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Gold By Esther Sternberg Philip'W. M. and

The belief that the mind plays an important role in physical illnessgoes back to the
the that From the time of the ancientGreeks toxic substances surgery,exacerbates diseases these or earliestdays of n.redicine. i accepted by .y.rem.grrad agai nrr:nfe(ti ou..i nfl amrna l tory.auroi m nr une, to the beginningofthe20th century,itwas generally mood disorders. both physicianand patient that the mind can affect the course and associated natural to apply this conceptin medical The clinical significance thesefindings is likely to prove of of illness, ard it seemed treatments ofdisease. After the discovery ofantibiotics,a new as- profound.They hold the promiseofextendingthe rangeoftheras that treatmentofinfectiousor inflammatorydis- apeutictreatments availablefor variousdisorders, drugspresumptionarose problems ease requires only the eliminationof the foreignorganismor viously known to work primarily for nervoussystem against immunemaladies, viceverand agentthat triggersthe illness.In the rush to discoverantibiotics are shownto be effective infectionsand diseases, fact that sa.They alsohelp to substantiate popularly held impression the the and drugsthat curespecific the body'sown responses influence can susceptibility disease (still discountedin somemedicalcircles)that our stateof mind to was largelyignoredby medicalresearchers. can influencehow well we resistor recoverfrom infectiousor and its course into infectious inflammatory diseases. It is ironic that research and inflammatorl dis The brain'sstress response system activated threatening is in ease first led 2Otl.r-century medicine to reject the idea that the phvsicalillness.and now resealchin the same situations. responds automaticallyto pathmind influences The irlmune system ogens and foreignmolecules. These two response sysfield-including the work ofour laboratories and ofour' collabolatorsat the National Institutesof Healthtemsarethe body'sprincipal meansfor maintaining A is proving the contrary. Nerv molecularand an internalsteady statecalledhomeostasis. subpharmacological for stantialproportion of human cellularmachinery tools haveuradeit possible is dedicated maintainingit. to us to idendfy the intlicate nenvork that exists When homeostasis disturbed or threatis betweenthe immune systen and the brain, a er-red,lepertoireofmolecular,cellularand bea network that allows the two systems signal to havioral responses comesinto play. Thesereeachother continuously and rapidly. Chemi e sponsesattempt to counteract the disturbing ccl .p ro duc ed ir nnr un c e l l " i g n a lth eb rrrn . b1 Iorcesin ordel to reestablish steadystate,They a and the brain in turn sendschemical signalsto Thesesamechemical can be specific the foreigninvaderor a particular to restrainthe imnune system. or and nonspecific signals also affect behaviorand the response to lIlM UN ERE S P 0 S Ecan be srress, they can be generalized N exceeds certain a Disruption of this communication network a lte redat the cel l ul arl evel when the threat to homeostasis stress. may themselves tl.rreshold. adaptiveresponses The in any way, whether inherited or through drugs, b ! stressh0rmones. 82 scr r Nr r r r c enr c l N lM
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IMI\,{UNE ESPONSE R The imm!ne s gs iem o p e r a t e sa s a D ce ntra liz ed wo r k ,r e s p o n d i n g net a uto mat ic allg o a n g t h i n g r h a t t Inva desordis ru p t s t h e b o d V . r m u ne tsgenerate di n t h e b o n e cel r n af i o w,l Umph node s ,s p t e e na n d llr g musc omm un i c a t ew i t h o n e D t h erusi ngs ma pr o ( e i n s . h e s e T c n emtc aJ es s en g e r s a n a l s o m c s en d g nalst o t he b r a i n ,t h r o u g h si ) jt h er the bloods t re a ma r t h r o u g h n erv epat hwag ss u c h a s t h e va gusnet uet o t h e n u c l e u s 0t t he t rac t u s s o l i t a r i u s .

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turn into stressors capable producing of \J(/e disease. are just beginningto under. standthe interdependence the brain and of the immune system, how they helpto reg, ulate and counterregulate eachother and how theythemselves canmalfunctionand producedisease. The .rre.cresporrte promote< phyriological and behavioralchanges threatin e n rn g r ax ings ir ulr r o n sfo r i n " ta n c e , or . when we are facing a potentially lifethreatening situation,the brain'sstress responsegoes actionto enhance fointo our cusedaftention,our fear and our fight-orflight response, while inhibitingbehaviors, suchasfeeding,sexand sleep,that might lessen chanceof immediatesurvival. the The stressresponse,however, must be

to the pituitary gland, which liesjust be( nearh brai n. R H cau\eq p ir uir . r r y rhe rhe to release adrenocorticotropinhormone (ACTH) into the bloodstream, rvhich stimulates adrenalglandsto produce the cortisol, the best-knownstress hormone, Corti.ol i' a steroid hormonerharin creases rate and sffengthofheaft conthe tractions, sensitizes blood vessels the to actionsof norepinephrine adrenaline, (an like hormone)and affectsmany metabolic functions-actions that help the body .' ' ,:, I :. :. .: . meeta sffessful situation.In addition,corBoTH sYsTtMS alsorely on chemical tisol is a potent immunoregulator and mediatorsfor communication.Electrical anti-inflammatory agent.Irplaysa crucial s t8 n a l s l o n8 nerve parhw ay..i or i n a role in preventing the immune system stance,are convertedto chemicalsignals from or erreacring inluries to and damagat the synapsesbetween neurons. The ing tissues. Furthermore,cortisol inhibits

T h ec e ntral nervous rmmune and ' 1s tems,however,are more similar than diffelent in their raodesof receiving,recognizingand integlatingvarioussignalsand in their structuraldesignfor accomplishing thesetasks.Both the central nervous systemand the imnune systempossess '\en.ory' elenrenr,, which recerve infor mation from the environmentand other partsofthe body, and "motor" elements, which carry out an appropriateresponse.

regulated be neitherexcessive subto nor optimal; otherwise,disordersof arorisal, thought and feelingemerge. job The irnmunesystem's is to bar foreignpathogens from the body and to recognize nd de.rroytho\erhJrpenerrafe a ir. shield.The immune sysremmust also neutralizepotentially dangeroustoxurs, fa ci l rrarre epar r dam a g e d r w o rn ri .of o sues, dispose and ofabnormal cells.Irs re \ponse\are\o powerfulrharrheyrequire constantreguLation ensurethat they to are neither excessive nor indiscriminare a n d ye r r em ar n eliec c i v e . e n rh e i mWh mune\) \fem e\Capes regulAtion,utOim a muneand inflammatory diseases rnror mune deficiency syndromesresult. The immune and centralnervoussystem\ appear,ar fir.t glance.to be organized in very differentways. The bram rs usually regarded as a centralized command center,sendingand receivingelectricalsignalsalong fixed pathways,much l i l e c re lephone work l n c o n trrs r, e ner . th immune systemis decentralized, and its organs(spleen,lymph nodes, thymus and bonemarrow) are locatedthroughout the b o d 1 .t he c la' s ic al ievri . rh a r rh e i m v mune systemcommunicates releasrng by immune cells into the bloodstreamthat travel to new locations to deliver their messages to perform other functiols. or

chemical messengers produced by im- the rel er.e of C R H by rhe hypor halmune cells communicate not only with amus-which keeps this component of other partsofthe immunesystem also the stressresponse but under control. Thus, with the brain and nerves.Chemicaisre- CRH and cortisol directly link the body's leasedby nelve cellscan act as signalsto brain-regulated stress response its rmand immune cells.Hormones from the body mune response. travelto the brain in the bloodstream, and CRH-secretingneuronsof the hypothe brain itselfmakes hormones. lndeed, thalamus send fibers to regions in the the brain is perhapsrhe most prolific en- brain stemthat help to regulatethe symdocrine organ in the body and produces patheticnervoussystem, well asto an, as many hormones that act both on the other brain stem area calledthe locus brain and on dssues throughoutthe body. ceruleus,The sympatheticnervous sysA key hormote sharedby the cer.rtr:al rem. w hi ch mobi l i ze'rhe body dur ing n e r\o u \ a n d i mmunesystems corri co stress,also innervatesimmune organs, ir tropin-releasing hormone (CRH); pro- such as the tl-ryn-rus, lymph nodes and ducedin the hypothalamus and several spleen, helpsto control inflammatory and other brain regions, unitesthe stress it and responses throughout the body. Stimulaimmuneresponses. hypothalamus The re- tion of the locusceruleus leadsto beluv l e a re "C R H i nro r speci al i zed ood ioral arousal, bl fearand enhanced vigilance. streamcircuit that conveysthe hormone Perhaps evenmore important for the
tSTHR M. andPHlLtpW.GjLD carrgout their research stressand immune on sgstems 'TRNBRG at the National Institute Mental of Health. Sternberg chiefofthesection neu_ is on roendocrine immunologg behaviorand and directorofthe Integrative Neural lmhuneprogram, andGold chiefofthe is clinical neuroendocrinologg branch. Sternberg received M.D. her from M c G illU n i v e r s iHg .r w o r k o n t h e m e c h a n i s m s a n d m o l e c u l a r b a s i s oa l i m m un e co m te neur f munication ledto a growing has recognition oftheimportance ofmind_bodg interaction. She is alsotheauthoroflhe BolonceWithin:The Science Connecting Heolthondtmotions [2000]. Beforejoiningthe in 1974, NIMH Gold received medicaltrajningDuke his at Universitg Har_ and vardllniversitV. andhisgroup He wereamongthe to introduce first dataimplicating corticotropin-releasing hormone its related and hormones the pathophgsiologgmelancholic in of andatgpical depression in the mechanisms action antidepressant and of of drugs. THE HIDDEN NlIND

84 scre rrrrrc enrclr'r lu

inductionof fear-related behaviors the is amygdala, whereinpLlts from the sensory regions of the brain ale chargedas stresslul not. CRH-secreting or neurons I n l h e ..e nt r dlr r uc leu' , r frh e rml g d a l a sendfibersto the hypothalamus, lorhe cus ceruleus,and to other parts of the brain stem. TheseCRH secreting neurons are targetsof messengers released by immune ceJls during an immunersponse. By recruiting the CRH secreting neurons, the immune signalsnot only activate cor tisol-mediated restraintof the immurrc response also inducebehaviors but that assist lecoveryfrom iilness injury. in or CRH-secreting neuronsalso have connections with hypothalanric regions that regulate food int.rLe and reproducrive hehavior.In addition,otherhormonaland nerve systems-such as the thyrord, growth and femalesex hormones, and pathways (conthe sympathomedullary nections the sympathetic of nervous systen-r and medulla) influence interactions between blain anclthe the immunesystem.

many other typesof celisanclorgans,in c l u d rg p .trt.o f the br.ri n.C yrnkrne. . i the more genelalterm for biologicalrnolecules that many differentkinds of cells u \( to c o mmtrnrcJte. Lrch ,l tOki rrer .t i distinctproteinnolecule,errcoded a by gene! separate thilt targets particularcell a type.A cytokinec:rneitherstimulate or inhibit a response depending the pres on enceof other cytokines other stimuli or and the current stateof metabolicactrvr ry .I hi . fl e r' h i l iy a' l ou\ l hei rnmu \y. r ne te mto ta k eth c n ro\rrpl ropr:rl e a(ti ori to stabilize localcellularenvironmenr the and to rnaintain homeostasis. Cytokinesfrom the body's immune system can sendsignals the brain 1n to \(v e rJ l\\J )\. Ordi nrri l y.r " hl ooJ-hr.ri r b .-rrri e r" re l d .the central rervt)l l \\y\ 'h tem from potentiallydangerous molecules the bloodstream. in During inflammation or illness, holvever, this barlier'

becomes more pelmeatrle, and cvtokines may be carriedlcrcss into the brain \\'ltlr nutrientsflom the blood. Certain cytokines,on the other hand,readilypass througl rI.ck1 rreJ. i r rhe l ' l ood-l 'r air r barrier at anv time. But cytokincsdo not haveto crossthe blood brain barrierLo exertfheir effects. Cytokinescanattachto their receptorsin the lining of blood vesin sels the brainand stimulate release the lf \econdJ chern -rl.igral. irr rhc brl rn ry i( tissuearounclthe blood vessels. C r rokrnes.l nrl .o.i gnr rl -ebr.rinr i. r di rect nerre route\. \l l ch .r. the \ag u. ncrve,rvhich innervates hexft, stomthe ach,smallintestine and other orglns of the abdonrinal cavity.Injectionof IL-1 into thc abdominalcavitv activates thc oi rru.l eu. thetrl i rrrs.ui i r.rri rrr. prr n rhc iipal region,rf rlrehrrrr .renrlor rc.cipt ol visceral sensory signals. Cutting the va gur n.rr r bl " i L..l rl i \ruon,' i rhr. hr. r ir r

STRESS RESPONSE SYSTEM

T H E IMMUNT -RE S poNS E a n e l e g a n r r ts and finelytuned cascade ofcellular events aimed at ridding the body of foreignsub' stances, bacteriaand viruses.One of the r nri o r d i .c ov c r ie'of c onte rn p o ra rlm i munology is that white blood cellsproduce srnall proteins that indirectly coordinate the responses other parts ot the of lmmune systemto pathogens. For example, proteinirterleukin-1 the (lL-1) is madeby a typeof white blood cell called a monocyte or macrophage.IL-1 stimulatesanother type of white blood cell, the lymphocyte, to produce interleukin-2(IL-2),which in tum induces lyrrr phocytes developinto matureimmune to cells.Somemature lymphocytes, called plasma cells,makeantibodies rharfighrrnfection,rvhereas others, thecytotoxiclymph o i yte '.I ill r ir u. e'dr r ec rl y . e ri rte rOrh leukinsmediatethe activafionof immune cellsthat are involvcdin allergic reactions. Th e i nr er leu r n' wer e o ri g i n .rl l y I named for what was considered be to r l'ei rp ri mar yf unc r ion: om n u rr c at i o n c r i among ("inter-") the white blood cells ("leukins"). But interleukins alsoact as chemicalsignals amongimmunecellsand
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HPAAXIS th e in te r pl aU amongthehgporhal amus,thepi t!i targandtheadrenal gl ands-i sacen tral co m p o n e n o fth e b rai n'sneuroendocri ne t response stress Thehgpothaamus,w hen sti mu ared, to se cr e te s 1 1 ico tropi n-rel easi ng co hormone R H ]i nto the hgpophgseal por!al s!stem,w hl chsuppl i e s IC b lo o dto th e a n te r ior tui tafUC R H mul ates pi tul tarUred offow ssho',,( mul otorg pi . sti the pothw dgs)to sti l t se cr e lea d r e n o co rc otropi n hormone C THi J the bl oodstream. C TH nto A causes the adrenal gl ands to {A r e le a se r tiso l,lh e assi c resshormone co cl si that arouses bodgto meet a chelengi ng tuati on. ut the si B co n iso lth e nm o d u lal eshe stressresponse i i i etecrs] bg acri ngon the Ib/ueorrow s ndi cote nhi bi totg h g p o th a la m uto in hi bi tthe conti nued ease s rel ofC R HA l soa potenti mmunoregul aror, solactson . coni m a n Up a r tso f th e immunesV S tem prevent i fromoverreacri ng harmi ng to i and heal thgcel l sandti ssue

T HE H I D D E N I N O 8 5 M

nucleusby IL-1. Sending signalsalong nerve routes is the most rapid mechanism-on the order of milliseconds-by which cytokinessignalthe brain. Activation of the brain by cytokines from the peripheralpans of the body rnduces behaviors of the stressresponse, such as anxiery and cautious avoidance, that keepan individualout of harm'sway until fullhealing occurs.Anyonewho has experienced lethargyand excess sleepinessduring an illnesswill recognizethis setof responses "sickness as behavior,"

brain tissueof patientsliving with AIDS, concentratedin areasaround the grant macrophagesthat invade the patients' brain tissue.Immune factors, however, are not alwaystoxic to neurons.Specific activatedT lymphocytesplay an importantrole in preventing neuronalcelldeath after injury. This discoveryis leadingto new approaches treatingand preventto ing paralysis following spinalcord injury. An 1 d i srupti onof communi cati on betweenthe brain and the immune sysrem leadsro grearer suscepribilir) inro

ders them highly susceptible.Further proof comes from studies in which the transplantation of hypothalamic tissue from disease-resistant into the brarn rats of susceprible improvesrheir resis' rats ranceto peripheralinflammation. These animal studies demonstratc that disruption of the brain's stressresponseenhances body's response the to inflammarory disease, reconsriturion and reduces ofthe stress response susceptibility to inflammation. One implication of these findings is that disruption of the

'fhe IMMUNE RESPONSE an elesant is anel f i n clytultec1casca O f c e l l u l :reverlts cle r airned

lndeed,patientsreceivingcytokine treatrnent for immunosuppressionin cancer and AIDS may experience symptornsof depression and even suicidality.These symptomscan be preventedby pretreatment with antidepressants. Neuronsand nonneuronalbrain cells also producecytokines.Cytokinesin the brain regulate nerve cell growth and deathand canbe recruitedby the immune systemto stimulate the release CRH. of Some haveproposedthat brain cytokrnes may play a role in symptoms of depression in the absence known sickness of or infection.ThelL-1 cytokine system the in brainis currentlythe bestunderstood-all its componentshave beenidentified, rncluding receptorsand a naturally occurring anragonirr that bindsro Il - I receptors without activating them. The anatomical and cellular locationsof such cytokine circuitry are being mappedout in detail, and this knowledgewill aid researchers designing in drugsthat block or enhancethe actions of such circuits and the functionsthey regulate. Excessive amountsofcytokines in the hraincanberoxicro nerves. genericalIn ly engineeredmice, inserted genesrhat overexpress cytokinesproduceneurotoxic effects. Someofthe neurologicalsymptoms of AIDS in humans may also be caused overexpression by ofcenain cytokinesin the brain. High levelsofIL-1 and other cytokines have been found in tne flammatory diseaseand, frequently, to increased immunecomplicarions. in For stance,animals whose brain-immune communications have been disrupted or lthroughsurgery drugs)are highlyli able to lethal complications inflamof matory diseases infectiousdiseases. and Susceptibility inflammatorydisto easethat is associatedwith genetically impaired stressresponsecan be found across species-in rats, mice, chickens and, thoughthe evidence less is direct,humans.For instance, Lewisstrainofrat the is naturally prone to many inflammatory diseases impairmentof because severe ofa its HPA (for hypothalamus, pituitary and adrenal) axis, which greatly diminishes CRH secretionin responseto stress.In contrast,the hyperresponsive HPA axrsrn the Fischer strain of rat providesit with a strongresistance inflammatorydisease. to Evidenceof a causallink berweenarr impairedstress response and susceptibility to inflammatory disease comes from pharmacological and surgical studies. Pharmacological intervention such as treatmentwith a drug that blockscortisol receptorsenhances autoimmune inflammatory disease, Injectinglow doses ofcortisol into disease-susceptible eniances rats their resistance inflammation. Strong to evidencecomes from surgical intervention. Removalofthe pituitaryglandor the adrenalglandsfrom rats that arenormalIy resistantto inflammatory disease renbrain-immunecommunicationsystem by inflammatory, toxic or infectiousagents could contributeto someof the variations in the course rhe immunesl srem's of inflammatory response.

and Depr ess n io CRH

A LTH oU cH TH E R o LE ofthesf f essr esponsein inflammatory diseasein humans is more difficultto prove.thereis growing evidencethat a wide variety of suchdiseases associated are with imparrment of the HPA axis and lower levelsof CRH secretion, which ultimately results in a hyperacrive immune system.Furthermore,patientswith a mood disorder called atypical depressionalso have a blunted stress response and impaired CRH function, which leadsto lethargy, fatigue,increased and increased eatsleep ing that often resultsin weight gain. Patientswith other illnesses characterized by lethargy and fatigue, such as chronic fatigue syndrome,6bromyalgia and seasonalaffective disor:der(SAD), exhibit featuresof both depressionand a hyperactiveimmune system.A pe$on with chronic fatigue syndromeclassically manifestsdebilitating lethargy or fatiguelastingsix monthsor longerwith no medicalcause, well as as demonstrable feverishness, achesin joints and muscles, allergic symptoms and higher levels of antibodies a varietyof viral antigens to (including Epstein-Barrvirus).
TH E H ID D E N MIN D

luentcnl 86 screrrrrrc

Patientswirh fibromyalgia sufferfrom muscle aches,joint painsand sleep abnor:malities, symptoms similarto early, mild rheumatoid arthritis. Both theseillnesses associared ar-e with a fatigue like that in atypical depression. SAD, which usually occurs in winrer, is typifiedby lethargy, fatigr.re, increased food intake and increasedsleep,symptoms similar.to those of atypical depression. A deficiencyof CRH couldcontribute to lethargyin patients with chronicfatrgue syndrome.lnjectionofCRH intothese patientscauses delayed blunted a and ACTH secretionby the HPA axis.That sameresponseis also seenin patientswhosehypothalamushasbeeninjuredor who have a tumor, Also, fatigueandhyperactivity of the immune response associated are with cortisol deficiency, which occurs rvhen CRH secretiondecreases. hornrorrc The levels and responses patientswith fain tigue syndromessuggest-but do not prove-that their HPA axis functionsare impaired, resultingin a decrease CRH in r nd cu rti .o l ) ec r er ion a n i n c re rren and i inmune systemactivity. Togethet these findings indicatethat humanillness S M char- BRAN AND lN{ ltlUNEY S TE can ei thersti mul ateIred orrow s]or i nhi bi tIb/ueoffow s] eachother. lm m u n ece llsp r o d uce toki nes cU throughthe aite ri ze dh1 [ at igue Ichemi calsi gnal s]thatsl i mul atethe hU pothal amus and hyp e ri rn m u n i rl o i , i could possiblybe tleatedby drugsthat b lo o d str e a m r via nervesel sew heren the bodg.ThehormoneC R Hproducedn the hgpotnaramus , a ctiva te s e HPA xi s.Therel easeof corti sol tunes th a dow nthe i mmunesgstem.C R Hacti ngon the , mimic CRH actionsin the brain. b r a inste m , stim u lates the sgmpatheti c nervoussgstem,w hi chi nnervatesmmuneorgansand i In contrast, the classicforrn of de r e g u la le s fla m m atorV in responses throughout the bodg.D i srupti on ofthese communi cati onsn anU i pression,melancholia, actuallynot a wa g le a d sto g r e a lersuscepti bi l i tg di seaseand i mmunecompti cati ons. to is stateof inactivation and suppression of thought and feeling;rather it presents as patientswith major depression deter- sponse to supportthe concept that melan\ an o rg a n i zedr ar eoi. t n\ ie ry .fh e a n \i - minervhet rheexce)5ive el ot .orri her le\ cholia is associated with a chronic strcss ety of melancholiais chieflyabout the sol associated with depression correlates t.g.pon.e. ret,'.reguJlr'. nut a!ure, In hut self.Melancholicpatients feelimpover- with suppressed immuneresponses. Some administrationof the tricyclicantidepresished and defective and often express hare founda correlarion ber,,r hyper- sant imipramine signi{icantlylowers the een hopelessness about the prospects their cortisolism for and immunosuppression; oth, level'of ( RH precur.ors rhehl porha in lunworthy selvesin either love or work. ershavenot. Because depression have amus.lmipramine can givenfor two monthsto The anxious hyperalousalof melan a varietyofmental and biochemical caus- healthy peoplewith normal cortisol levcholic patients also manifests a perva- es,only somedepressed as patientsmay be elscauses gradualandsustained a decrease sivesense vulnerabiliry. of immunosuppressed. i n C R H .ecreti on and orher H P A ar is Melancholicpatientsalsoshow be The excessive secretionof cortisol il funcrrons. icar rhcr dovr irrd ing rr-regution la havi o ra a l t er c r r on'ugge. ri vo f p h y ' i o - m e l a c h o l i cp a ri enr\r\ predomi nanrl y ofimportant components l r e n ofthe stress relogical hyperarousal.They characterrstr, rh e re < u l ro f h ypersecreri on t R H , .ponse .rnintrin<ic of is effecr imipramine. of cally suffer from inson.rnia (usually early- causedby a defectin or above the hyp<-,, D epre" i oni . rl .o ar.oci ai ed i i h i r r w morning awakenimg)and experience rh rl rn ru s . fh u ., rhe cl i ni .el and bi o- flammatorydisease. About 20 percentof inhibitior.r eating,sexual of acriviry and chemicalmanifestationsof melancholia patientswith rheumatoid arthritis develmenstruation.One of the most widely reflecta generalized stressresponse that op cl i ni caldepre.ti orr. que.rronna ir e A found biologicalabnormalities patients hasescaped usualcounterregulation, commonly usedby cliniciansto diagnose in the " with melancholiais that of sustained hy- re m a i n i n g .ru c in Lhe on" po.i ti ol . l depression containsabout a dozenquespersecretion cortisol. of The effectsof tricyclic antidepressant tion. tharc reolmostalrray' antt'r ered fa Many studies havebeencorlducted on drugs on components of the stressre- firmatively by patientswith arthritis.
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INTERACTIONTHEBRAIN OF ANDIMMUNE SYSTEM

T H EH I D D E N I N D 87 M

ln the past,thc associrrtion benveen an inflanlmatorydisease stress and rvasconsidered doctorsto be secondary rhe by to chronicpair and debilitation the disof ease. recent The discovery ofthe common underpinning the immuneand stless of responses proviclean explanationof may why ir pirtient can be susceptible l.xrth to inflammatory disease depression. and The hormonrl dvsregullrtion that Llnderlies both inflamnrarory clisease depresand .iun ian le3cl eitherillne". dcpenrling to , 'n rvh e rher he per t ulh i n gs ti n ru l u s s r i pro-infilammatolyor psychologically stressful. irtmrv explain Th why thewax-

dividual's susceptibility infectious to disI e.rse'. he regul.rtiorr rhe imrnu .y'' oI ne tem by the neurohormonalstress systen't providesa biologicalb:rsisfor understandinghow stress might affectthese diseases. Thus, stresshormonesreleased fron the brain, corrisol from thc adrenal glands,and nervechemicals released frorl nelve endings(adrenalinlike molecules norepinephtine epinephrine) modand all i fv rh erb i l i rl o f i rrmunecel l ' ro fi ghri nfe,. ti<rur .tgentr rrrd f,,reign rnolecule.. There is evidence that srress doesaffecthumanimnrune responses viruses to :rnd bacteria. studies In with volunteers

es, such as herpesand influenzavirus. A ni rral strrdi e. pr,rvi dcfurrherevidencethat stress affectsthe courseand severity viral illncss, of bacterial disease and septic shock.Stress miceworsens in the severiry ofinfluenza infectionthrough both the HPA axis :rnd the symparhenc nervoussystem. Animal studies suggest that neuroendocrine mechanisrls could play a similarrole in infections rvith other viruses, including HIV, and providea mechanism urderstanding for clinicalo[rseryati()lrs that stress mav exacerbate the course AIDS. Stress, of throughcortisol, i ncreares the.Lrscepri bi lof nri ce ini ry ro

STRESS CAN AFFE,CT

ing and rvaning depression arthntrc of in paiierts dues ro!.ll\virr. eoirrcidc rvrrhinflammatorvflare-ups. The populalbeliefthat stress exrcerI 'cte 'i nfl r m r nat' r y illnc : .an d rh ;r l e l arr rrtioD renlovil of 5lres5 or itIlleliurrtc5 it nrayindeed havca b:rsis fact.The rnin teractions thc stless of and innrune svstemsand the hormonal responses they have commoncouldexplainhow conin sclousattemptsto tone dolvn respollsrvlt1,to stresscould affectirrmuneresponses. given a standarddose of the common fection rvith mycobacteria,the bacteria cold virus (rhinovirus), individuals rvho that causestuberculosis. has becn It irre simultaneously exposed to stress shownthat an intactHPA axis prorects show more viral particles and produce rats againstrhe lethalsepriceffectsof salmorc nlLlcLrs than do nonstressed indi- monella bacteria.Finally, new underviduals. Medicalstudents receiving hep- standingof interactions the immune of atitisvaccin:rtion duringtheirfinalexams and stress responses helpexplain can the do rrorJerelopfull prorccrron hell- puzzling psychoagJinst obse :rtionthat classic These findings irtitis. haveimportantrm- logical conditioning animals influof can plications publichealth. for People who encetheir immure responses. exarr For ilre vaccinated during periodsof stress ple,rvorkingwith miceand rats,Robert rn i g h tb e l e s s i kel l to derel op[ul l anri Ader and Nicholas Cohen of the Univerl bodyprotection. Chronicstress pro- si ty oi R ochester red pai also t ln ' rcehari n longswound healing. voredrvrterwrrhan imnrunosupprcssive Nerv researchshorvsthat at physlo- drug.Eventually saccharin pro the alone logicalconcenrr:rtr,rns trnder .rnd cerlain duced deereese irnlnune a in funcnon \inrconditionsthe stresshornone cortisol ilar ro tl.rat the drug. of not only is immunosuppressive also but may enhance certainaspects immune of function.Furthcrmore, eachpart of the \ l l i l \\ :,J(,1u\l Y l \ P crs< rrra l is bur stress response-the brainJrorntonal,the perceived through the prisrr.r socialinof nerve gland teractions. irdrenalinlike andtheadrenal Theseinteractions eiuer can .td rc n a l rn -i sr egrrl rtcd rndepcndenrl y. add to or lcssen psychological sress and depending tlre natureof the stressful effect our hormonal resf\on\es it. on lo stimulus.Tlris specific narureof the stress rvhicbin turn crrnalterimmule responsresponse explainshow differcnrkinds es. Thus,thc social-psychological stresses and parterns stress of rtur affectillness differ- th.lf we expenence af[e,.'t ,'rrrcepaan ently.Therefore, whereas chronicstress tibiliry to inflammatoryand infectious is generallyimmunosuppressive, acute diseases well asthecourse these as of and stress enhance can cell-mediated imnru otherdiseases. instance, humans, For in nity ald exacerbate contircrdermatitis loneliness associated is with a "threar," typesof allergic patternof activation skin reactions. Further- or adrenalinlike of more, animal studiesshorv that social the srress response and high blood presstress and physical havedifferent sure, lvhereasexercisingis associated stress effccts infection on rvith differentvirus- with a "cl.rallenge" patternof highblcxrd
TH E H ID D E N MIN D

Hov N!ucH ofthe responsivity stress ro is genetically determined horv rluch and can be consciouslycontrolled is not known. The set point of the stressrely : \p o n \e\ l( , \ O nr e t entg e rre ti c a l d e i ex termined.In addition, factorsin early dev e l o p menrI.e, r r ning, , r r rd re l e ' ,p e ri l .r contlibuteto differences stress ences in re \n o n siv ene\A.n ev c nrth l r i . p h y ' i o \ logicallyhighl,v stressful one individual to may be mucb lessso to :rnother,dependrngon rhe srrmoi c.rchper'\on ger)elic s tendencv l'rormonalreactiviryand their to previous experience. degree rvhich The to rrrcrs rldprecipir.rte erlcerbatcdis, rl cur rvouldthen depend ease not onlv on the intensityand duration of the stressful stimulus alsoon the person's but learned perception the eventas stressful of and on the set point of the stresssysteD. .rlc'r carraffcct.rninPslchol,rgic.rl

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I t " l l ,l u NE I G NAL T 0 T H EBR A I N i a t h e S S v bo odstr eam c ano c c u r d i r e c l l U o r i n dir e ctlg . a lr nmune ellss uc ha s m 0 n o c g l e s , t g peo f!./h a te c b o odcell,produce a h e m i c a l m e s s e n g e r ca lle d c ln lerl e uk in" l lL-1 1w h l c ho r d i f a r i l !w ll n o t p a ss { , r h r ough he blood - b r a ib a f i i e rB l t c e rta ln t n l c e re brabloodv ess es c o n t a i ne a k U j u n ctio n s, wh i cha lowlL'lmo l e c u l e s t o p a s s i n l o th e b fa in . a T here e! c an ac t i v a l e h e H P A x i sa n do th e r rh t ne ural s gs t emslL - l a l s o b l n d s t o r e c ep lo r so n th e th ve en do(hellalc ells a t I n e c e r e b r a l b l o o d sses. T hi sb i n ding an c a u s e n z u m e sn t h e ce llsto c e pr oduce c ox id e r p r o s l a g l a n d i nw h ich s, nilr o o d f f u se n lot he bra n a n da c t d i r e c t l g n n e u r o n s.

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flow and cardiacoutput. Studies have shownthat peopleexposed chronicso to fol cial stresses more th:rn two months to have increased susceptibility the common coid. hr OL h e strrd ies r e. hnr rn r h rt th ci m r mune responses long-termcalegivers, of patients, of suchas spouses Alzheimer''s Inrmune responses durbecome blunted. ing mariral discordarealsobluntedin the (usually wife)who experiences the spouse and feelings the greatestamountof stress ofhelplessness. sucha scenario, In studies Leakgj uncti o n i n bl oodhave found that the levelsof stressborC gcl ooxggenase brai n barri er monesare elevated the affected in spouse. Prostaglandins On the othel hand, a positivesupjr:ldrf portiveenvironment extensive of social networksor grouppsychotherapy e[- brain and immune systemprovidesa fect the immune systemmay be usefulin can disorders. There hance inmune response resistance and to physiological explanationof why such treatingsomepsychiatric Disruptionof is growing evidence that our viervof ourhave curessometines\,vorked, disease-even cancer. Some studies our.ryl e uf handl i rrg network leadstc-, au .el re. arrdorhers. shown that q'omenwith breastcancer, this communicatior-r r'r and stresses) our geneticmakeup can afand in to for irr'trrtce. ho re,eire .rrong.po.irire increase susceptibility disease .).trm. :i r i l arr thel ei ' y. rhe have can worsen the course of the illness. fecr i mmune socialsupportduring their illness n goodevidence thatdiseases associated with longellife spans than women R e .to ra ti o n t th rr cornrnuni .arron significar.rtly ' ).significantlyaffect tem, whether through phalr.racological chronic jnf1arnmation without suchsupport. or ofa spa,can one'smood or levelof anxiety.Finally, Fol centuries, taking the cure at a agents the relaxingeffects that of findingssuggest classilication mountairlsanatorium a hot-springs be the first stepon the road to recovery. these or into spefor A corollaryofthese findings that psy- illnesses medicaland psychiatric is spawas the only available treatment that and nany chronic diseases. understand- choactive New drugsnlay be usedto treat some cialties, the boundaries havedemind and body, are artificial. m the inflammatory diseases, drugsthat af- marcated and ing of the communication between

Measuring Stress: Guide Health Social A for and Scientists. lJnderwood Ediled Sheldon bg Cohen, aldC.Kessler Lgnn Ron and 60rdon. 0xford Universitg Press, 1998. Guideto Stress-Related 0isease Whg Zebras Don't Ulcers:An 6et Updated 1998. andCoping. Robert Sapolskg.H.Freeman CompenU, lvJW. and Barrier. L.Rubin J. M.Staddon L. and TheCell Biologg ofrheBlood-Brain inAnnuolReview of Neuroscience, 22,pages Vol. 11-28;1999. bU and The Biological Basis Mind for Bodg Interactions. Edited E.A.lVaUer B. ProgressEroin in Reseorch,Vol. t22.Elsevier Science,2000. C. Saper. The Autonomic Nervous Sgstem Health 0isease. in and 0ekker, 2001. 0avid Goldstein. S. [4arcel

H The B al anceWi thi n:TheS ci enceC onnecti ng eal th and E moti ons. 2001]. H , E sther14. ternberg. enrgH oh and companU2000 [paperbound, S of S ci enceof Mi nd-B od!:A n E xpl orati on Integrati veMechani sms. 26 N Insti tutesofH eal th, vl arch 28, l V i deocastof conference, ati onal 2 001. Thevi deocast can be foundonl i neet http://vi deocast.ni h.gov/P estE vents.asp?c+1& s+51 N euroendocri ne egul ati on Il nmuni tg.JeanetteL Webster, R of of Tonel l i and E stherl V .S ternberBn,4nnual R evi ew i Leonardo l mmunol ogg,V ol .20,pages 125 163;2002. N eurall mmune Interacti onsi n H eal th and D i sease.E stherM.S ternberg l and J. l . Webster n Fundomentolmnunol ogg.Fi fth edi ti on.E di tedbg i Li Wi & Wi l l i amE . P aul . ppi ncott l l i ams Wi l ki nsIforrhcomi ng].

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