ContentslistsavailableatScienceDirect
Developmental
Cognitive
Neuroscience
j ou rn a l h om ep a ge :h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / d c n
Reduced
cerebellar
brain
activity
during
reward
processing
in
adolescent
binge
drinkers
Anita
Cservenka
a,
Scott
A.
Jones
b,
Bonnie
J.
Nagel
a,b,∗ aDepartmentofPsychiatry,OregonHealth&ScienceUniversity,Portland,OR,UnitedStatesbDepartmentofBehavioralNeuroscience,OregonHealth&ScienceUniversity,Portland,OR,UnitedStates
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:Received19December2014 Receivedinrevisedform28May2015 Accepted26June2015
Availableonline30June2015 Keywords: Adolescence Alcohol Binge Reward Cerebellum
a
b
s
t
r
a
c
t
Duetoongoingdevelopment,adolescencemaybeaperiodofheightenedvulnerabilitytotheneurotoxic effectsofalcohol.Bingedrinkingmayalterreward-drivenbehaviorandneurocircuitry,thereby increas-ingriskforescalatingalcoholuse.Therefore,wecomparedrewardprocessinginadolescentswithand withoutahistoryofrecentbingedrinking.Attheirbaselinestudyvisit,allparticipants(age=14.86±0.88) werefreeofheavyalcoholuseandcompletedamodifiedversionoftheWheelofFortune(WOF)functional magneticresonanceimagingtask.Followingthisvisit,17youthreportedbingedrinkingon≥3occasions withina90dayperiodandwerematchedto17youthwhoremainedalcoholandsubstance-naïve.All participantsrepeatedtheWOFtaskduringasecondvisit(age=16.83±1.22).Nosignificanteffectswere foundinaregionofinterestanalysisoftheventralstriatum,butwhole-brainanalysesshowed signifi-cantgroupdifferencesinrewardresponseatthesecondstudyvisitintheleftcerebellum,controllingfor baselinevisitbrainactivity(p/˛<0.05),whichwasnegativelycorrelatedwithmeannumberofdrinks consumed/drinkingdayinthelast90days.Thesefindingssuggestthatbingedrinkingduringadolescence mayalterbrainactivityduringrewardprocessinginadose-dependentmanner.
©2015TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Adolescenceisa period markedbycontinuedstructural and functionaldevelopmentinthebrain(forreview,seeBlakemore, 2012),aswellasmanyassociatedbehavioralandcognitivechanges (forreview,seePaus,2005).Adolescenceisalsoatimeofincreased risk-takingbehavior, includingexperimentationwithdrugs and alcohol(Eatonetal.,2012).Onepossibleexplanationforincreased risk-takingobserved duringadolescenceinvolvesthecontinued development of reward-related neurocircuitry (Galvan, 2010). Brainregions,suchastheorbitofrontalcortex(OFC),medial pre-frontalcortex(mPFC),andstriatumhavebeenimplicatedaskey componentsinthebrain’srewardsystem(McClureetal.,2004; Schultz,2000)and are regions that undergo development dur-ingadolescence(Goddingsetal.,2014;Gogtayet al.,2004).For example,dopaminereceptorlevelsandbindinginthestriatumare higherduringadolescencethanadulthood(Seemanetal.,1987) andareaccompaniedbyanincreaseindensityofdopaminergic
∗ Correspondingauthorat:OregonHealth&ScienceUniversity,Departmentof Psychiatry,3181SWSamJacksonParkRoad,MC:DC7P,Portland,OR97239,United States.Tel.:+15034944612.
E-mailaddress:nagelb@ohsu.edu(B.J.Nagel).
projections to the prefrontal cortex (Kalsbeek et al., 1988; RosenbergandLewis,1994;Tunbridgeetal.,2007).These devel-opmentalchangesintherewardsystemduringadolescencemay impacthowthebrainrespondstoreward.Specifically,some neu-roimagingstudieshave foundgreaterreward-relatedactivation duringadolescence,comparedtothatseeninadultsandchildren, inregionssuchastheventralstriatumandmPFC(VanLeijenhorst etal.,2010),which maybeassociatedwithan increasein ven-tralstriataldopaminerelease observedduringrewardingevents (Jonassonetal.,2014;Koeppetal.,1998).Thisheightenedplasticity oftherewardsystemduringadolescencemayrenderthe adoles-centbrainmorevulnerabletotheneurotoxiceffectsofdrugsof abuse.
Currently,themostcommonformofsubstanceuseamong ado-lescentsistheuseofalcohol.IntheUnitedStates,bytheendof the12thgrade,68%ofadolescentshavereporteddrinking alco-hol,52%reportbeingdrunkintheirlifetime,and26%reportbeing drunkwithinthelast30days(Johnstonetal.,2014).Furthermore, bingedrinking,themostcommonformofalcoholmisuseamong adolescents(Deas,2006),isreportedbyover22%ofadolescents (Johnstonetal.,2014).Inlinewithfindingsofcontinued develop-mentoftherewardsystemduringadolescence,pre-clinicalmodels havefoundthattherewardsysteminadolescenceresponds differ-entlytoalcoholthanduringadulthood.Increaseddopaminerelease http://dx.doi.org/10.1016/j.dcn.2015.06.004
withintheventralstriatumduringacutealcoholexposureis promi-nentinadolescents(Pascualetal.,2009;Philpotetal.,2009)and appearstobeassociatedwithgreaterrewardingeffectsofalcohol duringthisdevelopmentalstage(Pautassietal.,2008;Ristuccia andSpear,2008),whichmaypromotefuturedrinking.Insupport ofthisnotion,rodentmodelsindicatethatalcoholexposure dur-ingadolescence,comparedtoadulthood,increasesrewarddriven behavior(McMurrayetal.,2014;Schindleretal.,2014).
Agrowingbodyofliteraturehasdocumentednumerous abnor-malities in brain structure and functioning among adolescent alcoholusers.Bingedrinkingduringadolescencehasbeen asso-ciatedwithdifferencesinfrontallobecorticalthickness(Squeglia etal.,2012)andreductionsin cerebellarvolume (Lisdahletal., 2013),aswellaswidespreadreductionsinwhitematterintegrity withandwithoutcomorbidmarijuanause(Jacobusetal.,2013). Additionally,bingedrinkinghasbeenshowntohaveaneffecton brainactivityduringaffectivedecisionmaking(Xiaoetal.,2013) andspatialworkingmemory(Schweinsburgetal.,2008;Squeglia etal.,2011).Cross-sectionalneuroimagingstudieshavebegunto exploretheeffectsofalcoholonrewardprocessinginthebrain, butthisworkhasbeenlimitedtoadults.Alcohol-dependentadults haveshownincreasedactivationintheventralstriatumandmesial frontalcortex duringreward notification compared to controls (Bjorketal.,2008b),aswellasreducedrewardoutcome-related positivityinthebrain,measuredwithevent-relatedpotentials, sug-gestiveofdeficientrewardprocessing(Kamarajanetal.,2010).This latter“rewarddeficiency”findingisfurthersupportedbystudies inadultalcoholicswhichfoundhyporesponsiveactivityinthe ven-tralstriatumduringrewardanticipation(Becketal.,2009;Wrase etal.,2007).Whilebothhyper-andhyporesponsiveactivityinthe ventralstriatumhavebeenseeninhumanadults,preclinical mod-elsinadolescentsprimarilysupporttheideaofrewarddeficiency, suchthatrepeatedalcoholexposureleadstoa hypodopaminer-gicstate(Philpotetal.,2009),andalcohol-inducedchangestothe rewardsystemcorrelatewithincreasedalcoholseekingbehavior andvoluntaryconsumptioninadultratsthatexperienced adoles-centalcoholexposure(Pascualetal.,2009).Nolongitudinalstudy, toourknowledge,hasinvestigatedtheeffectsofbinge-levelalcohol useonreward-relatedbrainactivationinanadolescentpopulation. Thecurrentstudysoughttoexpandonthisbodyofliterature by examiningneuralactivation toreward in a groupof binge-drinking adolescents compared to alcohol/drug-naïve controls usingaprospective,longitudinalapproach.Adolescentsperformed amodifiedversionoftheWheelofFortune(WOF)task(Ernstetal., 2004), a reward-based decision-making task, during functional magneticresonance imaging(fMRI). Basedonpreviousfindings inadultalcoholicsofdecreased reward-relatedactivation(Beck etal.,2009;Wraseetal.,2007),aswellasalcohol’spropensityto affecttherewardsystemduringadolescence(Pascualetal.,2009; Philpotetal.,2009),wehypothesizedthatbinge-drinking adoles-centswould showreduced brainactivationtorewardoutcome, comparedtotheirnon-usingpeers,inrewardprocessingregions, suchasthemPFCandventralstriatum.
2. Materialsandmethods
2.1. Participantrecruitmentandscreening
Over200participants,ages12–16,wererecruitedaspartofa longitudinalstudyonriskfactorsforandconsequences of alco-hol use on brain and behavior during adolescence (Cservenka etal.,2012,2013,2014a,b;CservenkaandNagel,2012;Mackiewicz Segheteetal.,2013).Recruitmentwasconductedthrough com-munity mailings and local advertising. The participating youth andoneoftheirparentsorguardianswereinterviewedbyphone
duringapre-screentodetermineinitialeligibility,followingwhich studyconsentandassentwereobtainedfromparentsandyouth, respectively.Next,alongertelephonescreeninginterviewwas con-ductedwiththeyouthandparent,separately.Duringthisscreen, theStructuredClinicalInterview(Brownet al.,1994), the Diag-nostic Interview Schedule for Children Predictive Scales (Lucas et al., 2001), and theFamily History Assessment Module (Rice et al., 1995)were administered to assess thepresence of psy-chiatricconditionsintheyouth,anddeterminefamilyhistoryof psychopathology.YouthwhometDSM-IVcriteriaforanAxisI dis-orderwerenotincludedinthestudy.Otherexclusionarycriteria forstudyparticipationwere(1)lackoffamilyhistoryinformation, (2)presenceofpsychoticdisordersinfirst-degreebiological par-ents(i.e.schizophreniaorbipolarI),(3)parentreportofprenatal alcoholexposure,(4)MRIcontraindications(includingpregnancy), (4)headinjurywithlossofconsciousness,(5)useofpsychotropic medication, (6) left-handedness (Oldfield, 1971), and (7) seri-ousmedical/neurologicalconditions.Furthermore,sincethisstudy wasaimedatunderstandingtheneuralconsequencesof initiat-ingheavydrinkingduringadolescence,youthwereexcludedfrom theinitialstudyvisitiftheyreported>10lifetimealcoholic bev-erages,>2 drinks/occasion,>5lifetimeuses ofmarijuana, or>4 cigarettes/day(BriefLifetimeversionoftheCustomaryDrinking and Drug Use Record (CDDR,Brown et al. (1998)). Finally, the Hollingshead Index of Social Position (Hollingshead, 1957) was administeredtotheparticipatingparentorguardiantoestimate socioeconomicstatus (SES) of theyouth, based ontheparents’ educationalandoccupationalattainment.Allprocedureswerein accordancewiththeethicalguidelinesoftheOregonHealth& Sci-enceUniversity(OHSU)InstitutionalReviewBoard.
2.2. Studyproceduresandfollow-upassessments
Eligiblemaleyouthwerescheduledforstudyvisitsatanytime, whilefemaleyouthwerescheduledduringthefirst10daysoftheir menstrualcycle(follicularphase)toaccountforcycle-related varia-tionsinhormonelevels.Attheinitialbaselinestudyvisit(agerange: 13.15–16.34),participantsunderwentneuroimaging,duringwhich theycompletedamodifiedversionoftheWOFfMRItask(Cservenka etal.,2013;CservenkaandNagel,2012;Ernstetal.,2004)anda structuralMRI scanfor co-registrationoffunctional data(other componentsoftheMRIscanarenotreportedinthisstudy). Fur-thermore,youthcompletedaneuropsychologicalbattery within one week of theimaging session, which included estimates of intellectualfunctioningusingtheWechslerAbbreviatedScaleof Intelligence(WASI,Wechsler(1999)).Pubertalstatuswasassessed withgender-specificlinedrawingsrepresentingpubertal develop-mentwithTanner’sSexualMaturationScale(Tayloretal.,2001). TheChildren’sDepressionInventory(Kovacs,1985)andthe State-TraitAnxietyInventory(Spielbergeretal.,1973)wereadministered ateachstudyvisittoassessdepressivesymptomsandstateanxiety, respectively.
Followingcompletion of the initialstudy visits, participants couldelecttoparticipateinthelongitudinalportionofthestudy. Ifyouthassentedtoparticipating,theywerecontactedbyphone approximatelyevery3 months.During thesephone interviews, youthwereaskedtoprovideinformationondrinkingbehaviorin thepast90days withtheCDDR(Brownet al.,1998),following whichthe90-dayTimelineFollowback(TLFB)(SobellandSobell, 1992; Sobelletal.,1986)wasusedtocollectdetailed informa-tiononalcohol,marijuana,nicotine,andotherdruguse,ifanyuse wasreported.Basedontheseinterviews,youthwhoreportedbinge drinking(≥5drinks/occasionformalesand≥4drinks/occasionfor females)onatleastoneoccasioninthepast90days,andhadat leasttwootheroccasionsof≥4drinks/occasioninthat3-month
period, were invited backfor a second study visit1 with iden-ticalneuroimagingproceduresandneuropsychologicalmeasures asadministeredduringtheirbaselinevisits.Youthwereaskedto abstainfromalcoholand/orotherdrugusefor72hpriortothe sec-ondstudyvisit.Atthetimeofthesecondstudyvisit(agerange: 14.51–18.68),absenceofacute alcoholintoxication priortothe neuroimagingsessionwasconfirmedwithabreathalyzer,which wasnegativeforallyouth.Aurinetestwasalsocollectedatthistime toassessforotherdrugsyouthmayhavetaken.Nineyouthfrom thebinge-drinkinggrouptestedpositivefortetrahydrocannabinol, whileoneoftheseninealsotestedpositivefortricyclic antidepres-sants,althoughuseofthismedicationwasnotreported.17youth metbinge-drinkingcriteriatobeinvitedbackforarevisit(except onemaleyouthwhoselargestbingewas4drinks,butalso com-pletedtherevisitstudyprocedures),andtheseyouthwerematched to17controlswhohadnotinitiatedanyalcoholorsubstanceuse. Alcohol-usingyouthwerematched onage,puberty,and sexto controlsandtheseadolescentsalsocompletedtheidenticalrevisit studyprocedures.Theintervalbetweenvisitswasvariableacross subjectsassomeyouthemergedintobingedrinkingmorequickly thanothers.Youthcompletedrevisitsbetween0.60and4.45years ofbeinginthestudy.Bingedrinkersandcontrolswerematchedon timebetweenvisits(meanforbingers=2.05±1.18years;meanfor controls:1.90±1.01years;t32=−0.40,p=0.69).
2.3. WheelofFortunefMRItask
Amodifiedversion(Cservenkaetal.,2013;CservenkaandNagel, 2012)oftheWOFfMRItask(Ernstetal.,2004)wasadministered toallyouthduringboththeirbaselineandsecondstudyvisits.This taskhasbeendescribedindetailelsewhere(Cservenkaetal.,2013; CservenkaandNagel,2012),butbriefly,procedureswereas fol-lows.Thetaskconsistedoftworunsof36trialseach,dividedinto threephasespertrial,with1–11secondfixationperiodsjittered betweentrials.Wheelsdividedintotwoportions,werepresented inthefirstphaseofeachtrial.Eachportionofthewheelwas asso-ciatedwiththeprobabilityofwinningacertainmonetaryreward. Inthefirstphaseofeachtrial,participantsmadeadecisionabout whichportionofawheeltheywantedtopick,inthesecondphase, theyanticipatedwhetherornottheywouldwin,andinthethird phase,theyreceivedfeedbackonwhetherornottheywon. Win-ningwasbasedonwhetherthechoiceinthedecision-makingphase ofthetaskmatchedthepre-definedprobabilitiesthatwere pro-grammedinthetask.Theportionsofeachwheelwerecategorized aseitherrisky(10%chanceofwinning$7or30%chanceofwinning $2),safe(90%chanceofwinning$1or70%chanceofwinning$1), orchance(50%chanceofwinning$2)(Cservenkaetal.,2013).
Toassess reward processing differencesbetween adolescent bingedrinkersandcontrols,thethirdphaseofthetaskwas ana-lyzed.Thecontrast of interestin thethird phase was behavior andbrainresponsetoWinsvs.NoWins.Winswereclassifiedas thosetrialsinwhichparticipantswontheportionofthewheelthey selectedafterarisky,chance,orsafechoice.NoWinswerethose trialsinwhichparticipantsdidnotwintheportionofthewheel theyselectedafterariskyorchancechoice.Sincenotwinningafter makinga safechoicewasrare,butcouldrepresentthegreatest expectancyviolationduringthetaskbasedonexpectedvalues(0.90 for10/90wheelsand0.70for30/70wheels),thesetrialswerenot includedintheregressorrepresentingNoWinbrainresponse. Fur-thermore,toensureyouthwereengagedinthetaskduringreward notification,theywereaskedtomakea buttonpresswiththeir indexfingeriftheywon,orabuttonpresswiththeirmiddlefinger,
1 Exceptforonemaleyouthwhocompletedthesecondvisitafterconsumingfour drinksonfouroccasionsina90dayperiodbeforehisrevisit.
iftheydidnotwinduringeachtrial.Accuracyandreactiontimeon thesetrialswasrecorded.AllparticipantspracticedtheWOFtask priortoenteringthescanner.
2.4. Imageacquisition
ParticipantswerescannedwithaSiemens3TTimTriosystemat OHSU’sAdvancedImagingResearchCenter.Amirrorwasmounted ona12-channelheadcoil,sothatparticipantscouldviewthetask projectedona screenattheendof thescannerbore.Allyouth weregivenearplugsandheadphonestoreducenoisefromtheMRI scanandallowcommunicationwiththescanoperatorthroughan intercomsystem.Pillows wereplacedaroundeach participant’s headtolimit headmotionwhilelyingin thesupineposition.A fourbuttonopticalbuttonbox, placedin theparticipant’sright hand,wasusedtomakeresponsesduring theWOFtask. A T1-weightedstructuralMPRAGEscan(timerepetitions(TR)=2300ms, time to echo (TE)=3.58ms, inversion time (TI)=900ms, flip angle=10◦, field of view (FOV)=240mm×256mm, voxel size=1mm×1mm×1.1mm, 160slices,acquisitiontime=9:14) wasacquiredsagittallyforco-registrationofthefunctionaldata totheparticipant’sanatomicalimage.T2*-weightedechoplanar imaging, acquired in theaxial plane,was usedto measurethe bloodoxygenlevel-dependent(BOLD)responseduringtheWOF task (TR=2000ms, TE=30ms, flip angle=90◦, FOV=240mm2,
voxel size=3.75mm×3.75mm×3.8mm, 33 slices, acquisition time=2runsof300TRs,lasting10:00mineach).
2.5. Imagepreprocessing
Imagepreprocessingfollowedconventionalprocedures previ-ouslydescribedinotherreports(Cservenkaetal.,2013;Cservenka andNagel,2012).AnalysisofFunctionalNeuroImages(AFNI)was usedfor all image preprocessing(Cox, 1996).Briefly, following image reconstruction,anatomical masks wereskull-stripped to remove non-brain skull and tissue. First, functional data were subjectedtoslicetimingcorrection,identificationofmovement artifact,andrealignmentofTRstothevolumerequiringtheleast amountofadjustmentofrigidbodyheadmotionfollowingaleast squaresalgorithm(Coxand Jesmanowicz,1999).Then, TRsthat requiredmorethan2.5mmor2.5degreesofadjustmentwere cen-soredprior tofurtheranalysestolimit artifactinducedbyhead motionorothernoise.Functionaldatawereblurredwitha6mm fullwidthhalfmaximumGaussian kerneltoincrease signal-to-noiseratio,fractionizedtotheanatomicalimage,andnormalizedto convertvaluestorelativepercentsignalchange.Thetworunsofthe WOFtaskwerethenconcatenatedaswerethesixmotion regres-sorsfromeachrunofthetask.Thehemodynamicresponsefunction (HRF)wasmodeledwithdurationoftheeventdefinedasthelength ofeachphaseofthetrial,whilemodelingdelaysintheHRF. Regres-sorsofinterestwererepresentedbyWinsandNoWins(asdefined above),whileothertask-relatedregressors,includingrisky,safe, andchancedecisions,andrisky,safe,andchanceanticipationswere alsomodeled(asdefinedabove),butwerenotexaminedforthe currentanalyses.AFNI’sbaselinemodelincludedthesixmotion regressorsofnon-interest,unmodeledfixation,lineardrift,andthe averageBOLDsignalfromtheentiretimecourseofthetask.Data werere-sampledinto3mm3voxelsandtransformedto
standard-izedTalairachspace(TalairachandTournoux,1988). 2.6. Group-levelanalyses
2.6.1. Demographicsandbehavior
Demographicvariablesanddependentvariablesfromtask per-formancewereexaminedfornormaldistributionusingIBMSPSS Version 20.0 (Corp. Released, 2011). Mixed model analysis of
Fig.1.Conjunctionmapoftask-relatedbrainactivityduringrewardprocessing.Task-relatedactivitymapsforeachgroupateachstudyvisit(baselineandrevisit)were voxel-thresholdedatp<0.05andaconjunctionmapwascreatedforWin>NoWinbrainresponsetodetermineareascommonlyactivatedacrossparticipantsregardlessof groupstatusortimeofstudyvisit.Occipital,superiorparietal,dorsolateralprefrontal,caudate,andventralstriatalbrainactivitywereseenintheWin>NoWincontrast overlaidonAFNI’sTalairachtemplatebrainintheaxialview.
variance(ANOVA)examinedeffectsofgroup,time,and group-by-timeinteractionsfordemographicvariables.Non-normalvariables, includingpubertal stageand accuracy identifyinga Win or No WinduringthefeedbackphaseoftheWOFtask,werecompared betweengroupsforeachstudyvisitwithMann–WhitneyUtests, whileothervariableswerecomparedbetweengroupsusing inde-pendentsamplest-tests.Outliersondrinkingmeasuresorbrain activitygreaterthan2.5standarddeviationsfromthemeanwere excludedfromcorrelationalanalysesrelatingbrainactivitywith drinking behavior. Cigarette and marijuana use characteristics wereseverelypositivelyskewed,sotheywere log-transformed priortocorrelationalanalyses.
2.6.2. Imaging
ToillustratesignificantWOFtask-relatedactivity,regardlessof groupstatusandstudyvisit,weconductedaconjunctionanalysis, voxelthresholdedatp<0.05(Fig.1),which confirmedexpected reward-relatedand task-positivebrain regionsactivatedbythe taskintheWinvs.NoWincontrast,includingtheventralstriatum, occipitalcortex,andfronto-parietalregions.TheWinvs.NoWin contrastappearstobea validmeasureofrewardprocessing,as
opposedtomoregeneralincentivesalienceprocessing,asareas activatedinthecurrentstudycloselyresemblethoseinprevious adolescentstudiesofrewardvs.norewardbrainactivity,which showdistinctpatternsfromlossvs.nolossBOLDresponse(Bjork etal.,2008a,2010).
Forgroup-levelanalyses,anaprioriregionofinterest(ROI) anal-ysisoftheventralstriatumwasconductedbyusingtheTalairach DaemonatlasinAFNI,andapplying4-mmradiusmasks(10voxels each)oftheleftandrightventralstriatumwithpeakcoordinates at12,−8,−8(rightventralstriatum)and−12,−8,−8(leftventral striatum).Theventralstriatalmaskswereresampledto3mm3to
matchthefunctionaldata.PercentsignalchangefortheWinvs. NoWincontrastwasextractedfromleftandrightventralstriatal masksforeachparticipantandmixedmodelANOVAsexaminedthe effectofgroup,time,andgroup-by-timeinteractionsfortheWin vs.NoWincontrastinSPSS.
Next, for thewhole-brain analysesexaminingdifferences in rewardprocessingbetweenbingedrinkersandcontrols,one sam-plet-testswerevoxelthresholdedatp<0.05foreachgroupand addedtogethertoformamapoftask-relatedbrainactivityatthe secondstudyvisit.AFNI’s3dttest++wasusedtocomparegroupson
Table1
Demographiccharacteristicsatthebaselinevisitandrevisit.
Baselinevisit Revisit T2–T1e
Bingedrinkers T2–T1 Controls Bingedrinkers(n=17) Controls(n=17) p Bingedrinkers(n=17) Controls(n=17) p p p
Female(n) n=7 n=7 n=7 n=7 Age 14.90(1.01) 14.82(0.75) 0.81 16.94(1.28) 16.72(1.19) 0.60 <0.00001 <0.00001 PubertalStatusa 4.50(0.63) 4.00(0.82) 0.06 4.81(0.40) 4.75(0.45) 0.78 0.06 0.005 IQb 111.59(9.25) 112.00(7.23) 0.89 114.18(11.08) 110.82(9.90) 0.36 0.18 0.68 Socioeconomicstatusc 31.41(15.57) 30.59(8.54) 0.85 35.80(14.86) 30.33(12.51) 0.48 0.23 0.14 %Riskydecisions 69.68(24.13) 59.46(22.56) 0.21 74.26(19.78) 66.02(24.70) 0.29 0.44 0.29 RMSd(Headmovement) 0.17(0.09) 0.32(0.26) 0.03* 0.22(0.16) 0.24(0.18) 0.71 0.31 0.12 CDIf 40.76(4.12) 41.29(5.88) 0.76 43.50(7.93) 38.93(4.77) 0.07 0.20 0.19 STAIg 40.89(5.19) 40.35(7.30) 0.81 37.10(6.04) 37.95(7.39) 0.72 0.053 0.13
Mean(standarddeviation).
aTanner’sSexualMaturationScale(Tayloretal.,2001);missingforonebinge-drinkingandonecontrolyouthatrevisit. b WechslerAbbreviatedScaleofIntelligence(Wechsler,1999).
c HollingsheadIndexofSocialPosition;higherscoresindicatelowerSES(Hollingshead,1957);missingfortwelvebinge-drinkingandeightcontrolyouthatrevisit. d Rootmeansquare.
eRevisitvs.BaselineVisit.
f Children’sDepressionInventory(Kovacs,1985);missingforthreebinge-drinkingandtwocontrolyouthatrevisit. gState-TraitAnxietyInventory(Spielbergeretal.,1973).
differencesinbrainactivityduringWinsvs.NoWins,restrictedto thepre-definedtask-relatedactivitymask.Resultsofthisanalysis weremultiplecomparisoncorrectedusingMonteCarlosimulation withbothavoxelandclusterthreshold(p/˛<0.05)(Formanetal., 1995),yieldingaminimumclustersizeof102voxels.Percent sig-nalchangefromtheclusterinwhichsignificantgroupdifferences emergedatthesecondstudyvisitwereextractedwith3dROIstats, andsignalfromthebaselinestudyvisitwasalsoextractedfrom thisregion.HierarchicalregressionsinIBMSPSSVersion20.0(Corp. Released,2011)testedwhethergroupdifferencesremained signif-icantafteraccountingforbrainactivityinthisclusteratthefirst studyvisit,ageatrevisit,andtimebetweenscans.Significant find-ingsfromthisanalysiswereoverlaidonaTalairachbraintemplate inAFNI,whilebargraphscreatedinGraphPadPrismversion5.00 forWindows,GraphPadSoftware,SanDiegoCalifornia,USA,www. graphpad.com,wereusedtoillustratepercentsignalchangeineach groupatfirstandsecondstudyvisitsinboththesignificantcontrast ofinterest(Winvs.NoWin)andforWinvs.baseline,andNoWin vs.baselinebrainactivity.
Inordertoexaminewhethergroupdifferencesinbrainactivity werepresentbetweenyouthwhoemergedintobingedrinkingand controls,anidenticalwhole-brainanalysistothatdescribedabove wasconductedatbaseline(controllingforbaselinedifferencesin headmovement;p/˛<0.05,≥94 voxels).Furthermore,two-way ANOVAsexaminedeffectsofgroup,sex,andgroup-by-sex inter-actionsinclusterswheresignificantdifferencesinBOLDresponse werepresentbetweenbingedrinkersandcontrolsatrevisit.
3. Results
3.1. DemographiccharacteristicsandWOFtaskbehavior
Participantcharacteristicsateachstudyvisitareillustratedin Table1(baselinestudyvisitandrevisit).Seventeenyouthmet crite-riaforbingedrinkinginthestudyandcompletedthesecondstudy visit.Theseyouthwerematchedto17controlswhohadabstained fromalcoholanddrugs.ValidWOFtaskdatawereavailablefromall youthateachstudyvisit.MixedmodelANOVAsexamined group-by-timeinteractionsandmaineffectsforalldemographicvariables inTable1,exceptforSES,whichwasmissingforeightcontrolsand 12bingedrinkersatrevisit.Nosignificantgroup-by-time interac-tionswerepresentforanyofthevariables.Maineffectsoftime werepresent for age (F1,32=109.92, MSE=0.60, p<0.0001,
par-tial2=0.78),pubertalstatus(F
1,32=16.48,MSE=0.27,p<0.0005,
partial 2=0.36), and state anxiety (F
1,32=6.86, MSE=23.72,
p=0.01, partial 2=0.18). Youth were older, more pubertally
mature,andlessanxiousatrevisitcomparedwithbaselinevisit.No maineffectsofgroupwerepresent.Whenexamininggroups sep-aratelyateachstudyvisit,significantdifferencesinpubertalstage andheadmovementwereseenatthebaselinestudyvisit,suchthat youthwholateremergedintobingedrinkingweremorepubertally matureatthistime,whileyouthwhoabstainedfromalcoholuse hadmoreheadmovementduringtheWOFtask(Table1).No differ-encesinanyofthedemographicvariableswerepresentbetween thegroupsatthesecondstudyvisit.Nosignificantdifferencesin taskperformance(meanreactiontimeandaccurateidentification ofwinningornotwinning)werepresentateitherstudyvisit(all p’s>0.10,Table2).
3.2. Alcoholanddruguse
Drinkingcharacteristicsinthebingedrinkersatthetimeofthe secondstudyvisitarelistedinTable3.TheCDDR(Brownetal., 1998)and TLFB(Sobelland Sobell,1992)wereadministeredto assessprevious90-dayalcoholandsubstanceuse.Lifetime meas-uresofalcohol,marijuana,andcigaretteusewerealsocalculated basedonsummingtheamountof drinksconsumed,amountof timesmarijuanawasused,andnumberofcigarettessmokedfrom timeofstudyentrythroughthetimeofthesecondstudyvisit.Other substanceusecharacteristics,includingageofonsetofcigaretteand marijuanausearealsolistedinTable3.Allbuttwobinge-drinking youth,hadusedmarijuanaatleastonceintheirlifetimebythetime ofthesecondstudyvisit.Noneofthecontrolshadeverreported consumingalcoholorusinganyothersubstancesinthisstudy. 3.3. Neuroimaging
Thea priori ROI analysisof Win vs. No Winbrain response in theventralstriatumdidnot showany significantgroup dif-ferences in brain response at revisit controlling for baseline brainresponseintheseregions(leftventralstriatum:F2,31=1.31,
R2=0.003, p=0.28, ˇ=−0.05, t=−0.30, p=0.76; right ventral
striatum: F2,31=0.21, R2=0.003, p=0.81, ˇ=−0.06, t=−0.32,
p=0.75).Tofollow-uponthesenegativefindings,intra-class cor-relationcoefficients(ICC)usingbaselineandrevisitbrainresponse werecalculatedinIBMSPSSVersion20.0(Corp.Released,2011)for thecontrolgrouponlytolimitconfoundsrelatedtoalcohol’seffects ontheBOLDsignalinthisregion.Forthecontrolgroup,theICCs
Table2
WOFtaskperformanceateachstudyvisit.
Bingedrinkers(n=17) Controls(n=17) p-value
Female(n) n=7 n=7 Baselinevisit Winaccuracy(%)a 98.63(4.26) 99.78(0.63) 0.95 Nowinaccuracy(%)b 92.25(23.88) 97.58(3.75) 0.52 WinRT(ms)c 1237.53(261.62) 1318.11(335.87) 0.44 NowinRT(ms)d 1200.51(243.37) 1317.39(342.97) 0.26 Revisit Winaccuracy(%)a 96.59(13.10) 99.43(1.17) 0.79 Nowinaccuracy(%)b 98.11(2.56) 98.91(2.59) 0.15 WinRT(ms)c 1167.99(238.91) 1083.50(253.78) 0.33 NowinRT(ms)d 1119.80(229.03) 1057.47(251.77) 0.46
Mean(standarddeviation),RT=reactiontime.
aWinaccuracyfollowinga10%,30%,50%,70%,or90%selection.
bNowinaccuracyfollowinga10%,30%,or50%selection(70%and90%werenotincludedinbehavioralorimaginganalysesduetoexpectancyviolations). c Winreactiontimefollowinga10%,30%,50%,70%,or90%selection.
d NoWinreactiontimefollowinga10%,30%,or50%selection(70%and90%werenotincludedinbehavioralorimaginganalysesduetoexpectancyviolations).
were0.62and0.50forleftandrightventralstriatum,respectively. TheseICCscorrespondtofairtogoodrangesforreliability(Fleiss, 1986),andfallwithinacceptedrangesforneuroimaginganalyses (Aronetal.,2006).
Forthewhole-brainanalysis,asignificantgroupdifferencein brain activity to Wins vs. No Wins was seen in the left cere-bellum(lobule VIIa/crusI) atrevisit,while nosignificantgroup differences in Win vs.No Win BOLD response werepresent at thebaselinevisit.Inthiscluster,bingedrinkersshowedreduced Win vs.No Win brainresponse at thesecondstudy visit com-paredwithcontrols(Fig.2).Examinationofthesimplecontrasts ofWinvs.baselineandNoWinvs.baselinebrainactivityto inter-prettheresultsindicated thatthis effectwasdrivenbygreater brainresponseduringWinningincontrolscomparedwithbinge drinkers(t32=2.95,p=0.007).Bingedrinkersshowedno
signifi-cantdissociationbetweenBOLDresponsetoWinsandNoWinsat thesecondstudyvisit(t16=2.07,p>0.05),butdistinctbrain
activ-itywasseenbetweenthesetwoconditionsinthecontrolgroup Table3
Drinkingandsubstanceusecharacteristicsofbingedrinkersatrevisit.
CDDRa Bingedrinkers(n=17)
Agefirstdrank 14.65(1.66)
#ofdaysdrank/monthinpast90days 2.57(2.63) #ofdrinks/drinkingday(past90days) 4.72(1.66) #ofdrinks/drinkingoccasion(past90
days)
4.52(2.35) Largestamountdrankononeoccasion
(past90days)
6.38(1.84) Averagetimetoconsumelargestbinge
(hours)
1.87(1.26) Range:0.01–4.4 Lifetimedrinksatrevisit 70.29(69.71)Range:16–311.5 AgefirstusedMarijuanab 14.40(1.84)
LifetimeMarijuanauseoccasionsb 81.87(129.63)Range:2–476 Agefirstsmokedcigarettesc 14.67(1.94)
Lifetimecigaretteuseoccasionsc 213.89(326.60) Range:4–800
Otherdrugused n=6
Mean(standarddeviation).
aCustomaryDrinkingandDrugUseRecord(Brownetal.,1998). bn=15.
c n=9.
d One participant reported using psychedelic mushrooms and 3,4-methylenedioxy-methamphetamine (once each/lifetime), a second participant reportedusingpsychedelicmushrooms,3,4-methylenedioxy-methamphetamine, andlysergic aciddiethylamide (threetimes,six times,and onetime respec-tively/lifetime), a third participant reported using psychedelic mushrooms, 3,4-methylenedioxy-methamphetamine, and lysergic acid diethylamide (three times,sixtimes,andonetime,respectively/lifetime),afourthparticipantreported using 3,4-methylenedioxy-methamphetamineonce/lifetime, a fifth participant reportedusingnitrousoxideonce/lifetime,andasixthparticipantreportedusing psychedelicmushroomsonce/lifetime.
(t16=4.95,p=0.0001).Atthebaselinestudyvisit,however,there
werenodifferencesinWinvs.baseline(t32=0.97,p=0.34)orNo
Winvs.baseline(t32=0.31, p=0.76)brainactivityinthis region
betweenbingedrinkersandcontrols.Infact,bothgroupsshowed elevatedBOLDresponsetoWinscomparedwithNoWins(Bingers: (t16=2.38,p=0.03);Controls:(t16=2.56,p=0.02))intheabsence
ofanyheavydrinking.
Next,maineffectsofgroup,sex,andagroup-by-sexinteraction wereexaminedusingatwo-wayANOVAatbothrevisitand base-linevisit.Maineffectsofgroup(F1,30=15.72,MSE=0.02,p<0.0005,
partial2=0.34) and sex(F
1,30=8.23, MSE=0.02, p=0.007,
par-tial2=0.22) werepresent for Winvs. NoWin BOLDresponse
atrevisit(Fig.S1B).Posthoct-testsindicatedsignificantlylower Winvs.NoWinbrainresponseinbingedrinkerscomparedwith controls(t32=3.53,p=0.001)andsignificantlylowerWinvs.No
Winbrainresponseformalescomparedwithfemales(t32=2.40,
p=0.02).Afollow-upANOVAonthesimpleeffectcontrasts sug-gestedthiswasdrivenbyWinvs.baselineBOLDresponse,asmain effectsofgroup(F1,30=9.68,MSE=0.07,p=0.004,partial2=0.24)
andsex(F1,30=4.12,MSE=0.07,p=0.049,partial2=0.12)were
alsopresentforthiscontrast,suchthatbingedrinkershadlower brainresponsethancontrols,andmaleshadlowerbrainresponse thanfemales.Nogroup-by-sexinteractionincerebellarresponse waspresentatrevisit.Nomaineffectsofgrouporsex,andno group-by-sexinteractionwerepresentforBOLDresponseinthecerebellar clusteratthebaselinevisit(Fig.S1A,allp’s>0.10).
Todeterminewhethergroupdifferencesinbrainactivityatthe secondstudyvisitcouldhavebeenrelatedtopreexistingbaseline groupdifferencesinbrainresponse,ageatrevisit,ortimebetween visits,weconductedahierarchicalregression,controllingforthese variables. Group differences in pubertalstage and head move-ment(rootmeansquare)werenotsignificantlyrelatedtobaseline cerebellaractivity,sowerenotcovariedforintheanalyses. Con-trollingforbaselineactivityinthisregion,ageatrevisit,andtime betweenvisits,differencesinleftcerebellaractivitybetweenbinge drinkersandcontrolsremainedsignificantatthesecondstudyvisit (F4,29=5.0,R2=0.28,p=0.003,ˇ=−0.54,t=−3.68,p=0.001).
DrinkingcharacteristicswereexaminedincorrelationwithWin vs. No Win, Win vs. baseline, and No Win vs. baseline BOLD responseintheleftcerebellarcluster.Oneyouthwithpercent sig-nalchangegreaterthan2.5 standarddeviations fromthemean wasexcludedfromcorrelations.Onesignificantcorrelationwas presentwhenrelatingpast90daydrinks/drinkingdaywithreward outcome-relatedbrainactivity(Fig.3).Averagedrinksconsumed inthepast90dayswasnegativelyrelatedtoNoWinvs.baseline BOLDresponseintheleftcerebellum,indicatinggreaternumberof drinks/drinkingdayconsumedinthelast90dayswasassociated
Fig.2.Bingedrinkershadreducedcerebellarbrainactivityduringrewardprocessingcomparedwithcontrols.(A)Significantlyreducedposteriorcerebellar(lobuleVIIa/crus I)activityduringWinvs.NoWinwasseeninbingedrinkersatthetimeofrevisit,comparedwithcontrols,whileaccountingforbaselinebrainactivityinthisregion.Results aredisplayedinthesagittal,coronal,andaxialviewoverlaidonAFNI’sTalairachtemplatebrain.(B)Bargraphsofpercentsignalchangeillustratingsignificantdifferencesin brainactivityinthecontrastofinterest(Winvs.NoWin)andinsimpleeffectsaredisplayedforeachvisit.Atrevisit,bingedrinkershadsignificantlyreducedbrainresponse duringWinvs.NoWin.SimpleeffectsshowthiswasattributedtoreducedactivityduringWinvs.baselineinbingedrinkers,comparedwithcontrols.Whilecontrolsshowed elevatedbrainresponseduringWinvs.baselinecomparedwithNoWinvs.baseline,brainactivitywasnotdistinctinbingedrinkersduringrewardreceiptorabsence.This isincontrasttobrainresponseinthisregionatthebaselinevisit,whenbothgroupsshowedmoreactivityinresponsetoWinsthanNoWins.*p<0.05.
Fig.3.Drinksconsumed/drinkingdayinthepast3monthswasnegativelyrelatedtocerebellarbrainresponseinbingedrinkers.Averagedrinks/drinkingdaywasnegatively associatedwithreward-relatedactivityinbingedrinkers.Winvs.baselineactivityisplottedonthelefty-axis,whileNoWinvs.baselineactivityisplottedontherighty-axis.
withreducedBOLDactivityinthisregion.Marijuanaandcigarette usecharacteristicswerealsoexaminedforrelationshipswithbrain activity,since15ofthe17bingedrinkershadusedmarijuanaat leastoncebythetimeofthesecondvisit,while9ofthe17binge drinkershadsmokedcigarettesbythistime.Ageoffirstmarijuana use,lifetimemarijuanause,ageoffirstcigaretteuse,andlifetime cigaretteuse,werenotsignificantlycorrelatedwithWinvs.NoWin, Winvs.baseline,orNoWinvs.baselinebrainresponseattimeof revisit(allp’s>0.10).
4. Discussion
Toourknowledge,thecurrentfindingsarethefirsttoreport alterationsinbrainfunctioningduringrewardprocessingin adoles-centbingedrinkers,usingaprospectivelongitudinaldesign.Since bingedrinkingisacommonlyobservedalcoholusepatternduring adolescence,reportedbynearlyaquarterofyouthin12thgrade (Johnstonetal.,2014),itisimportanttounderstandwhetherthis pattern of alcohol usemayalter adolescent reward processing. Alcohol-induced neurotoxicity during adolescence (Jacobus and Tapert,2013)mayhave long-termeffectsthat extendwellinto adulthood,thussignalingtheneedtoidentifybrainareasaffected byheavyalcoholconsumptionduringneuromaturation.
4.1. Cerebellumandalcohol-inducedneurotoxicity
IncontrasttoourhypothesisofreducedventralstriatalormPFC activity,wereportasignificantdifferencebetweenbingedrinkers andcontrolsinleftcerebellar(lobuleVIIa/crusI)activity,driven byreducedBOLDresponseinthisregioninheavyalcoholusers comparedwithcontrolsduringrewardreceipt.Apreviousstudy foundthatventralstriatalactivitywassimilarinalcohol-dependent adultsvs.controls,andthatpersonalitycharacteristicsaccounted for more variance in nucleus accumbens activity than alcohol-drinkingstatus (Bjork etal.,2012), whichmayhelpexplainthe negativefindingsin thisregion.Furthermore,it ispossiblethat effectsinmesolimbiccircuitrymayonlybepresentafterprolonged, heavyalcohol use, asseen inadults withalcohol usedisorders (AUDs)(Becketal.,2009;vanHolstetal.,2014;Wraseetal.,2007). Itiscurrentlyunknownwhetherlong-termheavyalcoholusethat isinitiatedduringadolescencemayalterreward-relatedventral striatalresponse.Inthecurrentstudy,ICCvaluesofpercentsignal changeintheventralstriatumwerefairtogood(butnot excel-lent),making itdifficult todetermineifthe negativeresultsof bingedrinking-relatedeffects inthisregionweredue tolackof powerorlackofeffect.Importantly,thesemodestvaluesmayalso beimpactedbydevelopmentalchangeinthisregion,rendering reli-abilityovertimeinthisagerangedifficulttoassess.However,the negativefindingsintheventralstriatalROIshadsmalleffectsizes (Cohen’sf2=0.003–0.004),suggestingthatevenwithalarger
sam-ple,wemaynothaveobservedsignificantgroupdifferencesinthis region.
Nevertheless,the directionalityof thefindings doessupport hyporesponsivecerebellaractivityduringrewardreceiptinbinge drinkers.We foundthat compared totheirbaseline studyvisit, bingedrinkersshowedsignificantreductionsincerebellarbrain responseduringrewardprocessing,whilecontrolyouthdidnot. Theabsence of significantdifferences in brainactivityin these youthpriortotheinitiationofheavyalcoholuseprovidesgreater confidencethatthecurrentfindingscouldbeassociatedwith alco-hol consumption, rather than preexisting neural alterations in bingedrinkerspriortoheavyalcoholuse.Asignificant relation-shipwithmeannumberofalcoholicbeveragesconsumed/drinking dayinthepast3monthswasnegativelyrelated toreward out-comeprocessinginlobuleVIIA/crusI,providingfurthersupport
fordose-dependentalcohol-relatedchangesinbrainfunctioning. Additionally, cerebellar brain response hasbeen seen in other reward processingstudies duringboth reward anticipationand feedback(Dichteretal.,2012;Koenekeet al.,2008; Neesetal., 2012).For example,cerebellarcrus Iactivitywasfoundduring theoutcomephaseofawheel-of-fortunegamewithchocolatebar rewardswhereindividualpreferenceforrewardswascorrelated withcerebellarcrusIactivityduringrewardreceipt(Koenekeetal., 2008).Thus,cerebellarcrusIactivitymaybeanimportantregion forexaminingrewardoutcomeprocessing.
Thecurrentstudyemployedtheuseofadecision-makingtask todeterminealcohol’seffects onadolescent rewardprocessing, becauseanimal and humanstudiessuggest that reward-driven behavior(McMurrayetal.,2014;Schindleretal.,2014)isaltered afterheavyalcoholconsumptionduringadolescence.However,it isunclearwhetherreward-relatedresponseishyper-or hypoac-tiveinhumanAUDs(Becketal.,2009;vanHolstetal.,2014;Wrase etal.,2007).Thepresentfindingssupportreducedrewardresponse in binge-drinking youthin the cerebellum, a brain regionthat hasconsistentlybeenassociatedwithvolumetric(Andersonetal., 2010;Chanraudetal.,2007,2010;DeBellisetal.,2005;Sullivan etal.,2000,2010)andfunctional(Desmondetal.,2003;Jungetal., 2014;Piteletal.,2013;Rogersetal.,2012;Sullivanetal.,2003) abnormalitiesinadultsandyouthwithheavyalcohol consump-tion.Rodentmodelsindicatethatchronicethanolintakeinduces apoptosis of both Purkinje and granulecells in thecerebellum (Oliveiraetal.,2014),andreducessynapticplasticity(Valenzuela etal.,2010).Humanneuroimagingstudieshavefoundthat cerebel-larvolumeandconnectivityinalcoholicsareassociatedwithmotor (Sullivanetal.,2000)andcognitive(Chanraudetal.,2007,2010; Jungetal.,2014)impairments.Theserelationshipsareexplainedby thecerebellum’sroleinclassicmotorfunctioning(Ito,2006),but alsoitsfunctionalconnectionswithexecutivecontrolregions,such astheprefrontalcortex(Diamond,2000;KellyandStrick,2003; KrienenandBuckner,2009;SchmahmannandPandya,1997). Addi-tionally,cerebellardamageresultsincerebellarcognitiveaffective syndrome(Schmahmannand Sherman,1998), characterizedby emotionalregulationdeficits,implyingconnectivitywiththe lim-bicsystem(Heathetal.,1978;SchutterandvanHonk,2005).Itis believedthatcerebellarcognitiveaffectivesyndromemay,inpart, accountforcognitiveandemotionaldeficitsobservedinalcoholics withcerebellardamage(Fitzpatricketal.,2008).Thus,prefrontal and limbicconnectivitywiththecerebellumcouldexplainwhy brainactivitymaybealteredinheavyalcoholusersinthisregion duringtaskswithhighemotionalsalience,suchasareward-based decision-makingtask.
Intermsofadolescent-specificdrinkingbehavior,thecurrent findingssupportpreviousreports–thatapatternofbinge drink-ingduringadolescencemaybeneurotoxictothecerebellum.Not only has reduced volume beenreported in alcoholics (Sullivan etal.,2000,2010)andyouthwithAUDs(De Bellisetal.,2005), butarecentstudyalsofoundreducedcerebellarvolumein binge-drinkingadolescents, related totheparticipants’recent alcohol consumption(Lisdahletal.,2013).Thecurrentstudycomplements thisfindingbyprovidingevidenceforbingedrinking-relatedeffects oncerebellarrewardresponse,alsorelatedtorecentalcohol con-sumption.Whilepaststudieshavereportedbingedrinkingeffects during adolescence onbrain response duringworking memory (Squegliaetal.,2011),verbalencoding(Schweinsburgetal.,2010, 2011),andaffectivedecision-making(Xiaoetal.,2013),thisisthe firststudytoreporteffectsonrewardprocessing.Itispossiblethat emotionalsalienceoftrialswithrewardreceiptisreducedinvalue forbingedrinkers,whichcouldexplainreducedcerebellar activ-itytorewardandcomparableresponseinthisregionregardless ofwhetherfeedbackindicatedrewardpresenceorabsence.This interpretationissupportedbythefindingthatreducedresponse
torewardinbingedrinkerswaslocalizedtolobuleVIIa/crusI,a posteriorpartofthecerebellumimplicatedmoreincognitiveand emotionalfunctionsbasedonitsconnectivitypatterns,asopposed tomotorfunctionsthatarelocalizedtoanteriorportionsofthe cerebellum(Stoodley,2012).Itisdamagetothisposteriorportion thathasbeenreportedtoresultincognitiveandemotionaldeficits (StoodleyandSchmahmann,2010).Thesefindingssuggestan emo-tionalcomponenttocerebellarresponseduringrewardprocessing thatissupportedbythespecificcerebellarregioninwhichblunted rewardresponsewasobservedinbingedrinkers.Futurestudies willneedtoexamineregionalspecificityofcerebellaralterations inactivityandvolumeinheavyalcoholuserstodeterminewhether motorand/orcognitive/affectivedeficitswouldbeexpected.
Sincehypoactiverewardresponsehasbeenreportedinthe ven-tralstriatumofalcoholicsinpreviousstudies(Becketal.,2009; Wraseetal.,2007),thecurrentfindingscouldalsobeexplainedby modelsthatsuggestchangesinthecerebellumwithitsfunctional relationshipstoreward-relatedbrainregionsinaddiction(Moulton et al., 2014).Reciprocal dopaminergic projections betweenthe basalgangliaandthepontinenucleiprovideconnectivitytothe cerebellarcortex(BostanandStrick,2010).Thisconnectivityprofile couldexplainahypoactivepatternofcerebellarresponsetoreward receiptinbingedrinkersifthispathwayisalteredbyheavyalcohol use.Additionally,crusIhasbeenshowntobefunctionally con-nectedtobrainregionsinvolvedinemotionalsalience,suchasthe anteriorinsulaandanteriorcingulatecortex(Buckneretal.,2011), whichprovidesfurtherevidenceforposteriorcerebellar involve-mentwithaddiction(Moultonetal.,2014).Thecurrentfindings maysuggestthatheavyalcohol usehasreducedthesalienceor valueofrewardsinbingedrinkers,whichcouldleadtoapathof increasedreward-seekingbehaviorthatmayultimatelyheighten vulnerabilityforthedevelopmentofAUDs.
4.2. Strengthsandlimitations
Thestrengthsandlimitationsofthepresentstudymerit dis-cussion.First,bycollectingdataonparticipantsatbothabaseline andsecondstudyvisit,wewereabletoexaminegroupdifferences inalcohol-relatedeffectsonbrainfunctioningbyaccountingfor preexistingdifferencesinpatternsofbrainactivityinyouthwho havenot yetengagedin heavyalcohol use. Thepresentresults canconfirmwithgreaterconfidencethatthecurrentfindingsare morelikely duetodifferences inalcohol consumptionbetween thegroups, rather than a premorbiddifference in vulnerability towardalcoholuseintheseyouth.Infact,therelationshipobserved betweennumberofdrinksconsumed/drinkingdayinthe3months leadinguptothesecondstudyvisitwithcerebellarbrainactivity, suggeststhat,infact,theremaybeadose-responserelationship betweenalcohol useand cerebellarreward processing inbinge drinkers.Additionally,toourknowledgethisisthefirst longitu-dinalstudytoreportontheeffectsofadolescentbingedrinking duringrewardprocessing.Giventhatmultiplestudiesreport aber-rantrewardprocessinginadultalcoholics(Becketal.,2009;van Holstetal.,2014;Wraseetal.,2007),thecurrentfindingssuggest thatalcohol-inducedreward-relatedalterationsduring neurode-velopmentmayalreadybetakingplaceprior totheonsetofan AUD.
Despiteprospectivemethodologicalrigor,thesizeofthecurrent samplewastoosmalltoexaminesex-by-alcoholuseinteractions onbrainfunctioningatthewhole-brainlevel.However,weexpect additionalyouthtoemergeintobingedrinkingduringthe longi-tudinalstudy,and thusanticipatea largersamplewillallowus toanswer important questions related tosex interactions that havebeenreportedintheadultalcoholismliterature. Addition-ally,thecurrentsampleofadolescentbingedrinkersreporteduse of other substances that may have limited detection of purely
alcohol-relatedeffects.Amajorityofthebingedrinkershadused marijuanabythetimeofthesecondstudyvisit,andhalfhadused cigarettes.Thisisnotsurprising,ascigaretteandmarijuanauseare highlyco-morbidwithalcoholuseduringadolescence(Mossetal., 2014;Palmeret al.,2009).Thus,itis difficulttoexaminebinge drinkerswhohavenotusedanyothersubstancebutalcohol. How-ever,giventhatnoneofthecigaretteormarijuanausevariables relatedtobrainactivityinthecurrentstudy,itismorelikelythatthe currenteffectsarealcohol-related,especiallyconsideringthe cor-relationsfoundwithdrinkingvariablesandBOLDresponse.Finally, while a relationship between alcohol use and cerebellar brain responsewasfoundatrevisit,thepossibilityofotherconfounding variablesthat werenotassessed(i.e.earlylifetrauma, cumula-tivestressfullifeevents),whichcouldhaveincreasedbetweenthe baselinevisitand revisit,ordifferedbygrouporsex,mayhave influencedthecurrentfindings,andcouldbeassessedinfuture studies.
5. Conclusions
Toourknowledge,thisisthefirststudytoreportonadolescent bingedrinkersandbrainactivityduringrewardprocessing,using alongitudinaldesign.Thecerebellumhasconsistentlybeen impli-catedinalcohol-relatedbraindamageacrossstudiesofadultsand adolescents.Wecontributetothisliteraturebyshowingthatbinge drinkershavereducedreward-relatedresponseintheleftposterior cerebellum(lobuleVIIa/crusI),apatternthatwasnotpresentprior toheavyalcoholuse.LobuleVIIa/crusIoftheposteriorcerebellum isaregionimplicatedinaffectiveprocessing,cognitive function-ing,as wellasreward salience(Moultonet al.,2014; Stoodley, 2012).Thissuggests that response toreward presence maybe bluntedinbingedrinkersduetoalterationsofpathwaystolimbic and/orrewardsystems,whichcouldpotentiallydrivefurtherrisky drinkingbehavior.Importantly,thesefindingsmaycontributeto targetedearlyinterventionstrategiesinadolescentbingedrinkers, asitsuggeststhatrewardfunctioningmaybealteredinyouthwho havejustbeguntoengageinheavyalcoholuse.
Conflictofinterest
Allauthorshavemadesignificantcontributionstothis work, andthemanuscripthasbeenreadandapprovedbyallauthors.This manuscriptcontainsoriginalmaterial,andhasnotbeensubmitted, norisitinpressorpublishedelsewhereinanyform.Theauthors ofthismanuscriptensurethatallworkwascompletedwithcare toensurescientificintegrityoftheresearch.Noconflictsofinterest arepresent.
Acknowledgements
ThisstudywassupportedbytheNationalInstituteonAlcohol AbuseandAlcoholism(R01AA017664–Nagel;U01–AA021691 –Nagel,andP60AA010760–PI:Crabbe).Wewouldliketothank theresearchassistantsandvolunteersoftheDevelopmentalBrain ImagingLabfortheirassistancewithdatacollection.
AppendixA. Supplementarydata
Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.dcn.2015.06.004
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