Developmental changes in adolescents’ neural response to challenge

DevelopmentalCognitiveNeuroscience1 (2011) 560–569

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Developmental Cognitive Neuroscience

j o ur na l h o me p ag e :h tt p : / / w w w . e l s e v i e r . c o m / l o c a t e / d c n

Developmental changes in adolescents’ neural response to challenge

Nicole M. Strang

, Jens Pruessner

, Seth D. Pollak

aUniversityofWisconsin–Madison,Madison,WI,UnitedStates

bMcGillUniversity,Montreal,Quebec,Canada

a rt i c l e i n f o

Articlehistory:

Received14March2011

Receivedinrevisedform17June2011 Accepted20June2011

Keywords:

Adolescents fMRI

Emotion×cognitioninteraction Anteriorinsula

a b s t r a c t

Adolescentsoftenfailtoadaptivelyregulatetheiremotionsandbehaviors.Thisismost clearly demonstrated bythemarkedincreaseduringthis periodinfatalitiesthatare attributabletopreventablecauses.Usingfunctionalmagneticresonancemethodology,this studyexploredwhetheradolescentsandadultsdifferedintheirengagementofprefrontal circuitryinresponsetoacognitiveandemotionalchallenge.Twenty-fouradolescentsand twenty-threeadultswerescannedwhiletheysolveddifficultmathproblemswithinduced failureandnegativesocialevaluation.Dataisreportedfrom23adolescentsand23adults.

Adultandadolescentparticipantsshowedsimilarincreasesinheartratewhenresponding totheexperimentalchallenge.Despitethesimilarityoftheautonomicresponse,adoles- centsrecruitedamorerestrictednetworkofprefrontalregionsascomparedtoadults.Both adolescentsandadultsrecruitedthedorsalanteriorcingulatecortexandthedorsolateral prefrontalcortex,howeveradultsadditionallyrecruitedtheanteriorinsula.Functionalcon- nectivitybetweentheanteriorinsulaandotherprefrontalregionswasstrongerinadults ascomparedtoadolescents.Further,foradults,themagnitudeofactivityintheinsula predictedlowerautonomicactivityinresponsetothechallenge.Differencesbetweenado- lescentsandadultsengagementofprefrontalnetworksmayrelatetoadolescents’poor behavioralandemotionalregulation.

© 2011 Elsevier Ltd. All rights reserved.

1. Introduction

Adolescence is a period in development character- ized by increased emotional reactivity and risk taking (Steinberg,2010).Seventy-twopercentofadolescentmor- talitystemsfrompreventablecauses(Eatonetal.,2008).

Despitethefactthatadolescentsidentifyhypotheticalrisks as well as adults (Bogin, 1994; Steinberg, 2005), ado- lescents often fail to effectively regulate their behavior in realworldsituations. Oneexplanationforthis differ- ence betweenadolescents’ abilities to reason and their poorbehaviorcontrolin emotionally-evocativecontexts

∗ Correspondingauthorat:WaismanCenterandDepartmentofPsy- chology,UniversityofWisconsin–Madison,1500HighlandAve,Madison, WI53705,UnitedStates.Tel.:+16088902525;fax:+16088902424.

E-mailaddress:nstrang@wisc.edu(N.M.Strang).

isthatemotionsimpairoroverwhelmprefrontalsystems (Casey et al., 2008), which are essential for executive functionssuchasattention,errorprocessing,andcogni- tivecontrol(MillerandCohen,2001).Infact,inaddition to structural changes (Gogtay et al., 2004), prefrontal networkscontinuetomatureover thecourseofadoles- cence(Poweretal.,2010).Butrelativelyfewstudieshave examinedthewhetherengagementoftheseregionsdif- fers between adolescents and adults in the context of emotional challenge.Therefore, the present experiment comparestherecruitmentprefrontalcircuitry inadoles- centsandadultsinanemotionallyevocative,challenging context.

Studiesofadultssuggestthatprefrontalregionssuch asthedorsolateralprefrontalcortex(DLPFC)andanterior cingulatecortex(ACC)areimportantfortheregulationof cognitionandemotion(OchsnerandGross,2005).Regu- lationundoubtedlyconsistsofanumberofmorespecific

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processes, and consistent with this notion, these brain regionshavebeenimplicatedinanumberoffunctions.The DLPFCappearstoplayandimportantroleinmaintaining information forbrieftemporal intervals andmanipulat- inginformation (MacDonaldet al., 2000)in addition to emotionregulation(Johnstoneetal.,2007;Ochsneretal., 2004).Similarly,theACChasbeenimplicatedinconflict detection(Botvinicketal.,2001;Kernsetal.,2004),error monitoring(Miltneretal.,1997),aswellasregulationof autonomicactivity(MedfordandCritchley,2010;Luuand Posner,2003).Anemerging literature suggeststhat the anteriorinsulaalsoplaysan importantrolein avariety ofprocessesinvolvedinemotionalandcognitivecontrol (Brass and Haggard, 2007; Singer et al., 2009). Further, theanteriorinsulaisfunctionallyconnectedwiththeACC (Dosenbachetal.,2006),and togethertheseregionsare importantforbehavioralandautonomicadaptationtotask demands(Sridharanetal.,2008).

It hasbeen well establishedthat prefrontalsystems are important for behavioral, cognitive and emotional regulation in adulthood.For this reason, the emotional and behavioral dysregulation frequently observed in adolescents has been attributed to the developmental immaturityofprefrontalsystems(Yurgelun-Todd,2007).

Casey and colleagues (2008) have expanded this the- orybysuggestingthatdysregulatedadolescentbehavior occurs most frequently in emotionally evocative con- texts because immature adolescent prefrontal circuitry isunabletocope withtheadditionaldemands ofemo- tional experiences. Indeed, a number of investigations have demonstrated differences betweenadolescent and adultprefrontalactivityin responsetoemotional infor- mation (Eshel et al., 2007; Galvan et al., 2006; Monk etal.,2003;Somervilleetal.,2010;VanLeijenhorstetal., 2010).

While these experiments have provided preliminary evidenceinsupportofCaseyandcolleagues’(2008)theory, alimitationof theextantliteratureis thatallthestud- iesarebasedontrial-by-trialanalysesofbrainactivation.

Thiscapturesprocessingofemotionalstimuli–butmay notapproximatetheemotionalcontextofdecision-making inreal-worldsituations,ormeasurepersistentchangesin neuralprocessesthat resultfromcontextualchallenges.

Thismaybeaparticularlyimportantlinktounderstanding adolescentbehavior.Consistentwiththisideaofcontex- tual influences, recentinvestigations demonstrated that thepatternof PFCdifferences betweenadolescentsand adultsdiffersdependingonwhetherananalysisisdirected towardevent-relatedbrainactivityorsustainedprocesses (Velanovaetal.,2009).

The present experiment seeks to extend previous researchbyexaminingwhetherpersistentengagementof prefrontalsystemsdiffersbetweenadolescentsandadults duringepochsofchallenge.Inordertoaddressthisques- tion,we designeda paradigmthat elicited acontextual challengeandconcurrentlymeasuredautonomicnervous system activity to validate the emotion manipulation.

Wehypothesizedthatinanemotionallychallengingcon- text,adultswoulddisplayengagementofregulatorybrain regions,suchastheACC,DLPFC,andanteriorinsulatoa greaterextentthanadolescents.

2. Materialsandmethods 2.1. Participants

Twenty-fourmaleadolescentsand23maleadultspar- ticipatedintheexperiment.Oneadolescentwasrandomly excluded in order to have an equal number of partic- ipants in each group. Analyses described below were conductedwith23adolescents(M=13years,SD=8month, range=12–15 years) and 23 adults (M=20 years, nine months,SD=14months,range18–23years).Participants inthisinvestigationwerelimitedtomales.Thisdecision wasmadeonthebasisofliteraturesuggestingthatthere areimportantdifferencesinthemannermalesandfemales respond to cognitive and emotional challenge (Taylor, 2006).Asthefocusofthis investigationwasdirectedat age-relatedchangeswesoughttolimitthevariancebyonly includingonegender.Inageneralhealthscreening,allpar- ticipants(orparentsofadolescentparticipants)indicated thattheyhadnohistoryofneurologicalorpsychiatricdis- order.Eachgaveinformedconsent(parentalconsentand minorassentforadolescents)foraprotocolapprovedby theHealthSciencesInstitutionalReviewBoardofUniver- sityofWisconsin–Madison.

2.2. Experimentaltask

Participants were tested using a paradigm designed toinclude allof thefeaturesthat reliably elicita stress response,includingbothintellectualchallengeandsocial evaluation (Dickerson and Kemeny, 2004). The task included3conditions,eachofwhichinvolvedmathemat- icalequationsthathadintegersolutionsbetween0and9.

Participantsindicatedtheirsolutionstothemathproblems viaabuttonboxthatcontrolledarotarydialonthescreen.

Theyweretoldtousethebuttonundertheirindexfinger tocirclethedial,andthebuttonundertheirmiddlefinger toselecttheresponse.Inallconditions,trialsweresepa- ratedbya500msinter-trialinterval,andsubsequenttothe participant’sresponsefeedbackwasdisplayedfor500ms.

We included two control conditions, one to evalu- ate neuralactivity in response to thePerceptual/Motor features and another toassess the cognitiveoperations involvedinthetask.InthePerceptual/MotorControlpar- ticipantssawasolved mathematicalequationandwere simply requiredto selectthesolution thatwas present onthescreen.Therewasnotimelimit,andparticipants received text feedback of “Correct” or “Incorrect”, con- tingent ontheirresponse. In theBaselineMathControl condition, participants sawthe same interface, but the equationswereunsolved.Theequationswereengagingbut nottaxinginthattheywerelimitedto2or3one-digitinte- gers,andtheoperandswerelimitedto+or−(example:

2+9−7).AsinthePerceptual/MotorControl,therewasno timelimit,andfeedbackwasdisplayedinthesamemanner.

Ourmainhypothesiswastestedbyathirdexperimen- tal condition.This conditionwas designed tochallenge the adolescents. One way in which participants were challenged was that the equations were more difficult, including up to 4 integers, the +,−, * and / operands, andnumbersinthe2-digitrange(example:12*12/8−9).

Fig.1. Depictionofascanningrunandtaskinterface.DuringeachrunparticipantscompletedthePerceptual/MotorControl,BaselineMath,andChallenge conditions,andalsoviewedfixation.Theinterfaceforeachconditionisillustratedaboveitslabel.Eachrunbeganandterminatedwith20soffixation.In boththeBaselineMathconditionandtheChallengeconditioneachtrialbeganwith500msoffixation.IntheBaselineMathconditionparticipantshadan unlimitedamountoftimetorespondtothetrial.Oncearesponsewasmade,feedbackbasedontheparticipant’sresponse(i.e.,eithertheword“Correct”

or“Incorrect”)appearedinthelowerlefthandcornerforthedisplay.Feedbackwasdisplayedfor500ms.Afteranother500msoffixationanewmath problemwaspresentedinthesamedisplayandtherotarydiarywasresetsothatposition0washighlighted.Trialsproceededidenticallyinthechallenge conditionwiththeexceptionthattherewasatimelimit,andifaresponsewasnotmadewithintheallottedamountoftime,theword“Timeout!”was presentedinthefeedbackportionofthescreenandthetrialended.

Inaddition,unlikePerceptual/MotorControlandBaseline MathControlconditions,a timelimitwasintroducedto furtherinduceasenseofpressureonparticipants.Atthe beginningoftheChallengecondition,thetimelimitwas set at 5000ms, and throughout the condition the time limitchangedbasedontheparticipantsreactiontimeand accuracy.Iftheparticipantansweredaseriesof3consec- utivetrialscorrectly,thetimewindowforaresponsewas reducedto10%lessthantheaveragetimeforthe3correctly answeredtrials.Conversely,iftheparticipantanswereda seriesof3consecutivetrialsincorrectly(bothtrialswhere theparticipantrespondedincorrectly,andoneswherethe timelimitelapsed),thetime limitwasincreasedforthe followingtrialby10%.Ifa participantrespondedwithin thetimelimit,feedbackwasdisplayedsubsequenttohis response. However,if the participant failed torespond withintheallottedtime,thetrialterminatedandtheword

“Timeout!”appearedonthescreenfor500ms.Athirdfea- tureofthisconditionwasthataperformanceindicatorwas presentonthetaskinterface,indicatinghowthepartic- ipantwasperformingrelativetoothers.Astablemarker represented what participants were told wasthe aver- ageperformanceofpreviousparticipants.Anothermarker depictedthecurrentparticipant’sperformance.Becauseof theadaptivetimelimit,itwasimpossibleforparticipants toachieveanaccuracyrateinthesamerangeasthefalse averageparticipantmarker.Together,thesethreefeatures capturethevariouskindsofmanipulationsthathavebeen reliablyshowntoelicitemotionalresponsesacrossindi- viduals(DickersonandKemeny,2004;Kirschbaumetal., 1993;Pruessneretal.,2008).Stimuliwerepresentedusing E-Primesoftware(PsychologySoftwareTools,Pittsburgh, PA)viaafiberopticgogglesystem(Avotec,Stuart,FL)with ascreenresolutionof800×600pixels.

Theexperimentconsistedof4runswhicheachlasted 5minand10s.Withineach run,participantscompleted 60sofPerceptual/Motor Control, 90sof BaselineMath, and120sofChallenge.TheorderofthePerceptual/Motor ControlandBaselineMathconditionswasrandom,butthe Challengewasalwaysthelastconditioninarun.Addition- ally,therewere20soffixationatthebeginningandendof

eachrun(Fig.1).Inordertoreinforcethattheperformance indicatorwasimportantandrelatedtosocialevaluation, theparticipantwasbroughtpartwayoutofthescanner betweenrunstwoandthree,andwastoldbytheexperi- menterthathewasnotdoingaswellasotherparticipants andheneededtotryanddobetter.

2.3. Heartratedataacquisitionandanalysis

Heartrate(HR)wascollectedcontinuouslyduringthe fMRIscanusingaGeneralElectricfiberopticphotoplethys- mograph(GEMedicalSystems,Waukesha,WI)ontheleft indexfinger(100Hzsampling).Heartbeatswereautomat- icallyidentifiedusingcustomsoftwaredevelopedinhouse forMatlab.Thedatawasmanuallyreviewedtoensurecor- rectidentificationofR-waves,andsegmentsofthedatain whichR-waveswerenotvisuallyapparentduetoartifacts wererejected.Inter-beatintervalswerecalculated from theremainingR-waves,andthedatawassegmentedby taskcondition.MeanHRwascalculatedforthefirst60s ofeachconditionandaveragedacrossallfourruns.Any runinwhich10%ormoreofthedatawascontaminated byartifactswasrejected.Additionally,participantsneeded tohaveaminimumoftwousablerunstobeincludedin thegroupanalyses.Accordingtothesecriteria,17adoles- centsand21adultswereincludedintheHRanalyses.The effectsofagegroupandconditionweredeterminedusing repeatedmeasuresANOVA.

2.4. Imageacquisition

ImageswerecollectedonaGeneralElectric3Teslascan- ner(GEMedicalSystems,Waukesha,WI)equippedwith astandard clinicalwhole-headtransmit-receivequadra- ture head coil. Functional imageswere collected using aT2*-weightedgradient-echo,echoplanarimaging(EPI) pulsesequence[30sagittalslices,4mmthickness,1mm interslice gap; 64×64 matrix; 240mm (FOV); repeti- tion time (TR)/echo time (TE)/Flip, 2000ms/30ms/90^◦, 155 whole-brain volumes per run]. A high-resolution T1-weighted anatomical image was also acquired (T1-

weightedinversionrecoveryfast-gradientecho;256×256 in-plane resolution; 240mm FOV; 124×1.2mm axial slices).

2.4.1. Imageanalysis

Individualparticipantdatawasslice-timecorrectedand motioncorrected using AFNI(Cox, 1996), and fieldmap correction was done using FSL (Smith et al., 2004). In ordertoevaluateparticipants’movementobjectively,we used software that was developed in house to identify frames where a point chosen relative to the center of rotation was displaced more than 2mm. A priori, we decided that any participants who had more than 25%

of frames excluded within any run would beexcluded fromfurtheranalyses.None oftheparticipantsmetthe thresholdforexclusion, however,4adults(M=14.5/620 frames, SD=21), and 14 children (M=11.5/620 frames, SD=15.3) had frames censored.In theframes retained, averagemotion(in-planeandtranslational)didnotdiffer betweenadultsandadolescents.Forbothgroups,motion was less than 1mm (adults: x=0.05, y=0.29, z=0.51, roll=0.08, pitch=0.35, yaw=0.07; adolescents: x=0.07, y=0.34, z=0.45, roll=0.09, pitch=0.55, yaw=0.11).Due totechnical problems2 participantsin theadult group hadonly3usableruns.AnomnibusGLMwasconducted foreach participant usinga separateregressor for each condition,andasecondorderpolynomialusedtomodel thebaselineandslowsignaldrift.Regressorsconsistedof asetof three boxcarfunctionsconvolvedwithan ideal hemodynamicresponse.Unlikeinvestigationsfocusedon disentanglingtherelativecontributionsofsustainedand event-relatedactivity(Velanovaetal.,2009),wedidnot includeevent-relatedregressors.Simpleblockdesignsare mostsensitivetosustainedeffects(Burgundetal.,2006), but may potentially confound consistent event-related activitywithsustainedactivity.Theparameterestimates, obtainedfromtheGLM,wereconvertedtopercentsignal changevalues,normalizedtotheMNI152standardbrain spaceusingtheAFNIprogram@autotlrc,andsmoothed usinga6mmfull-widthathalf-maximumGaussianfilter.It hasbeendemonstratedthatdespiteanatomicaldifferences relatedtodevelopment,normalizationdoneinthisway resultsinbrainmorphologythatdoesnotdifferbetween children and adults (Burgund et al., 2002). The group analysespresentedin thispaperarelimitedtothecon- trastsbetweentheBaselineMathandChallengeconditions.

Thesmoothed,single-participantcontrastmapswerethen entered intoa mixed-effectsGLM withparticipantas a randomfactornestedinthefixedfactorsofgroup(Ado- lescent,Adult)and condition(BaselineMath, Challenge) toassessthemaineffectsofgroupandcondition,aswell astheinteractionbetweengroupandcondition.Allsta- tisticalmapswerethresholdedatp<0.001,andcorrected formultiplecomparisonsusingclustersizethresholding basedonMonteCarlosimulations. Withthistechnique, theoverallfamily-wiseerrorrate(FWE)iscontrolledby simulationnulldatasetswiththesamespatialautocor- relations as found in the residual images and creating frequencydistributionsofdifferentclustersizes.Clusters withasizethatexceededtheminimumclustersize(42 voxels)thatcorrespondedtothea priorichosenFWEof

p=0.05wereretainedforfurtheranalyses.Theleftanterior insulacluster,derivedfromthegroupbyconditionanaly- sis,whichextends52(2×2×2)voxels,centerofmass(xyz 31.4235.6),wasusedasamasktoextractindividualmean estimatesandadditionalanalyseswereconductedusing SPSS(SPSS,Chicago,IL).

2.4.2. Functionalconnectivityanalyses

Todeterminewhetherfunctionalcouplingbetweenthe anterior insulaand brainregions increasedin theChal- lengeconditionrelativetotheBaselineMathcondition,we performedapsychophysiologicalinteraction(PPI)analysis.

ThePPIanalysiswascarriedoutusingstandardprocessing steps(Fristonetal.,1997).Theaveragetimeseriesforeach subjectwasextractedfromasphericalROI,witharadius of6mm,centeredoverthepeak(xyz32226)ofthegroup byconditioneffect.Lineartrendremovalwasconductedon thetimeseries,andthetimeserieswasconvolvedwiththe timingoftheChallengeconditioncontrastedwiththeBase- lineMathcondition.AnomnibusGLMwasconducted,with thetaskregressorsservingasthepsychologicalregressors, thedetrendedtimeseriesasthephysiologicalregressor, andthetimeseriesconvolvedwiththetasktimingwasthe interactionregressor.Theresultingcorrelationmapswere transformedtostandard spaceandblurredwitha6mm full-widthathalf-maximumGaussianfilter.

We also conducted a simple functional connectivity analysis to examine whetherconnectivity between the anteriorinsulaandtherestofthebraindifferedbetween groups,independentoftaskmodulation.Theanalysiswas conducted asdescribed above,however, theinteraction regressorwasomittedfromthisanalysis.Anindependent samplest-testwasconductedbetweentheadultandado- lescent connectivity maps, and the search volume was restricted to brain regions which demonstrated a task effectin theactivationanalysis.Thestatisticalmapwas thresholdedatp<0.005,andcorrectedformultiplecom- parisonsusingclustersizethresholdingasdescribedabove.

Onlyclusterswithaminimumvolumeof58voxelswere retained.A conjunction analysiswasthenconductedso thatonlyclusterswithinregionsengagedbythetaskwere retained.

3. Results

3.1. Behavioraldata

The accuracy data is presented in Fig. 2. A 2 (Age Group)×2 (Condition) repeated measures ANOVA was performedtoinvestigategroupdifferencesintaskperfor- mance.Asexpected,theresultsindicatedthatparticipants had ahigher proportionoftrials correctin theBaseline Math(M=0.93,S.E.=0.010)ascomparedtotheChallenge (M=0.37,S.E.=0.009)condition,F(1,44)=2959,p<0.001.

Theanalysisalsorevealedthatadults(M=0.67,S.E.=0.011) performedbetterthanadolescents(M=0.63,S.E.=0.011), F(1, 44)=7.27, p=0.010, and there was and interac- tion between Age Group and Condition, F(1, 44)=8.73, p=0.005.Follow-upindependentsamplest-testsrevealed that adults(M=0.96, S.E.=0.007) performedbetterthan adolescents (M=0.89, S.E.=0.017) in the Baseline Math

Fig.2.ProportionoftrialscorrectintheBaselineMathandChallenge conditions.

condition,t(44)=3.69,p=0.001.IntheChallengecondition, however, adults (M=0.38, S.E.=0.017) and adolescents (M=0.37,S.E.=0.017)performedequivalently,t(44)=0.61, p>0.05.

3.2. Validationofchallengemanipulation

Inthecontextofparadigmsthatinvolvecognitiveor socialchallenges,increasedheartrateisoftenusedtoval- idateexperimentalmanipulations,andisalsoassociated withself-report ratingsof anxiety(Wageret al., 2009).

BothAdults’andAdolescents’heartratewashigherinthe Challenge(M=78.70,S.E.=2.96)ascomparedtotheBase- lineMathcondition(M=74.80,S.E.=1.92),F(1,32)=31.74,

p<0.001.TherewasnoeffectofagegrouponheartrateF(1, 32)=1.86,p>0.05.Similarly,therewasnotaninteraction betweenagegroupandconditionF(1,32)=1.21,p>0.05.

3.3. Prefrontalactivationtochallenge

Both adolescents and adults showed activation of a numberofprefrontalregionsinresponsetotheChallenge manipulation,asshowninTable1.Ofnote,bothgroupshad increasedactivationinregionsimplicatedincognitivecon- trolincludingthedorsolateralprefrontalcortex(DLPFC), anddorsalanteriorcingulatecortex(dACC),andanterior insula(seeFig.3,BrownandBraver,2005;Dosenbachetal., 2006;MacDonaldetal.,2000).

3.4. Age-relateddifferencesprefrontalactivationto challenge

Outofthenetworkofprefrontalregionsengagedbythe Challengecondition,therewerenogroupdifferences,and onlytheleftanteriorinsula(peakxyz−32226)differedas aneffectofgroupandcondition(allbrainregionsdemon- stratingaGroup×ConditioneffectarelistedinTable2).

Inadults,activityinthisregionwasgreaterintheChal- lenge condition (M=0.65, S.E.=0.11) than the Baseline Mathcondition(M=0.34,S.E.=0.08),t(22)=5.31,p<0.001.

Inadolescentsactivationinthisregiondidnotdifferfrom theBaselineMathtotheChallengecondition,t(22)=0.86, p>0.05(Fig.4).Weconducted analyseswherewe used group differences in behavioral performance (accuracy, reactiontime,andnumberoftrials)asacovariate,andinall analysestheeffectofGroup×Conditionintheleftanterior insularemainedsignificant,p>0.05.

Table1

Peakregionsdemonstratingamaineffectofcondition(Challenge–BaselineMath).

Talairachcoordinates Brainregion t

x y z

−4 44 −4 MedialPFC −4.58

52 30 24 Rightmiddlefrontalgyrus 8.47

2 24 44 Rightmedialfrontalgyrus 8.97

44 24 38 Rightmiddlefrontalgyrus 8.30

−32 24 0 Leftanteriorinsula 5.68

42 18 0 Rightanteriorinsula,BA47 8.05

−14 10 −12 Leftcaudate/putamen −5.69

−50 8 34 Leftmiddlefrontalgyrus,BA9 7.75

2 6 28 RightdorsalACC 4.71

46 4 26 Rightinferiorfrontalgyrus,BA9 7.50

26 −4 54 Rightmiddlefrontalgyrus 7.04

62 −8 4 Rightsuperiortemporalgyrus,BA22 −6.42

48 −14 6 Rightsuperiortemporalgyrus,BA22 −5.69

−42 −16 4 Leftposteriorinsula −5.69

4 −20 10 Thalamus(MDN) 7.73

−2 −34 8 PAG 8.54

46 −44 46 Rightinferiorparietallobule,BA40 10.01

−40 −46 36 Leftinferiorparietallobule,BA40 9.6

8 −52 52 Rightprecuneus,BA7 8.57

−50 −64 −10 Leftmiddleoccipitalgyrus 8.13

−28 −64 44 Leftsuperiorparietallobule 10.51

30 −66 46 Rightsuperiorparietallobule 12.43

50 −66 6 Rightmiddletemporalgyrus 8.17

−38 −80 −6 LeftInferiororbitalgyrus 6.6

32 −84 12 Rightmiddleoccipitalgyrus 10.55

−30 −84 16 Leftmiddleoccipitalgyrus 9.75

Fig.3.DifferencesinBrainactivationforthecontrastofChallengeminusBaselineMathconditionsfortheadolescentsandadults.Bothgroupshadgreater activationintheDLPFCandACCtotheChallengeascomparedtotheBaselineMathcondition.

Table2

RegionsthatweresignificantintheinteractionbetweenGroup(Adolescent,Adult)andCondition(BaselineMath,Challenge).

Talairachcoordinatesofpeakvalue Brainregion MaxF Clustersize(voxels)

x y z

−28 −70 50 Leftprecuneus,BA7 25.30 203

34 −62 54 RightprecuneusBA7 19.26 102

−10 −64 28 Leftposteriorcingulate 20.95 60

−32 22 6 Leftanteriorinsula 20.11 52

Toexplorewhetheractivityintheleftanteriorinsula related toindividual differences in the response to the Challengecondition,weregressedeachparticipant’sactiv- ityintheleftanteriorinsula(peakxyz−32226)onhis heartrateduringtheChallengecondition.Amongstadults, themagnitude of activity withinthis brain region was negatively associated with HR, F(1, 20)=6.86, p=0.017.

Conversely,amongst theadolescents,therewasnorela- tionshipbetweenbrainactivityinthisregionandHR,F(1, 16)=0.027,p>0.05(Fig.5).

3.5. Age-relateddifferencesprefrontalconnectivity

ThePPIanalysisdidnotrevealanybrainregionswhere connectivitytotheanteriorinsulawasmodulatedbytask.

Thiswasnotsurprisingasthephysiologicalregressorand interactionregressorareoftenhighlycorrelated,andasa resultthisanalyticalapproachoftenlackspower.

Thesimplecorrelationanalysisrevealedtworegions, within the prefrontal cortex, that we more strongly related totheleftanteriorinsula inadults ascompared to adolescents. A cluster in the right DLPFC (peak xyz 44486; Fig. 6a) was more strongly related in adults (M=0.14,S.E.=0.01)thanadolescents(M=0.06,S.E.=0.02), t(44)=3.79,p<0.001.Similarly,aclusterinthedACC(peak xyz01026;Fig.6b)wasmorestronglyrelatedinadults (M=0.20,S.E.=0.02)thanadolescents(M=0.11,S.E.=0.02), t(44)=3.65,p<0.001.

4. Discussion

Thegoalofthisinvestigationwastodeterminewhether adolescents showed a different pattern of prefrontal engagement inresponse tochallenge relative toadults.

Asafirststepinaddressingthisquestion,wenotedthat bothadultsandadolescentshadincreasesinheartratedur-

Fig.4. Regionoftheleftanteriorinsulathatdifferedintheinteractionbetweengroup(Adolescent,Adult)andcondition(BaselineMath,Challenge).In adults,therewasincreasedactivityintheChallengerelativetotheBaselineMathcondition.Foradolescents,activitydidnotchangebetweenconditions.

ingthechallengecondition,suggestingthat,asplanned, theexperimentalparadigmwassomewhatdemandingfor theparticipants.Wethenfocusedontheneuralsystems that wereactivatedasparticipantssoughttocopewith

Fig.5.Correlationsbetweenactivityintheleftanteriorinsulaandheart rateintheChallengeconditionforadolescentsandadults.

thechallengepresentedtothem.Here,weobservedboth similarities and differences betweenolder and younger participants. Both adolescents and adults engaged the DLPFCanddACCinasimilarmanner.However,although adultsalsorecruited theanteriorinsula,adolescentsdid notshowanteriorinsulaactivation.Inadults,prefrontal regionsweremorestronglyfunctionallyconnectedtothe anteriorinsula,thantheywereinadolescents.Consistent withtheideathattheanteriorinsulaisimplicatedinreg- ulatorybehavior(MedfordandCritchley,2010),individual differences in anterior insula activation predictedheart rateregulationforadults;nosuchassociationemergedfor adolescents.Thesedatasuggestthatinresponsetochal- lenge,adolescentsfailtorecruittheleftanteriorinsula, andthisregionislessconnectedwiththeDLPFCanddACC thanitisinadults.Thesedifferencesinprefrontalactiva- tionandconnectivitymay,inpart,explainthedysregulated behavioroftenexhibitedbyadolescents.

Theoreticalaccountsoftheneuralcorrelatesofadoles- centbehaviorhaveallimplicatedimmaturityofthePFC (Lunaetal.,2010;SomervilleandCasey,2010;Yurgelun- Todd,2007).Consistentwiththishypothesisanumberof developmentalneuroimaginginvestigationshavedemon- strated differences in functional brain activity between adolescentsandadults (Eshel etal.,2007;Galvanet al., 2006; Monk et al., 2003; Somerville et al., 2010; Van Leijenhorstetal.,2010).Amongsttheseinvestigationstwo haveexplicitlyfocusedontheinteractionbetweenemotion andcognitivecontrolandidentifiedprefrontaldifferences betweenadolescentsandadults(Somervilleetal.,2010;

Van Leijenhorst et al.,2010).It has beendemonstrated thatinthecontextofagamblingtask,whenthereceipt ofreward isuncertain,adolescentsdemonstrategreater activityintheanteriorinsula(VanLeijenhorstetal.,2010).

Additionally,ithasbeendemonstratedthatinthecontext ofa go–no-go task, in response toanappetitive stimu- lus(ahappyface),adolescentshavemoreactivityinthe inferiorfrontalgyrus relative toadults when inhibitory controlwasrequired(Somervilleetal.,2010).Whilethese

Fig.6.Differencesinleftanteriorinsulafunctionalconnectivitybetweenadolescentsandadults.(A)AdultshadgreaterconnectivityintherightDLPFC (peakxyz44486).(B)AdultsalsohadgreaterconnectivityinthedACC(peakxyz01026).

investigationsidentifiedage-relateddifferencesinregions withinorneartheanteriorinsula,thedirectionofeffect isnotconsistentbetweeninvestigations.BothSomerville andcolleagues(2010)andvanLeijenhorstandcolleagues (2010)foundgreateractivityinadolescentsascompared toadults, while we found that adolescents exhibit less activity.It is possiblethat ourresults differfrom these studies as the paradigms are quite different, it will be importanttofollowuponthisinvestigationtounderstand whetherchangesin anteriorinsula activationis a com- monfeatureofadolescencetoadulthood.However,these findingsarenotnecessarilyinconsistentwiththepresent investigationin thatboth studiesinvestigated transient, event-related activity, whereas the present experiment designis moresensitivetosustainedeffects. Consistent with the data reported here, Velanova and colleagues (2009)havedemonstratedthatadolescentsshowagreater transientneuralresponse,butalsolesssustainedneural activity.The resultsofourinvestigationprovidefurther evidencetosuggestthat theanterior insulais recruited differentlyinadolescenceascomparedtoadulthood.

It is often the case that differences in brain activ- ity between adults and children are simply dismissed as reflecting immaturity without much discussion of morecomplexfunctionalimplications(Lunaetal.,2010;

Poldrack,2010).Toaddressthis question,wecompared prefrontalconnectivitybetweenadolescentsand adults, andexaminedactivitywithintheleftanteriorinsulawith regardtoindividualdifferencesinresponsetochallenge.

Indeed,foradults,theanteriorinsulawasmorefunction- allyconnectedwiththeDLPFCanddACC,and increased insulaactivitywasassociatedwithlowerheartrateduring thechallenge.Thissuggeststhatinadulthoodthisregionis importantforregulation.Thisinterpretationisconsistent withabodyofresearchdemonstratingthat,inadults,coac- tivationofthedACCandanteriorinsulaisimportantfor autonomicregulation and visceralawareness(Critchley, 2005).Further,thefactthatactivitywithintheleftante- riorinsulaonly differedinthecontext oftheChallenge conditionpermitsustoconcludethatthefunctionaldiffer- encesarenotaconsequenceofmorphologicaldifferences,

anotherconcernfrequentlyraisedindevelopmentalimag- inginvestigations(Poldrack,2010).Insum,theresultsfrom ourinvestigationsuggestthatinthecontextofemotional andcognitivechallenge,adultsrecruitamoredistributed prefrontalnetwork,whichincludestheleftanteriorinsula;

foradultsonly,activitywithinthisregionwasassociated withdecreasedphysiologicalresponsetochallenge.

Thereisanextensivebodyofliteraturetosuggestthat the PFC is important in the regulation of emotion and behavior (Miller and Cohen,2001), andthere arestruc- tural (Gogtay et al., 2004) and functional (Eshel et al., 2007;Galvanetal.,2006;Monketal.,2003)changesin PFC networks into adulthood.While the PFC is often a regionofdifferencebetweenadolescentsandadults,itis nowrecognizedthatitistherelationshipbetweenthePFC and otherbrainregionsthat likelysubserves behavioral changesacrossdevelopment(Lunaetal.,2010;Somerville and Casey,2010).Consistent withthisview,ourspecu- lation is not that developmentof any one brainregion explainspooradolescentbehavioralregulation;rather,it seemsmoreplausiblethatprefrontalregulatorynetworks mightnot befullyintegratedorefficiently connectedin adolescence,andthiscontentionissupportedbyourfunc- tionalconnectivityanalysis.

Ourfindingofincreasedconnectivityduringdevelop- mentisconsistentwithanumberofdifferentfindingsin theliterature.Forexample,Fairandcolleagues(2007)have demonstrated that changes inbrain organizationacross developmentcanbecharacterizedbyashiftfromstrong connectivitybetweenspatiallyadjacentregionstostrong connectivitybetweenfunctionallyrelatedregions,which may not bein close spatial proximity. Under this per- spective,immaturebrainfunctioninadolescencemaybe best characterizedby the failure to activate the entire adultnetwork.Second,largemeta-analysisofcognitively demandingtasksthatincludedtentasksand183adultpar- ticipants,foundthattheanteriorinsulawasconsistently co-activatedwiththedorsalACC,andrelatedtomainte- nanceoftasksetanderrorprocessing(Dosenbachetal., 2006).Third,whilethedorsalACCandanteriorinsulaare functionallyconnectedinadulthood,theyarenotinclose

spatialproximity.Theresultsofourinvestigationprovide furtherevidencethatconnectivitybetweenbrainregions continuestomatureinadolescence.

Onecuriousfeatureofourfindingsisthatadolescents recruitedtherightanteriorinsulainasimilarmannerto adults;itisonlyinthelefthemispherethatisaregionof difference.Ithasbeensuggestedthattheleftanteriorinsula maybeinhibitorywhiletherightanteriorinsulaisexcita- tory(Craig,2005),andthereisevidencethatstimulationof theleftanteriorinsulaisrelatedtoadecreaseinheartrate (Oppenheimeretal.,1992).Ourdataisconsistentwiththe notionthatinadulthoodtheleftanteriorinsulaisrelated toregulation.Thisisalsoanareathatisinneedofmore developmentally-orientedresearch.

A potential criticism of this experiment is that our paradigmincludedanumberofelementsthatwerechal- lenging. We made the math problems more difficult, imposed a time limit, and introduceda negativesocial evaluation.Indoingso,werealizedthatwewouldnotbe abletodissociatetheeffectsof“cognitive”versus“social”

challengeastheyrelatetodifferencesinprefrontalengage- ment.We madethis decisionfor tworeasons.First,the developmentalliteraturesuggestedindividualdifferences in thekinds of situations that people find stressful. At thisstageofresearch,wesoughttocastawidenetthat wasmorelikelytoresultinnearlyallparticipantsfeeling challenged.Second,wewerespecificallyinterestedincre- atingacontext thathadconcurrentsocialandcognitive challenges.Futureresearchshouldunpacktherelativecon- tributionsofsocio-emotionalversuscognitive-intellectual challengesinadolescentregulation.

Adolescenceisaperiodindevelopmentripeforinves- tigations of changing brain–behavior relations. During this time, emotional context appears to exert a great influence on cognitive function and behavior. In rela- tively low emotionalcontexts, suchaslaboratorytasks, adolescents’cognitiveand behavioralperformanceoften matchesorexceedsthatofadults.However,inemotion- allyevocative situations, adolescents make maladaptive decisionsat a muchhigher ratethanadults, asdemon- strated bythehighnumber ofdeathsand harmrelated topreventablecauses.Thisisamajorpublichealthcon- cernthatcanbeaddressedthroughbetterunderstanding thebiologicalunderpinningsofadolescentbehavior.The apparent dissociation between emotional and cognitive abilitiesduringthisperiodoffersawindowintothebrain changesthataccompanytheemergenceofmatureemo- tional and cognitive processes. Future investigation of these processesoffersuntold promisein advancingour understandingoftheontogenesisofbrain–behaviorrela- tions.

Acknowledgements

ThisworkwassupportedbyResearchGrantMH61285 toS.D.P.,fundedbytheNationalInstituteofMentalHealth andtheChildren’sBureauoftheAdministrationonChil- dren, Youth and Families. We thank Michael Anderle, LisaAngelos,PatrickBauer,RistaPlate,andRonaldFisher for helpwithdatacollection,JohnOllingerandAndrew

Alexanderforhelpwithtechnicalissues,andJamieHanson andReginaLapateforinsightfulcomments.

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