Exposed to events that never happen: Generalized unsafety, the default stress response, and prolonged autonomic activity

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Neuroscience and Biobehavioral Reviews

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / n e u b i o r e v

Reviewarticle

Exposed to events that never happen: Generalized unsafety, the default stress response, and prolonged autonomic activity

JosF.Brosschot^a,∗,BartVerkuil^b,JulianF.Thayer^c

aHealth,MedicalandNeuropsychologyUnit,InstituteofPsychology,LeidenUniversity,Wassenaarseweg52,2333AKLeiden,TheNetherlands

bClinicalPsychologyUnit,InstituteofPsychology,LeidenUniversity,Wassenaarseweg52,2333AKLeiden,TheNetherlands

cDepartmentofPsychology,TheOhioStateUniversity,NeilAvenue,Columbus,OH43210,USA

a r t i c l e i n f o

Articlehistory:

Received22January2016 Receivedinrevisedform5July2016 Accepted19July2016

Availableonlinexxx

Keywords:

Defaultstressresponse Chronicstress Generalizedunsafety Perceivedsafety Heartratevariability Obesity

Loneliness

a b s t r a c t

Basedonneurobiologicalandevolutionaryarguments,thegeneralizedunsafetytheoryofstress(GUTS) hypothesizesthatthestressresponseisadefaultresponse,andthatchronicstressresponsesarecaused bygeneralizedunsafety(GU),independentofstressorsortheircognitiverepresentation.Threehighly prevalentconditionsareparticularlyvulnerabletobecoming‘compromised’intermsofGU,andcarry considerablehealthrisks:

(1)‘Compromisedbodies’:inconditionswithreducedbodilycapacity,namelyobesity,lowaerobicﬁtness andolderage,GUispreservedduetoitsevolutionarysurvivalvalue;

(2)‘Compromisedsocialnetwork’:inlonelinesstheprimarysourceofsafetyislacking,i.e.beingpartofa cohesivesocialnetwork;

(3)‘Compromisedcontexts’:incaseofspeciﬁcstressors(e.g.workstressors),dailycontextsthatareneutral bythemselves(e.g.ofﬁcebuilding,emailathome)maybecomeunsafebypreviouslybeingpairedwith stressors,viacontextconditioning.

Thus,GUTScriticallyrevisesandexpandsstresstheory,byfocusingonsafetyinsteadofthreat,andby includingriskfactorsthathavehithertonotbeenattributedtostress.

Contents

1. Theproblemofchronicstressresponsesanditsnewhypothesizedsolution.........................................................................00

2. Thegeneralizedunsafetytheoryofstress(GUTS)......................................................................................................00

3. Feelingunsafeinasafeworld:theneurobiologicalandevolution-theoreticalbasisofGUTS........................................................00

3.1. Prefrontalinhibitionofsubcorticalexcitation..................................................................................................00

3.2. Economicinhibition,quickandwastefuldisinhibition.........................................................................................00

3.3. Defaultstressresponse=/ defaultmodenetwork .............................................................................................. 00

4. Predictingstressorsandrecognizingsafety:aroleforthevagus......................................................................................00

4.1. Defaultstressresponsesto‘safe’stimuliandlowheartratevariability.......................................................................00

5. Deﬁcientsafetylearningduringdevelopment.........................................................................................................00

6. Three‘safety-compromised’domainswithchronicstressresponses.................................................................................00

6.1. Compromisedbodies:stressresponsesinlowﬁtbodies.......................................................................................00

6.1.1. Akilomoreoffatmeantalesssafeworld............................................................................................00

6.1.2. GUTS:moreparsimoniousexplanation...............................................................................................00

6.2. Compromisedsocialnetwork:lonelinessandperceivedunsafety.............................................................................00

6.3. Compromisedcontexts:context-conditionedstressresponseswithoutstressors............................................................00

6.3.1. Failuretorecognizecontextsassafe..................................................................................................00

∗ Correspondingauthor.

E-mailaddresses:brosschot@fw.leidenuniv.nl(J.F.Brosschot),bverkuil@fw.leidenuniv.nl(B.Verkuil),Thayer.39@osu.edu(J.F.Thayer).

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7. Concludingremarks ..................................................................................................................................... 00 Acknowledgements ..................................................................................................................................... 00 References..............................................................................................................................................00

1. Theproblemofchronicstressresponsesanditsnew hypothesizedsolution

Psychosocial stress, including chronic anxiety, is a major riskfactor for somaticdisease,including cardiovasculardisease (Kiecolt-Glaseretal.,2002;KrantzandMcCeney,2002;Kubzansky andKawachi,2000;Roestetal.,2010;Rosengrenetal.,2004;Searle andBennett,2001;Tullyetal.,2013).Thestressorsforwhichthis isbestdocumentedareworkstress(Bosmaetal.,1998;Matthews andGump,2002;Chandolaetal.,2008),maritalstress(Matthews andGump,2002;Orth-Gomeretal.,2000)andbereavement(Lee etal.,2003;Vitalianoetal.,2002).Still,theunderlyingpsychophys- iologicalmechanismsremainpoorlyspecified.Itiswidelyagreed thatchronicphysiologicalstressresponsesarethecrucialcausalfac- torleading todisease,but despitemore than halfa century of research,theprecisecausesofthesechronicresponseshavenot yetbeen sufficientlyrevealed.Conventional stresstheories still embracethereactivityhypothesisthatholdsthatmultipleintense responsesduringstressorsareimportant.Thesetheoriesneglect a crucial aspect: the duration of the exposure that often out- laststhestressfuleventsthemselves.Wepreviouslyhypothesized thatactuallyoccurringstressorsarefarlessimportantthanwhat happensinpeople’sthoughts,thatis,theircognitiverepresenta- tionsofstressors,termed‘perseverativecognition’(PC;Brosschot etal.,2006;seealsoFig.2a).PCmayevenbelargelyunconscious (Brosschot,2010;Brosschotetal.,2010)butstillleadstoprolonged physiologicalstressresponses(ibidem).PCisnotonlyacoreele- mentchronic stress,but alsoin chronic anxiety,and thelatter canbeeasilyconceptualizedasachronicpsychobiologicalstress responseintheabsenceofrealisticstressors(e.g.Hoehn-Saricetal., 2004;Lichtetal.,2009;Thayeretal.,1996).Despitegrowingevi- dencethatPCcausesprolongedphysiologicalresponses,especially forcardiovascularandendocrine(i.e.cortisol)activity(Brosschot etal.,2006;Ottavianietal.,2015;Verkuiletal.,2010;Zoccolaand Dickerson,2012),itisstillfarfromexplainingmostof,letalone allof,theoftenextremelyprotractedstressresponsesassociated withchronicstressorssuchasworkstress,maritalstressorloneli- ness,chronicanxiety,andtheirpsychophysiologicalconcomitants suchascontinuouslyincreasedrestlevelsofbloodpressure,cor- tisolorlowheartratevariability(HRV;RoblesandKiecolt-Glaser, 2003;Thayeretal.,2010).Whatcausesthese,oftentrulychronic, responses,whichovertimewillresultinbiologicaldysregulation (Brosschotetal.,2006),or‘allostaticload’(McEwenandSeeman, 1999)?Itseemsunlikelythatpeoplethinkincessantlyabouttheir stressors,eitherconsciouslyorunconsciously(thisproblemisillus- trated in Fig. 1a–c). Butif PCcannot sufficiently explain truly chronicresponseswhatelseexplainsthem?Inthisarticle,wetake aradicallydifferentviewpointbyposingthatnotPCbuttheauto- matic(i.e.largelyunconscious)‘generalizedperceptionofunsafety’is thecrucialexplanatorymechanism.Howmightthisnewideasolve theproblemofwhatcauseschronicphysiologicalresponsesthat, inthelongrun,leadtodisease?Usinganewtheoreticalapproach, calledthe“GeneralizedUnsafetyTheoryofStress”(GUTS),wepro- posethatthesolutionliesinthefactthatthewayinwhichthe problemisphrasediswrong.

2. Thegeneralizedunsafetytheoryofstress(GUTS)

Currentneurobiologicalevidence(e.g.Ahernetal.,2001;Amat etal.,2005;Motzkinetal.,2015;GrupeandNitschke,2013;see

below)andevolutionaryreasoning(e.g.Nesse,2005;Trimmeretal., 2013seebelow)implythatthestressresponseisadefaultresponse oftheorganism,andthatitistheresponsetheorganismautomat- icallyfallsbackuponwhennootherinformationisavailable.So, theproblemshouldnotbeformulatedas:“whatcauseschronic stressresponses?”butas“whatmechanismallowsthedefaultstress responsetobeturnedoff?—andwhendoesthis‘switchoff’mode failtowork?”Toanswerthislastquestionisthechiefgoalofthis article.We hypothesizethat themechanismthatexplainsmost chronicstressresponsesindailylifeisthegeneralizedperception ofunsafety(GU),thatislargelyautomatic(andasaresultmainly unconscious).Theargumentinanutshell:GUcausesthedefault stressresponsetoremainactivated,wheneverourphylogenetically ancientmind-bodyorganismfailstoperceivesafetyinawiderange ofsituationsinmodernsocietythatarenotintrinsicallydangerous.

Thisnewexplanationformsaradicalshiftfromcurrentstressthe- ory–includingourownPChypothesis–thatfocusesonstressors andPC.Itcomprisesacompletelynewtheorycalled,asmentioned, the“GeneralizedUnsafetyTheoryofStress”(GUTS).Akeyprin- cipleofGUTSisthatnot beingabletoswitchoff, orinhibitthe defaultstressresponseisnotdependentonactualstressorsorPC:

perceivedGUissufﬁcient,GUisthecrucialelementhere.Dueto GU,chronicstressresponsesoccurinanobjectivelysafeworld,with nothreateninginformation.TheGUTShasafargreaterexplanatory abilitythanothercurrentstresstheories.Mostesentially,aswewill explicatebelow,itpredictshowprolongedandevenchronicstress responsesoccurwhennoactualstressors(threats)arepresentatall, orevencognitiverepresentationsofstressors,becauseofthecon- tinuousfailuretoperceivesafety.Therefore,itcanexplainamuch highernumberofhypotheticalsituationsinwhichstressresponses mayoccur. Forlargegroupsofpeople,thismeansallsituations, e.g.inpeoplewithasocalled‘compromised’bodyorsocialnet- work,asweshallexplainbelow.GUTSisthuslikelytobefarbetter atexplainingprolongedorchronicstress-relatedphysiologicalactiv- ity.Withincreasingchronicstressaswellasboominghealthcare costsinoursocietyitisverytimelytotestthisnewtheory.Wewill furtherdetailthehypothesesofGUTSbelow.

Before doing so, we would like to point out that these hypothesespertainnotonlytostressbutalsotoanxietyandits (neuro)physiologicalconcomitants.Asmentionedabove,interms ofstresstheoryanxietycanbeviewedasastressresponsewith- outactualstressor,andneuroscientistscommonlytreatstressand anxietyasthesamesubjectbecauseoftheirsharedneurobiology.

WehavediscussedtherelevanceofGUTSforanxietyinmoredetail elsewhere(Brosschotetal.,2016).

3. Feelingunsafeinasafeworld:theneurobiologicaland evolution-theoreticalbasisofGUTS

Itmightfeelsomewhatcounterintuitivethatanintenselypow- erfulandprimarysurvivalmechanismsuchasthechronicstress responseissparkedoffbythemereabsenceofsomethinglikeper- ceivedsafety,insteadofthepresenceofsomethingprofoundlikea threateningsituation,ordisturbingthoughtsthereof.Yet,precisely becausethestressresponseisaprimarysurvival mechanism,it shouldbetheresponsetoautomaticallyandimmediatelyfallback uponwhentheonlyinformationthatcouldstopit,i.e.proofofsafety isnotavailable.Organismshavesurvivedinevolutionnotbywait- ingformoreevidenceofthreatbutinsteadbyerringontheside ofcaution(e.g.Nesse,2005;Trimmeretal.,2013),or,popularly

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Stressor Stressor Stressor Physiological

response

a Convenonalstress theory:stressors

Time → (e.g. 1 day)

Stressor Stressor Stressor

PC PC PC

b Perseverave cognion (PC) theory: stressors plus PC

PC PC

Safe?

PC c Idem, but: no stress response in theremaining me?

PC PC

Unsafe

d Generalized unsafety theory of stress (GUTS): Stressors, PC, plusunsafe stressor-condioned contexts

Safe

PC

Unsafe Safe

e Generalized unsafety theoryofstress (GUTS):Stressors, PC, plusunsafestressor-condioned contexts

Unsafe

f Chronic unsafety(e.g. ‘compromised bodies’& loneliness)

Fig.1. Hypotheticalstressresponses(e.g.increasedheartactivity)inagiventimeperiod(e.g.oneday):accordingtocurrentstresstheories(a)i.e.toactualstressors;

accordingtoperseverativecognitiontheory(bandc)i.e.tostressorsandtheir(unconscious)cognitiverepresentation(perseverativecognition;PC);accordingtoGeneralized UnsafetyTheoryofStress(GUTS)inthecaseofcompromisedcontexts(dande)i.e.tostressors,(unconscious)PCplustostressor-freebutstressor-conditionedcontexts(e.g.

‘chronic’stressors);andalsoaccordingtoGUTS,incaseofcompromisedsocialnetwork(e.g.loneliness)orcompromisedbodies(e.g.obese,old,aerobicunﬁt)(f)i.e.toall contexts/chronic.NB.Thisareschematicdiagrams:inreallife,thephysiologicalresponsemagnitudewillvaryacrosstimeasafunctionoftheextentofperceivedunsafety.

AdaptedfromBrosschotetal.,2016.

formulated,tobe‘bettersafethansorry’.Forthisreasonthestress responseisdefault,itis‘alwaysthere’,onthevergeofbeingacti- vated,onlybeinginhibitedwhensafetyisclearlyperceived.

Thisevolutionarylineofreasoningissupportedbyseveral–new butalsoold–neurobiologicalinsights,especiallyconcerningthe roleoftheprefrontalcortexinregulatingsubcorticalsympathoex- citatorydefaultactivity,andtheeaseandspeedofthedefaultstress response,andconversely, thelowcost natureofits(long-term) inhibition.

3.1. Prefrontalinhibitionofsubcorticalexcitation

Thestressresponseismediatedbysubcorticalareasinthebrain, i.e.thesocalledlimbicstructures,includingtheamygdala,andit isnormallyundercontinuous(‘tonic’)inhibitionbytheprefrontal cortex(PFC;Ahernetal.,2001),morespeciﬁcallybytheventrome- dialPFC(vmPFC;Motzkinetal.,2015).Whensafetyisindoubt, subcorticalinhibition bythevmPFC isdecreased and amygdala activityisenhanced(GrupeandNitschke,2013).Thishappenseven longafterastressorhasstopped,whensafetyisstillinquestion