doi:10.1093/scan/nsu141 SCAN(2015)10,913^920 Neural changes with attention bias modification for anxiety: a randomized trial Jennifer C. Britton,1,2 Jenna G. Suway,3,4 Michelle A. Clementi,1,5 Nathan A. Fox,3 Daniel S. Pine,1 and Yair Bar-Haim6 1SectiononDevelopmentandAffectiveNeuroscience,NationalInstituteofMentalHealth,Bethesda,MD,20892USA,2DepartmentofPsychology, UniversityofMiami,CoralGables,FL,33146USA,3DepartmentofHumanDevelopmentandQuantitativeMethodology,UniversityofMaryland, CollegePark,MD,20742USA,4JointDoctoralPrograminClinicalPsychology,SanDiegoStateUniversity/UniversityofCalifornia,SanDiego,San Diego,CA,92120USA,5DepartmentofPsychology,UniversityofHouston,Houston,TX,77204USA,and6SchoolofPsychologicalSciencesand SagolSchool ofNeuroscience, Tel Aviv University, Tel Aviv,69978 Israel D o w n Attention bias modification (ABM) procedures typically reduce anxiety symptoms, yet little is known about the neural changes associated with this lo a behavioral treatment. Healthy adults with high social anxiety symptoms (n¼53) were randomized to receive either active or placebo ABM. Unlike d e placeboABM,activeABMaimedtotrainindividuals(cid:2)attentionawayfromthreat.Usingthedot-probetask,threat-relatedattentionbiaswasmeasured d during magnetic resonance imaging before and after acute and extended training over 4 weeks. A subset of participants completed all procedures fro m (n¼30,15pergroup). Groupdifferencesinneuralactivationwereidentifiedusingstandardanalyses. Linearregressiontestedpredictive factorsof h symptomreduction(i.e.,traininggroup,baseline indicesofthreatbias).Theactiveandplacebogroupsexhibiteddifferent patternsofrightandleft ttp acomnytgradsatlapraioctrivtaotitornainwinitghetrxahiinbiintegd. Agcrreoastserasllympaprttoicmiparendtsucitriroens.peAcftteivreaocfcoguronutipn,ginfodrivbidausaellsinweitahmgyrgedaatlearalecfttivaamtioyng,daglraeaatcetrivsaytmiopntoimn trheeduthctrieoant-bwiaass s://ac a associatedwithassignmenttotheactivetraininggroup.Greaterleftamygdalaactivationatbaselinepredictedreductionsinsocialanxietysymptoms d e followingABM.Furtherresearchisneededtoclarifybrain-behaviormechanismsassociatedwithABMtraining. m ic .o u p Keywords: attention training;dot-probe; fMRI;amygdala; anxiety; treatment .c o m /s c a INTRODUCTION training (Taylor et al., 2013). Although the results should be inter- n/a Threatening cues capture the attention of individuals with anxiety to a preted with caution based on the statistical thresholds used, another rtic greater extent than for non-anxious individuals (Bar-Haim et al., 2007; fMRI study in adults with social anxiety disorder reported increased le-a Armstrong and Olatunji, 2012). Attention bias modification (ABM), right and left amygdala activation following internet-delivered ABM bs whichtargetsthreatbiasinattention,typicallyreducesanxietysymptoms relativetobaseline assessment, andincreased leftamygdala activation tra c (Hakamataetal.,2010;Beardetal.,2012).However,changesinunderlying following treatment was correlated with anxiety reduction (Mansson t/1 0 neuralcircuitryfollowingABMremainunclear.Thisfunctionalmagnetic et al., 2013). Although this work suggests that ABM might influence /7 resonance imaging (fMRI) study examined changes in neural circuitry fronto-amygdala function, the results are difficult to interpret due to /91 3 beforeandafterABMinadultswithelevatedsymptomsofsocialanxiety. eitherlackofabaselinescan(Browningetal.,2010)orlackofanABM /1 7 Todate, fewstudieshaveexamined neuralchangesfollowingABM control group (Mansson et al., 2013; Taylor et al., 2013). Here, we 3 7 designed to shift attention away from threat. In an event-related po- examined changes from before to after training in both active ABM 61 tential(ERP)study,adultswithhighanxietyscoresshoweddecreased andplacebo training groups. 1 b P2andP3andincreasedN2amplitudesfollowingsuchABMtraining WeexaminedthedegreetowhichABMspecificallyinfluencesbrain y g u (EldarandBar-Haim,2010).AlthoughtheseERPresultsspeaktothe regions that support top-down or bottom-up mechanisms (Bishop, es chronometry ofneuralchanges, theyare limited inspatial resolution. 2008; Heeren et al., 2013). Top-down mechanisms involve voluntary t o n fMRI studies in healthy adults shed light on this issue. One study oreffortfulcontrol(Ochsneretal.,2012),processesthoughttoengage 1 0 found greater dorsolateral and ventrolateral prefrontal cortex (PFC) the PFC. Bottom-up mechanisms involve threat sensitivity or threat A activation after ABM training relative to placebo training (Browning stoalieenngcaeg(eDtahveisamanydgdWalhaa.lTenh,u2s0,0p1r;ioPrhfaMnRetIaslt.u,d2i0e0s2i)m,pprloiccaetsisnegstthheouPgFhCt pril 2 etal.,2010);theotherreportedreducedrightandleftamygdala,insula 0 and subgenual anterior cingulate (sgACC) activation as well as inthreat-attention interactions (Monk etal.,2006)andtheamygdala 19 inthreatprocessing(Phanetal.,2006;Monketal.,2008)suggestarole increased PFC and visual cortex activation following active ABM for top-down and bottom-up mechanisms, respectively, in threat- related attention in individuals with anxiety. It remains unclear Received23May2014;Revised21September2014;Accepted20October2014 AdvanceAccesspublication24October2014 whether ABM alters top-down attention control and/or bottom- ClinicalTrialofFluoxetineinAnxietyandDepressioninChildren,andAssociatedBrainChanges,ClinicalTrials.gov up attention processes with the supporting neural architecture. Identifier:NCT00018057. Prior research examining neural changes on the dot-probe task ThisworkwassupportedinpartbytheIntramuralResearchProgramoftheNationalInstituteofMentalHealth, before and after cognitive behavioral therapy (CBT) or pharmaco- NationalInstitutesofHealth(P50MH078105toJ.G.S.),andtheBrain&BehaviorResearchFoundation,formerlythe NationalAllianceofResearchonSchizophreniaandDepression(NARSAD)(2009YoungInvestigatortoJ.C.B.).In logical treatment found changes in the ventrolateral PFC and right addition,J.C.B.wassupportedbyR00MH091183. and left amygdala, suggesting that various cognitive mechanisms and Previous versions of these findings were presented at annual conferences of the American College of brain structures could play a role in ABM (Maslowsky et al., 2010). Neuropsychopharmacology(ACNP)inMiami,FloridainDecember2012,theSocietyofBiologicalPsychiatryinSan Finally, individual differences in top-down or bottom-up mechan- Francisco,CaliforniainMay2013,andtheWorldCongressofBehaviorandCognitiveTherapiesinLima,PeruinJuly2013. isms, as well as their neural correlates, also appear to predict re- CorrespondenceshouldbeaddressedtoJenniferC.Britton,DepartmentofPsychology,UniversityofMiami,5665 PoncedeLeonBlvd,FlipseBuilding,CoralGables,FL33146,USA.E-mail:j.britton@miami.edu. sponse to CBT and pharmacological treatment (Faria et al., 2012; PublishedbyOxfordUniversityPress2014.ThisworkiswrittenbyUSGovernmentemployeesandisinthepublicdomainintheUS. 914 SCAN(2015) J.C.Brittonetal. Doehrmann et al., 2013; Klumpp et al., 2013; Ball et al., 2014). This translation/38 rotation in any direction from initial position). The raisesthepossibilitythatbaselinefunctioningandneuralactivationin latter criterion attempts to limit the overall movement to a voxel. thePFCand amygdala wouldalso predict response toABM. Finalanalysesincludedthoseindividualswhocompletedallprocedures In this fMRI study, attention bias of healthy adults with high self- and had usable fMRI data from both assessments. These criteria reported social anxiety was assessed before and after randomization yielded15participantsineachgroup(Figure1).Groupcharacteristics to active ABM or placebo training. These data were used to test two for the final sample are presented in Table 1. Groups were well specific hypotheses. First, we hypothesized that attention bias and matched on demographics, symptoms and task performance at base- neural activation would more robustly change with active ABM than line (allP>0.1).SeeSupplemental Information formore details. with placebo training. Specifically, compared with highly anxious adults receiving placebo training, those individuals receiving active Procedures trainingwereexpectedtoshowgreaterbehavioralandneuralchanges During the first MRI visit at NIMH, participants completed a dot- inthePFCandamygdala.Second,wepredictedthatbaselineattention probe task (Amir et al., 2009) to measure attention bias before (pre- bias and neural activation would predict symptom reduction post- training) and after acute-ABM training while in the MRI scanner. D training. Finally, because previous studies were mixed in relation to o Betweenattentionbiasmeasurements,participantscompletedtraining w the laterality of amygdala activation underlying ABM-related changes according to group assignment (i.e., active ABM or placebo) while nlo in anxiety, we separately tested our predictions using right and left remaining in the MRI scanner. Following the scan, participants com- ad e amygdala activation. pofleMtedareyxlatenndd(etdwAicBeMweterkaliynionvgerou4tswideeekosf).thAeftsecratnhneerexattenthdeedUtnriavienrisnitgy, d from MATERIALS AND METHODS participantscompletedasecondMRIscanattheNIMH,andattention h Participants bias and anxiety were again measured. Therefore, all three attention ttps Healthysociallyanxiousadults[LiebowitzSocialAnxietyScale(LSAS) bias assessments (i.e., pre-training, post-acute training and post- ://ac extendedtraining)wereconductedintheMRIscanner.Acutetraining a (Fresco et al., 2001) (cid:2)50] were recruited from the University of d MarylandandtheNationalInstituteofMentalHealth(NIMH)subject occurred during the first MRI visit and extended training was con- em ducted behaviorally over a4-week period. ic poolsfromOctober2010toFebruary2012.TheLSAScutoffapproxi- .o u mpleast.edLSthAeSuspcopreersqwuiatrhtiinletohfisscroarnegsecaorlleecmteodrefrloikmelycotlolegcehasrtaucdteenritzesatmhe- Dot-probe task p.com generalizedconcernsofsocialanxiety(Menninetal.,2002;Rytwinski In the dot-probe task, an angry and a neutral face of the same indi- /s c et al., 2009). The trial ended when complete MRI data from 15 indi- vidualwerepresentedsimultaneously.Inaddition,trialswithpairsof an vtyidpuicaallslyinueseadchfgorrounpeuwraosimaacghiinevgedretsoearrecahch(Cmairnteimr aeltsaaml.,ple20s0iz8e)s. nsteimuturalilfwaecrees(pnreeusetnratledtrivaelsr)tiwcaelrlyeuinsebdlaacskaacnodntwrohlitceonadnidtioconn.sTishteedfacoef /article Writteninformedconsentwasobtainedfromallparticipantsandpro- 12identitiesselectedfromtheNimStimFaceStimulusset(Tottenham -a b cMedaruyrleasndwaenred NcoIMndHucItnedstitiuntioancaclorRdeavniecwe Bwoiathrdsb.oth University of eetithael.r, 2th0e09)a.ngImrymfeadceiat(etlhyrefoaltlocwoinnggruthenetfatcriealp)aiorr, athperonbeeutrreapllafcaecde strac Allparticipantswerepaidvolunteers18–30yearsold,Englishspeak- (threat incongruent trial). Participants indicated the probe letter t/10 ing,andhadnormalorcorrected-to-normalvision.Tobeeligible,each (E orF) viabutton press asquicklyand asaccurately aspossible. /7/9 participanthadanIQ>70(WechslerAbbreviatedScaleofIntelligence, The pre-training, post-acute training and post-extended training 13 WASI(Wechsler, 1999)],and wasfreeof chronic medical illness, any dot-probe task consisted of 144 trials (48 threat congruent, 48 threat /17 psychotropic medication and contraindications to MRI. Any current incongruent,48neutraltrials).Eachtrialbeganwithacentralfixation 37 6 AxisIpsychiatricdisorderwasexclusionary.Therationaleforstudying cross (þ) for 500ms, then a pair of faces (angry–neutral, 11 non-diagnosed but symptomatic subjects related to ethical concerns neural–neutral) appeared vertically for 500ms. A 400ms probe (E or by about withholding effective treatment from subjects with an anxiety F)replacedtheangryorneutralfacewithequalprobability.Toreduce gu disorder. To assess psychopathology, experienced clinicians adminis- anticipationeffectsinthebehavioralresponse,trialswereseparatedby es teredtheStructuredClinicalInterviewforDSM-IV(Firstetal.,2002). a variable length inter-stimulus interval, which averaged 1100ms and t on In addition, indices of anxiety and depressive symptom severity were rangedfrom900to1300ms.Inaddition,48fixationtrialsperrunwere 10 measuredusingtheLSAS,Spielberger’sTraitAnxietyInventory(STAI) presented tobeableto deconvolve thehemodynamic signal. Ap (Spielberger, 1983), Fear of Negative Evaluations Scale (Watson and ril 2 Friend, 1969),and BeckDepression Index (Becket al.,1996). Attention training task 01 9 Of138potentialparticipantsrespondingtoinitialrequestsforpar- Using the dot-probe task, active ABM was designed to train ticipation and meeting eligibility criteria to participate in the study participants to attend away from threat (Bar-Haim, 2010). Thus, the based on phone screen, 74 were screened at the NIMH for psycho- probe always replaced the neutral face. In the placebo version, the pathology and 53 enrolled. After blocking for gender and LSAS score probereplacedtheangryfaceandneutralfacewithequalprobability. withinranges50–65,66–80andabove80,participantswererandomly Pairsofneutralfacesalsowerepresentedinbothversionsasacontrol assigned to an active ABM group (n¼26) or placebo training group condition (neutral trials). Of note, the four face stimuli in ABM/ (n¼27). Within each category, an online random number generator placebo task (Matsumoto and Ekman, 1989) were different from the repeatedlycreatedaclosedsequenceofeightvaluesassignedtoeither face stimuli presented during assessment to potentially demonstrate active or placebo (J.C.B). NIMH staff enrolled participants and as- generalization oftraining. signed the intervention based on the random assignment (M.A.C). Duringacutetraining whileinthescanner,480training trialswere Participants and staff administering ABM training were blind to the completed over three runs (160 trials each). ABM consisted of 384 treatmentcondition. Asinpreviouswork(Brittonetal.,2012,2013), threat incongruent trials and 96 neutral trials, whereas the placebo participants were excluded for non-compliance. Participants were traininghad192threatcongruent,192threatincongruent,and96neu- excluded if accuracy rates on the dot-probe task were below 75% or tral trials. In addition, there were 96 fixation trials. During extended if motion was excessive (more than 75% of MRI data had >3mm training conducted behaviorally, eight shorter training sessions with NeuralchangeswithABM SCAN(2015) 915 Enrollment Assessed for eligibility (n=74) Excluded (n=21) ♦ Not meeting inclusion criteria (n=20) ♦ Study ended (n=1) Randomized (n=53) D Allocation o w n Allocated to active ABM intervention (n=26) Allocated to placebo intervention (n=27) lo ♦ Received allocated intervention (n=26) ♦ Received allocated intervention (n=27) ad e d fro m h ttp s Follow-Up ://a c a d ♦Discontinued intervention (n=3) ♦Discontinued intervention (n=6) e m ic .o u p .c o m Analysis /s c a n Analyzed (n=15) Analyzed (n=15) /a ♦ Excluded for poor accuracy (n=4) ♦ Excluded for poor accuracy (n=2) rtic le ♦ Excluded for motion (n=3) ♦ Excluded for motion (n=6) -ab s ♦ Excluded for technical reasons (n=1) trac t/1 0 /7 /9 1 3 /1 Fig.1 Studyflow. 7 3 7 6 1 1 b y Table 1 Group characteristics ofindividuals includedin fMRIanalysis gu e s t o Activetraining Placebotraining n 1 0 Demographics A p NAguemb(yeerars) 1251.8(cid:3)2.9 1252.1(cid:3)3.2 ril 2 0 Gender(males) 3 7 1 9 IQ 119.1(cid:3)8.4 118.5(cid:3)9.5 Baselinesymptoms LSASaveragescreen 52.0(cid:3)16.3 54.6(cid:3)17.3 STAItrait 34.3(cid:3)8.8 36.4(cid:3)10.5 BDI 3.8(cid:3)3.8 4.6(cid:3)4.6 FNE 13.1(cid:3)8.1 11.0(cid:3)8.0 Dot-probeperformance Pre-training Post-acutetraining Post-extendedtraining Pre-training Post-acutetraining Post-extendedtraining Accuracy(%) 94.8(cid:3)3.4 91.2(cid:3)4.8 92.9(cid:3)6.8 94.5(cid:3)6.5 92.8(cid:3)5.5 93.7(cid:3)5.2 Threatbias (cid:4)2.5(cid:3)22.4 (cid:4)5.4(cid:3)27.0 (cid:4)6.5(cid:3)16.6 3.7(cid:3)17.8 5.2(cid:3)18.5 (cid:4)1.1(cid:3)13.8 RTcongruent 658.3(cid:3)85.3 637.3(cid:3)90.3 635.8(cid:3)66.4 703.4(cid:3)128.1 650.0(cid:3)110.9 673.9(cid:3)107.1 RTincongruent 655.8(cid:3)84.6 631.9(cid:3)91.6 629.3(cid:3)71.0 707.0(cid:3)116.6 655.2(cid:3)118.6 672.8(cid:3)107.9 RTneutral 657.4(cid:3)93.2 632.6(cid:3)93.5 630.5(cid:3)63.4 707.2(cid:3)137.5 651.2(cid:3)113.0 674.4(cid:3)101.6 MeansandS.D.IQ,¼intelligencequotientbasedonWechslerAbbreviatedScaleofIntelligence(WASI);LSAS,LiebowitzSocialAnxietyScale;STAI,SpielbergerTraitAnxietyInventory;BDI,BeckDepression Index;FNE,FearofNegativeEvaluationsScale;RT,reactiontime(ms). 916 SCAN(2015) J.C.Brittonetal. 160 trials each were completed twice weekly over 4 weeks (effectively models, regressors coded for threat congruent, threat incongruent yielding another 1280trials). and neutral conditions for each assessment run. These regressors of interest included only correct trials. Incorrect trials or trials with Apparatus and acquisition reactiontimesoutsideofthecriterialimitswereincludedasaseparate regressorofnointerest.Finally,sixmotionregressorscorrespondingto Stimuli were presented via standardized software (E-Prime, Inc., 2.0, translationandrotationineachxyzdirectionandregressorsmodeling Pittsburgh, PA)on aPC computer. Inthe MRI scanner, images were low-frequency drift were included. A series of estimated betas, one projected onto a screen and viewed by participants through a mirror for each regressor, was generated to minimize the error term within mounted onthehead coil. themodel. Foreachparticipant,MRIdatawerecollectedwitha3.0TGeneral A whole-brain voxel-wise analysis was conducted using random Electric Signa system scanner (Waukesha, WA) and an eight-channel effectsanalysis.Thebetacoefficientsgeneratedfromindividualanalyses gradientheadcoil.Aftershimming,aT2*-sensitivegradientechopulse were entered into a second-level model (i.e., AFNI GroupAna). The sequencewasusedforfunctionalimaging(TR¼2300ms,TE¼25ms, model examined interactions between Group (active, placebo), Time flip angle¼908, FOV¼24cm, 96(cid:5)96 matrix, 36 contiguous 2.6mm D (pre-training,followingacute-trainingandfollowingextendedtraining) o interleaved axial slices). To reach longitudinal magnetization equilib- w rium,fourinitialacquisitionimageswerecollectedpriortotaskonset. andCondition(threatcongruent,threatincongruent,neutral). nlo Finally, a high-resolution T1-weighted volumetric scan of the whole To correct for multiple comparisons in our omnibus analysis, we ade performed a family-wise error approach at the cluster level through d bserqauinenwceas (a1c2q4uire1d.2musming aaximalagsnleictiezsa;tioFnOVpr¼ep2a2re0dmmgr;adiNenEtXe¼ch1o; 1000 Monte Carlo simulation using AFNI’s AlphaSim program. The from TR¼TE¼min; matrix¼256(cid:5)192; TI¼725ms; bandwidth¼ cluster threshold was set at (cid:2)¼0.05 with a voxel-wise P-value of h 31.25kHz for 256 pixels). This anatomical scan was used for coregis- 0.005 and estimated smoothness values in our data, that is, ttps tration and normalization procedures. (cid:6)8.6mm. Statistical significance was defined as 80 voxels (1250 ://a mm3) for whole brain (92165 voxels, 1440078 mm3). To restrict ca d the search territory, regional masks were used for a priori regions e Data analysis m [i.e., amygdala (117 voxels, 1828 mm3), inferior frontal gyrus ic Changes in social anxiety symptoms (733voxels, 11453mm3)]. Based on these calculations, cluster sizes .ou p Changes in LSAS scores across the procedures were analyzed using a of 2 voxels (31mm3) for the amygdala and 14 voxels (219mm3) for .c o Repeated Measures Analysis of Variance (ANOVA) to examine inter- the inferior frontal gyrus were needed to yield a corrected p<0.05 m actions between Group (active, placebo) and Time (averaged screen- level. Coordinates are presented using Left-Posterior-Inferior (LPI) /sc a ing,scan 2). Significance wasdetermined using(cid:2)¼0.05. coordinate system. n/a Althoughstatisticalinferenceisbasedonthewhole-brainvoxel-wise rtic Attention bias measures analysis, post-hoc analyses were conducted to decompose the le -a Group(cid:5)Time(cid:5)Conditioninteractionwithineachsignificantcluster. b Attention bias was measured before training, after acute training and s afterextendedtraining.Foreachmeasurement,biasscoreswerecalcu- Similar approaches have been used widely as a means to describe the tra c latedbysubtractingthereactiontimeonthreatcongruenttrialsfrom effectsofcomplexinteractionsinwhole-brainanalysis(Shinetal.,2011; t/1 threat incongruent trials. Positive bias scores reflect a bias towards Killgoreetal.,2014;Whiteetal.,2014;Wigginsetal.,2014).Basedon 0/7 thegrouplevelanalysis,significantvoxelsineachclusterwereidentified. /9 threat and negative bias scores reflect a bias away from threat. 1 Attention bias calculations excluded trials with incorrect responses, These significant voxels included all voxels above a threshold of 3/1 trialswithreactiontimes<150msor>2000ms,andtrialswithreaction p<0.005thatlayinaclustersurpassingthemorestringent,corrected 73 7 times>2.5s.d.outsideofthemean(basedoncorrecttrialswithreac- statistical threshold. Across these voxels, the percent signal-change 61 tiontimesbetween150and2000ms).Thesecriteriawereappliedsep- values, relative to fixation, were averaged for each condition for each 1 b arately to each condition (threat congruent, threat incongruent, participant.Post-hocanalyseswereconductedontheseaveragedvalues y g neutral)withineachtimepoint(pre-training,followingacutetraining, withineachcondition,basedonthethreatbiascontrast(i.e.,threatin- ue s following extendedtraining). congruent–threat congruent). These analyses aimed to investigate the t o Behavioral indices were analyzed using a Repeated Measures patterns across conditionsas a function of group, time and condition. n 1 ANOVA to test interactions between Group (active, placebo) and Theseextractedvaluesalsoservedtopredictchangesinsocialanxiety. 0 A p Ttriamineing(p).reS-itgrnaiifnicinang,cefowlaloswdientgermacinueted utrsainingin(cid:2)g¼, 0fo.0l5lowanindgBoenxfteernrdoendi Predicting reduction in social anxiety using pre-training ril 20 1 correction wasapplied, when appropriate. baseline measures 9 Usingastep-wiselinearregression,groupandbaselinemeasures(i.e., Brain activation pre-training attention biasscores and pre-training right orleft amyg- fMRIdatawerepreprocessedusingAnalysisofFunctionalNeuroimages dalaactivationinresponsetothreatbias)wereusedtopredictoverall (AFNI, http://afni.nimh.nih.gov/afni). Pre-processing included slice- symptomreduction(i.e.,changeinLSASscoresbetweenscreeningand timingcorrectionandrealignment.Thereferenceimageforrealignment post-extended training). All variables were mean centered across par- correspondedtothefirstimageofeachseries.Thefunctionalserieswas ticipants. Separate analyses were conducted using the right and left coregistered to the anatomical image and normalized into Talairach amygdala. space using automated routines (Talairach and Tournoux, 1988). The After conducting group analyses and appropriate post-hoc analyses dataweresmoothedusinga6mmfull-width-at-halfmaximumisotropic on the imaging data, a group difference was found in both right and Gaussianfilterandscaled,convertingthedatatopercentsignalchange leftamygdalaactivationatbaseline.Theactivegrouphadlessrightand relative to baseline (i.e., fixation). After all pre-processing steps, the left amygdala activation in the threat-bias contrast (threat incongru- resultingimagescontainedisotropic2.5-mmvoxels. ent>threat congruent) at baseline compared with the placebo group Separate general linear models were created for each scan visit. [ts(28)>4.4, ps<0.001]. As a result, right or left baseline amygdala Individual models contained only bias assessment data. For all activation for this same threat bias contrast was entered into the NeuralchangeswithABM SCAN(2015) 917 prediction models in step 1 to minimize this initial pre-ABM group left:((cid:4)19,1,(cid:4)11),49voxels(766mm3),F(4,112)¼5.4,P<0.05cor- difference.Instep2,maineffectsofgroup(active,placebo)andbase- rected] (Figure 2). Post-hoc analyses were used to decompose this line attention bias were entered. Two-way interactions (Group*Pre- interaction. These analyses showed that, following extended training, training Attention Bias, Group*Pre-training Amygdala Activation, right and left amygdala activation in response to the threat bias con- Pre-training Attention Bias*Pre-training Amygdala Activation) were trast (threat incongruent>threat congruent) increased in the active entered in step 3, and the three-way interactions (Group*Baseline ABM group and decreased in the placebo group [Group(cid:5)Time Attention Bias*Pre-training Amygdala Activation) were entered in interaction: right: F(2,56)¼12.1, p<0.001, (cid:3)2¼0.30, left: p step4.Significant effects weredetermined using (cid:2)¼0.05. F(2,56)¼15.9, p<0.001, (cid:3)2¼0.36; follow-up contrasts in each p group,ps<0.001]. RESULTS Importantly, as noted above, interpretation of this three-way Changes in social anxiety symptoms interaction was complicated by the presence of significant group differences in amygdala activation to threat bias prior to training. Although no group differences or group interactions were found (ps>0.4), LSAS scores significantly reduced from screening (active: This baseline difference reflects the fact that the active group, D 52.0(cid:3)16.3, placebo: 54.6(cid:3)17.3) to post-extended training (active: prior to training, had less right and left amygdala activation in the ow n 42.9(cid:3)22.5, placebo: 49.4(cid:3)23.6) in the sample as a whole [F(1, threat bias contrast than the placebo group. Separate models for lo a 28)¼4.3,p<0.05, (cid:3)2¼0.13]. right and left amygdala were used to predict symptoms changes. de Attention bias meapsures Twhasermefionriem,tizheids pbrye-itnrcelautdminengtbgarsoeulinpedriifgfehrtenocreleifntaammyyggddaallaaaaccttiivvaattiioonn d from as step 1 in separate prediction models using left or right amygdala h No group differences or interactions were detected when examining data. ttps accuracy and attention bias at any point (ps>0.6). No changes in Ofnote,nosignificanteffectsinamygdalaactivationweredetected ://a attention bias across time were detected (p>0.6), and neither group c when examining angry trials (i.e., collapsing angry incongruent and a d showed an attention bias towards or away from threat after acute or congruent trials) relative to neutral trials (all p>0.1). Furthermore, em extended training (p>0.1)(Table 1). amygdala activation in response to neutral trials wasnot significantly ic .o differentbetweenactiveandplacebotraininggroupsduringanyofthe u p Brain activation three assessments (pre-training, post-acute training, post-extended .co m Wholebrain,random-effectsanalysesindicatedthree-wayinteractions training)(all p>0.3). /s (Group(cid:5)Time(cid:5)Condition) in the right and left amygdala: [right: Noother regions(i.e.,prefrontal corticalregions)survivedapriori ca n (16,(cid:4)1,(cid:4)9),54voxels(844mm3),F(4,112)¼4.3,P<0.05corrected; cluster-level correction. However, a Group(cid:5)Time(cid:5)Condition /a rtic le -a b s tra c FF t/10 7.5 /7 /9 1 3 /1 7 3 7 6 RIGHT AMYGDALA LEFT AMYGDALA 1 1 b 00 y g u e s Pre-Training Pre-Training t o for nge fn±SD)Mean 0000...3321 * AExctuetned-Terda iTnrinagining for nge n±SD)Mean 0000...3321 AExctuetned-Terda iTnrinagining * n 10 April 2019 Chant Signal Perceast (ias Contrahreat Bi --00..120 l Chaent SignalPercerast (Bias Contrhreat B --00..120 T T -0.3 * * -0.3 * * Active Placebo Active Placebo Fig.2 NeuralchangesassociatedwithABMtraining.Wholebrain,random-effectsanalysesindicatedthree-wayinteractions(Group(cid:5)Time(cid:5)Condition)intherightandleftamygdala:[right:(16,(cid:4)1,(cid:4)9), 54voxels(844mm3),F(4,112)¼4.3,p<0.05corrected;left:((cid:4)19,1,(cid:4)11),49voxels(766mm3),F(4,112)¼5.4,p<0.05corrected].Todecomposethisthree-wayinteraction,thepercentsignal-change values, relative to fixation, across significant voxels in each whole-brain cluster were averaged for each condition for each participant. Post-hoc analysis examined the threat bias contrast (i.e. threat incongruent>congruent). 918 SCAN(2015) J.C.Brittonetal. interaction was detected in a non-a priori region, the cerebellum [(9, emerged.First,greaterleftamygdalaactivationtothethreatbiascon- (cid:4)74,(cid:4)16),119voxels(1859mm3),F(4112)¼4.3,p<0.05corrected]. trastatbaselinewasassociatedwithgreatersymptomreductionacross bothtraininggroups.Second,afteraccountingforgroupdifferencesin Predicting reduction in social anxiety symptoms using baseline amygdala activation, assignment to one or theother training pre-training measures conditionfurtherpredictedchangesinsymptoms,withgreatersymp- tom reduction intheactive ABM group. Right amygdala Thepredictivemodelusingrightamygdalaactivationwasnotsignifi- Brain activation cant (allp>0.1). Based on the whole-brain analysis, the active ABM group exhibited increased bilateral amygdala activation to thethreat bias contrast fol- Left amygdala lowingextendedtrainingcomparedwithbeforetraining;whereas,the As shown in Table 2, the model using left amygdala activation was placebo group exhibited decreased bilateral amygdala activation fol- significant [F(6,29)¼2.8, p<0.04] and accounted for 42.0% of the lowingextendedtrainingcomparedwithbeforetraining.Theseresults D variance in LSAS symptom reduction. After accounting for baseline ow intheactiveABMtraininggroupcontrastwithrecentfindingsshow- n amygdalaactivation(step1),groupassignmentsignificantlypredicted ingpre-to-posttrainingreductionsinbilateralamygdalaactivationin loa reduction in social anxiety symptoms. As shown in Figure 3, greater d an emotional matching task following active ABM training (Taylor e symptomreductionwasassociatedwithgreaterbaselineleftamygdala d activationirrespectiveofgroupassignment(Unstandardized(cid:4)¼94.0, et al., 2013). These potentially conflicting results could relate to dif- fro ferencesinthetasksused.Unlikepreviousworkusingnon-dot-probe m SE¼42.0, p<0.04), and with assignment to the ABM relative to pla- h cebocondition (Unstandardized (cid:4)¼9.5,SE¼4.1,p<0.03). tasks, the threat bias contrast used in the current study compared ttp Baseline attention bias score did not significantly predict symptom tishrteraatineindcoanwgaryuefrnotmanthdretahtreinatthceonagcrtuiveentABcMondgirtoiounps,.thAestahtrteeanttiionn- s://ac reduction(p>0.8)andindividualsshowingavoidantbiasesatbaseline a congruent condition may become increasingly salient in this trained d didnotsignificantlydifferintermsofsymptomreductionorchanges e group, leading to increased amygdala activation over time. m inamygdala activation (all p>0.1). ic Furthermore, threat-incongruent trials in the active ABM group may .o u signal the need to shift attention away from threat, which might be p DISCUSSION facilitatedbyamygdalaengagement.Inaddition,thestimulustypethat .co m This study examined both neural and behavioral predictors of social becomes most salient may differ by ABM group, which may lead to /s c anxiety symptom reduction following ABM training. Two findings oppositepatternsofamygdalaactivation.Nosucheffectsareexpected an /a rtic le Table 2 Parameters fromstep regression modelpredicting symptom reduction change using screening measures -a b s tra Variable R2 (cid:2)R2 F Significant Unstandardized t p ct/1 0 B SE(B) /7 /9 1 3 Step1: 0.04 0.04 1.13 0.30 /1 Constant 4.15 4.34 0.95 0.35 73 Pre-trainingleftamygdalaactivationtothreatbiascontrast 94.0 42.03 2.24 0.04 76 Step2: 0.14 0.10 1.35 0.28 11 Group 9.45 4.09 2.31 0.03 b y Pre-trainingthreatbias (cid:4)0.04 0.17 (cid:4)0.22 0.83 g Step3: 0.42 0.29 2.78 0.04 ue GGrroouupp(cid:5)(cid:5)PPrere-t-rtarianiinngingLefTthAremaytgdbaialasActivation 302.5.35 309..3073 01..8530 00..4125 st on Pre-trainingthreatbias(cid:5)Pre-trainingleftamygdalaactivation 0.45 3.55 0.13 0.90 1 0 A Inclusionofthethree-wayinteractioninstep4wasnon-significant(p>0.4);therefore,unstandardizedB,SEofB,t-andp-valuesassociatedStep3arereported. pril 2 0 1 9 A B 60 60 Active on 40 on 40 Placebo cti cti Mean u u d 20 d 20 e e R R om 0 om 0 pt -0.4 -0.2 0 0.2 0.4 pt m m y -20 y -20 S S -40 -40 Pre-Training Left Amygdala Activation to Threat Bias Fig.3 Predictorsofsymptomreduction.PanelA:Acrossbothgroups,leftamygdalaactivationtothreatbiascontrastpriortotrainingpredictedsymptomreduction(scoresonLSASfromscreeningtopost- extendedtraining).PanelB:Theactivegroupshowedgreatersymptomreductionthantheplacebogroup. NeuralchangeswithABM SCAN(2015) 919 intheemotionalmatchingtaskusedinpriorwork(Tayloretal.,2013). continues to change, and there is a need for large-scale randomized Importantly, however, regardless of the direction of change in neural controlledtrials(RCTs).Inlightofournegativefindings,thechanging activation the amygdala emerges as a key player in ABM induced landscape of research in this area, and the need for such large RCTs, threat-related attentional changes across thetwostudies. questionsonthedegreetowhichABMcanproducechangesinsymp- tomsandproducefarorneartransfereffectsonassociatedpsychology processes remain. Here, our negative findings were complicated by Predicting reduction in social anxiety symptoms between-group differences in baseline levels of amygdala activation, AcrossboththeplaceboandABMgroups,individualswithgreaterleft whichwerecovariedinourpredictionmodels.Inthislatterstatistical amygdala activation to the threat bias contrast prior to training ex- model, assignment to the active group (i.e. training to attend away hibitedthegreatestreductioninanxietysymptomsfollowingextended from threat) did in fact predict larger reductions in symptom reduc- training.Thecurrentfindingsofamygdalaactivationpredictingsocial tion than the placebo group. This pattern does suggest that, in the anxietysymptomreductionwerespecifictotheleftamygdala.Several contextofABMtrainingdeliveredalongsideneuroimaging,theability studies report amygdala changes with treatment of anxiety (Furmark todetecttraining-relatedreductionsinanxietysymptomsmaybeim- etal.,2002;Fariaetal.,2012;Hauneretal.,2012;Manssonetal.,2013; D provedbyaccountingforamygdalaactivation.Indeed,MRIscanscan ow Phan et al., 2013; Taylor et al., 2013). Some work shows reduced n amygdala activation bilaterally after treatment (Furmark et al., 2002; induce stress, particularly in anxious participants (Monk et al., 2006; loa Perez-EdgarandBar-Haim,2010),andstresshasbeenshowntoalter d Faria et al., 2012; Taylor et al., 2013), while others have found later- e alized effects either in the left (Hauner et al., 2012; Mansson et al., t2h0r1e2a)t.-rNeleavteerdthaetlteesns,tiionnterppartetetartnison(Wofatldhisetlaattle.,r2fi0n1d1i;ngShferochmneoruretparel.-, d fro 2013) or right amygdala (Phan et al., 2013). In one study, amygdala m dictionanalysisshouldbeinterpretedwithcaution,duetothepoten- h activation decreased more for treatment responders than non- tial problems in controlling for confounding variables (Miller and ttp r2e0s0p2o)n.dIenrsy,etpaanrtoictuhelarrlsytuidny,tdhiefferriegnhttshuebmreigsipohnesreof(tFhuermamarykgdeatlaailn., Chapman,2001). s://ac a eachhemispherewereassociatedwithtreatmentresponse(Fariaetal., d e 2012). Clearly, more work is needed to specify the laterality of these m Limitations ic effects. .o These findings should be considered in light of several limitations. u Surprisingly, the association between left amygdala activation and p reductions in symptoms in the current study occurred regardless of First,oursampleincludedhealthyvolunteerswithhighsocialanxiety .co m traininggroup.Attheneuralactivationlevel,itispossiblethatrather symptoms. Healthy volunteers may retainabilities to flexibly alter at- /s thanobservingspecificeffectsoftrainingattention‘away’fromthreat tention;therefore,futurestudiesshouldexamineeffectsinaclinically can ianbitlhiteyactotivmeroerleatirvoebtuostthlyeptrlaacinebogecnoenradlitiaotntesn,twioeninfflaexctibdlyet,ecwthAicBhMi’ss ayniexldioeudsgproopuuplatdiiofnfe.reSneccoesndi,nrabnildaotemralasasimgnymgdeanlat uascitnivgastimonallpsraimorplteos /article evident in both conditions. Therefore, repeated trials that alternate training.Tominimizethedifferencesacrossgroups,baselineamygdala -a b between face pairs containing a threat and target probes may benefit aocutrivraetgiornesstioonthme tohdreelast. bHiaoswceovnert,ratshtiswiassninoctluadnedidienalthsoelufitrisotns,tespincoef stra both training groups. Alternatively, both active and placebo training c groups are exposed to repeated presentations of mildly threatening cautioniswarrantedwhenusingacovariatetoexplainbaselinegroup t/10 stimuli and greater between-session habituation may be associated differences(MillerandChapman,2001).Importantly,randomassign- /7/9 with greater symptom reduction (Fischer et al., 2003) and supported ment to active and placebo ABM groups is unlikely to have caused 13 by changes in amygdala reactivity. Further investigation is needed to baseline differences in amygdala activation. However, small studies /17 testthese alternatives. such as ours, where multiple between-group baseline variables are 37 6 Itisimportanttonotethatourstudypossessedbothadvantagesand examined, run the risk of Type I errors. Thus, larger samples may be 11 disadvantages, relativeto prior imaging studies ofABM.Unlike prior needed to overcome such unintended consequence of randomization by workfindingPFCchangesassociatedwithABM(Browningetal.,2010; (Ioannidis etal.,2014). gu e Eldarand Bar-Haim, 2010;Taylor etal., 2013),ourwhole-brain ana- s lysisidentifiedinteractionsonlyintheamygdala,andnotinthePFC. t on PreviousfMRIstudiesusedemotionalmatchingandselectiveattention CONCLUSIONS 10 tasks to assess the neural changes associated with ABM (Browning Despite limitations, this neuroimaging study is the first to examine Ap et al., 2010; Mansson et al., 2013; Taylor et al., 2013), which have predictive factors of symptoms change associated with both ABM ril 2 advantages of examining how attention training generalizes to tasks and placebo training. These findings have important implications for 01 beyondthetaskonwhichsubjectshadbeentrained.Thus,procedures treatment. For example, traditional CBT strategies may enhance top- 9 inourstudycannotidentifyhowtraininggeneralizedtodifferentcog- down processes through explicit strategies intended to reduce threat nitive-affectivetasks(i.e.fartransfer).Rather,thecurrentstudyexam- appraisalsandincreaseemotionregulationthroughrepeatedexposure. ined activation to the threat bias contrast during assessment and Alternatively, here we have shown that ABM may utilize bottom-up training using similar dot-probe tasks (i.e. near transfer). By doing processestoimplicitlytrainbiasedthreat-relatedattention(Bar-Haim, so, our findings may more closely characterize the specific neural 2010). Understanding the underlying mechanisms of treatments may mechanism of dot probe-based ABM, at the expense of failing to help optimize treatment approach, producing maximum benefit to elucidate effects on other important cognitive processes that might individuals with particular neurobehavioral profiles. For example, in- contribute to any effects of ABM. Future studies should attempt to dividualswithexaggeratedamygdalaactivationmaybenefitmorefrom examinebothfarandneartransferbyincludingbothdotprobebased ABM. Further, for certain patients, perhaps with high left amygdala and other fMRItasks probingemotional and attention processes. activationatbaseline,ABMcouldbeappliedalongsideothertreatment Givenpreviousmeta-analysesofABMstudiesshowingreductionsin optionssuchasCBTthattargettop-downcognitiveprocesses.Further anxiety symptoms (Hakamata et al., 2010; Beard et al., 2012), it is research is needed to understand the brain-behavior relations asso- surprising that changes in symptoms were not statistically different ciated with ABM training and to refine this treatment for individuals across groups. It is important to note that the state of ABM research withanxietydisorders. 920 SCAN(2015) J.C.Brittonetal. 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Neural changes with Attention Bias Modification (ABM) for anxiety

Similar Neural changes with Attention Bias Modification (ABM) for anxiety