Barratt Impulsivity and Neural Regulation of Physiological Arousal

17 Pages·2015·0.59 MB·English

RESEARCHARTICLE
Barratt Impulsivity and Neural Regulation of
Physiological Arousal
ShengZhang1*,SienHu1,JianpingHu1,2,Po-LunWu1,3,HertaH.Chao4,5,Chiang-shan
R.Li1,6,7*
1 DepartmentofPsychiatry,YaleUniversity,NewHaven,CT06519,UnitedStatesofAmerica,
2 DepartmentofPsychology,SouthChinaNormalUniversity,Guangzhou,China,3 Departmentof
Psychiatry,ChinaMedicalUniversity,Tai-Chung,Taiwan,4 DepartmentofMedicine,YaleUniversity,New
Haven,CT06519,UnitedStatesofAmerica,5 DepartmentofMedicine,VAConnecticutHealthcare
Systems,WestHaven,CT06516,UnitedStatesofAmerica,6 InterdepartmentalNeuroscienceProgram,
YaleUniversity,NewHaven,CT06520,UnitedStatesofAmerica,7 DepartmentofNeurobiology,Yale
University,NewHaven,CT06520,UnitedStatesofAmerica
* [email protected](SZ); [email protected](CRL)
Abstract
Background
OPENACCESS
Theoriesofpersonalityhavepositedanincreasedarousalresponsetoexternalstimulation
Citation:ZhangS,HuS,HuJ,WuP-L,ChaoHH,Li
inimpulsiveindividuals.However,thereisadearthofstudiesaddressingtheneuralbasisof
C-sR(2015)BarrattImpulsivityandNeural
RegulationofPhysiologicalArousal.PLoSONE10 thisassociation.
(6):e0129139.doi:10.1371/journal.pone.0129139
Methods
AcademicEditor:ChristianSchmahl,Central
InstituteofMentalHealth,GERMANY
Werecordedskinconductancein26individualswhowereassessedwithBarrattImpulsivity
Received:January20,2015 Scale(BIS-11)andperformedastopsignaltaskduringfunctionalmagneticresonanceim-
Accepted:May5,2015 aging.ImagingdatawereprocessedandmodeledwithStatisticalParametricMapping.We
usedlinearregressionstoexaminecorrelationsbetweenimpulsivityandskinconductance
Published:June16,2015
response(SCR)tosalientevents,identifytheneuralsubstratesofarousalregulation,and
Copyright:©2015Zhangetal.Thisisanopen
examinetherelationshipbetweentheregulatorymechanismandimpulsivity.
accessarticledistributedunderthetermsofthe
CreativeCommonsAttributionLicense,whichpermits
unrestricteduse,distribution,andreproductioninany Results
medium,providedtheoriginalauthorandsourceare
Acrosssubjects,higherimpulsivityisassociatedwithgreaterSCRtostoptrials.Activityof
credited.
theventromedialprefrontalcortex(vmPFC)negativelycorrelatedtoandGrangercaused
DataAvailabilityStatement:Allrelevantdataare
skinconductancetimecourse.Furthermore,higherimpulsivityisassociatedwithalesser
availableinthepaperanditsSupportingInformation
files. strengthofGrangercausalityofvmPFCactivityonskinconductance,consistentwithdimin-
ishedcontrolofphysiologicalarousaltoexternalstimulation.Whenmen(n=14)and
Funding:ThisworkwassupportedbyNIHgrants
R01DA023248,R21AA018004,R01AA021449, women(n=12)wereexaminedseparately,however,therewasevidencesuggestingasso-
K02DA026990,R03CA138121.Thecontentissolely ciationbetweenimpulsivityandvmPFCregulationofarousalonlyinwomen.
theresponsibilityoftheauthorsanddoesnot
necessarilyrepresenttheofficialviewsoftheNational
Conclusions
InstitutesofHealth.
Together,thesefindingsconfirmedthelinkbetweenBarrattimpulsivityandheightened
CompetingInterests:Theauthorshavedeclared
thatnocompetinginterestsexist. arousaltosalientstimuliinbothgendersandsuggestedtheneuralbasesofaltered
PLOSONE|DOI:10.1371/journal.pone.0129139 June16,2015 1/17
ImpulsivityandArousal
regulationofarousalinimpulsivewomen.Moreresearchisneededtoexploretheneural
processesofarousalregulationinimpulsiveindividualsandinclinicalconditionsthatimpli-
catepoorimpulsecontrol.
Introduction
Characterizedbybehavioraldisinhibitionandrashactions,traitimpulsivitymaydisposeindi-
vidualstonegativeconsequences.Animportantdimensionoftraitimpulsivityconcernsthe
regulationofphysiologicalarousal.Anumberofleadingtheoriesofpersonalitypositthatim-
pulsivity–asacomponenttraitofextraversion–ischaracterizedbyunder-arousalatrestand
greaterincreasesinarousalinresponsetostimulation[1–5].Impulsiveindividualsseek
stimulationtomaintainanoptimallevelofarousal.
Insupport,manystudiesdemonstratedincreasedphysiologicalarousaltostimulationinin-
dividualshigheronimpulsivity.Forinstance,impulsivityinassociationwithrisktakingbehav-
iorwascorrelatedtoincreasedskinconductancereactivitytoarousingstimuli[6].Impulsivity
wasassociatedwithincreasedheartratetoanauditoryattentiontaskinmen[7].Indomestic
violenceoffenders,traitimpulsivitywasassociatedwithincreasedskinconductanceresponse
(SCR)duringapreparatoryperiodtoconfrontstress[8].Inadouble-blindstudyofindividual
differencesinacutesubjectiveresponsestoamphetamine,hightraitimpulsivitywassignifi-
cantlyassociatedwithgreaterarousalandeuphoria[9].Gamblersshowedincreasedheartrate
duringthegame,inpositivecorrelationwithsubjectivereportofarousalandsensationseeking
[10].Frequentgamblerswerefoundtohavesignificantlyhigherlevelsofarousal,whichcontin-
uetoriseafterplay,incontrasttoinfrequentandnon-gamblers[11].InchildrenwithADHD
performingadelayedreactiontimetask,rewardevokedhigherSCRandledtomoreimpulsive
responses,ascomparedtocontrolparticipants[12].Highimpulsivemenexhibitedslower
heartrateunderrestalongwithgreaterreactivitytoabehavioralchallenge[7].Alsoinsupport
ofthehypothesisarestudiesreportingincreasedorientingERPsduringsensorystimulationin
impulsiveindividuals[13,14].
Ontheotherhand,nostudiestoourknowledgehaveexaminedtheneuralbasesofarousal
regulationinassociationwithimpulsivity.Here,weaddressedthisissuebystudying26healthy
adultsinastopsignaltaskincombinationwithfunctionalmagneticresonanceimaging(fMRI)
andconcurrentrecordingofskinconductance.First,weexaminedwhetherimpulsivity,asas-
sessedbyBarrattImpulsivityScale(BIS-11),isassociatedwithskinconductancelevel(SCL)
andSCRtoinfrequent,salientevents.Second,ourpreviousfMRIstudydemonstratedthatthe
timecourseoftheventromedialprefrontalcortex(vmPFC)isnegativelycorrelatedwithSCL
andthestrengthofGrangercausalityofvmPFConSCLisnegativelycorrelatedwithSCRtosa-
lientstimuli,suggestingaprefrontalcorticalmechanismofarousalregulation[15].Oursecond
aimwastoexaminehowinter-subjectvariationinimpulsivityrelatestovmPFCregulationof
skinconductance.Third,thereisevidenceforgenderdifferenceintheassociationbetween
traitimpulsivityandriskybehavior[16–20].Thus,weexaminedwhethertheassociationbe-
tweenimpulsivityandphysiologicalarousalaswellastheneuralbasisofarousalregulation
variesbetweenmenandwomen.
MaterialsandMethods
Subjects,behavioraltask,andBarrattImpulsivityScale
Twenty-sixadulthealthysubjects(14males,18–52yearsofage,allright-handedandusing
theirrighthandtorespond)participatedinthisstudy(Table1).Thissamplecomprised20of
the24participantsreportedinourpreviouswork(Zhangetal.,2014;theother4werenot
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Table1. Demographicsofthesubjects.
Subjectcharacteristic All(n=26) Male(n=14) Female(n=12) p-value
Ages(years) 30.6±10.3 31.1±11.2 29.9±9.5 0.78*
Race(EA/AA/Others) 21/3/2 12/1/1 9/2/1 0.74^
Education(years) 16.6±3.2 16.5±3.9 16.8±1.9 0.77*
Note:valuesaremean±S.D.;p-valuesarefromstatisticcomparisonbetweenmalesandfemales
*two-tailedtwo-samplettest
^chi-squaretest
doi:10.1371/journal.pone.0129139.t001
assessedforimpulsivityandthusnotincluded)and6newsubjects,allstudiedunderanidenti-
calprotocol.Allparticipantsdeniedmedicalincludingneurologicalillnesses,historyofhead
injuries,currentuseofanymedications,oruseofanypsychotropicmedicationsinthepast
year.TheywerealsofreeofanypsychiatricdiagnosesasassessedwiththeStructuredClinical
InterviewforDiagnosticandStatisticalManualDisorders[21],denieduseofillicitsubstances,
andshowedanegativeurinetoxicologytestonthedayoffMRI.Allsubjectswerepaidtopar-
ticipateandsignedawrittenconsentafterdetailsofthestudywereexplained,inaccordanceto
aprotocolapprovedbytheYaleHumanInvestigationCommittee.
Weemployedasimplereactiontime(RT)taskinthisstop-signalparadigm,asdescribedin
detailspreviously[22–24].Briefly,thereweretwotrialtypes:“go”(~75%)and“stop”(~25%),
randomlyintermixed.Asmalldotappearedonthescreentoengageattentionatthebeginning
ofagotrial.Afterarandomizedtimeinterval(fore-period)between1and5s,thedotturned
intoacircle,promptingthesubjectstoquicklypressabutton.Thecirclevanishedatbutton
pressorafter1shadelapsed,whichevercamefirst,andthetrialterminated.Aprematurebut-
tonpresspriortotheappearanceofthecirclealsoterminatedthetrial.Inastoptrial,an“X,”
the“stop”signal,appearedandreplacedthegosignal,instructingthesubjectstowithholdbut-
tonpress.Likewise,atrialterminatedatbuttonpressorafter1shadelapsed.Therewasan
inter-trial-intervalof8stoallowadequatespacingbetweeneventsofinterestandidentification
ofelectrodermalresponsesassociatedwiththeseevents.Thetimeintervalbetweengoandstop
signalsorstopsignaldelay(SSD)startedat200msandvariedfromonestoptrialtothenext
accordingtoastaircaseprocedure,increasinganddecreasingby64ms,eachafterasuccessful
andfailedstoptrial[25,26].Withthestaircaseprocedure,a“critical”SSDcouldbecomputed
thatrepresentsthetimedelayrequiredforthesubjecttosucceedinhalfofthestoptrials[25].
ThestopsignalreactiontimewascomputedbysubtractingthecriticalSSDfrommediango
RT.Subjectswereinstructedtorespondtothegosignalquicklywhilekeepinginmindthata
stopsignalcouldcomeupinasmallnumberoftrials[27].Withthestaircaseprocedurewean-
ticipatedthatthesubjectswouldsucceedinwithholdingtheirresponseinapproximatelyhalf
ofthestoptrials.Afterapracticesessionoutsidethescanner,eachsubjectcompletedsix
10-minrunsofthetaskinthescanner.
IndividualimpulsivitywasquantifiedfromthetotalscoreontheBarrattImpulsiveness
Scale,version11orBIS-11[28,29].ThreesubscoresoftheBIS-11werealsocomputedfor“at-
tentionalimpulsivity”oraninabilitytofocus,“motorimpulsivity”oractingwithoutprior
thought,and“nonplanningimpulsivity”ornotthinkingandplanningcarefully[29].Eachsub-
scalecomprises10questionswithsomeitemstobereverse-scoredtocontrolforresponsebias.
TheBIS-11iswidelyusedinpersonalityandclinicalresearchtocaptureindividualtendency
towardrashandriskbehaviors.TheBISsubscoresaremissingforamalesubject.Thus,inthe
followinganalysis,only25subjectswereusedforsubscoresrelatedanalysis.
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Skinconductanceacquisitionandanalysis
WithaBiopacMP150system,skinconductancewascontinuouslyrecordedduringfMRIfrom
thepalmersurfacesoftheindexandmiddlefingersofthelefthand.TheBiopacsystemuseda
AcqKnowledge4.1software(BiopacSystems,USA)andtheBiopacelectrodermalactivityam-
plifiermodule(GalvanicSkinResponse[GSR]100c)setatachannelsamplingrateof31Hz
andagainof5μSiemens(μS)pervolt(resultinginaresolutionof0.0015μS).Recordingof
skinconductanceissynchronizedwithbehavioraltaskandimageacquisition.Asmoothing
functionwithamovingaverageof500mswasappliedinordertoeliminatehigh-frequency
noise[30].TheSCLwascomputedbyresamplingtheskinconductancewaveformtomatch
theTR(2s)usedinfunctionalimagingdataacquisitionandanalysis[31,32].Becauseeachin-
dividualtriallastedlongerthan10s,weuseda10-swindowalignedwithgosignalonsetto
computetheSCRforeachtrial.TheSCRwascomputedastheonset-to-peakamplitudediffer-
enceinskinconductanceinthis10-swindowasinapreviousstudy[33].
Skinconductanceresponse:impulsivityandgenderdifferences
Wecomputedtheskinconductanceresponses(SCR)togo(G),stopsuccess(SS),andstop
error(SE)trials.Inananalysisofvarianceweexaminedthemaineffectsoftrialtypeandgen-
derandtheirinteractioneffectonthemagnitudeofSCR,followedbyplannedcomparisons.
WithPearsonregressionsweexaminedthecorrelationbetweeneachSCRandBIS-11total
scoreformenandwomencombinedaswellasseparately.Incaseswheretheresultswerestatis-
ticallysignificant,were-examinedthecorrelationofSCRtotheattention,motor,andnonplan-
ningsubscoresofBIS-11.
Imagingprotocolanddatapreprocessing
ConventionalT1-weightedspinechosagittalanatomicalimageswereacquiredforslicelocali-
zationusinga3Tscanner(SiemensTrio).Anatomicalimagesofthefunctionalslicelocations
werenextobtainedwithspinechoimagingintheaxialplaneparalleltotheanteriorcommis-
sure–posteriorcommissure(AC–PC)linewithTR=300ms,TE=2.5ms,bandwidth=300
Hz/pixel,flipangle=60°,fieldofview=220×220mm,matrix=256×256,32sliceswithslice
thickness=4mmandnogap.Functional,bloodoxygenationlevel-dependent(BOLD)signals
werethenacquiredwithasingle-shotgradientechoechoplanarimaging(EPI)sequence.Thir-
ty-twoaxialslicesparalleltotheAC–PClinecoveringthewholebrainwereacquiredwith
TR=2000ms,TE=25ms,bandwidth=2004Hz/pixel,flipangle=85°,fieldof
view=220×220mm,matrix=64×64,32sliceswithslicethickness=4mmandnogap.
BrainimagingdatawerepreprocessedusingStatisticalParametricMappingversion8
(WellcomeDepartmentofImagingNeuroscience,UniversityCollegeLondon,U.K.).Images
fromthefirstfiveTRsatthebeginningofeachsession/runwerediscardedtoenablethesignal
toachievesteady-stateequilibriumbetweenradiofrequencypulsingandrelaxation.Imagesof
eachindividualsubjectwerefirstcorrectedforslicetimingandrealigned(motioncorrected).A
meanfunctionalimagevolumewasconstructedforeachsubjectforeachrunfromthere-
alignedimagevolumes.ThesemeanimageswerenormalizedtoanMNI(MontrealNeurologi-
calInstitute)EPItemplatewithaffineregistrationfollowedbynonlineartransformation[34].
Thenormalizationparametersdeterminedforthemeanfunctionalvolumewerethenapplied
tothecorrespondingfunctionalimagevolumesforeachsubject.Finally,imageswere
smoothedwithaGaussiankernelof8mmatFullWidthatHalfMaximum.
AdditionalpreprocessingwasappliedtoreducespuriousBOLDvariancesthatwereunlikely
toreflectneuronalactivity[35,36].Thesourcesofspuriousvariancewereremovedthrough
linearregressionbyincludingthesignalfromtheventricularsystem,thewhitematter,andthe
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wholebrain,inadditiontothesixparametersobtainedbyrigidbodyheadmotioncorrection.
First-orderderivativesofthewholebrain,ventricularandwhitemattersignalswerealsoin-
cludedintheregression.
Voxelwiselinearcorrelationwithskinconductance
Wecomputedforindividualsubjectsthecorrelationcoefficientbetweentheskinconductance
level(SCL)andthetimecoursesofeachvoxelforthewholebrain.Notethattheskinconduc-
tanceimpulseresponsefunctionisverycloseinshapeandlatencytothatofthecanonicalhemo-
dynamicresponsefunction[31,37].Thus,SCLcouldbecrosscorrelatedwithBOLDsignals
withoutadditionalprocessing.Wethenconvertedtheseindividualcorrelationmaps,whichwere
notnormallydistributed,tozscoremapsbyFisher’sztransform:z=0.5loge[(1+r)/(1−r)].Thez
mapswereusedinthesecondlevelrandomeffectsanalysis[38].Aone-samplet-testwasapplied
tothe‘zmaps’acrossallsubjectstoidentifyregionalactivitiescorrelatedtoskinconductance.
Functionalregionsofinterest(ROIs)weredefinedbasedonactivatedclustersatacorrected
thresholdfromwhole-brainanalysis.AllvoxelactivationswerepresentedinMNIcoordinates.
GrangercausalityanalysisofbrainactivityandSCLtimecourse
BOLDandskinconductancesignalswereexaminedwithGrangercausalityanalysis(GCA,
[39]),whichhasbeenwidelyusedtodescribe“causal”influencebetweensetsofEEGorfMRI
timeseries[40–46],asdescribedindetailsinourpreviousstudies[47–49].Briefly,weused
multivariateautoregressive(MAR)modeling[46,50]toperformGCA.Inanunrestricted
modelofthetimeseries
Xp
YðtÞ¼ AYðt(cid:2)iÞþεðtÞ;t ¼1;2;...;T; ð1Þ
i
i¼1
Y(t)isacolumnvector[y1(t),y2(t),...,yn(t)]inwhicheachelementyj(t),j=1,2,...,n,istheav-
eragetimeseriesofaregionofinterest(ROI)orSCLattimepointt;Tisthenumberoftime
points;nisthenumberofROI/SCL;andε(t)isacolumnvector[ε1(t),ε2(t),...,εn(t)]ofresid-
ualsattimepointt.ThemodelorderisrepresentedbypandAiisan-by-nmatrixgivenby
2 3
aðiÞ aðiÞ (cid:3)(cid:3)(cid:3) aðiÞ
6 11 12 1n7
66aðiÞ aðiÞ (cid:3)(cid:3)(cid:3) aðiÞ77
Ai ¼666 ...21 ...22 ... ...2n777;i¼1;2;...;p; ð2Þ
4 5
aðiÞ aðiÞ (cid:3)(cid:3)(cid:3) aðiÞ
n1 n2 nn
estimatedbyordinaryleastsquares[51].Todeterminethemodelorder,weemployedthe
BayesianInformationCriterion[52,53].TheapplicationofMARmodelingrequiredthat
eachROIorSCLwascovariancestationary,whichweexaminedwiththeAugmented
DickeyFuller(ADF)test[54].TheADFtestverifiedthattherewasnounitrootinthe
modeledtimeseries.TotestwhethervariablexGrangercausesy,wherex,y2Y(t),x6¼y,
wecomputedtheregressionEq(1)withoutvariablex(therestrictedmodel)andobtained
theresiXdualsumofsquaresRSSXrofvariabley.Theresidualsumofsquaresofyisgivenby
RSS¼ T ðyðtÞ(cid:2)^yðtÞÞ2 ¼ T εðtÞ2,wherey^representsthepredictedvalueofy.These
t¼1 t¼1
residualswereusedtocomputetheGrangercausalitystrengthmeasures(F-values)ofeach
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possibleconnectionbetweenROIsandskinconductance[54]:
ðRSSr(cid:2)RSSurÞ=
F ¼ p; ð3Þ
RSSur=
ðT(cid:2)2p(cid:2)1Þ
whereRSSuristheresidualsumofsquaresofvariableyintheunrestrictedmodel.Wetested
thesignificanceoftheGrangercausalitybetweentimeseriesbyanFtestandusedbinomialtest
toassessstatisticalsignificanceingroupanalysisasdescribedindetailsearlier[47–49].For
eachconnection,wecountedthenumberofsubjectsthathadsignificantconnectionsandesti-
mateditssignificanceusingabinomialdistributionwithparametersn=26,andp=q=0.5
(sameprobabilitytoobserveaconnectionornot).Foreachsubject,wehadatotalof1770(295
x6)timepointsforGrangercausalityanalysis.
ToassesshowthestrengthofGrangercausalityrelatestoevent-evokedarousal,weexam-
inedthecorrelationacrosssubjectsbetweenthecausalitystrengthmeasures(F-values)and
stimulus-evokedSCRwithalinearregression.
Impulsivityandventromedialprefrontalcorticalregulationofskin
conductance
Asdescribedabove,ourearlierworkwithGCAsuggestedaregulatoryroleoftheventromedial
prefrontalcortex(vmPFC)onskinconductance[15].ThestrengthofGrangercausalitywasin-
verselycorrelatedwiththeSCRtostoptrials.Thus,here,weexaminedwhetherthisGranger
causalityiscorrelatedtoBIS-11totalscoreinmenandwomencombinedandseparately.
Results
Impulsivity,behavioralperformanceandskinconductanceresponse
Acrosssubjects,BIS-11totalscoresrangedfrom42to85withamean±S.D.of60.2±11.9.In
pairwisecorrelation,thesubscalescoresshowedacorrelationbetweenattentionandmotorim-
pulsivity(p=0.00007),betweenattentionandnon-planningimpulsivity(p=0.003),butnot
betweenmotorandnon-planningimpulsivity(p=0.06).Menandwomendidnotdifferinei-
thertotal(men:63±12;women56±12)orsubscalescores(allp’s>0.14).
Acrosssubjects,participantsrespondedin97.8%±3.5%ofgotrialsand55.0%±2.9%of
stoptrials.Theaverageresponsetimeofstoperrortrials(606±92ms)wasshorterthanthego
responsetrials(669±67ms,p<0.00001,pairedsamplettest).Thestopsignalreactiontime
(SSRT)was236±32msacrosssubjects.Theseresultsaretypicalofstopsignaltaskperfor-
mance.MenandwomendidnotshowadifferenceinSSRT(p=0.29)norwasthereacorrela-
tionbetweenBIS-11totalscoreandSSRTinmenandwomencombined(p=0.62)orinman
(p=0.20)orwomen(p=0.29)alone[55].
Skinconductanceresponses(SCR)duringtheSSTareshowninFig1.Asdescribedinthe
Methods,wequantifiedtheSCRbysubtractingtheamplitudeatthebaselinefromtheampli-
tudeatthepeakina10-secondwindowafterstimulusonsetforeachtrial.Acrossall26sub-
jects,go(G),stopsuccess(SS)andstoperror(SE)trialsshowedsignificantdifferencesinSCR
(p=0.002,trialmaineffect,two-wayANOVA),asdidplannedcomparisons:Gvs.SS
(p=0.02),Gvs.SE(p=0.0002),andSSvs.SE(p=0.0002),withtwo-samplettests.Therewas
alsoagendermaineffectwithmenshowinggreaterSCRthanwomen(p=0.009)butnointer-
actioneffectbetweentrialandgender(p=0.54).
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Fig1.SkinconductanceresponsesintheSST.Skinconductanceresponses(SCR)togo(G),stop
success(SS)andstoperror(SE)trialsintheSST.DatabarsshowSCR(mean±S.E.)formen(n=14)and
women(n=12)separately.Acrossall26subjects,G,SSandSEtrialsshowedsignificantdifferencesinSCR
(p=0.002,trialmaineffect,two-wayANOVA),asdidplannedcomparisons:Gvs.SS(p=0.02),Gvs.SE
(p=0.0002),andSSvs.SE(p=0.0002),withtwo-samplettests.Therewasalsoagendermaineffectwith
menshowinggreaterSCRthanwomen(p=0.009)butnointeractioneffectbetweentrialandgender
(p=0.54).
doi:10.1371/journal.pone.0129139.g001
Impulsivityandskinconductanceresponse
Acrosssubjects,BIS-11totalscorecorrelatedpositivelywithSCRtoSSandSEbutnotGtrials
(Fig2).Inregressionsconductedseparatelyformenandwomen,onlywomendemonstrated
significantcorrelationsbetweenBIS-11andSCRtoSSandSEtrials(Fig2).
WefurtherexaminedthecorrelationbetweenBIS-11subscoresandSCR.Theresults
showedthatSCRisrelatedtoattentionalandmotorbutnotnonplanningimpulsivityin
womenandSCRisnotsignificantlycorrelatedtoanyofthesubscoresinmen(Table2).
ArousalrelatedbrainactivationandGrangercausalityanalysis(GCA)
Asexpected,weobservedthattheventromedialprefrontalcortex(vmPFC,x=2,y=25,z=
-14)showedsignificant(peakvoxelp<0.001andclusterlevelp<0.05,FWEcorrected)nega-
tivecorrelationwithskinconductance(Fig3).
Fig2.CorrelationbetweenBIS-11totalscoreandSCR.CorrelationbetweenBIS-11totalscoreandSCRto(a)G,(b)SS,and(c)SEtrialsacrossall26
subjects(black)aswellasacross14men(green)and12women(red)separately.
doi:10.1371/journal.pone.0129139.g002
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Table2. AsummaryofcorrelationsbetweenBIS-11subscores(Attention,Motor,andNonplanning
Impulsiveness)andSCR.
Attention Motor Nonplanning
p r p r p r
Allsubjects:
SCRofG 0.06 0.38 0.08 0.35 0.86 0.04
SCRofSS 0.006 0.54 0.01 0.51 0.27 0.23
SCRofSE 0.01 0.49 0.002 0.59 0.30 0.21
Men:
SCRofG 0.34 0.28 0.65 0.13 0.62 0.14
SCRofSS 0.13 0.42 0.28 0.31 0.24 0.34
SCRofSE 0.25 0.33 0.18 0.38 0.27 0.31
Women:
SCRofG 0.26 0.37 0.02 0.67 0.87 -0.06
SCRofSS 0.04 0.63 0.004 0.79 0.61 0.17
SCRofSE 0.02 0.68 0.0002 0.89 0.64 0.16
*Pvaluesarenotcorrected.
doi:10.1371/journal.pone.0129139.t002
TheresultsofGCAshowedthatBOLDsignalsofthevmPFCGrangercausedtheSCL
(p<0.05forindividualGCAandp=0.04,binomialtestforgroupanalysis),buttheSCLdid
notGrangercausevmPFCactivity(p=0.16).Moreover,individualsvariedinthestrengthof
GrangercausalityasindexedbytheFvalue(mean±SD:5.0±4.5;range:0.4to18.6).Across
allparticipants,PearsonregressionsshowedthathigherGrangercausalitystrength(F-values)
ofthevmPFCwasassociatedwithlessSCRelicitedtogo(p=0.008,r=-0.52),stopsuccess
(p=0.006,r=-0.54),andstoperror(p=0.02,r=-0.47)trialsduringthestopsignaltask.
WeassessedhowthestrengthofGrangercausalityofvmPFConSCLisrelatedtotheBIS-
11totalscoreandsubscores.Theresultsshowedasignificantnegativecorrelationbetweenthe
Fvalueandtotalscore(p=0.04,r=-0.41)inmenandwomencombined,butnotinwomen
(p=0.12)ormen(p=0.54)alone.Fortheentiresample,Fvaluewasalsosignificantlycorrelat-
edtoattentionsubscore(p=0.007,r=-0.52),motorsubscore(p=0.04,r=-042)butnotnon-
planningsubscore(p=0.36).Analyzedseparatelyformenandwomen,inattentionimpulsivity
showednegativecorrelationwiththeGrangercausalitystrengthinwomen(p=0.01,r=-0.71)
butnotmen(p=0.40)(Fig4).Motorandnon-planningimpulsivitywasnotcorrelatedwith
thecausalitystrengthinwomenormenalone.
Fig3.Brainregionnegativelycorrelatedwithskinconductance.Theventromedialprefrontalcortex
(vmPFC,x=2,y=25,z=-14)showedsignificantnegativecorrelationwithskinconductanceacross26
subjects(peakvoxelp<0.001andclusterlevelp<0.05,FWEcorrected).
doi:10.1371/journal.pone.0129139.g003
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Fig4.CorrelationbetweenGrangercausalitystrengthandBIS-11sub-scores.CorrelationbetweenGrangercausalitystrengthandBIS-11sub-scores
of(a)attention,(b)motor,and(c)nonplanningacrossall26subjects(black)aswellasacross14men(green)and12women(red)separately.
doi:10.1371/journal.pone.0129139.g004
Discussion
ThecurrentresultsshowedthatBarrattimpulsivityisassociatedwithheightenedskinconduc-
tanceresponse(SCR)tosalientevents.Furthermore,Barrattimpulsivityisassociatedwithde-
creasedventromedialprefrontalcorticalregulationofphysiologicalarousalinwomen.These
findingssupportthehypothesisofalteredarousalregulationinimpulsiveindividualsanda
prefrontalmechanismunderlyingthisassociationinwomen.Thesefindingsareofclinical
importanceinthatimpulsivityandarousaldysregulationarebothbiologicalhallmarksof
addiction[56–60].Furthermore,impulsivityisknowntobeadimensionaltraitthatvariescon-
tinuouslyinthegeneralpopulation[61–63].Unravelingtheneuralprocessesofarousalregula-
tionwouldadvanceourunderstandingofthebiologicalbasesofimpulsivityinhealthand
illness.Wediscussthesefindingsinthebelow.
Impulsivityandphysiologicalarousal
Asdescribedintheabove,ourfindingsshowedthatimpulsivityisassociatedwithincreased
physiologicalarousaltosalientevents.Ontheotherhand,asmallernumberofstudiesreported
contrastingfindings.Inanauditorytaskwhereparticipantsweretodetectan“odd-ball”
amongstandardtones,individualshighonimpulsivityandsensationseekingshowedlessSCR
tothedeviation[64].Instudiesofacousticstartlereflex,highsensationseekingindividuals
demonstratereducedstartlereactivity[65,66].Inagamblingtask,electrodermalreactivityin-
creasedtolossesascomparedtowinsandthisdifferenceisnegativelycorrelatedwithtraitim-
pulsivityinadolescents[67].Together,thesestudiessuggestlowerarousaland/orarousability
inassociationwithimpulsivity.Studiesofphysiologicalarousalatrest,asindexedbyskincon-
ductancelevel(SCL),arefewerinnumberbutsimilarlydepictaconflictingpicture.Inchildren,
proactiveaggressionandhighimpulsivityisassociatedwithincreasedrestingskinconductance
[68].However,inboyswithattentiondeficithyperactivitydisorder,symptomaticseverityisas-
sociatedwithlowersympatheticandhigherparasympatheticactivity[69].
Itisnotclearwhatmayaccountforthesediscrepantfindings.Onepotentialfactoristhat
manyofthesestudiescomprisedvariousclinicalpopulationsorindividualswhodemonstrated
varyingextentofriskybehaviorsincludinghabitualgamblingandmultiplesexualpartners.
Further,manystudiesfocusedonlyonmenandfewhaveconsideredgenderindataanalyses.
Morestudiesclearlyareneededtoaddressthisissue.
Impulsivityandneuralbasesofphysiologicalarousal
Agrowingbodyofresearchemploysbrainimagingtounraveltheneuralbasesofimpulsivity.
Forinstance,inotherwisehealthyindividuals,impulsivityisassociatedwithincreased
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ImpulsivityandArousal
responsesoftheanteriorcingulatecortexandamygdala[70]anddecreasedresponsesofthe
anteriorpre-supplementarymotorarea[71]toanticipationofreward,anddecreasedactivation
oftherightinsulaandmiddlefrontalcortexinprocessingsalientstimuli[55].Impulsivity,as
indexedbytemporaldiscounting,isassociatedwithincreasedstriatalsubcorticalconnectivity
[72].Inadolescents,impulsivityisassociatedwithloweractivityinthesubstantianigraand
subthalamicnucleusbuthigheractivityinthepresupplementarymotorareaandprecentral
gyrusduringsuccessfulresponseinhibition[73].Together,theserecentfindingssuggestadi-
versepictureofcerebralfunctioninginlinkwithimpulsivityandmultifacetedneuralbasesof
impulsivebehavior.
Changesinphysiologicalarousalaccompanyattention,decision-making,affectiveregula-
tion,andothermotivatedbehaviors,processesknowntobealteredinimpulsiveindividuals
[74–79].Theventromedialprefrontalcortex(vmPFC)isconsistentlyimplicatedincerebralre-
sponsestophysiologicalarousal[37,80–85].IthasbeenpostulatedthatthevmPFCmayplaya
roleinregulatingphysiologicalarousal[32,76,83].Indeed,hereandearlierwedemonstrated
thatvmPFCactivitynotonlynegativelycorrelateswithbutGrangercausesskinconductance
levelandthestrengthofcausalityisnegativelyassociatedwithSCRtosalientevents[15].
Furthermore,weshowedthat,inwomen,attentionimpulsivityisassociatedwithdecreased
GrangercausalityinvmPFCregulationofskinconductance.Thisfindingsuggeststhatimpul-
sivity-linkedincreasesinarousalresponsestosaliencymayberelatedtodeficientprefrontal
controlinwomen.ThestrongertheregulatoryinfluenceofthevmPFC,thelesstheskincon-
ductanceresponsestoinfrequentevents,andthisneuralmechanismofcontrolisdisruptedin
impulsivewomen.
Genderdifferencesinarousalregulationandtheroleofimpulsivity
MendemonstratedsignificantlyhigherSCRtoeventonsetsinthestopsignaltask,ascompared
towomen.Thisfindingisconsistentwithanumberofstudiesofgenderdifferencesinarousal
responses.Forinstance,incontrasttowomen,menaremoresusceptibletoframingeffectsand
exhibitedgreaterSCRconcurrentwithdefensiveororientingresponsesinanUltimatumgame
[86].Animagingstudyexaminedstresscircuitactivitieswhileparticipantsviewednegativeva-
lence/higharousalversusneutralstimuli[87].Menshowedgreatersignalchangesthanwomen
inlatefollicular/lutealphasesbutnotwomenduringfollicularphase,suggestingthatstress-
elicitedgenderdifferencesinarousalresponsearemediatedbysexualhormones.Duringa
Strooptest,menshowedhighersystolicbloodpressureandepinephrineplasmaconcentrations
thanwomen[88].Whenconfrontedwithangryorfearfulfaces,menshowedgreateranterior
cingulateandvisualcorticalresponsesinassociationwithheightenedvigilancethanwomen
[89].Comparedtoblackwomen,blackmenshowedincreasedsympatheticresponsesincluding
elevatedepinephrinelevelduringrecallofangerandnegativeaffect[90].Duringviewingofaf-
fectivepictures,therelationshipsbetweenself-ratedarousal,bloodpressureandcardiacstroke
volumeweremainlyexhibitedbymen,suggestingthatincreasesinthesympatheticinotropic
effecttotheheartwithself-ratedarousalmaybelargerinmenthaninwomen[91].
MenandwomendidnotdifferinBIS-11totalscoreoranyofthesubscores,andinter-sub-
jectvariationinBarrattimpulsivityisrelatedtotheSCRinwomenbutnotmen.Theseresults
suggestafewnon-exclusivepossibilities.First,aswediscussedinanearlierwork,BIS-11ad-
dressesonlycertaindimensionsandmaynotcapturethefullspectrumofimpulsivitytrait
[55].FutureworkshouldincludeotherimpulsivitymeasuressuchasEysenck'sscales,which
considersimpulsivenessandventuresomeness[4]andUPPS(urgency,premeditation,perse-
verance,andsensationseeking)impulsivebehaviorscale[92].Second,impulsivitymaynotbe
themostimportantpersonalitytraitindeterminingarousalresponsesinmen.Previousstudies
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