课件文稿分析anxiety disorderthe neurocircuitry of fear stress and disorders

TheNeurocircuitryofFear,Stress,andAnxietyLisaMShin*,1,2andIsrael3AnnArbor,MI,USA;DepartmentofPsychiatry,UniversityofMichigan,AnnArbor,MI,USAthebraincircuitsthatunderliethem.Researchontheneurocircuitryofanxietydisordershasitsrootsinthestudyoffearwellasneuroimagingstudiesofanxietydisorders.Ingeneral,thesestudieshavereportedrelativelyheightenedamygdalaactivationinresponsetodisorder-relevantstimuliinpost-traumaticstressdisorder,socialphobia,andspecificphobia.Activationintheinsularcortexappearstobeheightenedinmanyoftheanxietydisorders.Unlikeotheranxietydisorders,acquiredsignsofthedisordersorvulnerabilityfactorsthatincreasetheriskofdevelopingthem,(3)linkthefindingsoffunctionalneuroimagingstudieswiththoseofneurochemistrystudies,and(4)usefunctionalneuroimagingtopredicttreatmentresponseandassesstreatment-relatedchangesinbrainfunction.Anxietydisordersaremarkedbyexcessivefear(andavoidance),ofteninresponsetospecificobjectsorsituationsandintheabsenceoftruedanger,andtheyareextremelycommoninthegeneralpopulation.Accordingtoarecentepidemiologicalstudy,thelifetimeprevalenceofanyanxietydisorderis28.8%(Kessleretal,2005).Anxietydisordersareassociatedwithimpairedworkplaceperfor-manceandheftyeconomiccosts(Greenbergetal,1999),aswellasanincreasedriskofcardiovascularmorbidityandmortality(Albertetal,2005;Kawachietal,1994;Smolleretal,2007).Giventhatanxietydisordersareasignificantprobleminthecommunity,recentneuroimagingresearchhasfocusedondeterminingthebraincircuitsthatunderliethemtoinformtheuseofexistingtreatmentsandguidethepossibledevelopmentofnewtreatments.Inthefuture,neuroimagingstudiesofanxietydisordersmayalsoprove

*Correspondence:DrLMShin,DepartmentofPsychology,TuftsUniversity,490BostonAvenue,Medford,MA02155,USA,Tel:+6176272251,Fax:+6176273181,Email:tobeclinicallyhelpfulinthepredictionoftreatmentresponse.Giventhatexcessivefearisakeycomponentofanxietydisorders,itisnotsurprisingthatthesearchfortheneurocircuitryofanxietydisordershasitsrootsinandhasbeencloselyintertwinedwithstudiesoffearcircuitsinanimalmodels.Alargevolumeofexperimentalworkhasexaminedtheneurocircuitryassociatedwithfearresponses,mainlyinrodents,usingprimarilyfearconditioning,inhibitoryavoidance,andfear-potentiatedstartlemodels.Keycomponentsoffearcircuitryincludingtheamygdala(anditssubnuclei),nucleusaccumbens(includingbednucleusofstriaterminalisBNST),hippocampus,ventro-medialhypothalamus,periaqueductalgray,anumberofbrainstemnuclei,thalamicnuclei,insularcortex,andsomeprefrontalregions(mainlyinfralimbiccortex)havebeenidentifiedinthesestudies(forrecentreviewsseeDavis,2006;Maren,theirrespectiverolesinthevariouscomponentsoffearprocessingsuchastheperceptionofthreatorofunconditionedstimuli,thepairingofanunconditionedstimulusandconditionedresponse(learning/conditioning),theexecutionofefferentcomponentsoffearresponse,andthemodulationoffearresponsesthroughpotentiation,contextualmodulation,orextinction.Somekeyfindingsfromanimalliterature,suchasthecentralroleofamygdaloidnucleiintheacquisitionoffearconditioningandexpressionoffearresponses,theinvolvementofthehippocampusincontextualprocessing,andtheimportanceoftheinfralimbiccortexinextinctionrecall,havebeenreplicatedacrossdifferentstudiesandlaboratories.Thesebasiccomponentsoffearcircuitryarewellpreservedacrossspeciesandlikelysupportsimilarfunctionsinhumans.Animalworkusinginvivoelectrophysiologicalrecording,tracingandlesions/reversibleinactivationtechniqueswasindispensableinacquiringthisknowledge.SomerecentworkhadevensuggestedthattheremightbeseparatefearandanxietysystemsorchestratedthroughthecentralnucleusoftheamygdalaandtheBNST,respectively(Davis,2006).Thesetypesoffindingsareparticularlyexcitingastheymightallowforabetterfocusontheneurocircuitsinvolvedinpathologicalanxiety.Ontheotherhand,otherimportantissues,suchastheexactneuroanatomicalregionthatstoresfearmemorytraces,ortheexactroleofaparticularprocess(eg,theroleofreconsolidationinfearmemory,NaderandHardt,2009),orofaparticularregion(eg,theinsularcortex)areintenselydebatedandactivelystudied.Nevertheless,thebasicfear-relatedneurocircuitryidentifiedinrodentsisausefulplacetostartexamininganxiety-relatedneurocircui-tryinhumans.Itisimportanttonotethattheexactrolesofmanybrainregionsareyettobefirmlyestablishedandcoulddifferacrossspecies.Evenregionssuchastheamygdala,hippocampus,andnucleusaccumbensmightbeinvolvedindifferent,additional,orevenuniquetasksinhumans(eg,theroleofthehippocampusinexplicitverbalmemoryinhumans).Finally,therearemajordifferencesbetweenhumananxiety/anxietydisordersandfearcon-ditioningmodelsinanimals.Thesedifferencesincludethefrequentabsenceofclearunconditionedstimuli(US)inhumananxietydisorders,andthecentralrolesofavoidanceandcognitivecomponents(eg,anticipatoryanxiety)inhumans.Theseuniquecharacteristicsofanxietydisorderssuggestpotentialinvolvementofotherbrainregionsinadditiontothoseidentifiedinrodents,suchasareasofprefrontalcortexthataremoreuniquetohumans.Thus,althoughanimalstudiesareindispensableinunderstanding

basicfearneurocircuitry,invivohumanstudiesarecriticalforunderstandingtheneurocircuitryofanxietydisorders.Inthisreview,wewilldiscussthreemaintopics:(1)fearneurocircuitryinhealthyhumans;(2)stressasanormalresponsetointernalandexternalstimuli,and(3)anxietydisordersasdefinedinhumanpsychopathology.ThefirstofthesetopicswillincludeadiscussionofPavlovianfearconditioningandextinction,pharmacologicallyinducedfearandanxietystates,andtheassessmentofemotionalstimuliinhumans.Inthethirdtopic,wereviewtheroleofbrainregionssuchastheamygdala,medialprefrontalcortex(includingtherostralanteriorcingulatecortex(rACC)anddorsalanteriorcingulatecortex(dACC)),hippocampus,andinsularcortexinanxietydisorders(Figure1).Finally,wediscusssomeofthelimitationsofneuroimagingstudiesofanxietydisordersaswellasthedirectionsthatweexpectthefieldtotakeinthenearfuture.(ForanoutlineofthisreviewseetheAppendix.)conditioninginvolvesrepeatedlypresentingapreviouslyunconditionedstimulus(US;eg,ashock).Afterrepeatedpairings,theCSalonecomestoelicitaconditionedfearresponse(eg,increasedfreezing,fear-potentiatedstartle,orbeenusedasatestableandtranslational,thoughadmittedlysimplistic,modeloftheacquisitionoffearsthatmightberelevanttosomeanxietydisorderslikephobiasandpossiblytosomeaspectsofpost-traumaticstressdisorder(PTSD).StudiesofPavlovianfearconditioninginnon-humanshavehighlightedtheimportanceoftheamygdalaintheacquisitionoffearconditioning(LeDoux,2000;LeDouxetal,1990;Pareetal,2004;SananesandDavis,1992).Similarly,functionalneuroimagingstudiesinhumanshavereportedamygdalaactivationduringfearconditioning(Alvarezetal,2008;BarrettandArmony,2009;Bucheletal,1998,1999;Chengetal,2003,2006;GottfriedandDolan,2004;Knightetal,2004,2005;LaBaretal,1998;Miladetal,2007b;MorrisandDolan,2004;Pineetal,2001;Tabbertetal,2006),evenwhentheCSispresentedbelowperceptualthresholds(Critchleyetal,2002;Knightetal,bbInsularHippocampusdorsalanteriorcingulatecortex(dACC)andtherostralanteriorcingulatecortex(rACC);and(c)theinsularcortex.2009;Morrisetal,2001)andevenwhenmorecomplexUSsareused(Doronbekovetal,2005;Kluckenetal,2009).Inaddition,amygdalaactivityhasbeenassociatedwithskinconductancechangesduringfearconditioning(Chengetal,2006;Furmarketal,1997;LaBaretal,1998;Phelpsetal,2001).Interestingly,amygdalaactivationinhumansalsohasbeenobservedinresponsetocuesfollowing(1)verbalinstructionsthatdiscriminatebetweencuesthatpredictshockvssafety(eventhoughnoshockwasactuallyadministered)(Phelpsetal,2001),and(2)observationalfearlearning,wherebyparticipantswatchavideoofanotherpersonexperiencingaPavlovianfear-conditioningpara-digm(Olssonetal,2007).Whatexactlyamygdaloidactivationrepresentsintheselatterparadigmsisnotentirelyclear.Itcouldsuggestforexamplethat:(1)higherordercentersthatdeciphertheanticipatedpredictivevalueofthecue,orthatlearnfromobservationusingempathy,conveyinformationtotheamygdala,or(2)alternatively,thatthehumanamygdalaislessspecificinitsresponsesandismoresensitivetocontextualmodulationintheabsenceofaUS.Theseinterpretationscouldhavepotentiallydifferentimplicationsfortheunderstandingoftheroleoftheamygdalainanxietydisorders.FearconditioningisalsoassociatedwithactivationinthedACCandrACC(Alvarezetal,2008;Bucheletal,1998,1999;Dunsmooretal,2007;Kluckenetal,2009;LaBaretal,1998;Marschneretal,2008;Miladetal,2007a,b;MorrisandDolan,2004;Phelpsetal,2004).ActivationinthedACCandrACCalsooccursduringobservationalfearlearning(Olssonetal,2007).Inaddition,dACCactivationispositivelycorrelatedwithdifferentialskinconductanceresponses(Miladetal,2007a).Fearconditioningstudies(involvingbothspecificCSsandcontexts)alsocommonlyreportinsularcortexactivation(Alvarezetal,2008;Bucheletal,1999;Bucheletal,1998;Critchleyetal,2002;Dunsmooretal,2007;GottfriedandDolan,2004;Kluckenetal,2009;Knightetal,2009;Marschneretal,2008;MorrisandDolan,2004;Phelpsetal,2001,2004)andhippocampalactivation(Alvarezetal,2008;Bucheletal,1999;Knightetal,2004,2009;Langetal,2009;Marschneretal,2008).Extinction.ExtinctionlearningoccurswhenaCSthatpreviouslypredictedaUSnolongerdoesso,andovertime,theconditionedresponse(eg,freezingorelevatedskinconductanceresponses)decreases.Extinctionlearningor,morelikely,thelaterrecallofthislearninginvolvestheventromedialprefrontalcortex(vmPFC)(MiladandQuirk,2002;Morganetal,1993;Quirketal,2000,2003,2006)inrodents.FunctionalneuroimagingstudiesofhealthyhumanshavereportedvmPFCactivationduringextinction(BarrettandArmony,2009;GottfriedandDolan,2004;extinction(Miladetal,2007b;Phelpsetal,2004).SkinconductancemeasuresofextinctionmemoryarepositivelycorrelatedwithvmPFCactivation(Miladetal,2007b;Phelpsetal,2004)andvmPFCcorticalthickness(Miladetal,2005).Activationoftheamygdalaandinsular

cortexalsomayoccurduringextinctionlearningorrecall(GottfriedandDolan,2004;LaBaretal,1998;Miladetal,2007b;Phelpsetal,2004),andgreateramygdalaresponsesduringextinctionhavebeenassociatedwithhighertraitanxiety(BarrettandArmony,2009).Finally,extinctioncanbemodulatedbycontext(ie,thesurroundingsinwhichextinctiontakesplace),andthehippocampushasaroleinthisprocess.Inrodents,dorsalhippocampallesionsreducethecontext-dependenceofextinction(Boutonetal,2006).InarecentfMRIstudy,hippocampalactivationtotheCS+occurredintheextinctioncontextbutnotintheconditioningcontext(Kalischetal,2006).HippocampalactivationwasalsopositivelycorrelatedwithvmPFCactivationinthisstudy(Kalischetal,2006),suggestingthathippocampal–vmPFCinteractionsmaybeimportantforthecontextualmodula-tionofextinction.FearStatesandResponsestoEmotionalPharmacologicalchallenge.AnotherwaytoexaminethemediatingfunctionalneuroanatomyoffearoranxietyistousespecificpharmacologicalagentstoprovokesuchstatesinhealthyindividualsduringPETorfMRIscanning.Forexample,cholecystokinin-4(CCK-4)isassociatedwithincreasesinsubjectivestatesoffearandanxiety,aswellasincreasedactivationintheamygdala,insularcortex,claustrum,cerebellum,brainstem,andtheACC(Benkelfatetal,1995;Eseretal,2009;Javanmardetal,1999;Schuncketal,2006).Inaddition,twostudiesreporteddACCincreasesduringanticipatoryanxietyprecedingtheCCKadministration(Eseretal,2009;Javanmardetal,1999).Itisimportanttokeepinmind,however,thatCCK-Breceptoragonistslikepentagastrinalsohavedirecteffectsonstressaxisstimulationindependentoftheireffectsonsubjectiveexperienceofdistress/fear(Abelsonetal,2005,2008).Procaineadministrationhasbeenassociatedwithelevatedsubjectiveratingsoffear/anxiety,activationoftheamygdala,ACC,andinsularcortex(Ketteretal,1996;Servan-Schreiberetal,1998),anddeactivationofneocorticalstructures(Servan-Schreiberetal,1998).Furthermore,amygdalaactivitywaspositivelycorrelatedwithsubjectivereportsofanxiety(Ketteretal,1996;Servan-Schreiberetal,1998).Interestingly,thosesubjectswhodidnothaveapanicattackinresponsetoprocainehadgreateractivationintherACCcomparedwiththosewhodidhaveapanicattack(Servan-Schreiberetal,1998),consistentwiththeideathattherACCmayperformaregulatoryorinhibitoryfunction(Mayberg,1997).Thealpha-2adrenergicantagonistyohimbinehaslikewisebeenassociatedwithincreasednormalizedbloodflowinmedialprefrontalcortex,insularcortex,andcerebelluminhealthyindividuals(Cameronetal,2000).Amajorcaveatintheinterpretationofpharmacolo-gicalchallengestudies,however,isthedifficultyindisen-tanglingtheeffectsthatarespecifictofearinductionfromthedirecteffectofapharmacologicalagentonregionalbrainactivityandfromthenon-specificeffectsofthepharmaco-logicalagent.Emotionalstimuli.Overthepasttwodecades,functionalneuroimagingstudieshaveshownthatacoresetofbrainregionsmediateresponsestoemotionalstimuliinhealthyhumans.(Forreviews,seePhanetal,2002;Phanetal,2004b).Therelevanceofthesestudiestofear/anxietycircuitryistwo-fold:(1)Asignificantnumberoftheseemotionalactivationparadigmsutilizestimulithatdepictand/orelicitfear,and(2)thesestudiesshedlightonmoregeneralemotion-generatingneurocircuitry.PETandfMRIstudieshavereportedamygdalaactivationinresponsetoemotionallynegativephotographs(Brittonetal,2006;Haririetal,2002;Irwinetal,1996;Laneetal,1997a;Paradisoetal,1999;Phanetal,2003b;Reimanetal,1997;Tayloretal,1998),odors(ZaldandPardo,1997)andtastes(Zaldetal,1998).Severalstudieshavereportedamygdalaactivationtopositivestimuliaswell(Garavanetal,2001;HamannandMao,2002;Hamannetal,1999,2002;Liberzonetal,2003),whichsuggeststhattheamygdalarespondsmorebroadlytoemotionallyarousingand/orsalientstimuli(Phanetal,2004b).Reappraisalofemotionallynegativephotographsisassociatedwithreducedamygdalaactivation(Ochsneretal,2002)andincreasedventromedialprefrontalcortexactivation(Urryetal,2006).Finally,amygdalaactivationduringencodingofemotionallyarousingstimuliiscorrelatedwiththesubsequentrecollectionofthosestimuli(Cahilletal,1996;Dolcosetal,2004,2005;Hamannetal,1999).Medialprefrontalcortex,includingtherACC,alsoactivatesinresponsetoemotionalpictures(Laneetal,1997a,b;Phanetal,2003a,b,2004a;Reimanetal,1997)andmaymediateself-referentialprocessing(Kelleyetal,2002;Laneetal,1997a;Zyssetetal,2002).Althoughthemedialprefrontalcortexmayactivateregardlessoftaskorvalence,therACCmaybemorelikelytoactivatewhenacognitivetaskisperformedduringscanning(Phanetal,2002).VentromedialPFCresponsestofear-relatedimageshavebeennegativelyassociatedwithcortisolreactivity(Rootetal,2009).ThedACCalsoactivatesinresponsetoemotionalphotographs(Brittonetal,2006;Teasdaleetal,1999)andaversivetastes(Zaldetal,1998).Finally,theinsularcortexisresponsivetoaversivestimuli(Phanetal,2004a),internallygeneratedsadness(Laneetal,1997b;Reimanetal,1997)anddisgust-relatedstimuli(Brittonetal,2006).Emotionalfacialexpressions.Interestingly,thesameneurocircuitrythathasbeenimplicatedinfear/anxietyresponsesinhumansisreadilyactivatedbystimulithatarenotintrinsicallythreatening,butmayconveyinformationregardingthepresenceofthreatintheenvironmentoraboutthefearfulemotionalstateofothers.Responsesintheamygdalaarereadilyelicitedbyphotographsoffacialexpressions,especiallythoseoffear(Breiteretal,1996a;DavisandWhalen,2001;Fitzgeraldetal,2006;Morrisetal,1996;VuilleumierandPourtois,2007;Whalenetal,2001),evenwhenpresentedbelowconsciousawareness(Morrisetal,1998;Whalenetal,1998,2004).EmotionalfacialexpressionshavealsobeenassociatedwithactivationinthedACC,rACC,medialfrontalgyrus,andinsularcortex(Fitzgeraldetal,2006;Gorno-Tempinietal,2001;Morrisetal,1996;Phillipsetal,1997,2004;Sabatinietal,2009;Sprengelmeyeretal,1998).

Brainresponsestotherelativelyambiguousfacialexpressionofsurprisehavebeenshown,insomestudies,todependontheextenttowhichindividualsubjectsinterpretedtheseexpressionsaspositiveornegative;morenegativeinterpretationswereassociatedwithgreateramygdalaandlowerventralmedialprefrontalcortexactivation(Kimetal,2003).Thesefindingsareconsistentwiththenotionthattheamygdalaandmedialprefrontalcortexarereciprocallymodulated(eg,Garciaetal,1999).Furthermore,theexperimentalmanipulationofthecontextinwhichsurprisefacialexpressionsarepresentedaltersbrainactivationpatternsinasimilarway:surpriseexpressionsassociatedwithanegativecontextelicitedmoreamygdalaactivationthanthoseassociatedwithapositivecontext(Kimetal,2004).TheseamygdalaactivationswereOfrelevancetoourlaterdiscussionofanxietydisordersarefindingsthatsuggestthathealthyindividualswithhighscoresonanxietymeasureshavegreateramygdalaandinsularcortexresponsestoemotional(angry,fearful,andhappy)facesandlessrACCactivationthanparticipantswithnormativescoresonthesemeasures(Bishopetal,2004a,b;Steinetal,2007).Similarly,traitanxietyhasbeenpositivelycorrelatedwithamygdalaresponsestoneutralfaces(Somervilleetal,2004).Studiesoffearconditioning,pharmacologicallyinducedfear,andresponsestoemotionalstimuliandfacialexpres-sionshaveprovidedevidencethatthehumanamygdala,althoughresponsivetomultiplesalientstimuli,respondsreliablyandpotentiallypreferablytostimulithatpredictthreatandcanbeinvolvedinmediatingfear/anxietystates.Giventhatpatientswithanxietydisordersexperiencefearanddistressinresponsetopossiblepredictorsofthreat,theamygdalahasbeenhypothesizedtobehyperresponsiveinsomeanxietydisorders.Inthenextsection,wewillreviewtheevidencerelatedtothishypothesis.StudiesofextinctionhavehighlightedthepotentialinvolvementofthevmPFCandhippocampusintheprocessoflearningandrememberingthatstimulithatusedtopredictthreatnolongerdo.Onepossiblereasonforexaggeratedfear,anxiety,anddistressinpatientswithanxietydisordersisthattheseemotionalresponsesfailtoextinguishorthatextinctionlearningisnotrecalledevenwhenspecificcuesnolongerpredictthreat.Indeed,somestudieshavereportedimpairedextinctioninseveralanxietydisorders,suchasPTSD(Blechertetal,2007;Miladetal,2008;Orretal,2000;Perietal,2000;WessaandFlor,2007).Thus,thevmPFCandhippocampusareclearregionsofinterestinfunctionalneuroimagingstudiesofanxietyFinally,boththeanimalliteratureandstudiesreviewedabovesuggestthatthedACC(anditslikelyhomologprelimbiccortex)andinsularcortexrespondtoemotionalstimuliorthosethatpredictthreat.Aswiththeamygdala,hippocampus,andvmPFC,theseregionsareinvolvedinmultipleotherfunctions;however,theymightalsohaveimportantrolesinspecificaspectsofanxiety.Forexample,theinsularcortexisthoughttomediatethemonitoringofinternalbodystates,andhasbeenfoundtobehyperresponsiveinanxiety-proneindividuals(PaulusandStein,2006).Insummary,researchonhealthyindividualshassuggestedthatallofthesebrainregionsareprimecandidatestoexamineinpatientswithanxietyAnimportantandoftenoverlookedaspectofthefear/anxietyneurocircuitryisitsoverlapandinteractionwiththeneurocircuitrythatorchestratesthestressresponse.Itisimportanttonotethattheconceptof‘stress’usedhereisrelativelyspecific.Itdoesnotencompassgeneralconceptsof‘subjectivedistress’or‘performanceload.’Althoughtheseareusefulconcepts,theyareheterogeneousbynatureandarenotlikelytobeassociatedwithaspecificneurocircuitry.Ontheotherhand,theconceptofastresssystemthatleadstoactivationoflimbic–hypothalamo–pituitary–adrenalaxis(LHPA)andsecretionofstresshormoneslikecorticotropin-releasinghormone(CRH),adrenocorticotropichormone,andcortisolisquitespecificandislikelytobehighlyrelevanttotheneurocircuitryoffearandanxiety.TheneurocircuitrygoverningLHPAactivationhasbeenthefocusofintensestudiesinrodents,primates,andhumansbecauseithasbeenrepeatedlylinkedtotheneurobiologyofmooddisorders(whichisaddressedindetailelsewhereinthisvolume),buttheevidencelinkingLHPAaxisabnormalitiestoanxietydisordershasbeenlessconsistent,sometimesconfusing,andoftenoversimplified.Atthesametime,someofthesamebrainregionsareimplicatedinbothanxietyandstressresponses,suggestingthattheseresponsesareinterrelatedandcaninfluenceeachother.Furthermore,anxietyandmooddisordersarehighlycomorbid,suggestingthatsomecommonabnormalitiesinneurocircuitrymightbepresentinbothdisorders.Inthefollowingfewparagraphs,webrieflyaddressonlythestructuraloverlapinneurocircuitsandtheeffectsofstresssystemactivation(orstresshormones)onanxiety/fearEpidemiologically,majordepressionishighlywithanxietydisorderslikePTSD,panicdisorder,andsocialphobia(Reigeretal,1990),andanxietysymptomsarehighlyprevalentindepression(Francesetal,1990).Furthermore,majorsubcorticalcomponentsoftheLHPAaxis(eg,hypothalamus,hippocampus,amygdala,andBNST)havealsobeenidentifiedaskeycomponentsofanxiety/fearneurocircuitry(albeitsometimesinvolvingdifferentsubnuclei,forexampleparaventricularnucleivsventromedialhypothalamusforLHPAandfearneurocir-cuitry,respectively).Morerecentlywiththeintroductionof

invivoimagingmethodologiesinLHPA/stressresearch,theroleofcorticalstructuresliketheinsulaanddorsalmPFCintheactivationandinhibitionofstressresponse,respec-tively,hasbeenreported(LiberzonandMartis,2006)aswellastheroleofsubgenualACCinself-inducedsadnessanddepression(Maybergetal,1999).Together,thesefindingssuggestasignificantoverlapinstructuresinvolvedinthestressresponseandthoseinvolvedinfear/anxietyresponses(egmedialprefrontalcortex,insula,amygdala,hippocam-pus,andBNST).Finally,withrespecttoneurotransmittersLHPAaxisactivityandmanyanxiety/fearresponses.(ForareviewseeHeimandNemeroff,2001.)Theactivationoftheseoverlappingregionsinactivationofboththefear/anxietyresponseandtheLHPAaxis.Asamatteroffact,activationoffear/anxietydoesnotfearful(phobic)individuals(Curtisetal,1976).Inturn,activationofLHPAaxisisnotnecessarilyexperiencedsubjectivelyasfearoranxiety.Forexample,morningawakening,foodintake,andnauseaallleadtoLHPAaxisactivationwithoutnotableincreasesinsubjectivesenseoffear.Itisbecomingincreasinglyclearthatspecificcharacteristicsofexperience(novelty,control,socialsupport,etc.)aremoresalientforLHPAaxisacti-vationthandegreeofsubjectivedistressorfear(Abelsonetal,2007).Thesefactshelptobetterunderstandthefindingsofnon-specific,orevensometimescounterintui-tive,findingsregardingtheLHPAandstressresponsesinanxietydisorderssuchaspanicdisorder(Abelsonetal,2007)andPTSD(Yehuda,2006;Yehudaetal,1991).ThisalsosuggeststhatactivationinspecificcorticalregionslikemPFCorinsulacannotbereadilyinterpretedasacomponentofthefearresponse,andhastobeconsideredwithinacontextofaspecificexperiment,subjectivereport,symptoms,neuroendocrineprofile,etc.Withthesecaveatsinmind,importantfindingsstressexposureandLHPAaxisactivationaffectingfear/anxietyresponseshavebeenaccumulating.Thesecanbeseenintwogeneralcategories:(1)theimmediateeffectsofstressorofstresshormonesonfear/anxietyresponses(eg,stressorstresshormoneexposureimmediatelyprecedes,orispresentduringthefear/anxietyresponses),and(2)delayedordevelopmentaleffects,(eg,stressexposureduringdevelopmentallysensitiveperiods,likeearlychild-hood,modulatesfear/anxietyresponseslaterinlife).Intheformercategory,ithasbeenreportedthatexposuretoacutestressinhealthyindividualspotentiatestheanxietyresponse(Grillonetal,2007).Inaddition,stressexposure(TrierSocialStressTest)ledtoenhancedgalvanicskinresponsestoconditionedstimuli(CS+)duringfearconditioning(Jacksonetal,2006).Interestingly,stressmodulatesfearresponsesdifferentiallyinmenandwomen.Differentialeffectsofstressonfear/anxietyinfemalesvsmalesalsohavebeendemonstratedinanimalstudies.Chronicstressexposureledtoimpairedextinctionrecalloffearconditioninginmalebutnotfemalerats(Baranetal,2009).Stressexposureinanimalstudiesalsoledtoenhancementincontextualfearconditioning(Corderoetal,2003).Theeffectsofstresshormoneexposurearesomewhatmoredifficulttointerpretbecausehigherendogenouscortisollevelswereassociatedwithhigherskinconductanceresponses(SCR)(Jacksonetal,2006),whereasadministrationofexogenouscortisolledtodecreasedSCR(Starketal,2006).Withrespecttodelayedeffectsofstressduringthevulnerabledevelopmentalperiod,thefindingsaresome-whatcomplex.Studiesofearlymaternalseparationinrodents(PlotskyandMeaney,1993)andvariableforaginginprimates(Coplanetal,1996)haverevealedlong-termalterationinstressaxisresponsesandkeyneurotransmittersystems(forreviewseeHeimandNemeroff,2001).Inaddition,recentfindingsofgene-by-environm