquired immunodeficiency syndrome and coronary heart disease (Miller & Cohen, 2005; Monroe & Hadjiyannakis, 2002; Pereira & Penedo, 2005; Rozanski, Blumenthal, & Kaplan, 1999; Wright, Rodriquez, & Cohen, 1998). This phenomenon is apparent across the entire lifespan. From early in childhood to late in adulthood, chronic stress is accompanied by worse health (Coe & Lubach, 2003; Kiecolt-Glaser & Glaser, 2001; Repetti, Taylor, & Seeman, 2002; Taylor, Repetti, & Seeman, 1997), and the magnitude of this effect is substantial: In some cases, exposure to chronic stress triples or quadruples the chances of an adverse medical outcome (S. Cohen et al., 1998; Sandberg, Jarvenpaa, Penttinen, Paton, & McCann, 2004). Scientists have long been interested in understanding the biological mechanisms by which chronic stress “gets under the skin” to affect health outcomes. One potential mechanism that has received widespread and persistent attention is the hypothalamic-

Gregory E. Miller, Edith Chen, and Eric S. Zhou, Department of Psychology, University of British Columbia (UBC), Vancouver, British Columbia, Canada. Our efforts on this project were generously supported by the Michael Smith Foundation for Health Research; the Canadian Institutes of Health Research; the National Heart, Lung, and Blood Institute; the National Alliance for Research on Schizophrenia and Depression; and the UBC Human Early Learning Partnership. Correspondence concerning this article should be sent to Gregory E. Miller, Department of Psychology, University of British Columbia, 2136 West Mall Avenue, Vancouver, BC V6K 3R4, Canada. E-mail: [email protected] 25

MILLER, CHEN, AND ZHOU

26

Cohen, Kessler, & Underwood, 1995), the idea being that it serves as a gateway to a broad array of conditions brought on by undesirable circumstances. In the vast majority of these models, stress triggers disease by increasing output of cortisol, thereby exposing bodily tissues to elevated concentrations of the hormone. If sustained, this process is thought to lead to tissue damage and subsequent dysregulation of biological systems. In contrast to these models, there also is now a handful of theories positing that stress-induced declines in cortisol output are the culprit mechanism (Heim, Ehlert, & Hellhammer, 2000; Sternberg, Chrousos, Wilder, & Gold, 1992; Yehuda, 2000). These models are generally advanced to explain how stress could exacerbate conditions in which deficient cortisol signaling contributes to disease pathogenesis (Raison & Miller, 2003). This may be the case with rheumatoid arthritis, chronic fatigue syndrome, and posttraumatic stress disorder (PTSD). Thus, current theories view cortisol deviations in both directions as potentially detrimental; whether elevations or declines are pathogenic depends on the condition.

Chronic Stress and Cortisol Output With cortisol so prominently featured in models of stress and disease, much effort has been devoted to understanding how undesirable circumstances modify its secretion. The earliest research with human subjects indicated that chronic stress (e.g., being a soldier in combat or having a child with pediatric cancer) was associated with reduced daily output of cortisol (Bourne, Rose, & Mason, 1967, 1968; Friedman, Mason, & Hamburg, 1963). These findings were puzzling to researchers, because they contradicted a central dogma of the period—that stress markedly increased cortisol secretion. This dogma had emerged from decades of research in animal models by Selye and his descendants (e.g., see Selye, 1956). As a result, the findings of reduced cortisol output were set aside, and work in this area languished for 10 –15 years. At that time, new research emerged showing that chronic stresses such as bereavement, unemployment, and man-made disasters were accompanied by elevated levels of cortisol output (Arnetz et al., 1987; Baum, Gatchel, & Schaeffer, 1983; Kosten, Jacobs, & Mason, 1984; Schaeffer & Baum, 1984). Perhaps because they were consistent with the large body of evidence from animal studies, these findings captivated the attention of researchers and provided an empirical foundation for models of stress, cortisol, and disease that followed. For the next 10 –15 years, research and theory in this area flourished, guided by the implicit assumption that HPA activity increases robustly with stress. However, in the mid to late 1990s, a series of studies emerged of patients suffering from PTSD, and they reported the surprising result that combat veterans, Holocaust survivors, and other trauma victims had reduced cortisol secretion as well as a host of other indicators of abnormal HPA activity (Yehuda, Boisonuae, Lowy, & Giller, 1995; Yehuda, Kahana, et al., 1995; Yehuda, Resnick, Schmeidler, Yang, & Pitman, 1998; Yehuda, Teicher, Trestman, Levengood, & Siever, 1996). This pattern was not uniformly observed in studies of PTSD (see e.g., Hawk, Dougall, Ursano, & Baum, 2000; Lemieux & Coe, 1995; Pitman & Orr, 1990). The most robust evidence came from patients who had chronic, intractable PTSD and had been exposed to trauma many years before cortisol assessment. Nevertheless, this pattern of reduced cortisol

output and blunted HPA activity was sufficiently common that some researchers began viewing it as a unique feature of (and a potential cofactor in) PTSD (Yehuda, 2000; Yehuda, Resnick, Kahana, & Giller, 1993). In the years that followed, broader evidence of this phenomenon began to emerge; low cortisol output was documented in chronically stressed but nonpsychiatric populations, such as victims of domestic violence and caregivers for ill family members (Miller, Cohen, & Ritchey, 2002; Seedat, Stein, Kennedy, & Hauger, 2003; Vedhara et al., 2002). Again, not all studies of chronic stress reported findings in this direction. However, by 2000, stress-related hypocortisolism had begun to attract considerable attention, and Heim, Ehlert and Hellhammer (2000) published a seminal review article on the topic. A number of other articles on this phenomenon soon followed (Fries, Hesse, Hellhammer, & Hellhammer, 2005; Gunnar & Vazquez, 2001; Raison & Miller, 2003), and today the field is squarely focused on hypocortisolism. Despite the enthusiasm, these findings have created significant confusion in the field. It is unclear how the recent findings can be integrated with older studies to arrive at a general conclusion about how HPA functions are influenced by chronic stress. Does cortisol output increase, as older work suggests? Or does it decline, as newer research indicates? Or perhaps more interestingly, is it capable of doing both? That is, might the nature and direction of the cortisol response depend on features of the stressor or on characteristics of the person who is coping with it? The answers to these questions have significant implications for research and theory across many areas of inquiry. Hence, the goal of this review is to synthesize findings over the past 50 years of research and generate answers to what was once considered a simple question: How is activity of the HPA axis modified by exposure to chronic stress?

What Shapes HPA Activity Following Exposure to Chronic Stress? If chronic stress is capable of increasing or decreasing HPA activity, what are some of the critical features that govern which outcome occurs? It is surprising that there has been little effort to develop psychological hypotheses that can explain this process. Thus, a second objective of this review is to outline and evaluate five hypotheses that may help to sort out some of the confusion in the literature. These hypotheses focus on (1) the time elapsed since stressor onset, (2) the nature of the threat posed, (3) the core emotions likely to be elicited by the stressor, (4) the controllability of the stressor, and (5) the psychiatric characteristics of the person.

1. Time Since Onset One possibility is that chronic stress both increases and decreases HPA activity, but does so at different times over the course of a threat. Shortly after the stress has begun, the axis may become activated, resulting in elevated cortisol output. However, with the passage of time, the body could mount a counter-regulatory response such that cortisol output rebounds below normal. This is a biologically plausible explanation, because the HPA axis is regulated by a potent negative feedback circuit, in which elevated levels of cortisol suppress output of CRH and ACTH by acting on glucocorticoid receptors in the hippocampus, hypothalamus, and

CHRONIC STRESS AND HPA ACTIVITY

pituitary. It is also a plausible explanation for the conflicting findings in the literature. Although hypotheses about the importance of timing have been articulated by several researchers (Fries et al., 2005; Hellhammer & Wade, 1993; Miller et al., 2002), they have not yet been tested with a proper longitudinal design. Thus, the existing literature may only seem contradictory because it is composed of a series of cross-sectional studies, each of which assesses its participants at a slightly different point in time with respect to stressor onset. In the current article, we use metaanalysis to evaluate this hypothesis. To the extent that it is correct, a correlation should emerge between timing and HPA activity, with more distant traumas being associated with hypocortisolism, and the reverse being true of recent-onset stress.

2. Nature of Threat Another possibility is that different forms of stress elicit different patterns of hormonal response. A number of theorists have argued that biological responses are stressor specific, having been shaped over time to maximize success at coping (Kemeny, 2003; Weiner, 1992). For example, a distinction can be made between forms of stress that pose a threat to the physical self (e.g., being in the midst of combat) and those that represent a threat to the social self (e.g., being in the midst of a divorce). According to specificity hypotheses, these situations should elicit different patterns of HPA activity because they pose different adaptational demands, which cortisol helps to support metabolically. Support for this view was recently obtained in a meta-analysis of cortisol responses to acute stress: Subjects exposed to laboratory situations that were high in social threat exhibited robust increases in cortisol secretion (Dickerson & Kemeny, 2004). When the situation had few elements of social threat, little in the way of a cortisol response was evident. The authors theorized that preserving social standing is a central motivation of humans; when this standing is threatened by a demanding situation, the HPA axis is mobilized to help manage the threat or its longer term consequences. It may also be useful to differentiate between traumatic and nontraumatic forms of stress. The former are defined as experiences that involve “actual or threatened death or serious injury, or a threat to the physical integrity of self or others” and have a special capacity to elicit feelings of “intense fear, helplessness, or horror” (American Psychiatric Association, 2000, pp. 427– 428). Because they are able to elicit such intense and distinct emotions, traumas may bring about more pronounced alterations in HPA function or qualitatively different profiles of hormonal output than do chronic, but nontraumatic, stressors. In the current review, meta-analysis is used to evaluate whether these distinctions—physical versus social and trauma versus nontrauma— help to explain the mixed findings in the literature on chronic stress and HPA outcomes.

3. Emotions Elicited by Stress A related hypothesis is that the direction and magnitude of the HPA response is governed by the emotion(s) elicited by the situation. According to this view, emotions represent the psychological mechanism connecting stressors to biology, so they should be the most powerful determinant of changes in HPA functions. One emotion that has been repeatedly discussed in this regard is shame. In studies in which subjects are exposed to acute stress in

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a laboratory setting, the extent of cortisol reactivity increases in a linear fashion with shame (Dickerson & Kemeny, 2004; Gruenewald, Kemeny, Aziz, & Fahey, 2004). Thus, feelings of shame appear to foster HPA activation during acute bouts of stress. It is interesting that the available evidence suggests an opposite pattern with more long-term, severe stress. At least in combat veterans who suffer from PTSD, shame is inversely related to daily cortisol output (Mason et al., 2001). This has led some researchers to suggest that shame may be a critical mechanism in stressor-related hypocortisolism. Feelings of loss also have been discussed as potential moderators. Life stress that involves a major loss has been shown to predict the onset of major depression (Kendler, Hettema, Butera, Gardner, & Prescott, 2003), and it has been argued that it does so by activating the HPA axis to persistently secrete cortisol (Meinlschmidt & Heim, 2005; Nicolson, 2004; Petitto, Quade, & Evans, 1992). Thus, the meta-analysis will examine whether two key emotional themes of chronic stress— shame and loss— can differentiate between studies that find increases versus decreases in HPA function.

4. Controllability of Stress Controllability represents another important dimension of chronic stress that has been proposed to influence HPA axis responsivity (Heim, Ehlert, & Hellhammer, 2000). In the context of acute stress, uncontrollability amplifies cortisol secretion, both in humans and in animals (Dickerson & Kemeny, 2004; Sapolsky, 1998). However, with stress that is more severe and persists longer, uncontrollability is thought to result in diminished HPA activity. This blunting may underlie the withdrawal and disengagement behaviors that often accompany uncontrollable chronic stress (Gold & Chrousos, 2002; Heim, Ehlert, & Hellhammer, 2000; Mason et al., 2001). Conversely, it may be a manifestation of the physiological toughening or steeling oneself that can occur when a person cannot escape from a difficult situation (Dienstbier, 1989; Gunnar & Vazquez, 2001a). By contrast, stress that has some element of controllability may activate the HPA axis, as its hormonal products provide metabolic support for active coping efforts (Gunnar & Vazquez, 2001a; Mason et al., 2001). Hence, to the extent that these theoretical formulations are accurate, the metaanalysis should yield positive associations between controllability and HPA products, which would help to explain variability in the existing literature.

5. Individual Psychiatric Sequelae A final possibility is that the psychiatric consequences of chronic stress, rather than features of the stress itself, are what govern the magnitude and direction of any HPA axis response. For example, research indicates that if a person exposed to trauma develops PTSD, he or she is likely to exhibit hypocortisolism (Yehuda, 2000; Yehuda, Resnick, et al., 1993). In contrast, depression following a trauma has been associated with increased cortisol output (Kaufman et al., 1997, 1998; Raison & Miller, 2003). Even when a trauma victim does not develop a full-blown psychiatric condition, research has suggested that the extent of subjective distress is positively associated with HPA activation (Baum, Cohen, & Hall, 1993; Davis et al., 2004; Rahe, Karson, Howard, Rubin, & Poland, 1990). To examine the contribution of

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psychiatric conditions and normative distress, we also conducted a separate meta-analysis involving only persons exposed to chronic stress. It asked the question, do individuals who experience chronic stress and develop a psychiatric diagnosis, or report greater subjective distress, differ in HPA function from those who experience chronic stress but do not develop a diagnosis or report distress?

Defining and Measuring Chronic Stress Most of the work in this area has relied on stimulus-based definitions of chronic stress, in which a target population is facing circumstances that most people would consider troubling and ongoing. Typical designs feature soldiers in the midst of combat, refugees displaced by war, victims of sexual assault, family caregivers for the ill, and people who have lost their jobs or spouses. Although these situations differ in a number of important respects, we believe they all can be viewed as chronic forms of stress. By stress we mean situations that the average person would appraise as threatening and exceeding his or her ability to cope (Lazarus & Folkman, 1984). By chronic we mean that the eliciting stimulus remains in the environment for an extended period of time (e.g., the family member who needs care indefinitely) or, alternatively, that the threat a stimulus poses to the self looms for an extended period of time (e.g., the sense of danger that follows a sexual assault), even if the stimulus itself does not. This definition grows out of the taxonomy proposed by Baum, Cohen, and Hall (1993), which views chronic stress as being composed of a stimulus from the environment, a person’s appraisal of that stimulus, and biobehavioral responses that support coping efforts. These dimensions are understood to be independent, and each can vary in duration from acute to chronic. As a result, this view of chronic stress encompasses situations in which the stressor persists for an extended period of time, as well as situations that last for a very short time but are likely to be seen as threatening for much longer.

Defining and Measuring HPA Activity HPA activity can be assessed in a variety of ways. The most common method is to measure output of cortisol. This can be done by collecting saliva (which contains biologically active cortisol, unbound to carrier proteins), blood, urine, or cerebrospinal fluid (all of which contain bound and unbound cortisol). Each of these fluids provides a slightly different temporal window on cortisol activity (Baum & Grunberg, 1995). Levels of hormone in blood and saliva reflect HPA activity in the past 10 – 60 min. Because it is usually collected over a 15–24-hr period, urinary cortisol provides a broader and more integrative profile of activity. In addition, cortisol has a diurnal rhythm (highest in the early morning, lowest in the evening), so the timing of assessments is an important factor. Some studies measure cortisol at specific times of the day (e.g., morning cortisol, evening cortisol). Others collect samples at multiple times throughout the day and either average across the day (as an indication of total cortisol output across the day) or calculate a slope (as an indication of cortisol’s rhythm across the day). Studies can also measure hormonal output at different points in the HPA axis. In addition to cortisol, measures can be taken of CRH (via cerebrospinal fluid) or ACTH (via blood) as additional indicators of HPA activity.

An alternative approach is to perform hormonal challenges. Researchers can introduce molecules such as CRH and ACTH into the system, as well synthetic versions of cortisol like dexamethasone, and measure secretion of downstream hormonal products. Normally, when cortisol levels are elevated, hypothalamic secretion of CRH declines, and this in turn diminishes ACTH and cortisol release. Challenge protocols are thus used to evaluate the sensitivity of the HPA axis’s negative-feedback circuit. Different molecules are used to assess the integrity of each axis component. CRH challenges provide a window into pituitary function, whereas ACTH challenges index sensitivity of the adrenals. Dexamethasone acts for the most part at the pituitary. In each of these tests, a response is considered “normal” when the challenge molecule suppresses circulating concentrations of the target hormone below a specified threshold in the hours following administration. For challenge protocols involving dexamethasone, cortisol is the target hormone, and it is measured 8 –17 hr after drug administration. For CRH challenges, ACTH and cortisol secretion are measured over a shorter window, usually 1–2 hr after drug administration. An “abnormal” response to these protocols occurs when a participant’s secretion of the target hormone is not influenced (or declines only modestly) following introduction of the challenge molecule. A final approach to measuring the HPA axis involves evaluating its influence on target tissues. For a hormone like cortisol to influence a biological system, it must bind to a specific receptor located inside a cell. The newly formed receptor-hormone complex translocates to the nucleus, where it is capable of modifying the cell’s program of genetic expression. To estimate how sensitive bodily tissues might be to cortisol’s regulatory influence, researchers in this area have sometimes measured the number of glucocorticoid receptors. This assessment is typically performed in white blood cells, as they can be easily extracted from humans and represent a target tissue of considerable theoretical interest. To the extent that a person’s cells express higher numbers of receptors, he or she is assumed to be more sensitive to cortisol’s actions in that tissue. It also bears noting that receptor expression is directly influenced by cortisol exposure; when high levels of the hormone are present, cells typically downregulate receptor numbers to maintain homeostasis. Thus, number of receptors is also sometimes understood as a marker of a tissue’s recent exposure to cortisol.

Method Literature Search Articles for the meta-analysis were initially identified through searches of the PubMed, Ovid MEDLINE, PsycInfo, EMBASE, and EvidenceBased Medicine Reviews databases for the years 1950 –2005. Each search crossed keywords reflecting chronic stress (assault, abuse, bereavement, caregiver, stress, trauma, unemployed, veteran, and war) with those reflecting HPA outcomes (cortisol, ACTH, CRH, adrenocortical). To augment the yield of the database search, we also combed reference sections of review articles in the area (Chrousos & Gold, 1992; Dickerson & Kemeny, 2004; Heim, Ehlert, & Hellhammer, 2000; Raison & Miller, 2003; Yehuda, 2000; Yehuda, Resnick, et al., 1993). As well, we did a cited-reference search on the ISI Web of Science, which involved entering the 10 most highly cited studies we found into the database and then having it locate articles that listed those studies in their reference sections.

CHRONIC STRESS AND HPA ACTIVITY To be eligible for inclusion in the meta-analysis, a study had to enroll subjects exposed to chronic stress, measure an indicator of HPA axis function, and provide enough data for us to compute effect sizes. We defined chronic stress as persistent circumstances that would normatively be appraised as threatening and exceeding coping resources (Lazarus & Folkman, 1984). To qualify as chronic, either the stressor itself needed to persist for a period lasting at least 1 month, or the circumstance needed to involve a brief event such as a natural disaster that was likely to be appraised as threatening for a similar duration. This definition is consistent with the broad view of chronic stress proposed by Baum et al. (1993). It encompasses situations in which the stressor persists for an extended period of time (e.g., caregiving for a family member with dementia), as well as situations that last for a very short time but are likely to be seen as threatening for much longer (e.g., being the victim of a sexual assault). In summary, for a situation to be included in the meta-analysis, either the stimulus and/or the presumed threat appraisal had to persist for 1 month. We also required the chronic stressor to be psychological in nature. Situations that were undesirable because of their physical health implications—such as long-term cold, pain, or disease—were excluded from the meta-analysis for two main reasons. First, our interest was in situations that primarily involved psychological stress. Second, exposure to stimuli like cold, pain, and disease can directly modify functions of the HPA axis, and this makes it difficult (if not impossible) to untangle the relative influences of the mental versus physical aspects of stress. With these eligibility criteria in place, our search efforts yielded 171 articles. A sizable number of these articles had to be excluded from the meta-analysis because they did not focus on a discrete chronic stressor (k ⫽ 24 studies). This created difficulties because the goal of our analysis was to identify features of chronic stress, such as its core emotional themes, that give rise to distinct profiles of HPA axis function. If a study included people facing divergent kinds of chronic stress, such as a job loss and combat experience, we were unable to assign it codes on these dimensions. (That is, unless it presented distinct statistics for each form of stress, in which case it was included in the meta-analysis.) A handful of articles also had to be excluded because they did not provide sufficient information for us to compute effect sizes (k ⫽ 13), or they were not designed with an appropriate control or baseline condition that was free of chronic stress (k ⫽ 15). To meet our criteria for good design, studies had to include a control sample free of chronic stress or compare subjects before and after they encountered difficulties. We also included studies in which all subjects had been exposed to stress, but the focus was on whether psychiatric symptoms explained variability in HPA outcomes. These studies were used to perform meta-analyses on the roles of PTSD, major depression, and normative distress. After studies had been excluded for these reasons, the pool of eligible articles totaled 119.

Coding Strategy The eligible studies were coded to derive features of the participants, the kinds of stress they faced, and the HPA outcomes being assessed. Coding was done by consensus of Edith Chen and Gregory E. Miller. Participant features. The coder extracted information regarding the size, mean age, gender balance, and psychiatric condition of the participants in each study. Stressor features. Four major features of each form of chronic stress were coded, corresponding to the hypotheses outlined in the introduction. To classify the nature of the threat, coders rated each form of stress according to whether it posed a physical (likely vs. unlikely) and a social threat (likely vs. unlikely). Physical threats were defined as stimuli that had the potential to diminish bodily integrity and bring about injury, disease, or mortality. Social threats were defined as stimuli that could diminish a person’s social standing or interrupt a major social role that he or she occupies. Studies were also categorized according to whether they focused on traumatic stressors (likely vs. unlikely). In line with current diagnostic

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standards for PTSD, traumas were defined as situations in which a person was likely to have experienced or witnessed “events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others” (American Psychiatric Association, 2000). To extract the core emotional theme of each form of stress, coders rated the likelihood that it would result in loss and humiliation. Loss was coded when there was an actual or potential loss of life to self or a close other or when the stress threatened an important relationship or social role. Humiliation was coded when the stress had the potential to cause shame or disgrace or leave the victim feeling devalued in the eyes of important others in his or her life. Ratings were made on a binary scale, with endpoints of likely and unlikely. The extent of control each kind of stress afforded participants was also coded. Control was defined as the ability to end the stress when desired. Because chronic stress never affords much in the way of control, coders assigned ratings of either uncontrollable or possibly controllable in this category. The temporal features of stress were coded in two ways. To estimate the duration of stress exposure, coders recorded the number of months since onset, because this is when HPA activity presumably begins. When this value was not provided, we either requested it from authors or estimated it using historical knowledge. The latter strategy was mostly used in studies of combat exposure in Vietnam, for which we estimated duration as months between the date of article publication and the height of U.S. involvement in the war (December 1968). Preliminary analyses of this variable revealed that it was distributed in a nonnormal fashion, so all values were log-10 transformed prior to use in the meta-analysis. To evaluate whether HPA functions differ according to the persistence of stress, we also recorded whether the stressor stimulus was present versus absent at the time of assessment. Circumstances that were still unfolding or required ongoing coping—such as caregiving for a disabled relative or seeking a job while unemployed—were rated by coders as being present. Those in which the outcome had already been determined—such as combat experience 30 years prior or adults who were abused as children—were rated by coders as being absent.

The Meta-Analysis Meta-analysis is a tool for synthesizing research findings. Its first stage involves computing an effect size for each study that is identified. The effect size reflects the magnitude of the relationship between predictor and outcome variables of interest, in this case, forms of chronic stress and various HPA axis functions. It is important to note that an effect size reflects the strength of an association and not its statistical significance; as such, it is not dependent upon the size of the sample from which it derives. In the next stage of meta-analysis, article-specific effect sizes are combined to derive an aggregate estimate across the literature. Study-level effect sizes. We used Cohen’s d as the effect size metric in this meta-analysis. We computed effect sizes for individual studies using descriptive statistics presented in the original published reports. When these statistics were not available, we requested them from authors. This strategy was successful in most circumstances. To compute d from descriptive statistics in between-subjects designs, we subtracted the control group mean from the chronic stress group mean and divided this value by the pooled standard deviation (Rosenthal, 1994). To compute d from descriptive statistics in within-subject designs, we subtracted the group mean at baseline from the group mean during stress and divided this quantity by the sample standard deviation at baseline. In cases in which descriptive statistics were not available, we computed d from inferential statistics using standard formulae (Rosenthal, 1994). These formulae had to be modified slightly for studies that used within-subject designs, because effect sizes are systematically overestimated when they are calculated from repeated-measures test statistics (Dunlap, Cortina, Vaslow, & Burke, 1996). In these situations, we derived effect size estimates using the formula d ⫽ tc [2(1 ⫺ r)n]1/2, where tc corresponds to the value of the t


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statistic for correlated measures, and r corresponds to the value of the correlation between outcome measures at pretest and posttest (Dunlap et al., 1996). Because very few studies reported the value of r, we used a value of .40 to compute effect sizes in this meta-analysis. To ensure that the meta-analytic findings were robust to variations in r, we conducted follow-up analyses using r values ranging from .20 to .60. Very similar findings emerged from these analyses, suggesting that the values we present below are reliable estimates of effect size. Aggregate effect sizes. The study-level effect sizes were subsequently aggregated by use of fixed-effects models in the software program Comprehensive Meta-Analysis Version 2 (Borenstein & Rothstein, 1999). We chose fixed-effect procedures because they are well suited to the goals of our review: to take stock of the data that have accumulated in this area over 50 years and to begin testing hypotheses about stressor and person features that give rise to distinct HPA profiles. When a meta-analysis has aims of this nature—to sort out existing findings, but not generalize more broadly—fixed-effects procedures are the method of choice (Hedges & Vevea, 1998). These models also have the (general) advantage of greater statistical power (Cohn & Becker, 2003), especially in cases in which the number of studies being synthesized is small. All that said, some caution needs to be exercised when the results of fixed-effects analyses are interpreted. Although they can help to sort out conflicts among existing studies, their findings need to be replicated in novel samples before large-scale generalizations can be made. Separate fixed-effects models were computed for each HPA outcome included in the meta-analysis. Each model yielded an aggregate effect size d, which reflects the difference between chronic stress and control groups in standard deviation units. d values of .20, .50, and .80 correspond roughly to small, medium, and large effects, respectively (J. Cohen & Cohen, 1983). Each d statistic was weighted before aggregation by multiplying its value by the inverse of its variance; this procedure enabled larger studies to contribute to effect size estimates to a greater extent than smaller ones. Weighting effect sizes is important because larger studies provide more accurate estimates of true population parameters (Shadish & Haddock, 1994). After each aggregate d had been derived, we evaluated whether it was significantly different from zero, using the criteria that its corresponding z value had to be greater than 1.96 and that its 95% confidence intervals could not include zero (Rosenthal, 1991; Shadish & Haddock, 1994). We also computed a heterogeneity coefficient with each model to evaluate whether it was composed of studies with similar findings. The heterogeneity coefficient is referred to as Q, and it is chi-square distributed with k ⫺ 1 degrees of freedom, where k is the number of studies included. When a Q statistic indicated there was significant variability across a group of studies, we examined whether person or stressor features explained the disparity. In cases in which the proposed moderator was scaled nominally or ordinally, we stratified studies using coder ratings and computed separate fixed-effects models for each subgroup. When the proposed moderator was continuous—for example, months since stressor onset—a fixed-effects meta-regression equation was constructed. These equations are similar to standard linear regression equations, except that the unit of analysis is “study” rather than “participant.”

Handling missing data. Occasionally studies failed to report the descriptive or inferential statistics needed to compute an effect size. In some of these cases, the authors noted that there was a significant difference between chronic stress and control groups. When this occurred, we computed effect sizes assuming that p values were equivalent to .05. This represents a conservative approach because the actual p values were probably smaller. In other cases, the authors noted that chronic stress and control groups did not differ with respect to an HPA outcome, but failed to provide any further statistical information. When this occurred, we computed effect sizes assuming that there was no difference at all between the groups, that is, a d value of 0.00. Because there is seldom no difference at all between two groups, this also represents a conservative strategy. Imputation was used in ⬍ 5% of cases. Handling dependent data. Meta-analysis assumes that each study-level effect contributing to an aggregate estimate is statistically independent (Rosenthal, 1991). We took a number of steps to avoid violating this assumption. First, when the same data appeared to have been published in multiple articles, we contacted authors to determine the extent of sample overlap. Second, in a handful of studies, multiple chronic stresses were assessed, and each was compared with the same pool of control subjects. In these cases the average d across stresses was used for aggregate estimates, unless a specific analysis permitted us to use stressor-specific values in a nondependent fashion. Finally, a small group of studies used longitudinal designs, assessing HPA outcomes on multiple occasions over the course of stress. For these studies, we used the average d across occasions to derive aggregate estimates.

Results Preliminary Findings The meta-analysis is based on 107 independent studies from a total of 119 published manuscripts. A total of 8,521 individuals participated in these research projects. On average, 53% of participants were male, 47% were female, and their average age was 38.39 (SD ⫽ 16.23). They faced many forms of chronic stress: 38 of the studies focused on combat/war experience (35.5%), 27 involved abuse/assault (25.2%), 15 involved death or loss of a major relationship (14.0%), 10 involved caregiving experiences (9.3%), 8 involved natural disasters (7.5%), and 5 involved job loss and/or unemployment (4.7%). Table 1 provides a summary of how each kind of stress was rated along the various dimensions of our coding scheme. With respect to outcomes, the most common HPA indicator was morning cortisol (k ⫽ 65; 60.7% of studies), followed by daily output of cortisol (k ⫽ 33; 30.8%), then afternoon/evening cortisol measures (k ⫽ 31; 29.0%), postdexamethasone cortisol (k ⫽ 21; 19.6%), ACTH (k ⫽ 16; 15.0%), post-CRF cortisol (k ⫽ 7; 6.5%), post-CRF ACTH (k ⫽ 6; 5.7%), cortisol rhythm (k ⫽ 5; 4.7%),

Table 1 Ratings of Features for Commonly Assessed Stressors Characteristic

Studies of combat/war

Studies of abuse/assault

Studies of death/loss

Studies of caregiving

Studies of disaster

Studies of job loss

Months since onset (Mdn, range) Physical threat rated as likely (%) Social threat rated as likely (%) Trauma rated as likely (%) Rated as likely to be uncontrollable (%) Feelings of loss rated as likely (%) Feelings of shame rated as likely (%)

300.0 (1–720) 100.0 30.0 100.0 100.0 100.0 26.7

69.5 (1–400) 100.0 50.0 100.0 100.0 44.0 100.0

61.4 (1–360) 8.3 91.7 36.4 91.7 100.0 16.7

42.0 (6–144) 0.0 100.0 0.0 22.2 100.0 0.0

12.0 (1–78) 62.5 12.5 100.0 87.5 75.0 12.5

18.0 (8–24) 0.0 100.0 0.0 33.3 100.0 100.0


glucocorticoid receptor numbers on lymphocytes (k ⫽ 4; 3.7%), CRF (k ⫽ 3; 2.8%), and white blood cell function following glucocorticoid administration (k ⫽ 3; 2.8%). Several outcomes were included in only 1–2 studies, including post-ACTH cortisol, postdexamethasone ACTH, postdexamethasone glucocorticoid receptor numbers, and cortisol or ACTH challenge studies that administered other types of HPA-challenge molecules. On average, studies in the meta-analysis reported on two different HPA indicators (M ⫽ 2.0, SD ⫽ 1.3), though nearly half of them presented only a single outcome (60 of 119, or 50.4%).

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in hormonal response to CRH challenge or in the number of glucocorticoid receptors expressed by white blood cells. Inspection of the heterogeneity statistics (Q) in Table 2 revealed significant variability in the studies composing each aggregate d. This was true in all cases, except diurnal cortisol rhythm and CRH concentration. Thus, our next step was to explain the sources of this variability, using the stress–person hypotheses outlined earlier as a guide. The results of these analyses are presented below. Note that because only a handful of outcomes have been assessed regularly in this literature, we limit moderator analyses to categories in which five or more studies are available. This is the case for morning, afternoon/evening, and daily volume of cortisol; for ACTH measured at any time of day; and for the cortisol response to dexamethasone challenge. With all other outcomes, there were too few data points to make moderator analysis feasible. Table 3 summarizes the stressor and person features of studies that were included in each outcome category. As is evident from the data in this table, the kind of stress was generally similar across categories. War/combat and abuse/assault were the most frequently studied difficulties. Experiences with caregiving and bereavement were next most common, followed by natural disasters and job loss, which accounted for only a handful of studies in each category. On average, a good deal of time had elapsed since the onset of these stressors, though the range of durations was quite broad within each category. Stress was more likely to pose a physical versus social threat, was generally rated as being uncontrollable, and was more likely to elicit feelings of loss than shame.

General Findings: Chronic Stress and HPA Functions Table 2 presents aggregate effect sizes for each outcome. We have collapsed the findings across stressor and person features, to provide a general indication of how chronic stress modifies HPA axis functions. Note that to derive estimates of this nature, we had to restrict the analyses to studies that included stress and control conditions and to outcomes that were assessed in three or more separate studies. The results indicate that exposure to chronic stress is associated with significantly lower concentrations of morning cortisol (d ⫽ ⫺0.08), and more pronounced suppression of cortisol following dexamethasone challenge (d ⫽ ⫺0.23). It is also associated with greater concentrations of afternoon/evening cortisol (d ⫽ 0.18), a flatter diurnal rhythm (d ⫽ 0.39), and a higher daily volume of cortisol output (d ⫽ 0.31). Collectively, these findings suggest that chronic stress is accompanied by a dysregulated pattern of hormone secretion, with lower than normal morning output but higher than expected secretion across the rest of the day. This pattern gives rise to a flattened diurnal rhythm. In healthy persons not exposed to chronic stress, cortisol usually displays a robust diurnal rhythm, with values highest in the morning and lowest in the evening. Several additional outcomes were assessed in the literature. Although there was evidence that cerebrospinal fluid concentrations of CRH were significantly increased (d ⫽ 0.66), ACTH levels in participants facing chronic stress were similar to those in nonexposed controls. There also were no stress-related differences

Temporal Features of Stress To examine the relationship between months since onset and HPA outcomes, we estimated a series of fixed-effects metaregression equations. The results are summarized in Table 4 and illustrated in Figure 1. Analyses revealed a pattern of inverse associations for morning cortisol, daily volume, ACTH, and postdexamethasone cortisol. As time since the onset of stress increased, effect sizes for each of these outcomes decreased. These findings are consistent with the hypothesis that when a chronic

Table 2 Summary of Meta-Analytic Findings Across Studies and Outcomes

Outcome Cortisol Morning samples Afternoon/evening samples Daily output Diurnal rhythm Post-DST sample Post-CRH sample ACTH All samples Post-CRH sample CRH: All samples GC receptor expression

Standardized mean difference (d)

k

SEd

⫺.08 ⫹.18 ⫹.31 ⫹.39 ⫺.23 ⫺.07

54 30 27 4 17 4

.03 .04 .05 .11 .09 .18

⫺.14, ⫹.09, ⫹.20, ⫹.18, ⫺.40, ⫺.41,

⫺.08 ⫹.26 ⫹.66 ⫹.03

13 4 3 4

.09 .17 .25 .18

95% CI

p

Qw

p

⫺.03 ⫹.26 ⫹.41 ⫹.60 ⫺.07 ⫹.28

⬍.01 ⬍.01 ⬍.01 ⬍.01 ⬍.01 ⬍.71

258.13 61.25 265.72 4.99 27.09 13.27

⬍.01 ⬍.01 ⬍.01 ⬍.17 ⬍.04 ⬍.01

⫺.25, ⫹.10 ⫺.09, ⫹.60 ⫹.17, ⫹1.16 ⫺.32, ⫹.39

⬍.39 ⬍.15 ⬍.01 ⬍.86

18.77 19.83 3.04 38.92

⬍.10 ⬍.01 ⬍.22 ⬍.01

Note. Summaries are presented for outcomes assessed in three or more studies. Qw is the heterogeneity statistic. CI ⫽ confidence interval; DST ⫽ dexamethasone suppression test; CRH ⫽ corticotropin releasing hormone; GC ⫽ glucocorticoid.


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Table 3 Characteristics of Studies in Each Outcome Category

Stressor Types Combat/war (%) Abuse/assault (%) Death/loss (%) Caregiving (%) Natural disaster (%) Unemployment (%) Features Months since onset (Mdn, range) Physical threat rated as likely (%) Social threat rated as likely (%) Trauma rated as likely (%) Rated as likely be uncontrollable (%) Feelings of loss rated as likely (%) Feelings of shame rated as likely (%) Note.

Studies of morning cortisol

Studies of afternoon/evening cortisol

Studies of daily cortisol output

Studies of post-DST cortisol

Studies of ACTH

38.9 24.1 14.8 11.1 3.7 7.4

26.7 36.7 16.7 10.0 6.7 3.3

37.0 22.2 7.4 14.8 14.8 3.7

58.8 17.6 17.6 0.0 5.9 0.0

23.7 23.7 23.7 23.7 7.7 0.0

60 (1–720) 40.7 24.1 22.2 50.0 46.3 27.8

97 (1–720) 73.3 33.3 73.3 83.3 63.3 53.3

72 (1–720) 20.8 21.9 74.0 25.9 22.2 11.1

300 (1–360) 88.2 17.6 100.0 100.0 76.5 25.4

78 (1–300) 61.5 76.9 76.9 85.2 69.2 30.8

DST ⫽ dexamethasone suppression test; ACTH ⫽ adrenocorticotropin hormone.

stressor first arises, there is an initial activation of the HPA axis, which results in elevated levels of ACTH and cortisol. However, as time passes, this activity diminishes, and cortisol secretion rebounds to below normal. As another method of evaluating the impact of timing, we categorized stressor as present or absent at the time of HPA assessment. Within-category meta-analyses revealed that in studies in which the stressor was still present, morning cortisol (d ⫽ 0.12), afternoon/evening cortisol (d ⫽ 0.18), and daily output of cortisol (d ⫽ 0.54) were all significantly higher than controls. By contrast, in studies in which the initial stimulus was no longer present, morning cortisol (d ⫽ ⫺0.17) and postdexamethasone cortisol (d ⫽ ⫺0.24) were significantly lower, although afternoon/evening cortisol was higher (d ⫽ 0.21). Similar to the analyses of months since onset, these findings suggest the possibility that chronic stress initially boosts cortisol output but that, as time passes and the initial stimulus is removed, secretion rebounds to below normal concentrations.

Nature of Stress Table 5 describes the results of analyses focusing on the nature of the stress. In studies in which the stress was likely to involve a threat to the physical self, morning (d ⫽ ⫺0.16) and postdexam-

ethasone cortisol (d ⫽ ⫺0.31) were reliably lower, and afternoon/ evening (d ⫽ 0.22) and daily output of cortisol (d ⫽ 0.46) were reliably higher. Overall, these data suggest the possibility of a flattened diurnal rhythm in which morning output is somewhat reduced, but there is less decline across the rest of the day than would be expected. This pattern results in a significantly elevated daily volume of secretion. In studies in which physical threat was rated as unlikely, there was little in the way of reliable findings, except that morning cortisol was higher (d ⫽ 0.11). In studies in which the stress was likely to threaten the social self, morning (d ⫽ 0.27) and afternoon/evening (d ⫽ 0.26) cortisol output was higher than in nonexposed controls. These findings suggest that social threats may activate the HPA axis during the day hours. In contrast, in studies in which social threats were unlikely, both morning (d ⫽ ⫺0.17) and postdexamethasone cortisol (d ⫽ ⫺0.30) were significantly lower, and afternoon/evening cortisol (d ⫽ 0.15) and daily volume (d ⫽ 0.42) were higher. These latter findings are difficult to interpret because “unlikely social threat” is a nonspecific category that tells us little about the circumstances of the stress. The studies focusing on traumatic stressors yielded a pattern that was identical to those focusing on physical threats. They showed reliably lower morning (d ⫽ ⫺0.16), and postdexamethasone

Table 4 Meta-Regression of Hypothalamic-Pituitary-Adrenocortical Outcomes On Time From Stressor Onset Outcome

Slope coefficient

k

SE

Cortisol Morning samples Afternoon/evening samples Daily output Post-DST sample ACTH—all samples

⫺.13 ⫺.02 ⫺.80 ⫺.29 ⫺.29

52 25 27 17 13

.04 .06 .08 .10 .11

Note.

CI ⫽ confidence interval; DST ⫽ dexamethasone suppression test.

95% CI ⫺.21, ⫺.13, ⫺.95, ⫺.49, ⫺.50,

⫺.05 ⫹.10 ⫺.65 ⫺.09 ⫺.08

p ⬍.01 ⬍.76 ⬍.03 ⬍.01 ⬍.01


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Figure 1. Regression of effect sizes for daily volume on time since stressor onset. Each circle in the plot represents an individual study, and its size is directly proportional to its weight in the analysis.

morning (d ⫽ ⫺0.09) and post-DST (dexamethasone suppression test) cortisol (d ⫽ ⫺0.32) were reliably lower than in nonexposed controls, whereas afternoon/evening cortisol was reliably higher (d ⫽ 0.20). This pattern suggests that loss is associated with a flatter cortisol profile across the day. In contrast, for situations in which loss was unlikely, afternoon/evening cortisol (d ⫽ 0.17) and daily output (d ⫽ 1.11) were higher. When chronic stress was likely to involve shame, afternoon/ evening levels of cortisol (d ⫽ 0.16) were significantly higher than in controls. This suggests that forms of stress likely to elicit shame activate the HPA axis, similar to what was found for threats to the social self. By contrast, stress rated as unlikely to elicit shame was associated with a pattern of lower morning (d ⫽ ⫺0.17) and

cortisol (d ⫽ ⫺0.24), and significantly higher afternoon/evening (d ⫽ 0.22) and total daily cortisol (d ⫽ 0.51). Again, this pattern suggests a flat diurnal rhythm in which morning output is reduced, but there is less decline in the afternoon/evening than would be expected, leading to higher daily output. In studies in which trauma was unlikely following a stressor, the only reliable finding to emerge was higher morning cortisol (d ⫽ 0.16).

Emotions Elicited by Stress We next examined whether the emotion(s) likely to be elicited by each form of chronic stress was associated with HPA outcomes. Table 5 shows that when chronic stress involved a likely loss, both

Table 5 Effect Sizes (d) for Hypothalamic-Pituitary-Adrenocortical Outcomes According to Stress Features Cortisol Morning samples

Post-DST samples

Afternoon/evening samples

ACTH: All samples

Daily output

Nature of threat

d

SE

d

SE

d

SE

d

SE

d

SE

Physical threat Social threat Traumatic stressor Uncontrollable Potentially controllable Loss Shame

⫺0.16** ⫹0.27** ⫺0.16** ⫺0.15** ⫹0.21** ⫺0.09** ⫹0.07

0.04 0.05 0.04 0.03 0.07 0.03 0.05

⫺0.31** ⫹0.01 ⫺0.24** ⫺0.24** — ⫺0.32** ⫺0.01

0.09 0.09 0.09 0.09

⫹0.22** ⫹0.26** ⫹0.22** ⫹0.24** ⫺0.03 ⫹0.20** ⫹0.16**

0.05 0.08 0.05 0.05 0.10 0.06 0.06

⫹0.46** ⫺0.04 ⫹0.51** ⫹0.43** ⫺0.04 ⫺0.06 0.07

0.07 0.11 0.07 0.06 0.11 0.07 0.09

⫺0.10 0.17 ⫺0.03 ⫺0.03 ⫺0.14 ⫺0.17 0.22

0.13 0.23 0.11 0.11 0.14 0.10 0.18

0.10 0.16

Note. Values are standardized mean differences (d) with standard errors. Effect sizes are indicated for stress in which physical threat, social threat, trauma, loss, and shame were rated as likely. For controllability, effect sizes are indicated for stress that was uncontrollable and potentially controllable. Dashes indicate there were too few studies to estimate an effect size. DST ⫽ dexamethasone suppression test; ACTH ⫽ adrenocorticotropin hormone. ** p ⬍ .01.


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post-DST cortisol (d ⫽ ⫺0.32) and higher afternoon/evening (d ⫽ 0.20) and daily cortisol output (d ⫽ 0.44). This is the “high–flat” profile seen with other stress dimensions. However, because unlikely shame is a nonspecific category, these data are difficult to interpret.

Controllability of Stress Table 5 also presents the results of analyses for controllability. In studies in which the stress was rated as uncontrollable, there was evidence of reliably lower morning (d ⫽ ⫺0.15) and post-DST cortisol (d ⫽ ⫺0.24), and reliably greater afternoon/evening cortisol (d ⫽ 0.24) and daily output (d ⫽ 0.43), all relative to nonexposed controls. Again, these data suggest a flattened rhythm in which morning output is reduced, but the typical decline across the day was less than expected, resulting in high overall volume. By contrast, in studies in which the stress was potentially controllable, morning cortisol was reliably higher (d ⫽ 0.21). These findings suggest that when a person has a chance to control the outcome of chronic stress, his or her HPA axis is activated in the morning hours.

Individual Psychiatric Sequelae Table 6 presents the results of meta-analyses on psychiatric features of the victim. The studies composing these analyses generally compared individuals who had or had not developed a psychiatric condition following exposure to chronic stress. Among the studies that focused on major depressive disorder, there was evidence of significantly higher postdexamethasone cortisol (d ⫽ 1.13). These findings suggest that in the context of chronic stress, clinical depression interferes with the negative-feedback circuit of the HPA axis, allowing cortisol to partially escape from dexamethasone suppression. The analyses also indicated that among people who developed PTSD after stress exposure, postdexamethasone cortisol (d ⫽ ⫺0.25) and total daily output (d ⫽ ⫺0.34) were reliably lower, and afternoon/evening cortisol was reliably higher (d ⫽ 0.47). These findings indicate that compared with healthy adults who have been exposed to identical chronic stress, patients with PTSD are generally hypocortisolemic and have enhanced sensitivity to molecules that engage the HPA axis negative-feedback circuitry.

Some studies also investigated the role of distress in predicting HPA outcomes in persons facing chronic stress. These studies measured subjective distress as an individual difference variable, and typically correlated distress with HPA outcomes in a sample in which everyone was facing the same ongoing difficulty. In these samples more subjective distress was associated with lower morning (d ⫽ ⫺0.08), higher afternoon/evening (d ⫽ 0.45), and greater daily output of cortisol (d ⫽ 0.58). This pattern suggests that subjective distress is associated with a dysregulated (flat, high) pattern of cortisol secretion.

Where Is the Action? The meta-analyses yielded robust support for several of our hypotheses: (a) Time elapsed since onset was inversely related to most outcomes; (b) forms of stress that posed a physical threat, were traumatic in nature, and were uncontrollable elicited a specific hormonal profile; and (c) there was a consistent pattern of HPA output among those who developed PTSD after trauma. In an effort to untangle these findings, and discern the critical determinants of HPA response, we ran a final wave of meta-analyses. They were guided by three specific questions, each meant to isolate the influence of a single factor. As a result of the small pool of studies in this literature, these analyses were limited to the most frequently assessed outcomes: morning cortisol and daily output. Question 1: To what extent does PTSD status explain the other findings? Research in this area has been dominated by a focus on PTSD, and patients with this disorder were often subjected to physically threatening and uncontrollable stress, which by diagnostic necessity was traumatic in nature. So it could be that psychiatric diagnosis, rather than stress features, is the critical determinant of HPA response. Thus, we stratified articles on the basis of whether patients did versus did not suffer from PTSD, and then we computed another series of meta-analyses testing the major hypotheses. The results of these analyses convincingly demonstrated that PTSD does not account for the influences of timing, stress nature, and controllability. In the subset of studies in which no patients suffered from PTSD, months since onset remained negatively associated with morning cortisol (slope ⫽ ⫺0.11, SE ⫽ 0.05, p ⬍ .02) and with daily output (slope ⫽ ⫺0.65, SE ⫽ 0.08, p ⬍ .001). The earlier findings with physically threatening stress

Table 6 Effect Sizes (d) for Hypothalamic-Pituitary-Adrenocortical (HPA) Outcomes According to Psychiatric Status Cortisol Morning samples

Afternoon/evening samples

Daily output

Post-DST samples

ACTH: All samples

Status

d

SE

d

SE

d

SE

d

SE

d

SE

PTSD MDD Subjective distress

⫺0.03 — ⫺0.08*

0.09

⫹0.47* ⫹0.30 ⫹0.45**

0.24 0.20 0.12

⫺0.34** — ⫹0.58**

0.14

⫺0.25* 1.13** —

0.13 0.38 —

0.00 —

0.10

0.04

0.13

Note. Values are standardized mean differences (d) with standard errors. Effect sizes indicate disparity in HPA outcome attributable to psychiatric status over and above stress exposure. Dashes indicate there were too few studies to estimate an effect size. DST ⫽ dexamethasone suppression test; ACTH ⫽ adrenocorticotropin hormone. * p ⬍ .05. ** p ⬍ .01.


also were preserved: In non-PTSD samples, this kind of stress was associated with lower morning cortisol (d ⫽ ⫺0.17, SE ⫽ 0.04, p ⬍ .001) and with higher daily output (d ⫽ 0.61, SE ⫽ 0.07, p ⬍ .001). The same was true of the findings for uncontrollability. As was the case for the larger body of studies, in non-PTSD samples, uncontrollable stress was accompanied by lower morning cortisol (d ⫽ ⫺0.15, SE ⫽ 0.03, p ⬍ .001) and higher daily output (d ⫽ 0.68, SE ⫽ 0.08, p ⬍ .001). Together, these results suggest that the meta-analytic findings are not simply reducible to the influence of PTSD on HPA response.1 Question 2: Can the relative influences of physical threat, trauma exposure, and stressor controllability be separated? Throughout the meta-analysis, these three factors yielded similar patterns. They were all associated with lower morning cortisol, blunted responses to dexamethasone, higher afternoon/evening cortisol, and greater daily output. Despite attempts to separate the influence of these factors, they are highly confounded in the existing literature. Stressors that were rated as physically threatening were almost always rated as traumatic and uncontrollable and vice versa. This left too few instances of divergence for any meaningful separation to be achieved. Thus, the pool of studies at present does not allow us to determine whether it is physical threat, trauma, controllability, or some combination of these factors that gives rise to a distinct HPA profile. Question 3: Is the impact of timing distinct from that of stressor controllability? Readers may wonder whether more distant kinds of stress, such as combat experience and sexual assault, tended to be rated as more uncontrollable. If the answer to this question was yes, isolating the relative influence of these factors would be important. However, in our coding scheme, controllability was rated at the time the stressor was present in the victim’s life, not at the time the cortisol assessment was performed. This prevented timing and controllability from becoming confounded. This fact is borne out to some extent by the meta-analytic findings. For example, more distant stress was associated with lower daily cortisol output, whereas the opposite was true of uncontrollable stress. Nevertheless, to empirically assess whether the contributions of these variables were independent, we estimated associations between time since onset and HPA outcomes within the types of stress that were rated as uncontrollable. These analyses indicated that months since stressor onset continued to be negatively associated with morning cortisol (slope ⫽ ⫺0.08, SE ⫽ 0.04, p ⬍ .07) and with daily output (slope ⫽ ⫺0.71, SE ⫽ 0.07, p ⬍ .001) even when all the stress was uncontrollable. Thus, timing and controllability appear to shape HPA outcomes independently.

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Summary and Integration Time since onset. One of the most robust findings of the meta-analysis was that time since onset was negatively associated with HPA activity. That is, the more months that had elapsed since the stress first emerged, the lower a person’s morning cortisol, daily volume, ACTH, and postdexamethasone cortisol. Similarly, when chronic stressors were still present in a person’s environment (e.g., unemployment), morning, afternoon/evening, and daily cortisol output were significantly higher. By contrast, in cases in which the stressful stimulus was no longer present (e.g., combat situations), morning cortisol and postdexamethasone cortisol were significantly lower. These findings are consistent with the hypothesis that when chronic stress first begins, there is an initial activation of the HPA axis, which results in elevated concentrations of ACTH and cortisol. However, the findings suggest that as time passes, this activity diminishes, and cortisol secretion rebounds to below normal. A time-dependent pattern of this nature is consistent with theories advanced by several researchers (Fries et al., 2005; Miller et al., 2002; Hellhammer & Wade, 1993). Besides revealing the influence of timing on the HPA response, these findings clarify a major source of confusion in the literature. Across the last 5 decades, researchers have alternated between depictions of “hypercortisolism” and “hypocortisolism.” The meta-analysis indicates that rather than being contradictory, these depictions are probably all accurate, but simply reflect different timepoints during the stress process. Studies focusing on recent and ongoing stress have generally documented increases in HPA output (Arnetz et al., 1987; Baum et al., 1983; Kosten et al., 1984; Schaeffer & Baum, 1984), whereas those focusing on distant traumas have often found the opposite (Yehuda, Teicher, et al., 1996; Yehuda, Boisonuae, et al., 1995; Yehuda et al., 1998, Yehuda, Kahana, et al., 1995). Of course, this has not been true uniformly (Seedat et al., 2003; Miller et al., 2002; Vedhara et al., 2002), and these exceptions suggest timing is not the only critical factor. However, the general pattern of the meta-analytic findings suggests that it is, in the aggregate, a partial determinant of how the HPA axis responds to chronic stress. That said, our analysis of timing suffers from an important limitation. Because of the dearth of longitudinal research in this area, it relied heavily on studies with cross-sectional designs. Thus, although the question we sought to answer was whether the pattern of HPA activity changes as time since onset elapses, the available research forced us to modify it to “Do studies with shorter intervals since stress onset show different patterns of HPA activity than studies with longer intervals?” The difficulty with this sort of

Discussion We began this article by posing what has long been viewed as a simple question: How is activity of the HPA axis modified by exposure to chronic stress? Despite many claims that a simple answer to this question exists, the meta-analytic findings suggest that the situation is far more complex. Chronic stress has the capacity to increase or decrease HPA activity, and the pattern one sees depends on features of the stress and the person facing it. In the sections that follow, we discuss each of the stressor and person features tested in the meta-analysis, focusing on what the available evidence documents, what still needs to be discovered, and how researchers can best go about doing that.

1

Readers may wonder whether PTSD accounts for the distinct HPA profile associated with stressors coded as traumatic. Unfortunately, we are unable to answer this question with the available literature, as nearly all the studies of trauma involved patients with PTSD. Thus, there was not a sufficient quantity of trauma studies with non-PTSD subjects to compute effect sizes and disentangle the influence of these factors. Note also that the disparate findings for trauma coding in the Nature of Stress section and the PTSD coding in the Individual Psychiatric Sequelae section are likely due to the differences in methodology: The trauma analyses compared individuals who experienced a likely trauma with nonexposed controls, whereas the PTSD analyses compared individuals who did versus did not develop PTSD after being exposed to stress.

36


analysis is that time and study are confounded; it is therefore possible that some other study feature is the actual determinant of HPA response. We view this as an unlikely possibility, but it cannot be ruled out definitively.2 Thus, an important direction for future research will be to substantiate the meta-analytic findings using prospective longitudinal designs. So far, only a handful of research projects have enrolled subjects shortly after stress onset and followed them over time to determine whether activity of the HPA axis shifts (Anisman, Griffiths, Matheson, Ravindran, & Merali, 2001; Gerra et al., 2003; Spratt & Denney, 1991; Theorell et al., 1992). We recognize that this represents a logistically difficult undertaking, because most chronic stress arises unexpectedly, it takes time to locate and assess victims, and it can be difficult to keep such participants enrolled for a long time. However, research of this nature is absolutely necessary if we are to stringently evaluate the impact of timing and develop realistic accounts of its influence. This work will need to answer questions such as the following: At what point in time does HPA activity begin to decline from its peak? When does it drop below a person’s baseline? At what point does it reach asymptote and stop declining? In short, the next wave of studies will need to discern the shape of the time function, and they can best do so using prospective longitudinal designs with repeated assessments. Nature of stress. The meta-analysis also examined whether HPA activity varies according to the nature of the threat posed by the chronic stress. We found that stress that threatens physical integrity, like combat, elicits a diurnal profile of cortisol secretion that is high and flat. Although morning output is slightly lower, secretion in the afternoon/evening and evening is higher, leading to greater total daily hormone output. An identical pattern was found for stress that was traumatic in nature. These findings make sense when viewed from a functional perspective. In the midst of stress that poses a threat to survival, there would be adaptive value in maintaining persistently elevated HPA activity. This system’s hormonal products facilitate cognitive, metabolic, immunologic, and behavioral adaptations that maximize the chances of survival (Sapolsky et al., 2000; Weiner, 1992). When such a threat is not looming, the organism can afford a diurnal rhythm, in which hormonal availability declines across the day. The meta-analysis also indicated that stress posing a threat to the social self, like divorce, was associated with significantly higher cortisol at specific times in the day, including the morning and afternoon/evening. Why might this be the case? One potential explanation is that activation helps individuals mobilize resources to preserve their social standing when it is threatened. Researchers have argued that the need to be part of a social group is a fundamental human motivation and that people are driven to behave in ways that further their belongingness and group affiliation (Baumeister & Leary, 1995). A recent meta-analysis found support for this hypothesis by showing that cortisol secretion is boosted acutely when people are confronted with social evaluative threats, that is, situations that have the potential to diminish one’s standing in the eyes of others (Dickerson & Kemeny, 2004). These findings have been recently extended into a real-world context: Adults participating in competitive ballroom dancing, which involves a high degree of social evaluation, show marked increases in cortisol output that are not due to the physical components of dancing (Beulen, Chen, Rohleder, Wolf, & Kirschbaum, in press). These increases are much greater than those observed when the

dancers are practicing without an audience. Collectively, these findings suggest that social stressors, whether they are acute or chronic, reliably activate the HPA axis. One question that remains looming in this area of research, however, is why the observed elevations are not sufficient to yield higher daily cortisol volumes. Perhaps the hormonal consequences of social threats are limited to daytime hours, when people are actively coping with them or ruminating about them. If this was the case, and cortisol excretion was normal during sleep, it could explain the lack of daily volume findings. There are several limitations to the evidence provided by the meta-analysis in this area. Most important is our inability to determine the relative influences of physical threat, trauma exposure, and stress controllability. These factors overlap almost completely in the existing research, and this is also likely to be true in real-world contexts. Nevertheless, research that could isolate the influence of these dimensions would be extremely valuable. Second, although our approach of rating stress according to physical versus social threat proved to be useful, one should bear in mind that most studies in the meta-analysis focused on one or the other. Follow-up research is needed that compares HPA responses utilizing the same measures, taken at the same time points, for both physical and social stress within the same study. This would allow direct comparison of the HPA profiles for each type of stress. Moreover, assessment of the presumptive mediators of these phenomena would advance this research considerably. In the case of stress that poses a physical threat and is traumatic in nature, the potential mediators of hormone release might include fearful emotions. For stress that is more social in nature, reduced social standing would seem to be critical, as would the self-conscious emotions it elicits. To the extent that the influence of these mediators can be documented, and the concerns identified above can be addressed, the validity of stressor-specificity hypotheses will be enhanced considerably. Controllability of stress. Many researchers have proposed that one primary dimension of what makes a situation stressful is its controllability (Heim, Ehlert, & Hellhammer, 2000; Dickerson & Kemeny, 2004; Mason et al., 2001; Sapolsky, 1998; Weiner, 1992). We tested this hypothesis by categorizing each kind of chronic stress as either uncontrollable or potentially controllable. Uncontrollable stress elicited a flat, high diurnal pattern of cortisol secretion. This was manifested by a lower morning output and higher afternoon/evening secretion, which was sufficient to produce a significant elevation in total daily volume. These findings are generally consistent with the research on acute stress, which indicates that situational controllability is inversely related to cortisol output (Dickerson & Kemeny, 2004). However, they run counter to a number of recent theories seeking to explain hypocortisolism. These models suggest that when people encounter chronic stress that is uncontrollable, HPA activity declines mark2 In an effort to detect evidence of confounding, we examined whether the timing variable related to other methodological characteristics. There were no systematic relationships between timing and mean age of participants, percent who were female, nature of chronic stress, and type or quality of cortisol assessment. While these findings do not eliminate the possibility of confounding, they rule out some of the more plausible scenarios of it.


edly, and a constellation of withdrawal and disengagement behaviors emerge (Gold & Chrousos, 2002; Heim, Ehlert, & Hellhammer, 2000; Mason et al., 2001). There also has been speculation that diminished HPA activity emerges because people have toughened themselves in preparation for later stress (Dienstbier, 1989; Gunnar & Vazquez, 2001a). Despite the intuitive appeal of these theories, the meta-analytic findings do not support their basic prediction. One potential explanation is that most of these theories were formulated to explain blunted HPA activity in patients suffering from psychiatric disorders like atypical depression and PTSD (Gold & Chrousos, 2002; Heim, Ehlert, & Hellhammer, 2000; Mason et al., 2001). The theories may apply specifically to populations with psychiatric disorders, and our meta-analytic findings indicate that these processes may work differently in normal individuals facing chronic stress. Alternatively, these theories may have been derived from studies that relied largely on morning cortisol assessments. As seen in our meta-analysis, morning cortisol was lower for uncontrollable stress; however, across the whole day, cortisol was higher during uncontrollable stress. Turning to chronic stress that was rated as potentially controllable, the meta-analysis yielded evidence of significantly higher morning cortisol. This stands in contrast to the lower morning cortisol observed in conjunction with uncontrollable stress. How might these findings be explained? When a person is facing a challenge that is potentially controllable, he or she may engage in active coping behaviors, with the hope that they will eradicate the stressor or attenuate its impact. Higher levels of morning cortisol may help to mobilize biological systems for coping activities that will occur the rest of the day. Although this explanation is intuitively appealing, caution needs to be exercised in this area, as the findings were restricted to a single index of hormone secretion. It remains unclear whether controllable stress has effects on cortisol only at specific times of the day, or whether findings for controllable stress are less reliable than for other HPA outcomes. Clearly, further research is needed to sort this out and evaluate this coping mobilization hypothesis. Two limits of these analyses should be noted. The first is that the relative influences of uncontrollability, traumatic experience, and physical threat cannot be separated in this literature. The second is that our coding system is likely to have some built-in “noise” because it does not consider individual circumstances. Judgments of controllability are likely to vary a great deal across people, even when they are coping with ostensibly similar difficulties. For example, unemployment is a more controllable situation for a person with a marketable set of skills holding out for the right job than it is for someone laid off from an unskilled factory position in a tight labor market. Because our coding system could not contextualize individual ratings in this way, we almost certainly underestimated relations between control and hormonal outcomes. Future research can circumvent this difficulty and more precisely evaluate the impact of control by collecting subjective assessments of this construct from participants. Emotions elicited by stress. The meta-analysis also examined whether feelings of shame or loss were associated with specific patterns of HPA activity. Situations likely to elicit shame (e.g., sexual abuse) were associated with significantly higher afternoon/ evening cortisol, whereas those evoking loss (e.g., death of spouse) were accompanied by a flattened diurnal profile. This consisted of lower morning cortisol and higher afternoon/evening cortisol.

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What might these findings indicate? For situations that elicit feelings of shame, high afternoon/evening cortisol may be a result of troubling social interactions across the day, in which one’s standing within the social hierarchy has been diminished (Dickerson & Kemeny, 2004). It also could reflect rumination about such interactions. These possibilities would explain why no reliable shame findings emerge for morning cortisol; within the first hours of the day, people have not yet had time for rumination or troubling interactions. Nevertheless, the absence of other reliable hormonal alterations for shame makes us reluctant to speculate further or offer definitive conclusions. For stress that evokes feelings of loss, a flattened cortisol profile may reflect social isolation or a withdrawal from regular social activities. Social contact with others programs many of the body’s circadian rhythms, including those regulating the secretion of hormones like cortisol (Stetler, Dickerson, & Miller, 2004; Stetler & Miller, 2005). Thus if major losses significantly alter an individual’s social activities, this could result in a dysregulated cortisol rhythm that remains flat across the day, rather than a diurnal profile that is regulated by social contact. A major difficulty with the emotion findings is that they were not robust across outcomes. Shame was associated with only a single parameter, whereas the effects of loss were somewhat stronger, extending to three different outcomes. These findings could reflect what happens in real-world contexts; perhaps emotions are not a central determinant of the HPA response. However, we are more inclined to believe that the relatively weaker findings in this area stem from limitations of our coding system. In the same way that controllability ratings were decontextualized, our emotion ratings were made for situations more generally and could not account for individual differences in affective response. Thus, research would benefit greatly if future studies assessed the degree to which participants experience shame, loss, and other emotions during the course of chronic stress. Researchers could then test whether the intensity and/or frequency of negative emotional experiences is associated with HPA patterns. Future studies should also compare different negative emotional experiences within one study to determine whether emotions such as shame, loss, and sadness have unique HPA signatures. Individual psychiatric sequelae. There was consistent evidence that the psychiatric sequelae of chronic stress are reliable determinants of HPA activity. Individuals who developed a major depressive episode in the midst of chronic stress showed markedly higher cortisol after the dexamethasone-suppression test. This effect was quite large: They showed postdexamethasone cortisol levels more than one standard deviation greater than healthy adults who were also in the midst of chronic stress. This finding is consistent with the larger corpus of evidence on affective disorders, which shows that depression is associated with dexamethasone non-suppression, particularly in patients suffering from severe, melancholic subtypes of this disorder (Haskett, 1993). Despite the robust pattern of findings with dexamethasone, no other hormonal outcomes were studied in conjunction with depression. This will be an important undertaking for future research endeavors. Individuals who developed PTSD in the aftermath of chronic stress showed a reliable pattern of hormonal alterations. Compared with healthy adults who had been exposed to the same form of chronic stress, they showed lower daily output of cortisol, enhanced suppression of cortisol following dexamethasone adminis-

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tration, and higher levels of cortisol in the afternoon/evening. These findings parallel the existing literature on PTSD, which documents hypocortisolism and enhanced sensitivity of the HPA negative feedback circuit (Yehuda, 2000; Yehuda, Resnick, et al., 1993). Finally, the meta-analysis provided evidence that subjective distress is related to the magnitude of HPA alterations. To the extent that people reported higher levels of distress, they showed greater total daily output and afternoon/evening cortisol, though morning levels were somewhat lower. These findings suggest that even when a person does not develop a full-blown psychiatric condition, the extent of distress is positively associated with HPA activation. This is consistent with theories positing that distress is an important pathway linking stress and endocrine response (S. Cohen et al., 1995; Baum et al., 1993). The major limitation of work in this area is that it has been largely cross-sectional in nature. This design feature makes it impossible to determine whether hormonal alterations are caused by an individual’s psychiatric response or simply reflect trait features of the person that were present before the symptoms (or perhaps even the chronic stress) emerged. Indeed, research by Yehuda and colleagues has shown that reduced output of cortisol is evident in young adults at risk for PTSD, none of whom have exhibited symptoms of the disorder or have been directly exposed to trauma (Yehuda et al., 2000). These findings have generated speculation that blunted hormonal responses to stress may facilitate the development of PTSD (Yehuda, 2000; Yehuda, Resnick, et al., 1993). To the extent that further research shows these hypotheses to be accurate, it will demonstrate that relations between psychiatric response and HPA activity can play out in multiple directions. Regardless of how the work on PTSD evolves, future research in this area needs to be prospective and follow people over the course of a few years starting shortly after stress onset. Work of this sort will help untangle the complex relations between chronic stress, psychiatric response, and HPA activity. Other potential moderators. Although the meta-analysis identified several important features of stressors and persons, it was unable to consider a number of other potential moderators, which almost certainly influence the magnitude and direction of the HPA response. Development is one such factor. Exposure to chronic stress in the early years of life, when the nervous system is still developing, may result in a distinct and stable pattern of dysregulation. The importance of considering development has been highlighted in studies of rodents, in which early-life experiences have been shown to program HPA axis functions at the genomic level, such that they remain altered all the way into adulthood (Liu et al., 1997; Meaney & Szyf, 2005). At the other end of the developmental spectrum are older adults, who often face chronic stressors like caregiving, while at same time experiencing age-related changes in endocrine functions. There are good reasons to believe these factors will modify their HPA response to chronic stress (Kiecolt-Glaser & Glaser, 2001; Penedo & Dahn, 2005). Unfortunately, too few of the studies in the meta-analysis provided sufficient information for us to consider development as a moderator. Nevertheless, this line of inquiry should be a high priority for the next wave of research in this area. Genetics represents another potentially important moderator. Polymorphisms that could influence the HPA response to chronic stress are regularly being identified; some promising candidates include functional variants

present in the glucocorticoid receptor, the mineralocorticoid receptor, and the serotonin transporter (Barr et al., 2004; DeRijk & de Kloet, 2005). Though work of this nature is still in its infancy, it is likely to be a fruitful avenue for research in the years to come. Finally, the impact of chronic stress on hormonal dynamics is likely to be moderated by the victim’s previous exposure to stressful circumstances (Yehuda, 2004), ability to call forth effective coping strategies and social support (e.g., Miller, Cohen, & Ritchey, 2002), and need to manage other stressors that compete for his/her attention and resources. For example, a recent study found that chronic stress was associated with reduced expression of the glucocorticoid receptor, and this relationship was accentuated when an acute life event was superimposed upon the background difficulties (Miller & Chen, 2006).

Theoretical Implications These findings have several important theoretical implications. The first is that models positing an orderly and uniform HPA response to chronic stress are no longer appropriate. A new wave of theories needs to be developed to incorporate the moderating influences of timing, nature of stress, controllability, and individual psychiatric response. Such theories must provide answers to questions such as: What types of chronic stress and individual responses are required for the HPA axis to become persistently activated? How are these conditions different from those that dampen HPA activity? Although the meta-analysis does not provide sufficient information for this to be done immediately, it has identified a series of variables that are likely to figure prominently in any new theories. With further empirical research of the nature specified earlier, it should be possible to construct more elaborate and refined theories, which clearly specify the conditions when HPA activity goes up versus down. The many theories linking stress, cortisol, and disease outcomes also will need to be refined. Most of them posit that stress nonspecifically activates the HPA axis, and by doing so, contributes to the development and progression of medical illnesses. Our results suggest that the chain of events is unlikely to unfold in such a simple fashion. Newer models will need to acknowledge that chronic stress can elicit a variety of HPA responses and that their impact on disease outcome will depend on the condition being considered. When a person is early in the course of chronic stress, for example, he or she may become vulnerable to conditions in which high cortisol is pathogenic. This seems to be true in psychiatric disorders such as depression and schizophrenia (Nemeroff, 1996; E. F. Walker & Diforio, 1997) and medical illnesses like heart disease and the metabolic syndrome (Bjorntorp & Rosmond, 1999; G. D. Smith et al., 2005). However, as time passes and cortisol output declines to below normal, these effects on disease progression would likely subside (and perhaps reverse). The person may even become vulnerable to conditions in which deficient cortisol signaling contributes to adverse outcomes, such as rheumatoid arthritis, fibromyalgia, and allergic conditions (Heim, Ehlert, & Hellhammer, 2000; Raison & Miller, 2003). These are just simplified theoretical conjectures, of course, and the clinical picture is likely to be more complex. Nevertheless, they illustrate an important theoretical lesson—that future theories will need to match kinds of chronic stress, their likely HPA concomitants, and


disease processes to arrive at biologically plausible hypotheses regarding the linkages among these constructs. The findings also highlight the importance of developing more elaborate psychological hypotheses in this area of inquiry. Some intriguing relationships were documented between psychosocial characteristics and HPA activity; however, the cognitive, emotional, and behavioral mechanisms underlying them have yet to be identified. Future research needs to answer questions such as the following: Do potentially controllable forms of chronic stress elevate morning cortisol because of the coping efforts they mobilize? Do shame-eliciting forms of chronic stress increase afternoon/evening cortisol because of troubling social interactions or rumination about the stressor? Do loss-related forms of chronic stress dysregulate cortisol rhythms because of changes in social circadian rhythms that result from the loss? Once this has been done, more elaborate mechanistic models linking chronic stress and HPA function can be developed. The same issues pertain to biological mechanisms that are more proximal to the HPA axis. Little theory exists to specify what goes awry in the system when it faces chronic stress. Is the high, flat pattern of cortisol secretion across the day a result of dysregulation in the suprachiasmatic nucleus, the endogenous circadian pacemaker that regulates HPA rhythms? Or does chronic stress leave the suprachiasmatic nucleus’s functions intact, and instead modify downstream structures like the pituitary and/or adrenal glands? The fact that cortisol was reliably altered by exposure to chronic stress, and ACTH was not, suggests the possibility that much of the dysregulation lies at the level of the adrenals. Perhaps chronic stress modifies the sensitivity of the adrenal glands, such that cortisol is secreted at volumes disproportionate to ACTH signaling. By making use of ACTH and CRH challenge paradigms, which respectively evaluate functioning of the adrenals and the pituitary, future research can test these mechanistic hypotheses and accelerate the development of theory in this area.

Methodological Recommendations To ensure that further progress is made in this area of inquiry, the next wave of studies will need to institute a series of methodological innovations. As the summary statistics from the metaanalysis make clear, the field has relied heavily on morning cortisol as an outcome. In 25% of the studies we reviewed, it was the only HPA outcome to be assessed, and in all but a handful of studies, this was done on a single occasion. There are obvious methodological and conceptual limitations to this strategy. Single measures of a construct are notoriously unreliable, and all evidence suggests this is the case for cortisol as well (Stewart & Seeman, 2000). If future studies wish to maximize their chances of detecting stress-related disparities, they would be wise to increase the frequency of sample collection, so that multiple assessments are made each day for a period of several days. Apart from boosting statistical power to detect findings, this strategy provides a more comprehensive portrait of HPA activity. It is difficult to make accurate inferences about HPA activity being low or high from a single measure, because as our findings illustrate, the effects of chronic stress can differ in magnitude and direction over the course of the day. Guidelines for designing a sampling strategy that captures the entire diurnal rhythm of cortisol can be found online (see Stewart & Seeman, 2000).

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Progress in this area also will depend on researchers’ capacity to expand the repertoire of outcome variables. Half of the studies we reviewed presented findings for only a single indicator of HPA axis function. Fewer than 15% of the studies assessed ACTH. An even smaller number assessed CRH, but this is understandable, given that a medically invasive procedure (lumbar puncture) is required. Challenge paradigms also were used infrequently, and when they were, they typically involved dexamethasone suppression. By more routinely assessing output of ACTH and CRH, and performing challenge paradigms with these molecules, future research will gain detailed mechanistic insights into how stressors modify the function of structures comprising the axis. Given that much work in this area is concerned with hormonal influences on disease, there also would be much gained by assessing cortisol’s impact on target tissues. Some work of this nature has already begun. A recent study found that among people facing a severe chronic stressor, the immune system’s sensitivity to glucocorticoids was diminished (Miller et al., 2002). This was manifested by a reduction in dexamethasone’s capacity to suppress the production of inflammatory molecules in vitro. These findings suggest that chronic stress interferes with cortisol’s ability to perform an important regulatory function in the immune system. To the extent that such a deficit persists, it could enable inflammation to flourish, leading to a variety of adverse medical outcomes. More work of this nature would be valuable for the field, as it sheds light on the tissue-level consequences of differential cortisol secretion. In addition to assessing how immune system functions are influenced by glucocorticoids (DeRijk, Petrides, Deuster, Gold, & Sternberg, 1996; Rohleder, Schommer, Hellhammer, Engel, & Kirschbaum, 2001), researchers can study these processes in the vascular system through a noninvasive skin-blanching paradigm (Ebrecht et al., 2000; B. R. Walker, Best, Shackleton, Padfield, & Edwards, 1996) and in the nervous system through challenge molecules such as CRH, ACTH, and dexamethasone. Statistical power is another design feature that warrants additional consideration. The studies in our meta-analysis had an average of 80 participants and for the most part yielded effect sizes in the .20 –.50 range. These represent small- to medium-sized effects by conventional standards in behavioral science. Even at the high end of that effect-size range, however, studies need twice as many participants to have adequate power. Future research will need to boost enrollment substantially to maximize its chances of detecting alterations in the HPA axis.

Summary and Conclusions The notion that stress contributes to disease by activating the HPA axis is featured prominently in many theories. The research linking stress and the HPA axis is contradictory, however, with some studies reporting increased activation and others reporting the opposite. Our meta-analysis of this area showed that some of the variability in HPA response is attributable to stressor and person features. Timing is an especially critical element, as hormonal activity is elevated at stress onset but reduced as time passes. Stress that threatens physical integrity, is traumatic in nature, and is largely uncontrollable elicits a high, flat diurnal profile of cortisol secretion. Finally, HPA activity is shaped by the person’s response to stress; cortisol output increases with the extent of subjective distress and is generally reduced in those who


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develop PTSD. These findings highlight the importance of incorporating stressor and person features into models of chronic stress and HPA activity. They also suggest that relations among stress, cortisol, and disease are likely to be more complex than previously acknowledged. Because chronic stress can elicit such a wide variety of HPA responses, its impact on disease outcomes will be varied and depend on whether high versus low cortisol is pathogenic. The next wave of models will need to be refined to acknowledge this complexity. With better theories and further research of the nature suggested by the meta-analysis, the pathways through which chronic stress “gets under the skin” to influence disease will come into clearer focus.

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Received September 30, 2005 Revision received February 9, 2006 Accepted March 30, 2006 䡲

Call for Papers Journal of Experimental Psychology: Learning, Memory, and Cognition Special Section on Source Memory: Integrating Cognitive Behavioral and Cognitive Neuroscience Approaches The Journal of Experimental Psychology: Learning, Memory, and Cognition invites manuscripts for a special section on source memory, to be compiled by guest editors Marcia K. Johnson and Mieke H. Verfaellie, working together with journal Associate Editor John Dunlosky. The goal of the special section is to showcase high-quality research that brings together behavioral, neuropsychological, and neuroimaging approaches to understanding the cognitive and neural bases of source memory. We are seeking cognitive behavioral studies that integrate cognitive neuroscience findings in justifying hypotheses or interpreting results and cognitive neuroscience studies that emphasize how the evidence informs cognitive theories of source memory. In addition to empirical papers, focused review articles that highlight the significance of cognitive neuroscience approaches to cognitive theory of source memory are also appropriate. The submission deadline is June 1, 2007. The main text of each manuscript, exclusive of figures, tables, references, or appendixes, should not exceed 35 double-spaced pages (approximately 7,500 words). Initial inquiries regarding the special section may be sent to John Dunlosky ([email protected]), Marcia K. Johnson ([email protected]), or Mieke H. Verfaellie ([email protected]). Papers should be submitted through the regular submission portal for JEP: Learning, Memory, and Cognition (http://www.apa.org/journals/xlm/submission.html) with a cover letter indicating that the paper is to be considered for the special section. For instructions to authors and other detailed submission information, see the journal Web site at http://www.apa.org/journals/xlm.

C UR R E NT D I R EC TI ON S I N P SY CH O L O GIC A L S CI E NC E

Out of Balance A New Look at Chronic Stress, Depression, and Immunity Theodore F. Robles,1 Ronald Glaser,2, 3, and 4 and Janice K. Kiecolt-Glaser3, 4, and 5 Department of Psychology, The Ohio State University; 2Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine; 3The Ohio State Institute for Behavioral Medicine Research; 4The Ohio State University Comprehensive Cancer Center; 5Department of Psychiatry, The Ohio State University College of Medicine 1

ABSTRACT—Chronic

stress is typically associated with suppression of the immune system, including impaired responses to infectious disease and delayed wound healing. Recent work suggests that stress and depression can enhance production of proinflammatory cytokines, substances that regulate the body’s immune response to infection and injury. We provide a broad framework relating stress and depression to a range of diseases whose onset and course may be influenced by proinflammatory cytokines, particularly the cytokine interleukin-6 (IL-6). IL-6 has been linked to a spectrum of chronic diseases associated with aging. Production of proinflammatory cytokines that influence these and other conditions can be directly stimulated by chronic stress and depression. We suggest that a key pathway through which chronic stress and depression influence health outcomes involves proinflammatory cytokines. We discuss the evidence for relationships between psychosocial factors and proinflammatory cytokines, and important health implications of these findings.

KEYWORDS—chronic stress; depression; immunity; cytokines; inflammation

A long-standing idea in the field of psychoneuroimmunology (the study of interactions between the nervous system and the immune system) is that chronic stress suppresses the immune system. A recent review of the past 30 years of research on stress and immunity concluded that ‘‘the most chronic stressors were associated with the most global immunosuppression’’ (Segerstrom & Miller, 2004, p. 618). Our own research has previously demonstrated that immune suppression related to chronic stress has clinical implications, including impaired immune responses to infectious disease and delayed wound healing. Address correspondence to Janice K. Kiecolt-Glaser, Department of Psychiatry, Ohio State University College of Medicine, 1670 Upham Drive, Columbus, OH 43210-1228.

Volume 14—Number 2

Currently, researchers are changing their thinking about the relations among chronic stress, depression, and immunity. Recent research suggests that chronic stress and depression may actually enhance certain immune responses. One immune response in question is inflammation, a broad term that refers to immune processes triggered by damage to cells and tissues. Such damage occurs in a variety of ways, including infection and injury. The immune system initiates inflammatory responses that are critical to resolving infections and repairing the damaged tissue. Focusing on the inflammation-enhancing role of chronic stress and depression marks an important shift in how researchers conceptualize the complex interactions between the brain, behavior, and the immune system. Rather than supporting the model in which chronic stress and depression results in global immune suppression, the evidence reviewed here suggests a more complex and clinically relevant model in which chronic stress and depression result more generally in immune dysregulation. The body normally orchestrates a balanced response when faced with immunological challenges, but in the new model, chronic stress and depression disrupt this balance, suppressing some immune responses and enhancing others. This can have significant costs to an individual’s physical health, including prolonged cell and tissue damage, increased vulnerability to acute and chronic diseases, and even premature aging.

CYTOKINES AND IMMUNE REGULATION

The key substances involved in regulating inflammatory responses to infection and injury are cytokines. Released by a variety of cells, cytokines are proteins that serve as intercellular signals regulating immune responses. Much like hormones of the endocrine system, cytokines transmit messages by interacting with receptors on cell surfaces and communicate over long distances in the body. Cytokines can be differentiated into two broad classes on the basis of their effects on the immune response: proinflammatory (promoting inflammation) and antiinflammatory (restraining inflammation).

Copyright r 2005 American Psychological Society

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Chronic Stress, Depression, and Cytokines

Proinflammatory cytokines, including interleukin-1 (IL-1), IL6, and tumor necrosis factor-a (TNF-a), are produced by cells at the site of infection or injury (see Fig. 1). Subsequently, proinflammatory cytokines attract other immune cells to the affected site and prime them to activate and respond. Anti-inflammatory cytokines such as IL-4, IL-5, IL-10, and IL-13 dampen this immune response, inhibiting immune-cell activities, such as replication, activation, and synthesis of other cytokines. Proinflammatory cytokines initiate a variety of responses that regulate inflammation, in addition to stimulating production of other cytokines. Specifically, certain proinflammatory cytokines act on the brain, as shown in Figure 1, affecting the endocrine system and behavior. For instance, proinflammatory cytokines stimulate the hypothalamic-pituitary-adrenal (HPA) axis, a cascade of hormones from the hypothalamus and pituitary gland that results in production of the glucocorticoid hormone cortisol. Glucocorticoid hormones are steroid hormones produced by the adrenal cortex that can have anti-inflammatory effects by reducing the synthesis of proinflammatory cytokines, and thus complete a negative feedback loop that helps control inflammation. Proinflammatory cytokines also induce sickness be-

Fig. 1. Proinflammatory cytokine responses to infection or injury under normal conditions. Lines terminating in arrowheads denote stimulatory pathways, and lines terminating in flat lines denote inhibitory pathways. Infection and injury stimulate cells to secrete proinflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a), and IL-6. These cytokines attract other cells to the site and stimulate them to respond. In addition, proinflammatory cytokines travel to the brain and stimulate the hypothalamic-pituitary-adrenal (HPA) axis. This results in cortisol production, which helps to control inflammation and prevent the immune system from over-responding. Proinflammatory cytokines in the brain also induce sickness behavior, which helps the body maximize physical resources required to combat infection.

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havior, a cluster of behaviors—including fever, decreased appetite, and reduced motor activity—that facilitate energy regulation (Maier & Watkins, 1998). By maximizing physical resources (energy, heat) required by the body to combat infection, sickness behavior is considered adaptive in helping the organism fight off infectious disease. This review focuses on the proinflammatory cytokine IL-6, which has multiple effects on the immune, endocrine, and other tissue and organ systems, and thus serves as a good indicator of chronic inflammation. In addition, elevated IL-6 production is linked to key chronic diseases, such as cardiovascular disease and certain cancers, and to indices of physical health (Papanicolaou, Wilder, Manolagas, & Chrousos, 1998). Moreover, IL6 production is related to psychosocial factors, including depression and chronic stress. PSYCHOSOCIAL FACTORS AND PROINFLAMMATORY CYTOKINES

Several sociodemographic factors and health behaviors are related to elevated proinflammatory cytokines. Unlike other components of the immune system, which decline with age, IL-6 levels tend to increase with age (Papanicolaou et al., 1998). Men generally show higher levels of IL-6 than women, likely because of the effects of estrogen and androgens (Ershler & Keller, 2000). Higher IL-6 levels are associated with adverse health habits, including smoking, sedentary activity, and high body mass index; at the same time, elevated IL-6 levels are associated with higher rates of morbidity and mortality after controlling statistically for sociodemographic factors and health behaviors (Ferrucci et al., 1999). As stated at the outset, the past 30 years of research on chronic stress and depression focused on immune suppression. Accordingly, one might expect that chronic stress and depression are related to suppressed production of proinflammatory cytokines. However, empirical evidence strongly suggests that major depression, depressive symptoms, and chronic stress enhance production of proinflammatory cytokines. Major depression is related to enhanced proinflammatory cytokine levels, including IL-6, which can be reduced following successful treatment with antidepressant medications (Kenis & Maes, 2002). Elevated depressive symptoms also are related to elevated proinflammatory cytokine levels (e.g., Miller, Stetler, Carney, Freedland, & Banks, 2002). We recently found that higher levels of depressive symptoms were related to higher levels of IL-6 among older adults (Glaser, Robles, Sheridan, Malarkey, & Kiecolt-Glaser, 2003). More important, individuals reporting more depressive symptoms showed increased IL-6 levels 2 weeks after receiving a challenge to the immune system through an influenza virus vaccination, whereas there was little change in IL-6 among individuals reporting few or no depressive symptoms, as shown in Figure 2. In general, depressive symptoms were quite low in our sample of older adults, which


Theodore F. Robles, Ronald Glaser, and Janice K. Kiecolt-Glaser

suggests that even modest depressive symptoms may be sufficient in making the immune system hypersensitive to immunological challenges, resulting in amplified IL-6 production. Sensitization of inflammatory responses may have important health consequences, as amplified and prolonged inflammatory responses following infection and other immunological challenges could accelerate the progression of a range of age-related diseases. Overall, these data suggest that proinflammatory cytokines are a key mechanism whereby major depression and depressive symptoms may serve as a gateway to a broad array of health problems. Chronic stressors are also related to elevated production of IL-6. A study found that women who were caring for a relative with Alzheimer’s disease had higher levels of IL-6 than either women who were anticipating a housing relocation or women from the same community who experienced neither of these stressors (Lutgendorf et al., 1999). This finding was particularly noteworthy because the caregivers were 6 to 9 years younger, on average, than women in the other two groups. Given that IL-6 levels generally increase with age, what might be the impact of chronic stress on age-related increases in IL-6? We addressed this question by following older adults undergoing a chronic stressor for 6 years and assessing age-related change in their IL-6 levels during that period (Kiecolt-Glaser et al., 2003). Older adults experiencing the chronic stress of caring for a spouse with Alzheimer’s disease showed an average rate of annual IL-6 increase that was about 4 times as large as that of noncaregivers. There were no systematic group differences in chronic health problems, medications, or healthrelevant behaviors that might have accounted for the faster increase in IL-6 in caregivers. Moreover, the mean annual

Fig. 2. Levels of interleukin-6 (IL-6) as a function of depressive symptoms in a sample of 119 older adults. IL-6 levels were measured before participants received an influenza virus vaccination (baseline, represented by the white bars) and 2 weeks after they were vaccinated (dark bars). Depression symptoms were measured using the short form of the Beck Depression Inventory (BDI-SF). Individuals reporting depressive symptoms showed an increase in IL-6 2 weeks following vaccination compared to individuals reporting few or no depressive symptoms. Error bars denote standard error of the mean. Redrawn after Glaser, R., Robles, T.F., Sheridan, J., Malarkey, W.B., & Kiecolt-Glaser, J.K. (2003).


changes in IL-6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse. Based on these findings, we suggest that chronic stressors may be capable of substantially augmenting normal age-related increases in proinflammatory cytokine production. Put simply, chronic stress may contribute to premature aging of the immune system.

PSYCHOSOCIAL FACTORS AND MECHANISTIC PATHWAYS

Apart from influencing health-related behaviors, how might psychosocial factors contribute to elevated production of proinflammatory cytokines? Figure 3 depicts four potential pathways. Several pathways (i.e., A, C, and D) involve dysregulation of signals coming from the endocrine system, specifically the HPA axis. Stress-related HPA activity results in elevated levels of glucocorticoid hormones, including cortisol. As previously mentioned, glucocorticoid hormones reduce the synthesis of proinflammatory cytokines and thereby help prevent the immune system from overshooting, or mounting an overreactive immune response that could cause damage to cells and tissues, such as the damage observed in autoimmune diseases like multiple sclerosis or rheumatoid arthritis. If glucocorticoid signals are disrupted, the result may be reduced restraint on the immune system and overproduction of proinflammatory cytokines. Figure 3, Path A depicts that chronic stressors and depression disrupt glucocorticoid signaling in the brain by altering the function of glucocorticoid receptors (Raison & Miller, 2003). Figure 3, Path B depicts that chronic stressors and depression may decrease the responsiveness of target tissues to cortisol. For instance, chronic stress is related to decreased sensitivity of immune cells to the antiinflammatory effects of glucocorticoids (e.g., Miller, Cohen, & Ritchey, 2002). Another pathway through which psychosocial factors may contribute to enhanced production of proinflammatory cytokines involves stress-related immune suppression (Fig. 3, Path C). Chronic stress impedes the immune response to infection, increasing risks for catching contagious diseases and having prolonged illness episodes, delaying wound healing, and increasing the risk for wound infection after injury. Thus, immune suppression may contribute to repeated, chronic, or slow-resolving infections or wounds, which subsequently enhance secretion of proinflammatory cytokines, a process that can serve to further inhibit certain aspects of immune responses. Finally, elevated proinflammatory cytokines may themselves impair cortisol signaling, and thus HPA axis regulation, by altering the functioning of glucocorticoid receptors in the brain (Fig. 3, Path D). As a result, elevated proinflammatory cytokines impair the ability of the HPA axis to regulate inflammatory processes, further enhancing proinflammatory cytokine production.

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Chronic Stress, Depression, and Cytokines

Fig. 3. A theoretical model depicting how psychosocial factors and aging contribute to immune dysregulation. Lines terminating in arrowheads denote stimulatory pathways, and lines terminating in flat lines denote inhibitory pathways. Dotted lines denote disrupted signaling pathways. In this model, chronic stress, depression, and aging contribute to elevated proinflammatory cytokines—interleukin-1 (IL-1), tumor necrosis factora (TNF-a), and IL-6—in four ways: (A) Psychosocial factors may disrupt the functioning of glucocorticoid hormones (such as cortisol) in the brain by reducing the number of glucocorticoid receptors in certain brain regions or disrupting receptor functioning, which may result in dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis; (B) psychosocial factors may disrupt the functioning of glucocorticoid receptors on cytokine-producing cells, rendering those cells less sensitive to the anti-inflammatory effects of cortisol; (C) psychosocial factors may result in immune suppression, which inhibits the body’s ability to fight off infection and injury, leading to chronic infections; and (D) proinflammatory cytokines may reduce the number of glucocorticoid receptors in the brain or disrupt the functioning of those receptors. All four mechanisms may eventually lead to elevated production of proinflammatory cytokines and, over time, contribute to chronic disease and pathophysiology.

HEALTH IMPLICATIONS

Under normal conditions, elevated levels of proinflammatory cytokines are critical to resolving damage from infection and

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injury. However, chronic infections can result in persistent stimulation of immune and proinflammatory cytokine responses, leading to pathological effects (Hamerman, Berman, Albers, Brown, & Silver, 1999). For example, low levels of persistent inflammation may result when chronic infections such as periodontal disease, urinary tract infections, chronic pulmonary disease, and chronic renal disease continuously stimulate the immune system. In turn, chronic elevations in proinflammatory cytokines including IL-6 have substantially deleterious health implications, including links to a spectrum of conditions associated with aging. These conditions include cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers (including multiple myeloma, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia), Alzheimer’s disease, and periodontal disease (Ershler & Keller, 2000). The association between cardiovascular disease and IL-6 has received increased attention in the past decade, in part because of the central role that IL-6 plays in promoting the production of C-reactive protein (CRP), recently recognized as an important risk factor for myocardial infarction (Papanicolaou et al., 1998). Elevations in both IL-6 and CRP levels are related to risk of future cardiovascular disease, myocardial infarction, and mortality, even in apparently healthy adults (Taubes, 2002). More globally, chronic elevations in proinflammatory cytokines may be one key biological mechanism that fuels declines in physical function leading to frailty, disability, and, ultimately, death. Indeed, statistical analyses show that even after controlling for risk factors such as cholesterol levels, hypertension, and obesity, chronic IL-6 production continues to be an important indicator of physical decline among the very old (Ferrucci et al., 1999). For these reasons, the role of chronic stress and depression in promoting IL-6 production should also have clinical relevance. Moreover, stress-related increases in proinflammatory cytokines may be particularly harmful for older adults. For instance, in our study of chronic-stress-related increases in IL-6, the average caregiver reached IL-6 levels that doubled his or her mortality risk by the age of 75; the average control participant in the study did not reach similar levels until the age of 90 (Kiecolt-Glaser et al., 2003).

CONCLUSION

Research has identified a key mechanism whereby chronic stress and depression may promote the development of chronic disease and speed aging of the immune system: elevated proinflammatory cytokine levels. This work demonstrates the shift in the field of psychoneuroimmunology away from focusing solely on chronic stress and immune suppression, toward integrating chronic stress and immune dysregulation in a model that emphasizes the balance between two important and adaptive mechanisms: inflammatory and anti-inflammatory responses.


Theodore F. Robles, Ronald Glaser, and Janice K. Kiecolt-Glaser

Depression and chronic stress, by disrupting bidirectional communication between the brain and immune system, effectively damages the ‘‘brakes’’ that help restrain inflammatory responses, paving the way for increased production of proinflammatory cytokines through several distinct mechanisms. Depressive symptoms may increase production of proinflammatory cytokines following an infection or injury. Furthermore, chronic stress and depression accelerate age-related increases in production of proinflammatory cytokines, making these psychosocial stressors uniquely problematic for older adults. Current work continues to establish relationships among chronic stress, depression, and proinflammatory cytokines. Future research must firmly establish proinflammatory cytokines as a key mediator between psychosocial factors and chronic disease. This requires longitudinal follow-up studies that not only track chronic stress, depression, and inflammation over time, but also include assessments of clinical indicators of chronic disease, such as coronary artery calcification in atherosclerosis. Ultimately, intervention studies will be needed to determine if treating chronic stress and depression can eventually restore immunological balance and affect health.

Recommended Reading Irwin, M. (1999). Immune correlates of depression. In R. Dantzer, E.E. Wollmann, & R. Yirmiya (Eds.), Cytokines, stress, and depression (pp. 1–24). New York: Academic/Plenum Publishers. Kiecolt-Glaser, J.K., McGuire, L., Robles, T.F., & Glaser, R. (2002). Emotions, morbidity, and mortality: New perspectives from psychoneuroimmunology. Annual Review of Psychology, 53, 83–107. Kiecolt-Glaser, J.K., McGuire, L., Robles, T.F., & Glaser, R. (2002). Psychoneuroimmunology: Psychological influences on immune function and health. Journal of Consulting and Clinical Psychology, 70, 537–547. Miller, A.H. (1998). Neuroendocrine and immune system interactions in stress and depression. Psychiatric Clinics of North America, 21, 443–463.

Acknowledgments—Work on this article was supported by National Institutes of Health Grants P50 DE13749, P01 AG16321, AT002122, M01 RR034, and CA16058, and by a National Science Foundation Graduate Research Fellowship to the first author. REFERENCES

Ferrucci, L., Harris, T., Guralnik, J., Tracy, R., Corti, M., Cohen, H., Penninx, B., Pahor, M., Wallace, R., & Havlik, R.J. (1999). Serum IL-6 level and the development of disability in older persons. Journal of the American Geriatrics Society, 47, 639– 646. Glaser, R., Robles, T.F., Sheridan, J., Malarkey, W.B., & Kiecolt-Glaser, J.K. (2003). Mild depressive symptoms are associated with amplified and prolonged inflammatory responses following influenza vaccination in older adults. Archives of General Psychiatry, 60, 1009–1014. Hamerman, D., Berman, J.W., Albers, G.W., Brown, D.L., & Silver, D. (1999). Emerging evidence for inflammation in conditions frequently affecting older adults: Report of a symposium. Journal of the American Geriatrics Society, 47, 1016–1025. Kenis, G., & Maes, M. (2002). Effects of antidepressants on the production of cytokines. The International Journal of Neuropsychopharmacology, 5, 401–412. Kiecolt-Glaser, J.K., Preacher, K.J., MacCallum, R.C., Atkinson, C., Malarkey, W.B., & Glaser, R. (2003). Chronic stress and age-related increases in the proinflammatory cytokine interleukin-6. Proceedings of the National Academy of Sciences, USA, 100, 9090–9095. Lutgendorf, S., Garand, L., Buckwalter, K.C., Reimer, T.T., Hong, S., & Lubaroff, D. (1999). Life stress, mood disturbance, and elevated interleukin-6 in healthy older women. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 54A, M434– M439. Maier, S.F., & Watkins, L.R. (1998). Cytokines for psychologists: Implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychological Review, 105, 83–107. Miller, G.E., Cohen, S., & Ritchey, A.K. (2002). Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model. Health Psychology, 21, 531– 541. Miller, G.E., Stetler, C.A., Carney, R.M., Freedland, K.E., & Banks, W.A. (2002). Clinical depression and inflammatory risk markers for coronary heart disease. American Journal of Cardiology, 90, 1279–1283. Papanicolaou, D.A., Wilder, R.L., Manolagas, S.C., & Chrousos, G.P. (1998). The pathophysiologic roles of interleukin-6 in human disease. Annals of Internal Medicine, 128, 127–137. Raison, C.L., & Miller, A.H. (2003). When not enough is too much: The role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. American Journal of Psychiatry, 160, 1554–1565. Segerstrom, S.C., & Miller, G.E. (2004). Psychological stress and the human immune system: A meta-analytic study of 30 years of inquiry. Psychological Bulletin, 130, 601–630. Taubes, G. (2002). Does inflammation cut to the heart of the matter? Science, 296, 242–245.

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A STRESSZ HATÁSA BETEGSÉGEK KIALAKULÁSÁBAN

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