a systems approach to stress stressors and resilience in humans

00 Abbreviations: ACTH, adrenocorticotrophic hormone; ANS, autonomic nervous system; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; EEG, electroencephalogram; fMRI,

j o ur na l h o me p a g e :w w w e l s e v i e r c o m / l o c a t e / b b r

Review

A systems approach to stress, stressors and resilience in humans

Barry S Okena,b,∗, Irina Chaminea, Wayne Wakelandc

Q1

a Department of Neurology, Oregon Health & Science University, CR-120, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA

b Department of Behavioral Neuroscience & Biomedical Engineering, Oregon Health & Science University, CR-120, 3181 SW Sam Jackson Park Road,

Portland, OR 97239, USA

c Systems Science, Portland State University, P.O Box 751, Portland, OR 97207, USA

h i g h l i g h t s

•Stressphysiologywasreviewedfromasystemsscienceperspective

•Stressorspushbiologicalsystemsfrombaselinetowardlowerutilitystates

•Thesystemchangeisbasedonobjectiveattributesandperceptionsofthestressor

•Allostaticloadisutilityreductionduetostress-relatedstatechanges

•Resilienceaffectsabilitytoreturntohighutilitystatefollowingperturbations

a r t i c l e i n f o

Article history:

Received 25 November 2014

Received in revised form

18 December 2014

Accepted 21 December 2014

Available online xxx

Keywords:

Psychological stress

Systems science

Allostatic load

Resilience

a b s t r a c t

Thepaperfocusesonthebiologyofstressandresilienceandtheirbiomarkersinhumansfromthesystem scienceperspective.Astressorpushesthephysiologicalsystemawayfromitsbaselinestatetowarda lowerutilitystate.Thephysiologicalsystemmayreturntowardtheoriginalstateinoneattractorbasin butmaybeshiftedtoastateinanother,lowerutilityattractorbasin.Whilesomephysiologicalchanges inducedbystressorsmaybenefithealth,thereisoftenachronicwearandtearcostduetoimplementing changestoenablethereturnofthesystemtoitsbaselinestateandmaintainitselfinthehighutility baselineattractorbasinfollowingrepeatedperturbations.Thiscost,alsocalledallostaticload,istheutility reductionassociatedwithbothachangeinstateandwithalterationsintheattractorbasinthataffect systemresponsesfollowingfutureperturbations.Thisaddedcostcanincreasethetimecourseofthe returntobaselineorthelikelihoodofmovingintoadifferentattractorbasinfollowingaperturbation Oppositetothisisthesystem’sresiliencewhichinfluencesitsabilitytoreturntothehighutilityattractor basinfollowingaperturbationbyincreasingthelikelihoodand/orspeedofreturningtothebaselinestate followingastressor.Thisreviewpaperisaqualitativesystematicreview;itcoversareasmostrelevantfor movingthestressandresiliencefieldforwardfromamorequantitativeandneuroscientificperspective

©2014PublishedbyElsevierB.V

Contents

1 Introduction 00

2 Thehumanphysiologicsystem:brainstructureandnetwork(Fig.3) 00

3 Stressor 00

4 Measurementofstress 00

4.1 Peripheralbiomarkers 00

Abbreviations: ACTH, adrenocorticotrophic hormone; ANS, autonomic nervous system; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; EEG, electroencephalogram; fMRI, functional magnetic resonance imaging; HgbA1c, glycosylated hemoglobin A1c; HPA axis, hypothalamo–pituitary–adrenal axis; HRV, heart rate variability; PET, positron emission tomography; PTSD, post-traumatic stress disorder; SSRI, selective serotonin reuptake inhibitor.

∗ Corresponding author at: Oregon Health & Science University, CR-120, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA Tel.: +1 503 494 8873;

Q2

fax: +1 503 494 9520.

Q3

E-mail addresses: oken@ohsu.edu (B.S Oken), fonareva@ohsu.edu (I Chamine), wakeland@pdx.edu (W Wakeland).

http://dx.doi.org/10.1016/j.bbr.2014.12.047

0166-4328/© 2014 Published by Elsevier B.V.

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4.2 Brainchanges 00

4.2.1 Cognition 00

4.2.2 Structuralbrainchanges 00

4.2.3 Physiologicalbrainchanges:EEG,event-relatedpotential,fMRI 00

4.2.4 Geneticchangesinbrain 00

4.3 Allostaticload 00

4.4 Stressanddisease 00

5 Dynamicsofstresssystem–timecourseofstress-inducedphysiologicalchanges:state/traitandvariables/parameters(Fig.4) 00

6 Resilience 00

7 Environmentanditsperception 00

8 Stressandresiliencybiomarkerchangeswithtreatment 00

9 Utility 00

10 Conclusions 00

Acknowledgements 00

References 00

1 Introduction

Q4

Psychologicalstressis commoninoursociety Arecent

sur-vey indicated that 25% of Americans reported high stress and

50%identified a majorstressfulevent duringthepreviousyear

[1] Chronic psychological stress increases risk of health

prob-lemsandcontributestocardiovascularproblems[2,3],neurologic

andpsychiatricdiseasessuchasepilepsy[4],Parkinson’sdisease

[5],multiplesclerosis[6],eatingdisorders,addictions [7],

post-traumaticstressdisorder(PTSD),andsleepdifficulties.Therefore,

itisimportanttodevelopevidence-basedmethodsthatminimize

stressimpact.Afullerunderstandingofstressphysiologyand

psy-chologycanbeachievedbyapproachingthistopicfromdifferent

angles.Thisworkoffersareviewofstressphysiologyand

psychol-ogyfromasystemsscienceperspective

Systemsscienceisamethodologyusedtounderstandcomplex

systemsfromorganizational,structural,anddynamicperspectives

[8].Fromasystemsscienceviewpoint,stressoftencorrespondstoa

stateawayfromoptimalinadynamicalsystemwheretheoptimal

locationrepresentsahighutilityattractor.Anattractorbasinina

dynamicalsystemcorrespondstotheconceptualspaceoflocations

inwhichthesystemresidesovertime.Thestateofstressresults

fromaperturbationarisingfromtheinternalorexternal

environ-ment(stressor).Thisstressorcouldresultinthesystemreturningto

thebaselineoptimalattractorormovingintoalowerutility

attrac-torbasin.Theattractorbasinistheregionofspacethatsharesthe

sameattractorandthewholespacemayhavemultipleattractors

(Fig.1)

Theattractorinthehumansystemisnotafixedpointattractor

giventhemultidimensionalnatureand,almostinherent,

within-subjecttemporalvariabilityofthephysiologicalmeasuresofstate

Thenoisepresentinthemeasurementofthemanyvariables

con-stitutingthehumansystemimpliestheobservedhumansystem

isstochastic;thus,theattractorsareverydifficulttodescribe.In

addition,given thevaryingtimeframes overwhichthe

compo-nentsofthehumanphysiologicalsystemchange,thetermsstate

andvariabledescribing moreimmediatechangesand theterms

traitor parameter describing longer time framechanges

repre-sentanartificialseparationofthevariousphysiologicalmeasures

thathavedifferentunitsandwidelydistributedhalf-lives

What-evertheattractor,evenifthesystemreturnstothebaselinehigh

utilityattractor,thereisoftensomeunderlyingcost.Thiscostto

thesystemisa changein theunderlyingphysiology that may:

(1)decreasetherateofreturntothehighutilityattractoror(2)

decreasethelikelihoodofreturningtotheoptimalattractor

follow-ingafuturestressorperturbationbecausethesizeoftheattractor

basinissmallerortheattractorhasmovedclosertoaboundary

withanon-optimalattractorbasin.Themovementofthe

dynam-icalsystemintoadifferentattractorbasincouldalsobeduetoa

HEALTHY Aractor Basin (higher ulity than PTSD but less than in (a))

HEALTHY Aractor Basin (higher ulity)

PTSD Aractor Basin (lower ulity)

PTSD Aractor Basin (lower ulity) a) Higher Resilience Case

b) Lower Resilience Case

Fig 1.Attractor basins, utility, and resilience Hypothetical example of space of possible human physiological states with two attractor basins, one being a healthy higher utility condition and one a lower utility condition state of PTSD (in this fig-ure, higher utility is downward) The attractor basins can tolerate movement of the hypothetical person (solid circle) in the horizontal direction from an external stres-sor without leaving its basin of attraction However, with sufficient movement from

a stressor, one may go from a higher utility healthy condition basin to a lower utility PTSD basin The healthy condition in b has lower resilience than in a, with less stress required to shift it to the lower utility basin.

singleseverestressorpotentiallyviaadynamicalsystem catastro-phe,forexample,developmentofPTSDfollowingasingleevent (Fig.2)

Besidesnegativeeffects,thestressorcanalsoinducebeneficial changesleavingthesystemmoreresilienttofutureperturbations,

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Fig 2.Cusp catastrophe An example of a cusp catastrophe where the state space

of human physiology has a complex 3-dimensional shape, with no pictorial

repre-sentation of attractors, and there may be an abrupt state change In this example, as

stress increases at higher levels of depression there may be a sudden drop in

loca-tion to a new state, PTSD (marked by a dotted line) Here, utility is up rather than

down as in Fig 1

i.e.,causetheoppositeof (1)and (2)above.Thetermresilience

includesseveralconceptualaspects.Resiliencereferstohow

effec-tivelyandquicklythesystemreturnstobaseline[9].Thisincludes

whetherthehumandynamicalsystemavoidsmovingtoalower

utilitydiseasestatefollowingastressor[10].Arelatedtermis

sta-bilitywhichreferstohowwellthesystemcanmaintainitscurrent

highutilityconditionwithoutbeingpushedaway

Althoughastressormaycauseashort-termdecreaseinsome

measure of utility, sometimes it results in longer-term utility

increase.Inthecaseofhumans,thisisrelatedtolearningas

dis-cussedbelow.Thehumandynamicalsystemmayexperiencesome

low-stressenvironmentalperturbationthatresultsinarelatively

immediategaininrewardorutility,e.g.,obtainingfoodwhen

hun-gryorsomelonger-termgainin utility,e.g.,thebrainacquiring

a betterunderstanding of theenvironment There is an

appar-entinvertedu-shapedeffectofstressonlonger-termutility,such

thatoccasionalsmallamountsofstressmayimproveboth

short-andlong-termutilitybutexperiencingnostressorlargeamounts

ofstressmayhave negativelong-termeffects ontheorganism

Thoughtheterm“human”willbeused,mostofthis discussion

appliestootheranimalsandtosystemsingeneral

2 The human physiologic system: brain structure and

network ( Fig 3 )

Ahumanisadynamicalsystemcomposedofsubsystemsthat

help maximizeutility of theorganism Utility maybe defined:

(1)fromapurelybiologicalperspectivesuchasimmediate

repro-ductive successorobtaining foodor(2) from amore complex,

perhapshedonicorlonger-termperspectivesuchaslonger-term

reproductive success, obtaining more resources, gaining group

supportorenjoyinganamusementparkride.Longer-term

util-itycouldextendbeyondthelifespan,e.g.,survivaloftherelated

socialunitortheentirespecies(seeSection9formore

informa-tionaboututility) Theorganismismaintainedbymanycritical

systemsandsubsystems,suchascardiovascularandrenal,butthis

paperfocusesonthebraindynamicalsystemand its

communi-cationlinkswiththebodyviaautonomicnervoussystem(ANS),

hypothalamo–pituitary–adrenal(HPA)axisandneuroimmune

sys-tem.The limbic system is involved in psychological aspects of

stress, including neocortex activation by emotional states and

memoriesofeventsassociatedwithemotionalvalences.Olderand

morecaudalbrainpartsincludingthebrainstemandspinalcord

aregenerallynotcriticalforthefollowingdiscussionwithsome

MODERATING FACTORS Memory, State, Trait, Genes

Expression

Environmental Smulus

PERCEPTIO N Emoonal Valence:

- posive/ne gave

- degree

STRESS ACTIVATION

ANS

e n v i r o n m e n t a

Emoonal memo ry loud noise

PERCEPTIO N

+

STRESS ACTIVATION

+

e n v i r o n m e n t b

Fig 3.(a) Interpretation of stressors: brain processing and communication The brain’s perception of the emotional valence of an external event as a stressor is dependent on the current environment and modulated by previous experiences (memory), current physiological state, traits (e.g., neuroticism), and genotype The brain generates outputs to the autonomic nervous systems (ANS), the hypotha-lamo–pituitary–adrenal (HPA) axis, the immune system, gene expression and epigenetics (overall increasing time duration of stress activation components from left to right) These responses directly affect the body but also feedback to the brain Learning includes assessment of risks and rewards and it can be clinical designed

to reduce reactivity, e.g., allergy therapy or mindfulness meditation (b) Example of self-reinforcing stress response system that is pathological if in a non-threatening environment Normally, while stress activation from a loud non-threatening noise may initially activate a stress response, response to repeated loud noise will be attenuated through negative feedback (e.g., habituation) In PTSD emotional mem-ories and the stress activation itself may contribute to an auto-reinforcing positive feedback loop As mentioned in the text and Fig 2 , this PTSD attractor basin may be entered secondary to a single severe negative event via a catastrophic dynamical sys-tems event This pathological transition is more likely in those with predispositions, e.g., neurotransmitter alterations such as depression.

exceptionsincludingANScomponents.Thesympatheticportion

oftheANSinvolvingcentralcatecholaminergicsystemsis particu-larlyimportantforcommunicatingthebrainperceptionofstress

tothewholebody bycausing changes suchasincreasedblood pressureandheartrate.Thehypothalamusisanimportant commu-nicationlinksecretingneurohormones,e.g.,adrenocorticotrophic hormone(ACTH).Giventhisbackground,themostcommonly dis-cussedphysiologicresponsestoa stressorinvolvetheHPAaxis, thelocuscoeruleus–norepinephrine–sympatheticnervoussystem pathway,theparasympatheticsystem,theimmune system,and geneexpressionandalterationsincludingepigeneticchanges

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sys-tems (ANS, HPA, and immune) and the brain exist in part to

ensurethestress-relatedsystemsprovidefeedbackforlearningand

helpavoid over-reactivity.Thecommunicationsystembetween

the immune system and the brain constitutes an entire field

itself,psychoneuroimmunology[11].Theimmunesystem–brain

communicationissignificantlymediated bycytokines.Allthese

two-waycommunicationsystemsdirectlyimpactthebrainviaits

receptorsfornorepinephrine,ACTH,cortisol,andcytokines,with

prefrontalcortex,hippocampus,andamygdalabeingmost

promi-nent[12].Feedbackisofteninhibitoryandisnotperfect.Occasional

errorsinthistwo-waycommunicationsystemmayarise.For

exam-ple,amajorincreaseinheartrateinanexercisingolderadultwith

atherosclerosismightbeaccompaniedbyanattempttodecrease

theheartrate,but thisdecrease maybeinsufficienttoprevent

amyocardialinfarctionandevenasuddendeath[13]

Addition-ally,theawarenessofstressmayitselfbeastressor;however,this

typeofstressisdistinctfromexperiencingexternalenvironmental

stressors.Stressawarenessmaybecommonlyrelatedtothe“recall”

orassociationofparticularenvironmentalinputswithpriorstress

3 Stressor

Astressorisanenvironmentaleventthatsignificantlyperturbs

theentirehumandynamicalsystemawayfromtheoptimal

attrac-torresultinginastateoflowerutility.Thestressormaymovethe

physiologicalsystemtoadifferentattractorbasin,movethe

sys-temstateclosertotheedgebetweenitscurrent attractorbasin

andanotherattractorbasinofthephysiologicalsystem

(“precar-iousness”),orslowtherateatwhich thesystemreturnstothe

optimalattractor.Themovementofthesystemisnotdependent

solelyonobjectivemeasuresofthestressorbutalsoonthe

indi-viduals’traitsofdistresspronenessandtheirperceptionsofthe

stressor.Iftheperturbationisperceivedtoimpactanorganism

neg-ativelyorassociatedwithobviousthreats(hunger/visualizationof

aggressor),thereisanimmediateeffecttoreducethelikelihoodof

anegativestressorimpact.Forexample,seeingabearwithher

cubwhile hikingwillgenerate physiologicalchanges important

foraction(elevatedheartrateandbloodpressure)andincreased

attentiontoenvironmentalstimuli, thusimprovingencoding of

thesituationforfuturerecollection.Theseperturbationsincrease

likelihoodofsurvivalovertheshort-termbutifmaintained

long-termmayhavedeleteriouseffects.Forexample,atransientincrease

inbloodpressureistolerableandmaybehelpful,butachronic

increaseinbloodpressureisnothighutility.Stressdosesthatare

nothighenoughtocausesignificanthealthproblemssuchas

dis-easeordeathfromastatechangemayproducehigheraverage

utilitywithinthebasinbyalteringtheshapeofthebasinorby

movingtoadifferent,higherutilitybasin.Inanathleticsexample,

bothshort-termstressatanOlympiccompetitionandlonger-term

stressfromhigheffortathleticactivityoveratrainingperiodmay

improveathleticperformance.However,excessiveorrepeated

per-turbationsmayhaveacosttotheunderlyingsystemthatoutweighs

thebenefit

Stressorsmayincludeexternalenvironmentperturbationssuch

asextreme heat oricy roadswhile driving.Stressors mayalso

includeinternalenvironmentperturbationssuchasinfectionsor

elevatedglucose.Stressorsmaybepredominantlypsychological

andmediatedbybrainperceptionandfutureexpectancy.Stressors

arenotnecessarilyphysicalchangesintheenvironmentbutmay

involvelossofasignificantrelationship,financialstress,negative

neighborhoodcharacteristics,orsocialthreatsincluding

discrimi-nation[14–17]

Formostofthisdiscussion,thestressorreferringto

perturba-tionsundertightphysiologicalcontrolwillbeomitted.Information

signals from these perturbations such as alterations in serum sodium do not need to reach the brain level to be regulated Homeostasisreferstothedynamiccontrolofthesestatevariables maintainedwithinanarrowwindowforhumanstosuccessfully function.The dynamicalsystemrepresenting thewholeperson

isregularlyexposedtomoreheterogeneousstressorsthanserum sodiumchanges,includingpotentialstressorsthatareanticipated Allostasishasbeenusedtodescribe“activelymaintaining homeo-stasis”[18],butthepracticalityofthisdistinctionfromhomeostasis

isuncertain[19] Some stressors represent state perturbations to which the person may respond without any obvious long-term negative ramifications Some stressors, in part related to their chronic-ity,mayhavenegativelong-termramifications.Theperturbation may induce changes in several systems For example, as time passesfromthepreviousmeal,ahuman’sstomachisgrowlingand bloodsugarisgettinglower;thebrainsenseshungerand mobi-lizesto address theperturbation stressor.Part of the response

toa stressorwillbemediated directlybytheinternal environ-mentwithoutrequiringanymediationbythebrain,e.g.,hunger causing the release of hormonesto break downglycogen Part

oftheresponseisdirectlymediatedbythebrainresponsiblefor planninghowtointeractwiththeexternalenvironment,e.g., walk-ing into thekitchen to get food.The perturbation may induce changes in physiological parameters, e.g., DNA transcription or epigeneticmodificationstoalterneurotransmitterreceptor sen-sitivity.Respondingtothesestressperturbationsmayinducesome costtothesystem.Thiscostmayinvolvethemovementofthe systemintoanotherbasinofattractionoranincreaseinthe proba-bilitythatthesystemwillmoveintoanotherbasinfollowingfuture perturbations

Thoughthestressorhassomeobjectivequalities,itcanbe dif-ficulttoquantifybecausephysiological stresseffects arehighly dependent on the subjective perception Quantifying an indi-vidual’s stressors has been attempted [20] Some examples of stressorsincludeeventsthathavenovelty,unpredictability(any information-richinputbeyondthebrainprocessingability),threat

toone’sego,orsenseoflossofcontrol(NUTS)[21].Short-term lab-oratoryexperimentalstressorsarerelatedtotheseNUTSconcepts includingtheTrierSocialStressTest[22],theMontrealImaging StressTask[23],titratedStroopcolor-wordinterferencetask[24], physical (e.g., putting a hand in ice water) [25], or perceptual stressors(e.g.,thedisturbingpictures oftheInternational Affec-tivePictureScale[26]).Stressresponsescanalsobeconditioned [27]allowingforcomparisonbetweenhumansandotheranimals

Itismorechallengingtostudylong-termstressorsexperimentally butoccasionalmisfortunessuchaswarsandotherdisastershave generatedinformativeepidemiologicaldata,e.g.,theWorldTrade Centerdisaster.Stressorsmayinvolveawarenessofastressor,even

ifitiserroneous,e.g.,misperceptionofanenvironmentalchange Relevantexamplesincludeerroneousstressassociationswith ordi-naryloudsoundsthathavedevelopedfromexplosion-relatedPTSD

orapheochromocytomaproducingasurgeofcatecholamines per-ceivedasastressstatebecauseofdiaphoresisandafastheartrate

Ingeneral,frequentperturbations intoastressedstateaway fromthehighutilityattractorhaveacosttothesystem.Thecost

ofgoingtotherefrigeratorwhenfeelinghungryislow.However,

arelatedperturbation,thebloodsugarincreaseandtheneedto secreteinsulinduetoovereatinghigh-sugaritemsmayeventually causelong-termnegativeeffects.Ifrepeatedenough,itmay dimin-ishthehuman’sabilitytostayinapositivefunctionalattractor, andthelackofresponsivenesstoinsulinatthecellularlevel(i.e., insulinresistance)maycauseadulttype2diabetes.Thiscommon stress-relatedchangehasresultedinacommondiabetesmeasure, glycosylated hemoglobin HgbA1c, frequently used as a chronic stressbiomarker.Inhumans,allostaticloadisthecosttothesystem

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execut-ingthephysiological changesandthepotentialcostsofmaking

thechangesinarchitectureofthebasinsofattraction(theirsize,

depth,etc.)followingastressoraswellastheeventualimpacts

of thearchitecturechange.Allostasishasbeen usedtodescribe

thedynamicalcontroloverthesevariableperturbationsfor

main-tainingafunctionalstate.Thoughthereissomecontroversyover

whetherallostasisistrulydifferentfromhomeostasis[19],theterm

allostaticloadhasbeenusedasaconceptualmeasureofthe

phys-iologicalcostduetochronicstressors[28]andbewillbeusedin

thispaper.Attemptstodefineametricofallostaticloadfor

exper-imentalusearediscussedbelow

4 Measurement of stress

Thetermstressdescribesastateofphysiologicandbehavioral

responsestoastressorwiththebrainbeingthecriticalinterpreter

ofwhatisstressful.Thoughinconsistentlyused,thestressedstate

inhumansforthepurposesofthisdiscussionislinkedtodynamical

physiologicalchange.Thestressedstatealsoinvolvestheconscious

andunconsciousstressorinterpretationbythebrainincludingthe

consciousperceptionof thestressorsand theperceptionofthe

physiologicresponsegeneratedbythestressor[29–31].Stressors

resultinchangesinstatevariablesandparametersandhavebeen

measuredusingvariousbiomarkers

There are many objective ways to measure human

stress responses other than commonly used self-rated

scales As previously noted, physiologic responses to stress

include activation of the HPA axis, activation of the locus

coeruleus–norepinephrine–sympathetic nervous system

path-way, the parasympathetic system, immune system, and genes

[29,31–35].Importantly,thetimingofthesechangesisvariable

Whenmeasuredasstatevariables,theymayormaynotshedlight

onthedynamicalnatureofthephysiologicsystem,resilience,or

allostatic load Dynamical aspects of stress and resilience may

beestimated withrepeatedmeasurements over longerperiods

duringdailyroutinesorfollowingaknownexperimentalstressor

4.1 Peripheralbiomarkers

Eachbiological assessmenthasasamplingtimewindow.For

example,aperipheralblooddrawtoassesscortisolreflects

cumu-lativechanges over minutes, cortisolovernighturine collection

measurereflectscumulativechangesoverhours,andahairsample

mayreflectcumulativechangesovermonths

HPA axis activity biomarkers include glucocorticoids: free

cortisol(orcorticosterone in experimentalanimals), ACTH, and

corticotropin releasing hormone [36,37] In addition to acute

stressor-inducedchangesinthesebiomarkers,therearealterations

indiurnalfluctuationswithchronicstress,e.g.,incortisol

awak-eningresponse[38,39].Dehydroepiandrosterone(DHEA)andits

sulfate(DHEAS)acttocounter-regulatecortisol[40].DHEAisused

asastressmarkerbyitself[41]orasaratiotocortisolandhasbeen

affectedbydepression[42].Mineralocorticoidsmayalsobestress

biomarkers[43]

Severalautonomicactivitymeasuresareassociatedwithacute

orchronicstressincludingbloodpressure,electrodermalresponse,

skintemperature,respiratoryrate,heartrateandheartrate

vari-ability (HRV) [44] A variety of HRV measuresin the time and

frequencydomainshavebeenevaluated[45,46].WhileHRVmay

lookatdynamicalchangesoverlongperiods,e.g.,24hormore,

longer-termHRVrequiresmoresophisticateddataprocessingto

correctforexerciseandunrelatedtostressactivitiesmodifyingthe

heartrate

Many measures correlated withstress have beentreated as relativelystaticmeasures.Thereare alterationsinimmunologic functionincludingcytokines;geneand epigeneticmodifications involvingtelomerechanges;and metabolicactivityfluctuations resultingin generationof reactiveoxygenand nitrogenspecies damagingtocellularstructures[29,33,35,47–49]

Thereareotherbiomarkersnotdirectlyrelatedtothecurrently discussedphysiologicalstresspathways.Toassessstressresponses researchershaveusedmeasuresofmuscleactivitye.g.,using elec-tromyographic activity for biofeedback in treatment of muscle contractionand othertypesofheadaches.Biofeedbackhasbeen usedonmanyphysiologicalmeasureswithonlyfew(peripheral temperatureandelectrodermalactivity)beingclosely relatedto ANSactivation[50].Additionally,asmanyhavecasuallyobserved, stressaltersvoicecharacteristics[51]andpostureinachair[52] Otherbiomarkersarelistedbelowunderallostaticload

4.2 Brainchanges 4.2.1 Cognition Cognitive function including memoryis significantly altered

bystressinhumansandnon-humananimals[53–55].Cognitive declineassociatedwithstress(andthecloselyrelated construct depression)mayaffect speed,attention,and executivefunction [54,56].Prefrontalcorticaldysfunctionisparticularlyimpactedby stress[57].Thispathologicalrelationshipbecomesmoreevident withage[58],andhighlystressedelderssuchasdementia care-giversmaybeparticularlyatrisk[48]

4.2.2 Structuralbrainchanges Stress-related states suchasPTSD and fear conditioningare linkedtodecreasedhippocampalsize,declineinprefrontalcortex, increasedsizeofportionsoftheamygdala,anddecreased inhibi-tionoftheamygdalaandrelatedbrainregionsbythefrontallobes [55,57,59,60] Thebrain changesare atleast partiallymediated

bycortisolwithincreasedcortisolrelatedtosmallerhippocampi [61] Thetime courseofstructural changeismuch longerthan thehalf-lifeofcortisol;cortisolelevationneedstobesustainedto causelonger-lastingbrainchanges.Smallerhippocampiare com-monamongpeoplewithPTSDortraumaexposure[62,63]andthey alsoarelinkedtoincreasedriskforPTSDdevelopment[64]sothe causativerelationshipisuncertain.Further,PTSDsufferersareat higherriskofdementia[65]andthosewithsmallerhippocampi haveincreasedtheriskofdementia[66].Therefore,definingthe causativeaspectsoftheserelationshipsiscritical andcanaffect otherimportanthealthconcerns.Fromtheperspectiveof bene-ficialeffects,researchshowsincreasedhippocampalvolumeand improvedverbaldeclarativememoryinPTSDpatientsafterusing

aselectiveserotoninreuptakeinhibitor(SSRI)antidepressantfor 9–12months[67].ThisislikelyrelatedtoSSRI-related neurogene-sisincrease[68]

4.2.3 Physiologicalbrainchanges:EEG,event-relatedpotential, fMRI

EEG stress-related changes, particularly frontalasymmetries [69,70],andalterationsinevent-relatedpotentials[71]havebeen noted,but thesechanges havenot beenconsistent,inpartdue

tolackofdistinctionbetweenstateandtraitmarkersand limita-tionsinsignalprocessing[72].Chronicpsychologicalstressimpairs sleepandtheresultantsleepdeprivationmayimpactEEG.PETand fMRIdetectbrainactivationchangesduetoexperimentalstressors [73–75]

4.2.4 Geneticchangesinbrain Thereare differentfunctional gene classesthat underlie the diverseeffects of glucocorticoidsonbrainfunction, e.g.,energy

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metabolism,signaltransduction,neuronalstructure, and

neuro-transmittercatabolism[32].Stresseffectsontelomereshavebeen

mentionedbutassessmentsofhumantelomeresaregenerally

per-formedonperipheralbloodlimitingtheirdirectbrainassociation

4.3 Allostaticload

Theunderlyingbiologicaldefinition ofallostaticloadis very

broadsincethephysiologicalsystemrepresentsahighly

multidi-mensionalstatespacewithmanyparameters.Potentialexamples

ofunderlyingloadincludethecostofgenetranscription,metabolic

activity,andalterationincellreceptorsensitivity.FrequentDNA

processingmayproducechangesintelomerelength

Allostaticloadwasoriginallydevelopedasacompositemarker

ofchronicstress-related disequilibrium generatedfrom a

num-berofphysiologicalmeasures.Theoriginallydescribedallostatic

loadscorewasacompositeof10measures(systolicanddiastolic

bloodpressure;waist–hipratio;ratiooftotalcholesteroltohigh

densitylipoproteins;highdensitylipoproteincholesterol;

glyco-sylatedhemoglobin;overnight12-hurinarycortisol,epinephrine

and norepinephrine; and DHEA-S [76]) The score obtained by

summingthetenmeasures(0ifnormal,1if75thpercentileor

worse)wasassociatedwithmortality.Relatedcompositeallostatic

loadmeasureshavebeencorrelatedtochildhoodpoverty[77]and

measuresofworkexhaustion[78].Thelatterstudyaddedseveral

measures(tissuenecrosisfactor-alpha,C-reactiveprotein,

fibrino-gen,andD-dimer)andothermeasureshavealsobeenadded,e.g.,

pro-coagulantactivity.Despitethewidespreadinterestinallostatic

load,theoptimummeasurehasnotbeendefined;themeasures

currentlyusedarebasedonnon-experimentalapproaches(e.g.,

simpleavailabilityandapriorirationales).Asaresultthereismuch

varietyinthedefinitionofa compositemeasure[79],but there

needstobeimprovementinitsdefinitiontoadvancethefieldof

biomarkersforchronicpsychologicalstress.Thiscouldpotentially

resultfrombetteranalytictechniques

Allostaticloadmeasureshavehighlyvariabletimeframes.Some

maychangerelativelyquickly,e.g.,fibrinogen,someareintegrated

oversometimeperiod(e.g.,12-hurinarycortisol),andsomechange

muchmoreslowlyorareintegratedoverlongertimeframes(e.g.,

waist–hipratioorHgbA1c).Mostphysiologicalparametersarenot

onlystressindicatorsbutalsochangewithotherbiorhythms,e.g.,

circadianorprandial

Anotherrationale forallostaticloadasa composite measure

ofstresseffectsisthatdifferentpeoplelikelyhavedifferent

sub-systemsaffectedbystress.Somepeopleexperiencinghighstress

developheadaches,whileothersdevelopgastrointestinalorother

disorders.The particularorgan systemsaffectedby stressis an

interactionbetweenthesesystemsandthebrain.Theindividual

reactionstostressaredependentonanindividual’sgenes,

learn-ingandenvironment.Thus,itislikelythatdifferentpeoplehave

differentpatternsofalterationinstress-relatedbiomarkersor

allo-staticloadcomponentmeasuresthatmaypotentiallybediscerned

bybetteranalytictechniques,e.g.,structuralequationmodelingor

machinelearning.Itmayultimatelybeimportanttounderstand

theindividualrelationships,butatthisstateoftheresearchitmay

behelpfultohaveacombinedmeasure

4.4 Stressanddisease

Acutestressmayhavesomemetabolic,immunologicand

cog-nitivebenefits.Forexample,alterationsinsystempropertiesmay

produceahighertransientutility,decreasethelikelihoodthata

stressorwill movethestate of thesystemaway froman

opti-mal attractor (robustness), or increase the size of an attractor

basin(seehormesisbelow).Ahelpfulexampleistheimmune

sys-temwhichlearnstoreacttoforeignsubstanceswhenexposedto

non-virulentonesthatdonotresultindeath.Iftheimmunesystem

isnotexposedtosufficientforeignsubstances,theresultcouldbe over-reactivitytoforeignsubstancesorallergies[80].However,as statedintheintroduction,moreoftenimpairmentsinhealthand

abroadrangeofdiseasesareproducedbychronicpsychological stress

Chronicstressmaycausecognitivedecline,adverseeffectsin thehippocampus,andcontributetoneurodegenerativediseases eitherdirectlyorthroughstressmediatorsincludingallostaticload [3,18,81–83].Thenegativeeffectof psychologicalstresson cog-nitive functionmay be greater withaging [58,84,85] Stressors includinganesthesia,drugs,depressionmaybemorelikelytoresult

inastateofimpairedcognitivefunctionwithincreasedage Cog-nitivereserve,ameasureofhowwellthebrainworks[86],maybe oneaspectofresiliencetotheeffectsofstressoncognition

5 Dynamics of stress system – time course of stress-induced physiological changes: state/trait and variables/parameters ( Fig 4 )

Stress can cause a perturbation of state but the associated changestophysiologicalmeasuresoccuratvaryingtime scales Thetimecoursesofmarkerchangesinpsychologyaresometimes groupedinto fairly mobile,shorter-term changes reflecting the person’scurrentstateandlonger-term,morestablechanges reflect-ingtraits.Standardmeasuresofpsychologicalstressaspects,such

asanxiety,areoftenmeasuredbyawidelyusedinventory,e.g., theState-TraitAnxiety Inventory[87].However,evenrelatively stabletraits,suchasthepersonalitytraitneuroticism,often con-sideredstableoveralifespan,canbemalleablethuslimitingthe clear distinction between stateand trait Systems science uses termsanalogoustostateandtrait:variablesreflectingcurrentstate measuresandparametersreflectingmorestableattributesofthe system.Thechangeinparametersmaydecreasethelikelihoodof thesystemstayingintheoptimalattractorbasininthefaceof typ-icalenvironmentalfluctuations,butthedistinctionfromvariables

issimplythetimescaleandthusissomewhatartificial.This sec-tionisfocusedonthevaryingtimecoursesofphysiologicalmakers whichareonlymoderatelycorrelatedwithcommonlyused self-ratedmarkers.Allbiomarkermeasurements,includingcommon physiologicalmeasurements(e.g.,cortisol)andmanyanatomicand experimentalphysiologicalmeasurements(e.g.,hippocampalsize

orneuronalreceptorsensitivity)changeovertime,butthetime coursesdiffer

ThesympatheticbranchoftheANSisthequickesttorespond Stressresponse canbemeasuredbyheartrate,blood pressure, electrodermalactivity,orcatecholaminerelease[88].Epinephrine andnorepinephrinereleaseoccurinseconds.Thetwo-minute half-lifeofepinephrinehighlights thegenerallyshorttimecourseof thisresponse.ThisANSresponseispresumablygearedto short-actingflight-or-fightchangessuchasmetabolicneeds,bloodflow, andnon-specificalerting ofthebrain[89],withnorepinephrine projectingthroughoutthebraincontributingtobothphasicand tonic alertness [90,91] HPA activity has a slower time course andisactivatedbythreatsandnegativeconsequencesevenwhen onlyanticipated.Cortisolhaseffectsthroughoutthebodyandis impactedbymanyfactorsotherthanstress.Cortisolalsodirectly affectsthebrainviacortisolreceptorspresentinthepituitary, cere-bellum,hypothalamusparaventricularnucleusandinneocortex Thecortisolpeakonsetoccurs15–30minafterastressor[73,92] Stressoreffectsontheimmunesystemhavealong-timecourse, andeffectsonlearningandDNAhaveevenalonger-timeframe andareimportantforsustainedstresseffects.Somepersonality traitshavebeenlinkedtospecificgenotypes,e.g.,singlenucleotide polymorphisms For example, a specific genotype (5HTTLPR)

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a d

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h

STATE EXAMPL ES

due to inaenon, trait, etc

(0, 0, 0) Duraon

Fig 4. A three-dimensional model of stress-related states A rough schematic of

three dimensions related to stress Physiological activation can be low or high and

sustained for a short or long period of time The response can be to a stressor that is

relatively low from an objective or population perspective or relatively high Normal

function usually goes from relaxation state (a) to short duration high physiological

activation when exposed to a stressor (f) If the stressor response is too sustained or

occurs too frequently, there is some cost to the system.

relevantforstressaffectsserotonintransportandhasbeenrelated

tostressreactivity[93]andthepersonalitytraitofneuroticism

Particularlyrelevantforourdiscussioninvolvingtimecoursesin

humanstressarethebrainnetworkchangesalteringperception

of thestressfulness of anenvironmentalstimulus; this maybe

relatedtosuddenawareness(consciousness)ofthestressororof

theinducedphysiologicalstatechange.Asystemthatreacts

differ-entlyifconsciousnessisachievedandrespondsbasedonconscious

perceptionsandconcepts,suchastheperceptionofcausality,is

inherentlybiased

Therearedifferentapproachestomeasurestressandresilience

dynamically.One canmeasure themagnitude of thechangeat

sometimepointfollowingastressor,e.g.,thecortisolincreasefrom

baselineto15minafteranexperimentalstressor.Onecan

incor-porateamoresophisticatedtemporalmeasureestimatingthearea

underthecurveorhalf-lifeofabiomarkerstressresponseifenough

assessmentsareavailable.Anothermeasureisthetimeittakesto

returntobaselinefollowinganexperimentalstressor,e.g.,fMRI

changes2hafterastressor[74].Intheeventonedoesnotusean

experimentalstressor,onecanobserveresponsefollowinga

signif-icantenvironmentalstressor,asinepidemiologicalstudiesrelated

towarinjuriesorcatastrophes.Ifenoughmeasurementsover

suf-ficientnumberofdaysareavailableitispossibletocalculatethe

variabilityofthephysiologicalsystem.Thisvariabilityofthe

sys-temrelatestostressresponsesbutothervariables(e.g.,age)enter

aswell.Forexample,agingisassociatedwithincreased

variabil-ityofmeasuresofperformance,andthisvariabilitycanserveasa

markerforinsipientdementiaamongelders[94]

Ingeneral,theslowlychangingtraitsorparametersare

poten-tially harder if not impossible to measure empirically Given

thevariabletimeframeofthebiomarkers,assessmentbymany

repeatedmeasurementsovera prolongedperiodmayprovidea

betterrepresentationofthedynamicalstresssystemresponseto

psychologicalstressthan singletime-pointassessments Thisis

especiallytruebecauseeachbiomarkeralreadycapturesthe

phys-iologicalsystemoversomecumulativetimewindow.Themany

physiologicalmeasurementsneededoveraprolongedtimecanbe

obtainedoverdaysorweeksusingcontinuousrecordinginalab

orrepeatedassessmentsusingecologicalmomentaryassessment

[95,96].Lookingatreactivitytoanexperimentallaboratorystressor

mayalsoprovidegoodmarkersofthedynamicnatureofthe

phys-iologicalsystemrelatedtostress.Epidemiologicalstudiescanuse

dataacquiredfollowingpopulationexposuretoacommon stres-sor.Fig.4offersaschematicrepresentationoftheconditionsrelated

toshorter-andlonger-termstressorsandphysiologicalresponses Therearemanysystemssciencemethodologiesthatcouldbeused

toanalyzethemultidimensionalnatureofstressphysiology includ-ingsystemdynamicsmodeling,agent-based modeling,network analysis,discrete event analysis,Markov modeling,and control systemsengineering[8]

6 Resilience

Asdiscussedintheintroduction,thetermresiliencehasbeen usedindifferentways.Resilienceaffectshoweffectivelyandquickly thesystemreturnstoahighutilityattractorbasin[9].Despitethe neuroscientificinterestinresilience[10,97],itsdefinitionsremain variable.Resilienceorrobustnessisthecapacityofthesystemto returntoahighutilityattractorfollowingperturbation,the sys-tem’sabilitytoavoidshiftingtoanotherattractorbasinpresented

inthispaperasadysfunctionalordiseasedcondition,ormoving morequicklytoitsoptimallocationwithinitsoriginalattractor basin(Fig.1).Specificexamplesofresiliencefromasystems per-spectiveinclude:(1)thedistanceofalocationinoneattractorbasin

totheboundaryofanadjacentbasinofinferiorutility,i.e.,greater resiliencemeanstheattractorisfurtherawayfromboundarieswith lowutilityneighboringregions;and(2)thestrengthofthevector fieldinthebasin,whereresiliencemightmeanmorerapidreturn

totheattractor,soarepeatofastateperturbationbeforefullreturn willmakeleavingthebasinlesslikely.Fromabiological perspec-tive,resiliencemayrefersimplytotheabilityofapersontocope withasignificantexternalstressororinsult.Relatedtermsinclude: stability or resistance, indicating thedifficulty moving a system awayfromitsbaseline“optimal’region;precariousnesssuggesting systemproximitytosomethresholdofmovingintoanother attrac-torbasin,andlatituderelatedtothemaximumamountofchange thesystemundergoesbeforelosingitsabilitytoremainwithinits highutilityattractorbasin.Theresilienceofadynamicalsystemto maintainitselfwithinafunctionalhighutilityattractorbasinisvery importanttothelong-termhealthofthesystem.Resilienceisnot simplytheoppositeofallostaticload.Allostaticloadisameasure

ofphysiologicalsystemparametersthatmayimpactresiliencebut

italsohasothereffectsonlong-termhealthordiseaserisk

It isknownthat manyhumanstressorsarebest remediated

by significantbehavior changeaffectingstressor exposure(e.g., ingesting less glucose ifpre-diabetic or decreasingwork hours

inastressfuljobifhypertensive);somestressorsinhumansare relatedtotheperceptionofthestressormore thanthestressor itself.Forexample,someonewithPTSDisinapathologicallower utilityattractorthatcouldrelatetothebrainmisperceivingthe environmentinawayharmfultotheperson’shealth(e.g.,atruck backfirecausingaveterantoengageinrecollectionsandemotions associatedwithwar)

Resiliencetopsychologicalstressisevidentwhensomepeople avoidsignificantpsychopathology,suchasPTSD anddepression whenexposedtoastressor[10].IntheWorldTradeCenter disas-terresilience,measuredbyalikelihoodofdevelopingPTSD,was relatedtoage(olderdidbetter),gender(malesdidbetter),social support(moredidbetter),self-esteem(higherdidbetter)and life-timehistoryofdepression(worsewithapositivehistory),butwas notrelatedtoeducation[98]

Someamountofstressintheenvironmentmaybeusefulfor maximizing thesystem’s ability to respondto future stressors Humanslivingwithnostressorsmaylosetheabilitytorespondto futurestressors.Fromthebrainperspective,someamountofstress

isusefulformaximizinglearningandmaintainingcognitive func-tion.Systemsthatlearntocopewithsomeamountofstressmay

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responsetoastressor,“aprocessinwhichexposuretoalowdose

of environmentalfactorthatisdamagingathigherdosesinduces

anadaptivebeneficial effectonthecellororganism” [99].This

adaptationcouldbetoenvironmentalstressorssuchascoldand

exercise[100].Astressorcancausethesystemtobenon-optimal

for a shorttime but still result in returning to baseline.While

theremaybesomeallostaticloadcost,thestressormayinduce

changesinsystemphysiological parametersthatstrengthenthe

futureabilitytoreturntoitsgreaterutilitylocations,i.e.,increase

resilience.Thislowlevelofstressexposureoccursinsome

clini-caltreatments,e.g.,allergytherapyandexposuretherapyinPTSD

Insomesensesuchexposurestoalow-levelstressorisawayto

exercisetheresilienceaspectsofthesystem.Ingeneral,repeated

externalstimulielicitlessofaphysiologicalresponsebecauseof

habituationthatcanbemeasuredbyfMRI,event-related

poten-tialsorelectrodermalresponse[101,102].However,insomecases

repeatedexternalstressorsresultintheexcessiveresponse,asin

PTSD(e.g.,hyperarousaltoloudnoises)andbecomeself-reinforced

ratherthanextinguished

Thisdecreasedefficiencyandabilityofthehumandynamical

physiologicalsystemtostayinorgetbacktoafunctionallypositive

attractorbasinisthenegativeeffectofchronicstressorallostatic

load.Changingtheparametersofthehumansystemtobringthe

systembacktotheoptimalstate orhighutility attractoroften

entailsacosttothebasichumanconstituentsbutthechangescan

beusedtosimplyindicatepreviousstressexposure.Thiscouldbe

DNAmodification,receptorsensitivitychanges,orchangestoblood

vesselsfromhighbloodpressure.Anotherexampleofchangesto

theunderlyingsystemis aging,whichcanmakea personmore

likelytoexistinanon-optimalstateorattractorbasin.Itcouldbe

thattheattractorbasinbecomessmallerorlesssteep.Thechangeof

thestatespaceattractorbasinthatdecreasesthesystem’sabilityto

stayinitshigherutilitystateswithoutmovingtolowerutilitystates

initscurrentattractorbasinortoaloweraverageutilityattractor

basinrepresentsthechronicstresseffectorallostaticload.These

changesovertimecanbedefinedmathematically.Thesuboptimal

attractorbasinsdonotbecomenecessarilylarger;rather,thehigh

utilityattractorsbecomesmallerwithshallowersides.Thus,the

timerequiredforreturntothebaselinestatetendstoincrease

Froma probabilisticperspective,theresilienceofthesystem

couldbeconsideredtheprobabilitythat anenvironmental

per-turbationresultsinreturning tothehighutilityattractorbasin,

asopposed toending up in anattractor basin withlower

util-ity Thecapacity ofa systemto stay in a highutility attractor

basincouldbedefinedstochastically:thelikelihoodthat

follow-ingaparticularperturbationthepersonreturnstothehighutility

attractorbasin.Thecapacitytostayinthishighutilityattractor

basinisespeciallyrelevantwhen,following astressor,thestate

maybeclosertothebasinboundaryandbemorelikelytoshifttoa

non-optimalattractorbasinshouldanotherstressormanifest.Even

withoutchangingthespecificattractorbasinbutsimplytheshape

ofthebasin,resiliencecouldbedefinedbasedonthe

probabilisti-callyweightedaverageutilityinasingleattractorbasinfollowing

expectedstressors

PTSDisausefulexampleofstatespaceandattractorssincesome

ofthephysiologicresponsesmayinitiallyhavebeenanadaptive

responseduringspecifictimeandenvironmentbutwhenthey

per-sistinotherenvironments,theresultismovingtoalowerutility

attractorwheretheabnormalresponseisself-reinforcing.Ahigh

stressphysiologicalstatemaybehighutilityduringawarbutif

thatstatepersistsafterreturninghomeitcanbelowerutility.The

transitiontoPTSDisnotreversedimmediatelyassoonascauses

arereversedordisappear.Reversalmightrequiregoingalltheway

backtoanearlierstateinasystemwhichinducesthepossibility

foracuspcatastrophe(Fig.2)

7 Environment and its perception

Inadditiontoknowingthephysiological stateoftheperson, oneshouldalsoknowthestateoftheirenvironmentbecause cer-tainphysiologicalmeasuresmaybeareactiontotheenvironment

Itmustbereiteratedthatalthoughsomeenvironmentalstressors haveadirecteffectonstressresponses,e.g.,extremecold,stress responsesaresignificantlyrelatedtotheperson’sperceptionofthe stressor.Theperceptionoftheenvironment(Fig.3)isaffectedby

aperson’spriorexperiencesthroughattentionandmemory.Many environmentalstressorsarestressfulbecauseofthewaytheyare perceivedandprocessed.Apersonfocusedonanimportantphone callmaynotrealizeit’shailingoutsidebecauseoftheirattentionon call.Asaresult,onemaynotbeworryingaboutwhetherthecarwas leftoutsidethegarage.Attentionreferstosystemsinthebrainthat allowsomeinformationtobeprocessedmorethanother informa-tion[103].Memoryisabroadtermwithmanysubsystemsloosely dividedintodeclarativeandnon-declarativememory[104] Emo-tionalmemoryhascriticalbrainhubsnotrelevantforothertypesof memory.Theamygdalaratherthanthehippocampusiscriticalfor registeringtheemotionalvalenceofanevent[105].Beta-blockers thatblockaspectsoftheANScanhaveanimpactonemotional memorywithoutanyimpactonepisodicmemory[105,106].The memory-inducedchangesinneuralconnectivitythatresultfrom gene expressionandprotein synthesisrequire hourstodays.A personwithamemoryofapreviousenvironmentalstressorwill perceivetheperturbationdifferentlyfromthepersonwithnoprior associationstoit.Forexample,aphysicallyabusedwifemight asso-ciatethenoiseofherhusbandreturninghomewiththephysical abusethatoftenfollows.Thesoundofanopeningdoorwillhave differentneuralassociationstoherthanhernon-abusedneighbor High reactivity to negative events produces physiological changes[107].Infact,negativereactionstoeventsaremore predic-tiveofemotionalwell-beingthantheeventitself[108].Reactivity

tostress can beexamined thoughneuroticism, one of thefive factorsinthewidelyusedfive-factorpersonalityinventory[109] Neuroticismhasgenetic,neurobiological,andenvironmental con-tributions [85,110,111] High neuroticism contributes to many healthdisorders[112]andrelatestoincreasedage-related cogni-tivechangeandclinicalAlzheimer’sdiseaseinlongitudinalstudies [113–115] The cognitive deficits related to distress proneness arenotspecificandmostconsistentlyincludedfrontal-executive functionand perceptual speed [113,115],notdissimilar to cog-nitivechanges associatedwithaffectivedisorders suchasPTSD anddepression[116,117].Neuroticismwithitsnegativeeffectson cognitionisamodifiableriskfactor[118]withapotentiallylarge impactonpopulationhealth[119]

The internal physical componentsof the humanare partof thebrain environment, consideredtheinternal environment in contrasttotheexternalenvironmentlocatedoutsidethephysical body.Thebrainhaspartialawarenessoftheinternal (interocep-tion)andexternal(exteroception)environment.Interoceptionand exteroceptionmayproducebrainandotherphysiologicalchanges withoutawareness,buthumanscanbecomeawareoftheir inter-nalstatessuchasanxietyorstress.Interoceptionmaybetaught

asawareness and controlover internalorgans (e.g.,learningto modulateone’sbloodpressurethroughbiofeedbackormind–body practices)

Aspreviouslymentioned,theeffectofanenvironmentalstressor

onhealthmaybemodifiedbyhowthebrainperceivesthe envi-ronment.Thisperceptioncanbealteredbyhigherlevelconcepts beyondattentionand memoryashighlightedbytheconceptof hope.Fromahealthperspective,optimistsfarebetterthan pes-simists [120]and those withhigher religious involvement and spiritualitydobetterthanthosewithlowerinvolvement[121].The beneficialplaceboresponse,i.e.,theimprovementsinphysiological

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measuresorperceptions ofhealthfollowingadministrationofa

treatmentwithoutanydirectbiologicalaffect,canbeelicitedby

merelytellingsomeonethatatreatmentmaywork(evenifthere

isnodirectlyactivecomponentsinthetreatment) [122,123].It

islikelythatsomemechanismsofplaceboorexpectancyeffects

overlapwithsomeofthemechanismsunderlyingperceptionof

stress[124].Themajorstresshormonecortisolcanbealteredby

experimentalmanipulationofexpectancyinplaceboeffectstudies

[125,126]

8 Stress and resiliency biomarker changes with treatment

Therearephysiological and geneticmarkersassociated with

improved resilience to stress-induced physiological changes

[117,127,128],andtherearealsopsychologicaltoolstoincrease

resilience,ortheabilitytotoleratestressperturbationswithout

decreasingutility.Exposuretherapyhasbeenusedtoreducethe

person’sreactivitytostressors,e.g.,anallergenoranenvironmental

stimulusprecipitatingPTSDsymptoms.Mind–bodytechniquesand

biofeedbackprovidecognitivestrategiestodecreaseemotionally

activatedresponses,avoidunnecessarynegativeinternal

associ-ations(i.e.,senseof stress)tocurrent events, andto maximize

capacitytoreturntoapositivestateattractorfollowingastressor

A key facet of many mind–body therapies is mindfulness,

attendingtothepresentmomentinanon-judgmentalway.With

several ways to measure mindfulness, the judging and

nega-tiveappraisalofthoughts,emotions,andbehaviorfactormaybe

particularlyimportantforstressmanagement.The

mindfulness-non-judgmentalscore,i.e.,beingawareoftheenvironmentwithout

attachingan emotional tag[129],is diminishedby thechronic

stressindementiacaregiversandinveteranswithpost-traumatic

stressdisorder[85,130]

Mind–bodystudieshavesuggestedbiomarkerchangesrelated

tomindfulnessormindfulnesstrainingpartiallyoverlapwiththe

allostatic load biomarkers but in the opposite direction These

includetelomerase[131],immunefunction[132,133], cognitive

function [133,134], catecholamines [135], HRV [136], cortisol

[133,137–139],EEG[140],structuralMRI[141,142]andfMRI[143]

Meditationaltersphysiologicalresponsestoanexperimental

stres-sor[144].However,thepreferredorcompositebiomarkersrelating

tobenefitsofmind–bodymedicinehavenotbeenidentified

9 Utility

Utility is essentially the same as success of the organism

(e.g.,life,procreationor,inthecaseofhumans,earningmoney)

Long-termhealthisanimportantfocusoftheutilitydefinition

con-cerningstress-relatedimpactonhumanhealth.Whileutilityisthe

benefittotheperson(orgenes),thebenefitalsodependsonthe

environment,i.e.,thespecificcalculationofutilityvarieswiththe

environmentandthetimecourseoverwhichitiscalculated

Dur-ingwar,utilityismoreimmediate,perhapssimplysurvivingtothe

nextdaywithaveryhighdiscountforfuturesituations.Therefore,

utilityofaresponsetoastressordependsontheenvironmentand

onaperson’sdegreeofdiscountingfutureevents.Thus,the

calcu-lationofutilityindifferentenvironmentswillbedependentonthe

rewardsandpenaltiesinthecurrentenvironmentandonthetime

durationanddifferentialweightingusedforcalculatingtheutility

10 Conclusions

Thispaperhasdescribedhumanstressphysiologyand

psychol-ogyfromthesystemsscienceperspective.Specificallywefocused

onenvironmentalperturbationstressorsthatproducesignificant

long-termchangesinthehumandynamicalsystem.Acutestressors

usuallydonotproducelong-termnegativeeffectsalthougha

sig-nificantlypowerfulacutestressormaypushthebraindynamical

systemintoa new,functionalattractorbasinwithlowerutility

Ingeneral,chronicpsychologicalstressproduces changesinthe system,suchasaslowerresponsetoafuturestressororahigher potentialfor movingtoa newlowerutilityattractorbasin Ifa humanisexposedtoa“tolerable”doseofastressorthatresults

inreturntotheoriginalhighutilityattractorbasin,theoutcome maybeimprovedresilience.Fromasystemsscienceperspective, behavioralandphysiologicalmeasurementsattemptingtocapture thedegreeofstressofasystemshouldincorporatethedynamicsof thephysiologicalstressresponsesystemaswellassomemeasures

oftheenvironmentalstressorsandtheirperception.Understanding stresswillrequirealloftheinteractingcomponentsfromFig.3tobe measuredanddescribed,atleastpartially.Ingeneral,thesystems dynamicsofstressphysiologyhasmuchlesstemporalempirical datatoinformthemodelthan,forexample,meteorologicaldata becauseofthedifficultyacquiringthehumandata.Nevertheless, analyzingdynamicaldatawillbeimportanttobetterunderstand stressphysiologysincethetimingandstrengthoffeedbackloops likelycontributestodisordersofstressandresiliencetostress.In additiontomeasuringstressresponsesovertime,itmaybeuseful

torepeatadministrationofexperimentalstressorstounderstand self-reinforcingloops.Thesesystemsscienceconceptsandbetter measurementtechniqueswillleadtobetterunderstandingofthe stresssystemthatultimatelycanbeusedtoimprovetheresilience

ofthehumansystemandtherebyimprovelong-termhealth

Acknowledgements

FundedinpartbyagrantfromtheNationalInstitutesofHealth Q5

(AT005121).WeacknowledgeMartinZwick,PhDforreviewingan earlierversionofthepaper,ElenaGoodrichforhelpwithfigures, anddiscussionsaboutsometopicswithHelanéWahbeh,ND,MCR andothercolleagues

References

[1] NPR, Foundation RWJ, Health HSoP The burden of stress in America;

rwjf414295

[2] Bairey Merz CN, Dwyer J, Nordstrom CK, Walton KG, Salerno JW, Schneider

RH Psychosocial stress and cardiovascular disease: pathophysiological links Behav Med 2002;27:141–7.

[3] Lupien SL, McEwen BS, Gunnar MR, Heim C Effects of stress throughout the lifespan on the brain, behavior and cognition Nat Rev Neurosci 2009 [advance online].

[4] Novakova B, Harris PR, Ponnusamy A, Reuber M The role of stress as a trigger for epileptic seizures: a narrative review of evidence from human and animal studies Epilepsia 2013;54:1866–76.

[5] Hemmerle AM, Herman JP, Seroogy KB Stress, depression and Parkinson’s disease Exp Nephrol 2012;233:79–86.

[6] Burns MN, Nawacki E, Kwasny MJ, Pelletier D, Mohr DC Do positive or nega-tive stressful events predict the development of new brain lesions in people with multiple sclerosis Psychol Med 2014;44:349–59.

[7] Cleck JN, Blendy JA Making a bad thing worse: adverse effects of stress on drug addiction J Clin Invest 2008;118:454–61.

[8] Mobus GE, Kalton MC Principles of systems science New York: Springer; 2015.

[9] Holling CS Resilience and stability of ecological systems Annu Rev Ecol Syst 1973;4:1–23.

[10] Russo SJ, Murrough JW, Han MH, Charney DS, Nestler EJ Neurobiology of resilience Nat Neurosci 2012;15:1475–84.

[11] Ader R Psychoneuroimmunology 4th ed San Diego: Elsevier Academic Press; 2007.

[12] McEwen BS Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders Ann N Y Acad Sci 2004;1032:1–7.

[13] Vaseghi M, Shivkumar K The role of the autonomic nervous system in sudden cardiac death Prog Cardiovasc Dis 2008;50:404–19.

[14] Johns LE, Aiello AE, Cheng C, Galea S, Koenen KC, Uddin M Neighborhood social cohesion and posttraumatic stress disorder in a community-based sam-ple: findings from the Detroit Neighborhood Health Study Soc Psychiatry Psychiatr Epidemiol 2012;47:1899–906.

[15] Kemeny ME Psychobiological responses to social threat: evolution of

a psychological model in psychoneuroimmunology Brain Behav Immun 2009;23:1–9.

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839

840

841 842 843 844 845

846

847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885

[16] Young M, Schieman S When hard times take a toll: the distressing

con-sequences of economic hardship and life events within the family–work

interface J Health Soc Behav 2012;53:84–98.

[17] Harrell JP, Hall S, Taliaferro J Physiological responses to racism and

discrim-ination: an assessment of the evidence Am J Public Health 2003;93:243–8.

[18] McEwen BS, Wingfield JC The concept of allostasis in biology and

biomedicine Horm Behav 2003;43:2–15.

[19] Day TA Defining stress as a prelude to mapping its neurocircuitry:

no help from allostasis Prog Neuropsychopharmacol Biol Psychiatry

2005;29:1195–200.

[20] Dohrenwend BP Inventorying stressful life events as risk factors for

psy-chopathology: toward resolution of the problem of intracategory variability.

Psychol Bull 2006;132:477–95.

[21] Lupien S Well stressed: how you can manage stress before it turns toxic.

Mississauga, Ontario: Wiley; 2012.

[22] Kirschbaum C, Pirke KM, Hellhammer DH The ‘Trier Social Stress Test’—a tool

for investigating psychobiological stress responses in a laboratory setting.

Neuropsychobiology 1993;28:76–81.

[23] Dedovic K, Renwick R, Mahani NK, Engert V, Lupien SJ, Pruessner JC The

Montreal Imaging Stress Task: using functional imaging to investigate the

effects of perceiving and processing psychosocial stress in the human brain.

J Psychiatry Neurosci 2005;30:319–25.

[24] Gianaros PJ, Derbyshire SW, May JC, Siegle GJ, Gamalo MA, Jennings JR.

Anterior cingulate activity correlates with blood pressure during stress

Psy-chophysiology 2005;42:627–35.

[25] Lovallo W The cold pressor test and autonomic function: a review and

inte-gration Psychophysiology 1975;12:268–82.

[26] Lang PJ, Bradley MM, Cuthbert BN International affective picture system

(IAPS): technical manual and affective ratings Gainesville: University of

Florida, Center for Research in Psychophysiology; 1999.

[27] Berretta S Cortico-amygdala circuits: role in the conditioned stress response.

Stress 2005;8:221–32.

[28] McEwen BS, Lasley EN Allostatic load: when protection gives way to damage.

Adv Mind Body Med 2003;19:28–33.

[29] McEwen BS The neurobiology of stress: from serendipity to clinical relevance.

Brain Res 2000;886:172–89.

[30] McEwen BS Physiology and neurobiology of stress and adaptation: central

role of the brain Physiol Rev 2007;87:873–904.

[31] Joels M, Baram TZ The neuro-symphony of stress Nat Rev Neurosci

2009;10:459–66.

[32] Datson NA, Morsink MC, Meijer OC, de Kloet ER Central corticosteroid actions:

search for gene targets Eur J Pharmacol 2008;583:272–89.

[33] Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD Accelerated

telomere shortening in response to life stress PNAS 2004;101:17312–5.

[34] Bernston GG, Caciollo JT, Quigley KS Autonomic determinism The modes of

autonomic control, the doctrine of autonomic space, and the laws of

auto-nomic constraint Psychol Rev 1991;98:459–87.

[35] Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R

Psychoneuroimmunol-ogy and psychosomatic medicine back to the future Psychosom Med

2002;64:15–28.

[36] Habib KE, Gold PW, Chrousos GP Neuroendocrinology of stress Endocrinol

Metab Clin North Am 2001;30:695–728, vii–viii.

[37] Charmandari E, Kino T, Souvatzoglou E, Chrousos GP Pediatric stress:

hor-monal mediators and human development Horm Res 2003;59:161–79.

[38] Pruessner M, Hellhammer DH, Pruessner JC, Lupien SJ Self-reported

depres-sive symptoms and stress levels in healthy young men: associations with the

cortisol response to awakening Psychosom Med 2002;65:92–9.

[39] Wahbeh H, Kishiyama S, Zajdel D, Oken B Salivary cortisol

awaken-ing response in mild Alzheimer’s disease, caregivers, and non-caregivers.

Alzheimer’s Dis Relat Disord 2008;22:181–3.

[40] Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH Neurobiological

and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA

sulfate (DHEAS) Front Neuroendocrinol 2009;30:65–91.

[41] Noto Y, Sato T, Kudo M, Kurata K, Hirota K The relationship between salivary

biomarkers and state-trait anxiety inventory score under mental arithmetic

stress: a pilot study Anesth Analg 2005;101:1873–6.

[42] Young AH, Gallagher P, Porter RJ Elevation of the

cortisol-dehydroepiandrosterone ratio in drug-free depressed patients Am J

Psychiatry 2002;159:1237–9.

[43] de Kloet ER From vasotocin to stress and cognition Eur J Pharmacol

2010;626:18–26.

[44] Cacioppo JT, Tassinary LG, Bernston GG 3rd ed New York: Cambridge

University Press; 2007 p 898.

Q6

[45] Pumprla J, Howorka K, Groves D, Nolan MCJ Functional assessment of heart

rate variability: physiological basis and practical applications Int J Cardiol

2002;84:1–14.

[46] Mukherjee S, Yadav R, Yung I, Zajdel DBSO Sensitivity to mental effort and

test–retest reliability of heart rate variability measures in healthy seniors.

Clin Neurophysiol 2011;122:2059–66.

[47] Glaser R, Kiecolt-Glaser JK Stress-induced immune dysfunction: implications

for health Nat Rev Immunol 2005;5:243–51.

[48] Fonareva I, Oken BS Physiological and functional consequences of caregiving

for relatives with dementia International Psychogeriatrics 2014;26:725–47.

[49] Tomiyama AJ, O’Donovan A, Lin J, Puterman E, Lazaro A, Chan J, et al Does

cel-lular aging relate to patterns of allostasis? An examination of basal and stress

reactive HPA axis activity and telomere length Physiol Behav 2012;106:40–5.

[50] Schwartz MS, Andrasik F Biofeedback a practitioner’s guide 3rd ed New York: Guilford Press; 2003 p 930.

[51] Dietrich M, Verdolini Abbott K Vocal function in introverts and extraverts during a psychological stress reactivity protocol J Speech Lang Hear Res 2012;55:973–87.

[52] Arnrich B, Setz C, La Marca R, Troster G, Ehlert U What does your chair know about your stress level IEEE Trans Inf Technol Biomed 2010;14: 207–14.

[53] McEwen BS, Sapolsky RM Stress and cognitive function Curr Opin Neurobiol 1995;5:205–16.

[54] Lupien SJ, McEwen BS, Gunnar MR, Heim C Effects of stress through-out the lifespan on the brain, behaviour and cognition Nat Rev Neurosci 2009;10:434–45.

[55] Bremner JD Does stress damage the brain Biol Psychiatry 1999;45:797–805 [56] Gotlib IH, Joormann J Cognition and depression: current status and future directions Annu Rev Clin Psychol 2010;6:285–312.

[57] Arnsten AF Stress signalling pathways that impair prefrontal cortex structure and function Nat Rev Neurosci 2009;10:410–22.

[58] Stawski RS, Sliwinski MJ, Smyth JM Stress-related cognitive interference pre-dicts cognitive function in old age Psychol Aging 2006;21:535–44.

[59] Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, et al Regional cerebral blood flow in the amygdala and medial prefrontal cortex during trau-matic imagery in male and female Vietnam veterans with PTSD Arch Gen Psychiatry 2004;61:168–76.

[60] Garcia R, Vouimba RM, Baudry M, Thompson RF The amygdala mod-ulates prefrontal cortex activity relative to conditioned fear Nature 1999;402:294–6.

[61] Lupien SJ, de Leon M, de Santi S, Convit A, Tarshish C, Nair NP, et al Cortisol levels during human aging predict hippocampal atrophy and memory deficits Nat Neurosci 1998;1:69–73.

[62] Childress JE, McDowell EJ, Dalai VV, Bogale SR, Ramamurthy C, Jawaid A,

et al Hippocampal volumes in patients with chronic combat-related posttrau-matic stress disorder: a systematic review J Neuropsychiatry Clin Neurosci 2013;25:12–25.

[63] Woon FL, Sood S, Hedges DW Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disor-der in adults: a meta-analysis Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1181–8.

[64] Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko NB, Orr SP, et al Smaller hippocampal volume predicts pathologic vulnerability to psycholog-ical trauma Nat Neurosci 2002;5:1242–7.

[65] Yaffe K, Vittinghoff E, Lindquist K, Barnes D, Covinsky KE, Neylan T, et al Posttraumatic stress disorder and risk of dementia among US veterans Arch Gen Psychiatry 2010;67:608–13.

[66] Kaye J, Swihart T, Howieson D, Dame A, Moore M, Karnos T, et al Volume loss

of the hippocampus and temporal lobe in healthy elderly destined to develop dementia Neurology 1997;48:1297–2134.

[67] Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner JD Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder Biol Psychiatry 2003;54:693–702.

[68] Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S,

et al Antidepressants increase human hippocampal neurogenesis by activat-ing the glucocorticoid receptor Mol Psychiatry 2011;16:738–50.

[69] Perez-Edgar K, Kujawa A, Nelson SK, Cole C, Zapp DJ The relation between electroencephalogram asymmetry and attention biases to threat at baseline and under stress Brain Cogn 2013;82:337–43.

[70] Anokhin AP, Heath AC, Myers E Genetic and environmental influ-ences on frontal EEG asymmetry: a twin study Biol Psychol 2006;71: 289–95.

[71] Ceballos NA, Giuliano RJ, Wicha NY, Graham R Acute stress and event-related potential correlates of attention to alcohol images in social drinkers J Stud Alcohol Drugs 2012;73:761–71.

[72] Davidson RJ What does the prefrontal cortex do in affect: perspectives on frontal EEG asymmetry research Biol Psychol 2004;67:219–33.

[73] Dedovic K, Duchesne A, Andrews J, Engert V, Pruessner JC The brain and the stress axis: the neural correlates of cortisol regulation in response to stress Neuroimage 2009;47:864–71.

[74] Vaisvaser S, Lin T, Admon R, Podlipsky I, Greenman Y, Stern N, et al Neural traces of stress: cortisol related sustained enhancement of amygdala-hippocampal functional connectivity Front Hum Neurosci 2013;7:313.

[75] Pruessner JC, Dedovic K, Khalili-Mahani N, Engert V, Pruessner M, Buss C,

et al Deactivation of the limbic system during acute psychosocial stress: evidence from positron emission tomography and functional magnetic reso-nance imaging studies Biol Psychiatry 2008;63:234–40.

[76] Seeman TE, McEwen BS, Rowe JW, Singer BH Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging Proc Natl Acad Sci U S A 2001;98:4770–5.

[77] Evans GW, Schamberg MA Childhood poverty, chronic stress, and adult work-ing memory Proc Natl Acad Sci U S A 2009;106:6545–9.

[78] Bellingrath S, Weigl T, Kudielka BM Chronic work stress and exhaustion

is associated with higher alostatic load in female school teachers Stress 2009;12:37–48.

[79] Juster RP, McEwen BS, Lupien SJ Allostatic load biomarkers of chronic stress and impact on health and cognition Neurosci Biobehav Rev 2009,

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