Article. bulimia nervosa.

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1 Article A n fm R I Stu d y o f Se lf-r e g u l to ry C o n tro l n d C o n fl ict R e so lu tio n in A d o le sce n ts W ith B u lim i N e rvo s Rchel Mrsh, Ph.D. Guillermo Horg, M.D. Zhishun Wng, Ph.D. Pengwei Wng, Ph.D. Kristin W. Klhr, M.A. Lur A. Berner, A.B. B. Timothy Wlsh, M.D. Brdley S. Peterson, M.D. Objective: The uthors exmined functionl ctivity in the frontostritl systems tht medite self-regultory cpcities nd conflict resolution in dolescents with bulimi nervos. Method: The uthors used functionl mgnetic resonnce imging to compre blood-oxygen-level-dependent response in 18 femle dolescents with bulimi nervos nd 18 helthy femle ge-mtched subjects during performnce on Simon sptil incomptibility tsk. Byesin nlyses were used to compre the two groups on ptterns of brin ctivtion during correct responses to conflict stimuli nd to explore the effects of ntecedent stimulus context on group differences in self-regultion nd conflict resolution. Results: Adolescents with nd without bulimi nervos performed similrly on the tsk. During correct responses in conflict trils, frontostritl circuits including the right inferolterl nd dorsolterl prefrontl cortices nd putmen filed to ctivte to the sme degree in dolescents with bulimi nervos s in helthy comprison subjects. Insted, dectivtion ws seen in the left inferior frontl gyrus s well s neurl system encompssing the posterior cingulte cortex nd superior frontl gyrus. Group differences in corticl nd stritl regions were driven by the differentil responses to stimuli preceded by conflict nd nonconflict stimuli, respectively. Conclusions: W hen engging the selfregultory control processes necessry to resolve conflict, dolescents with bulimi nervos displyed bnorml ptterns of ctivtion in frontostritl nd defultmode systems. Their bnorml processing of the ntecedent stimulus context conditioned their brin response to conflict differently from tht of helthy comprison subjects, specificlly in frontl regions. It is suspected tht functionl disturbnces in frontl portions of frontostritl systems my relese feeding behviors from regultory control, thereby perpetuting the conflicting desires to consume fttening foods nd void weight gin tht chrcterize bulimi nervos. (Am J Psychitry Mrsh et l.; AiA:1 11) Bulimi nervos typiclly begins in dolescence nd primrily ffects women. It is chrcterized by recurrent episodes of binge eting (consumption of n excessive mount of food) followed by self-induced vomiting or nother compenstory behvior to void weight gin. An extreme sense of loss of control ccompnies these binge eting episodes (1, 2). Mood disturbnces nd behviorl dyscontrol tht includes impulsive, ggressive, nd compulsory behviors re lso common in persons with bulimi nervos, suggesting the presence of pervsive difficulties in behviorl self-regultion (2). Our previous functionl neuroimging findings in dult femle ptients with bulimi nervos suggest tht frontostritl systems tht re not engged my contribute to impired self-regultion (3). Women with bulimi nervos responded more impulsively, mking more errors thn helthy comprison subjects on the Simon sptil incomptibility tsk, which requires prticipnts to ignore tskirrelevnt feture of stimulus (e.g., the side of the screen on which n rrow ppers) when it conflicts with more tsk-relevnt feture (e.g., the direction tht the rrow is pointing). Therefore, self-regultory control is required in order to respond correctly in conflict-lden incongruent trils. During correct responses in these trils, frontostritl circuits including the inferolterl prefrontl cortex, inferior frontl gyrus, nterior cingulte cortex, putmen, nd cudte filed to ctivte to the sme extent in women with bulimi nervos s in helthy comprison subjects. In ddition, those with the most severe bulimic symptoms engged these regions the lest nd performed most poorly on the tsk. These findings suggest tht the inbility of frontostritl systems to engge ppropritely likely contributed to the origins of their binge eting nd other impulsive behviors in women with bulimi nervos. However, we could not know when dysfunction in frontostritl systems rose or how it chrcterized the erly disese process, disentngled from the effects of chronic illness. In the present rticle, we report on n event-relted functionl mgnetic resonnce imging (fmri) study in which we used modified version of the Simon tsk to investigte the neurl substrtes of self-regultory control AJP in Advnce jp.psychitryonline.org 1

2 Self-R eg u lto r y C o n tro l A n d C o n flic t R eso lu tio n In B u lim i N er v o s in femle dolescents with nd without bulimi nervos. This shorter tsk consisted of three rther thn 10 scn runs, mking it more suitble for younger prticipnts. In ddition, congruent nd incongruent stimuli ppered eqully s often, thereby eliminting potentil oddbll effects ssocited with the infrequent presenttion of incongruent stimuli nd reducing the priming effects ssocited with long repeted trils of congruent stimuli. Becuse this modified tsk is esier thn the stndrd version used in our prior study (3), we suspected tht the bulimi nervos nd helthy comprison groups would perform with similr rection times nd with few response errors on both incongruent nd congruent trils. However, we hypothesized tht similr to our findings in dults with the disorder, frontostritl regions in dolescents with bulimi nervos would not ctivte to the sme extent s in helthy dolescents during correct responses to incongruent stimuli, reflecting n inbility of these circuits to engge in the service of self-regultion nd conflict resolution. Behviorl studies of the Simon tsk suggest tht helthy individuls experience more cognitive conflict (i.e., they respond more slowly) in response to incongruent stimuli tht re preceded by congruent stimuli thn in response to incongruent stimuli tht re preceded by incongruent stimuli (4, 5). Conflict in preceding incongruent tril tends to enhnce self-regultory control in current incongruent tril, fcilitting processing nd mking responses fster nd more ccurte. Thus, the preceding stimulus context likely contributes to greter enggement of frontostritl regions needed to respond correctly in postcongruent conflict trils (6, 7). We therefore suspected tht the preceding stimulus context would contribute to group differences in brin ctivtion ssocited with correct responses to incongruent stimuli reltive to congruent stimuli. M e th o d Prticipnts Femle dolescents with bulimi nervos were recruited through flyers posted in the locl community nd dvertisements posted on Internet sites (e.g., crigslist.com nd eting disorderspecific websites) s well s through the New York Stte Psychitric Institute Eting Disorders Clinic, where some were receiving outptient tretment. Individuls receiving mediction tretment were not excluded. Helthy comprison femle dolescents were lso recruited through flyers nd Internet dvertisements. Prticipnts with bulimi nervos nd helthy comprison subjects were group-mtched by ge nd body mss index. The Institutionl Review Bord of the New York Stte Psychitric Institute pproved this study, nd ll prticipnts gve informed consent prior to study entry. The detils regrding exclusion criteri, clinicl nd behviorl ssessments, MRI pulse sequence, imge processing, behviorl nlysis, nd explortory imge nlyses re described in the dt supplement ccompnying the online version of this rticle. fmri Prdigm Stimuli were presented through nonmgnetic goggles (Resonnce Technologies, Inc., Los Angeles) using E-Prime softwre (Psychology Softwre Tools, Inc., Shrpsburg, P.). A series of white rrows pointing either left or right were displyed ginst blck bckground either to the left or right of white gze fixtion crosshir positioned t midline. Stimuli subtended 1 verticl degree nd 3.92 horizontl degrees of the visul field. Stimuli were congruent (pointing in the sme direction s their position on the screen), incongruent (pointing in direction opposite their position on the screen), or blnk ( crosshir positioned t midline). Prticipnts were instructed to respond quickly to the direction of the rrow by pressing button on response box using the index finger of their right hnd for left-pointing rrow nd the middle finger of tht hnd for right-pointing rrow. The button press recorded responses nd rection times for ech tril contining congruent or incongruent stimuli. Stimulus durtion ws 1,300 msec, with jittered interstimulus intervl (men=5,352 msec [SD=842]; rnge=4,009 6,857 msec). Ech scn run contined 55 stimuli (durtion: 5 minutes, 7 seconds), with 22 congruent stimuli (11 left-pointing rrows presented to the left of midline nd 11 right-pointing rrows presented to the right of midline), 22 incongruent stimuli (11 left-pointing rrows presented to the right of midline nd 11 right-pointing rrows presented to the left of midline), nd 11 blnk stimuli (longer periods of fixtion). These stimuli were rrnged nd presented in pseudorndom order. Ech experiment contined three scn runs, totling 66 congruent nd 66 incongruent stimuli. Imge Anlysis First-level prmetric nlyses were performed individully for ech prticipnt using modified version of the generl liner model function in SPM8 (Wellcome Deprtment of Imging Neuroscience, London [http;// Preprocessed blood-oxygen-level-dependent (BOLD) time series dt t ech voxel, conctented from ll three scn runs of the Simon tsk (420 volumes), were modeled using generl liner model, with the following five predictors corresponding to ech of the different tril types ( totl of 15 independent vribles): 1) congruent correct trils, 2) incongruent correct trils, 3) blnk trils, 4) fixtion trils, nd 5) ll incorrect trils (either congruent or incongruent). All of these events were then convolved with the cnonicl hemodynmic response function (8). For ech prticipnt, lest-squres regression ws used to estimte prmeters for ech of the 15 independent vribles. The prmeter estimtes for the three scn runs were summed to produce n incongruent correct versus congruent correct contrst for ech prticipnt tht ws used to ssess brin ctivity during the enggement of self-regultory control. Additionl plnned contrsts (incongruent correct versus blnk, incongruent correct versus fixtion, congruent correct versus blnk, nd congruent correct versus fixtion) were lso included to estblish the direction of BOLD signl ssocited with congruent nd incongruent events reltive to bseline events (blnk or fixtion trils). Becuse of the limited number of incorrect trils, contrsts involving these trils were not ssessed. Group differences in brin ctivtions were tested using second-level Byesin nlysis (9 11). We report voxels tht were identified s hving posterior probbility of 97.5%, using p- vlue threshold <25 nd cluster filter of t lest 25 djcent pixels, conjoint requirement tht, bsed on n pproximtion formul (12), yields conservtive effective p vlue tht is < The combined ppliction of sttisticl threshold nd cluster filter reduces substntilly the flse positive identifiction of ctivted pixels t ny given threshold (13). Hypothesis Testing We tested whether femle dolescents with nd without bulimi nervos differed in brin ctivity during correct responses for incongruent trils reltive to correct responses for congruent 2 jp.psychitryonline.org AJP in Advnce

3 M r sh, H o r g, W n g, Et A l. T b le 1. D e m o g r p h ic n d C lin icl C h rcte ristics o f Fe m le A d o le sce n ts W ith B u lim i N e rvo s n d A ge -M tched Fe m le H e lthy C o m p riso n Su b je cts Bulimi Nervos Adolescents (N=18) Helthy Comprison Adolescents (N=18) Anlysis Chrcteristic Men SD Men SD t df p Age (yers) Height (inches) Weight (lbs) Body mss index (kg/m 2 ) Durtion of illness (yers) Wechsler Abbrevited Scle of Intelligence IQ score Full Verbl Performnce Eting Disorders Exmintion rtings Objective bulimic episodes (pst 28 dys) Vomiting episodes (pst 28 dys) Preoccuption with body shpe nd weight HAM-D score b Children s Depression Rting Scle score BDI score Attention deficit hyperctivity disorder rtings Totl current Inttention Hyperctivity In the bulimi nervos group, three prticipnts hd history of norexi nervos (16%), four were receiving mediction tretment (22%), nd four presented with subclinicl bulimi nervos (22%); mong those presenting with subclinicl symptoms, three experienced less thn three objective binge eting episodes nd one experienced less thn three vomiting episodes per week over the pst 28 dys prior to prticiption in the study. b HAM-D scores were vilble for 12 dolescents with bulimi nervos nd nine helthy comprison subjects, nd Children s Depression Rting Scle scores were vilble for five dolescents with bulimi nervos nd five helthy comprison subjects. trils. A Byesin nlysis ws conducted to identify significnt group differences in frontostritl regions. Further detils of our explortory hypotheses re provided in the dt supplement. R e su lts Prticipnts Eighteen femle dolescents with bulimi nervos nd 18 ge-mtched helthy femle comprison subjects prticipted in the study. All prticipnts were right-hnded. The bulimi nervos group consisted of five outptients nd 13 individuls who were symptomtic but not receiving tretment. The men durtion of illness ws less thn 3 yers. Three individuls with bulimi nervos met criteri for mjor depressive disorder nd were receiving tretment with selective serotonin reuptke inhibitors, nd one ptient met criteri for ttention deficit hyperctivity disorder (ADHD) nd ws receiving tretment with methylphenidte. Additionl demogrphic nd clinicl chrcteristics of both groups re presented in Tble 1. Behviorl Performnce No significnt min effect of group or interction of group-by-stimulus type ws detected in either model, indicting tht there were no group differences specific to stimulus type; nmely, response ltency nd ccurcy scores were similr for congruent nd incongruent trils in both groups. All prticipnts demonstrted interfer- ence on the tsk (men response ltency for incongruent trils > men response ltency for congruent trils) nd, s predicted, both groups mde few errors in congruent nd incongruent trils (Tble 2). In both groups, interference ws greter following congruent trils thn incongruent trils (stimulus type-by-repetition interctions: bulimi nervos, p<01; helthy comprison, p=02 [Figure 1]), nd this interction effect did not differ significntly cross groups. Finlly, interference scores did not correlte significntly with symptom severity in the bulimi nervos group. A Priori Hypothesis N e u r l c tiv ity d u rin g co rre c t re sp o n se s. Significnt group-by-stimulus interctions tht derived from greter ctivtions in helthy comprison subjects were detected in right hemispheric frontostritl regions, including the nterior cingulte cortex (Brodmnn s re 32), dorsolterl prefrontl cortex (Brodmnn s re 9), inferior frontl gyrus (Brodmnn s re 46), nd putmen s well s the right hippocmpus (Tble 3, Figure 2). Significnt groupby-stimulus interctions tht derived from greter dectivtion in prticipnts with bulimi nervos were detected in the left inferior frontl (Brodmnn s re 46), left superior frontl (Brodmnn s re 8), nd right medil frontl (Brodmnn s re 6/8) gyri s well s in the posterior cingulte cortex (Brodmnn s re 31). Plots of the men bet AJP in Advnce jp.psychitryonline.org 3

4 Self-R eg u lto r y C o n tro l A n d C o n flic t R eso lu tio n In B u lim i N er v o s T b le 2. G ro u p D iffe re n ce s o n Pe rfo rm n ce M e su re s in Fe m le A d o le sce n ts W ith B u lim i N e rvo s n d A ge -M tched Fe m le H e lthy C o m p riso n Su b je cts Bulimi Nervos Adolescents (N=18) Helthy Comprison Adolescents (N=18) Anlysis Mesure Men SD Men SD t df p Men rection time incongruent (msec) Men rection time congruent (msec) Men rection time interference (msec) Error incongruent (%) Error congruent (%) Error effect T b le 3. Sig n ifi cn tly D iffe re n t B rin A ctiv tio n s in Fe m le A d o le sce n ts W ith B u lim i N e rvo s R e l tive to A ge -M tched Fe m le H e lthy C o m p riso n Su b je cts D u rin g R e sp o n se s to C o n g ru e n t n d In co n g ru e n t Stim u li Activted Region Side Brodmnn s Are Number of Voxels Pek Loction (x, y, z) Greter ctivtions in helthy comprison subjects men Right , 16, Hippocmpus Right , 23, Inferior frontl gyrus Right , 20, Anterior cingulte cortex Right , 53, Dorsolterl prefrontl cortex Right 9/46 1,650 20, 54, Greter dectivtions in bulimi nervos ptients Inferior frontl gyrus Left , 22, Medil frontl gyrus Right 6/ , 35, Superior frontl gyrus Left , 50, Posterior cingulte cortex Right , 52, Dt were not vilble for frontostritl nlysis in the putmen. t estimtes for congruent nd incongruent stimuli (Figure 3) reveled dectivtions reltive to bseline events in ech prticipnt in the bulimi nervos group. For prticipnts with bulimi nervos, greter dectivtion in the left inferior nd superior frontl gyri s well s the right posterior cingulte cortex ws seen in response to incongruent stimuli reltive to congruent stimuli, nd greter dectivtion in the right medil frontl gyrus ws seen in response to congruent stimuli reltive to incongruent stimuli. Explortory Anlyses C o n te x t e ffe c ts. The group differences in ctivtion (greter frontostritl ctivtion in helthy comprison subjects nd greter dectivtion of inferior nd superior prefrontl cortices bilterlly in prticipnts with bulimi nervos) derived from stimuli tht were preceded by trils displying congruent stimuli (postcongruent interference [Figure 4]), when interference effects were gretest in both groups (Figure 1). Becuse dectivtion ws seen in the posterior cingulte cortex in both groups in this contrst, no interction with group ws detected in this region. A group-bystimulus interction from stimuli tht were preceded by incongruent stimuli (postincongruent interference [Figure 4]) ws detected in the right posterior putmen nd derived from greter ctivtion in helthy comprison subjects. In ddition, group differences in prefrontl regions were driven by postcongruent interference effects in the bulimi nervos group (significnt group-by-preceding- by-current stimulus interctions in the right inferolterl nd dorsolterl prefrontl cortices nd in the bilterl superior frontl gyri [see Figure 1 in the dt supplement]). Finlly, group-by-stimulus interction from congruent stimuli preceded by incongruent stimuli compred with congruent stimuli preceded by congruent stimuli ws detected in the superior frontl gyrus nd derived from greter dectivtion in prticipnts with bulimi nervos (see Figure 2 in the dt supplement). C o rre l tio n s w ith sy m p to m se v e rity. Nonprmetric nlyses reveled tht the number of objective bulimic nd vomiting episodes in the bulimi nervos group correlted inversely with postcongruent brin ctivity in the left inferior frontl gyrus nd bilterl precuneus (Figure 5). As shown in Figure 5, sctterplots of these correltions indicted tht in response to postcongruent interference, the inferior frontl gyrus nd precuneus were dectivted the most mong symptomtic prticipnts. The number of bulimic episodes nd rtings of preoccuption with body shpe nd weight correlted inversely with postcongruent conflict ctivity in the right putmen, indicting tht this subcorticl region ws engged the lest mong the most preoccupied dolescents. Postincongruent conflict ctivity correlted positively with bulimic nd vomiting episodes in the left superior frontl gyrus nd with bulimic episodes in the left insul nd right nterior cingulte cortex. Those with more severe symptoms showed 4 jp.psychitryonline.org AJP in Advnce

5 M r sh, H o r g, W n g, Et A l. Fig u r e 1. R e sp o n se Tim e s A m o n g Fe m le A d o le sce n ts W ith B u lim i N e rvo s R e l tive to A ge -M tched Fe m le H e lthy C o m p riso n Su b je cts o n th e Sim o n Sp til In co m - p tib ility Tsk Helthy Comprison Fig u r e 2. G ro u p A ve r ge B rin A ctiv tio n s D u rin g C o rre ct Trils A m o n g Fe m le A d o le sce n ts W ith B u lim i N e rvo s R e l tive to A ge -M tched Fe m le H e lthy C o m p riso n Su b - je cts HC > BN HC BN 680 Response Time (msec) Congruent Incongruent Preceding Tril Hi GP Hi GP Thl Bulimi Nervos Response Time (msec) DLPFC DLPFC 580 Congruent Incongruent Preceding Tril Current tril displying congruent stimulus Current tril displying incongruent stimulus Response times re depicted s function of preceding nd current tril stimulus type (congruent, incongruent). MFG MFG the most ctivtion in these regions, which is consistent with the postincongruent ctivtion of corticl portions of frontostritl circuits in the bulimi group (Figure 4). M e d ic tio n n d co m o rb id ity e ffe c ts. A comprison of group verge ctivtion mps for only those bulimi nervos prticipnts who were not receiving mediction tretment with mp for helthy comprison subjects suggested tht mediction did not contribute to our findings. Likewise, history of norexi nervos, depressive, or ADHD symptoms were not ssocited with group differences in brin ctivtions (see Figure 3 nd Figure 4 in the dt supplement). D iscu ssio n Adolescents with nd without bulimi nervos performed similrly on rpid version of the Simon tsk. Both groups responded more slowly to incongruent stim- PCC p<01 p<25 p<01 The imges depict xil slices positioned inferiorly to superiorly (top to bottom). Group-by-stimulus (congruent versus incongruent) interctions (left) were detected in frontostritl regions (red). Min effects of stimulus condition (congruent versus incongruent) re shown for helthy (center) nd bulimi nervos (right) dolescents. Increses in signl during correct incongruent reltive to correct congruent trils re shown in red, nd decreses re shown in blue. Abbrevitions: HC=helthy comprison; BN=bulimi nervos; =nterior cingulte cortex; DLPFC=dorsolterl prefrontl cortex; Hi=hippocmpus; =inferior frontl gyrus; =putmen; GP=globus pllidus; Thl=thlmus; =superior frontl gyrus; PCC=posterior cingulte cortex; MFG=medil frontl gyrus. AJP in Advnce jp.psychitryonline.org 5

6 S e l f -R e g u l to r y C o n t r o l A n d C o n f l ic t R e s o lu t io n In B u l imi N e r v o s DLPFC PCC MFG HC>BN BN HC Fig u r e 3. R e g io n -o f-in te re st A n ly sis in F e m le A d o le sc e n ts W ith B u lim i N e rv o s R e l tiv e to A g e -M tc h e d F e m le H e lth y C o m p riso n S u b je c ts HC BN The mp of group-by-stimulus interctions is displyed gin (s in Figure 2), long with plots of the men bet estimtes for congruent nd incongruent stimuli for ech region, plotted seprtely for the bulimi nervos nd helthy comprison groups. Error brs indicte stndrd error of the men. The right side of the imge shows the right lterlized frontostritl regions tht were more ctive during correct responses to incongruent versus congruent stimuli in helthy comprison subjects thn in dolescents with bulimi nervos. The left side of the imge shows the regions in which dectivtion ssocited with responses to incongruent stimuli (left inferior frontl gyrus [], left superior frontl gyrus [], nd right posterior cingulte cortex [PCC]) nd congruent stimuli (right ) were greter in dolescents with bulimi nervos reltive to helthy comprison subjects. Abbrevitions: HC=helthy comprison; BN=bulimi nervos; =nterior cingulte cortex; DLPFC=dorsolterl prefrontl cortex; Hi=hippocmpus; =putmen; GP=globus pllidus; Thl=thlmus; MFG=medil frontl gyrus. uli reltive to congruent stimuli nd mde few errors on the tsk (Figure 6). Nevertheless, prticipnts with bulimi nervos did not demonstrte the sme mgnitude of neurl ctivity s helthy comprison subjects in the frontostritl systems known to subserve self-regultory control, including the right inferior frontl gyrus, dorsolterl prefrontl cortex, nd putmen. These findings re consistent with our prior fmri findings in dult femle ptients (3). We previously speculted tht the inbility of women with bulimi nervos to engge these systems my excerbte nd interfere with their bility to resolve their conflicting desires to consume fttening foods nd void weight gin. This inbility my lso contribute to their difficulty regulting binge-type eting nd other impulsive behviors. Our findings in dolescents with bulimi nervos suggest tht the inbility to engge frontostritl systems to 6 jp.psychitryonline.org resolve conflict nd regulte behviors my rise erly in the course of the illness. When responding correctly to incongruent stimuli compred with congruent stimuli, dectivtion ws seen in the left inferior frontl gyrus s well s neurl system encompssing the posterior cingulte cortex nd superior frontl gyrus in dolescents with bulimi nervos. The posterior cingulte cortex is mjor node of the defultmode network of brin res tht ctivte when individuls re engged in internlly driven thoughts nd decrese in ctivity when ttention is directed to tsk (14). The superior frontl gyrus is lso prt of this network (15), nd recent findings suggest tht the posterior cingulte cortex nd superior frontl gyrus re functionlly connected to the medil nd inferior frontl gyri (16). Dectivtion of ll of these brin res in response to the presenttion of AJP in Advnce

7 M r sh, H o r g, W n g, Et A l. Fig u r e 4. C o n te xt Effe cts in Fe m le A d o le sce n ts W ith B u lim i N e rvo s R e l tive to A ge -M tched Fe m le H e lthy C o m p riso n Su b je cts Postcongruent Interference Postincongruent Interference A. HC > BN B. HC C. BN D. HC > BN E. HC F. BN PCC DLPFC DLPFC PCC PCC MFG MFG p<01 p<25 p<01 Posterior probbility mps depict the group verge brin ctivity ssocited with the processing nd resolution of cognitive interference. Postcongruent interference=ctivtion contrst between incongruent nd congruent stimuli in tril following congruent tril; Postincongruent interference=ctivtion contrst between incongruent nd congruent stimuli in tril following n incongruent tril. Column A shows group-by-stimulus (congruent versus incongruent) interctions nd min effects of stimulus following congruent trils in helthy comprison subjects (column B) nd bulimi nervos prticipnts (column C). Column D shows group-by-stimulus interctions nd min effect s of stimulus following incongruent trils in helthy comprison subjects (column E) nd bulimi nervos prticipnts (column F). For ll current trils (columns A F), increses in signl during incongruent reltive to congruent trils re shown in red; decreses re shown in blue. Abbrevitions: HC=helthy comprison; BN=bulimi nervos; ILPFC=inferolterl prefrontl cortex; DLPFC=dorsolterl prefrontl cortex; =inferior frontl gyrus; =superior frontl gyrus; PCC=posterior cingulte cortex; MFG=medil frontl gyrus; =putmen. both congruent nd incongruent stimuli ws observed in dolescents with bulimi nervos, perhps suggesting tht they my hve been ttending to internlly driven thoughts, such s thoughts bout eting or body imge tht preoccupy individuls with eting disorders. Our nlyses suggest tht functionl bnormlities in frontostritl nd defult-mode systems in femle dolescents with bulimi nervos derived from ltered processing of cognitive interference, which depended on the presence or bsence of ntecedent conflict, nd were prticulrly driven by bnorml processing of cognitive interference tht followed congruent stimuli, when interfer- ence effects were gretest in both the bulimi nervos nd helthy comprison groups (postcongruent interference: incongruent preceded by congruent-congruent preceded by congruent contrst [Tble 4, Figure 1]). In this contrst, dectivtion in the inferior nd superior prefrontl cortices ws seen in femle dolescents with bulimi nervos, wheres ctivtion in the right frontostritl regions including the inferior nd dorsl prefrontl cortex nd putmen ws seen in helthy femle dolescents (Figure 4). Dectivtion in the posterior cingulte cortex in response to postcongruent interference ws found in both groups, but dectivtion in the posterior cingulte cortex AJP in Advnce jp.psychitryonline.org 7

8 Self-R eg u lto r y C o n tro l A n d C o n flic t R eso lu tio n In B u lim i N er v o s Fig u r e 5. M in Effe cts o f Sy m p to m Se ve rity in Fe m le A d o le sce n ts W ith B u lim i N e rvo s Postcongruent Interference Postincongruent Interference A. OBEs B. Vomiting C. Preocc. D. OBEs E. Vomiting F. Preocc. Thl Ins Pcu p<01 p<25 p< Precuneus ci cc 0 5 ci cc OBEs OBEs men ci cc OBEs Inverse correltions of the mgnitude of ctivtion during correct responding to postcongruent interference (incongruent preceded by congruent-congruent preceded by congruent contrst) with A) the number of objective bulimic episodes (OBEs), B) the number of vomiting episodes, nd C) rtings of preoccuption with body shpe nd weight (from the Eting Disorders Exmintion) re shown. Positive correltions (red) of the mgnitude of ctivtion during correct responding to postincongruent interference (incongruent preceded by incongruentcongruent preceded by incongruent contrst) with D) the number of OBEs, E) the number of vomiting episodes, nd F) rtings of preoccuption with body shpe nd weight re lso shown G). Sctterplots of the ssocitions of OBEs with postcongruent interference ctivity re depicted. Abbrevitions: Preocc=preoccuption rtings; MPFC=medil prefrontl cortex; =inferior frontl gyrus; =superior frontl gyrus; Ins=Insul; Cd=cudte nucleus. nd medil nd superior frontl gyri in response to both congruent nd incongruent stimuli ws seen in the bulimi nervos group (Figure 3). In ddition, greter dectivtion in these corticl regions indicted greter severity of symptoms, suggesting tht corticl dectivtion in the bulimi nervos group my hve represented the intrusion of self-referentil nd illness-relted thoughts when processing interference in the bsence of prior conflict. Dectivtion in the bulimi nervos group of the superior frontl gyrus nd posterior cingulte cortex in response to congruent stimuli tht were preceded by incongruent stimuli reltive to congruent stimuli (congruent preceded by incongruent-congruent preceded by congruent contrst [see Figure 2 in the dt supplement]) suggests tht dectivtion of these defult-mode regions ws specific to the nteceding conflict-lden context rther thn current conflict. This finding further emphsizes the contextul origins of the group differences in this network. 8 jp.psychitryonline.org AJP in Advnce

9 M r sh, H o r g, W n g, Et A l. Fig u r e 6. P ro ce ssin g o f C o n g ru e n t n d In co n g ru e n t Stim u li o n th e Sim o n Sp til In co m p tib ility Tsk A m o n g Fe m le A d o le sce n ts W ith B u lim i N e rvo s R e l tive to A ge -M tched Fe m le H e lthy C o m p riso n Su b je cts Helthy Adolescents Adolescents with Bulimi Nervos < + Incongruent < Congruent + Time (msec) T b le 4. Sig n ifi cn tly D iffe re n t B rin A ctiv tio n s in Fe m le A d o le sce n ts W ith B u lim i N e rvo s R e l tive to A ge -M tched Fe m le H e lthy C o m p riso n Su b je cts D u rin g C o rre ct R e sp o n se s to In co n g ru e n t Stim u li b y P re ce d in g Tril Stim u lu s Ty p e Activted Region Side Brodmnn s Are Number of Voxels Pek Loction (x, y, z) Postcongruent interference b Greter ctivtions in helthy comprison subjects Inferior frontl gyrus Right , 20, Dorsolterl prefrontl cortex Right 9/ , 52, Greter dectivtions in bulimi nervos ptients Inferior frontl gyrus Left , 21, Medil frontl gyrus Right 6/ , 18, Postincongruent interference c Greter ctivtions in helthy comprison subjects Posterior putmen Right , 16, Dt were not vilble for frontostritl nlysis in the putmen. b Activtion contrst between incongruent nd congruent stimuli in tril following congruent tril. c Activtion contrst between incongruent nd congruent stimuli in tril following n incongruent tril. t The number of objective bulimic nd vomiting episodes correlted inversely with ctivity ssocited with postcongruent interference in the left inferior frontl gyrus, region tht ws dectivted in response to incongruent stimuli in the bulimi nervos group. The number of bulimic episodes nd rtings of preoccuption with body shpe nd weight lso correlted inversely with postcongruent interference in the right putmen. Thus, in the bulimi nervos group, dectivtion in the inferior frontl gyrus ws seen the most nd ctivtion in the subcorticl portions of frontostritl circuits ws seen the lest when responding to postcongruent interference, consistent with our prior findings tht frontostritl ctivtion correlted with symptom severity in dult femle ptients with bulimi nervos (3). The tsk used in our previous study consisted of more congruent trils thn incongruent trils, nd thus the nlysis of interference effects (incongruent versus congruent comprison) in tht study ws most similr to the postcongruent interference contrst in the present study. Group differences in subcorticl ctivtions were driven by the differentil processing of cognitive interference following incongruent stimuli (incongruent preceded by in- congruent-congruent preceded by incongruent contrst [Tble 4]), which is the contrst tht produced the lest interference in both groups. Activtion in the frontostritl regions in this condition ws observed in both groups (i.e., postincongruent interference), but ctivtion in the subcorticl portions of these circuits ws seen in the helthy comprison group more thn the bulimi nervos group, suggesting tht the helthy subjects relied more on n utomtic response tendency bsed within the stritum (17) when responding to repeted conflict over successive trils nd tht this dptive hbitul responding my be deficient in dolescents with bulimi nervos. These differentil ptterns of brin ctivtion when resolving cognitive interference following congruent or incongruent stimuli, respectively, contributed to the overll group differences in our primry nlyses of corticl nd subcorticl brin ctivtion in processing cognitive interference tht we detected for nlyses of ll trils, regrdless of the presence or bsence of ntecedent conflict (Figure 2). Our findings suggest tht frontostritl functioning is impired in bulimi nervos erly in the course of illness. When engging the self-regultory control processes AJP in Advnce jp.psychitryonline.org 9

10 Self-R eg u lto r y C o n tro l A n d C o n flic t R eso lu tio n In B u lim i N er v o s necessry to resolve cognitive interference nd respond correctly in incongruent trils, dolescents with bulimi nervos did not disply norml ptterns of ctivtion in frontostritl circuits or dectivtion in defult-mode systems. Abnorml processing of the ntecedent stimulus context conditioned their brin responses to conflict differently, prticulrly in frontl regions when preceding stimuli were congruent nd conflict-free. Given tht the bulimi nervos nd helthy comprison groups performed similrly on the tsk nd tht our nlyses were limited to ctivtions ssocited with correct responses, these differences in brin ctivtion did not derive from performnce differences nd insted represented functionl disturbnces in neurl systems tht subserve selfregultion nd the resolution of interference. The Simon tsk used in this study differed from the longer version of the tsk used in our prior study of dults with bulimi nervos (3). Congruent nd incongruent stimuli ppered eqully s often using the shorter version, thereby mking it esier to inhibit the prepotent response tendency, nd s hypothesized, the groups performed similrly on the tsk. In ddition, context effects could be ssessed with this tsk design, contributing to our dditionl finding tht bnorml contextul processing likely ffects the neurl processing of conflict in dolescents with bulimi nervos. These findings of impired frontostritl functioning my inform clinicl prctice, suggesting tht strtegies for improving self-regultory control nd conflict resolution through cognitive remedition therpy my be promising tretment for bulimi nervos in dolescents. A limittion of this study ws the bsence of comprison group consisting of impulsive individuls with norml weight nd eting behviors, which would permit ssessment of the specificity of frontostritl bnormlities in dolescents with bulimi nervos. Other limittions were the modest smple size nd presence of comorbid illnesses in prticipnts with bulimi nervos, some of whom were receiving mediction tretment. In ddition, prticipnts hd vrying symptom severities, nd individuls with fullnd prtil-syndrome bulimi were included. However, given tht subthreshold eting disorders re most prevlent mong dolescents (18), our smple represented well the generl popultion of dolescents with bulimi nervos. Moreover, our inclusion criteri were consistent with the lower nd more developmentlly sensitive thresholds tht re more pproprite for dolescents nd tht hve been proposed for DSM-5 (19). Nevertheless, future studies should include lrger smples of dolescents with bulimi nervos nd ssess chnges in the functioning of frontostritl nd defult-mode systems in the sme prticipnts over time to understnd whether disturbnces in these systems my contribute to the development nd progression of the illness. Received Jn. 18, 2011; revision received Mrch 3, 2011; ccepted Mrch 17, 2011 (doi: /ppi.jp ). From the Division of Child nd Adolescent Psychitry, Deprtment of Psychitry, New York Stte Psychitric Institute nd the College of Physicins nd Surgeons, Columbi University, New York; the Eting Disorders Reserch Unit, Deprtment of Psychitry, New York Stte Psychitric Institute nd the College of Physicins nd Surgeons, Columbi University, New York. Address correspondence to Dr. Mrsh (MrshR@ childpsych.columbi.edu). Dr. Wlsh hs received reserch support from AstrZenec. Dr. Peterson hs received reserch support from the Ntionl Institute of Mentl Helth s principl investigtor for grnts 1 K02 MH , 2T32 MH , nd MH nd s co-investigtor for grnt 2R01MH nd co-principl investigtor for grnt MH ; he hs lso received reserch support s principl investigtor for the Simons Foundtion Simons Simplex Fmily Resource; he hs received reserch support from the Ntionl Institute of Environmentl Helth Sciences s co-investigtor for grnt RO1 ES nd from the Ntionl Institute on Drug Abuse s co-principl investigtor for grnt R01DA027100; nd he hs received reserch support s principl investigtor for NARSAD Distinguished Investigtor Awrd. All other uthors report no finncil reltionships with commercil interests. R e fe re n ce s 1. Wlsh BT, Klein DA: Eting disorders. Int Rev Psychitry 2003; 15: Kye W, Strober M, Jimerson DC: The neurobiology of eting disorders, in The Neurobiology of Mentl Illness. Edited by Chrney D, Nestler EJ. New York, Oxford University Press, 2004, pp Mrsh R, Steinglss JE, Gerber AJ, O Lery KG, Wlsh BT, Peterson BS: Deficient ctivity in the neurl systems tht medite self-regultory control in bulimi nervos. Arch Gen Psychitry 2009; 66: W ühr P, Ansorge U: Exploring tril-by-tril modultions of the Simon effect. Q J Exp Psychol A 2005; 58: Sturmer B, Leuthold H, Soetens E, Schroter H, Sommer W: Control over loction-bsed response ctivtion in the Simon tsk: behviorl nd electrophysiologicl evidence. J Exp Psychol Hum Percept Perform 2002; 28: Botvinick M, Nystrom LE, Fissell K, Crter CS, Cohen JD: Conflict monitoring versus selection-for-ction in nterior cingulte cortex. Nture 1999; 402: Kerns JG, Cohen JD, McDonld AW 3rd, Cho RY, Stenger VA, Crter CS: Anterior cingulte conflict monitoring nd djustments in control. 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11 M r sh, H o r g, W n g, Et A l. 16. Grigg O, Grdy CL: The defult network nd processing of personlly relevnt informtion: converging evidence from tskrelted modultions nd functionl connectivity. Neuropsychologi 2010; 48: Pckrd MG, Knowlton BJ: Lerning nd memory functions of the bsl gngli. Annu Rev Neurosci 2002; 25: Stice E, Mrti CN, Shw H, Jconis M: An 8-yer longitudinl study of the nturl history of threshold, subthreshold, nd prtil eting disorders from community smple of dolescents. J Abnorm Psychol 2009; 118: Brvender T, Brynt-Wugh R, Herzog D, Ktzmn D, Kriepe RD, Lsk B, Le Grnge D, Lock J, Loeb KL, Mrcus MD, Mdden S, Nicholls D, O Toole J, Pinhs L, Rome E, Sokol-Burger M, Wllin U, Zucker N; Workgroup for Clssifiction of Eting Disorders in Children nd Adolescents: Clssifiction of eting disturbnce in children nd dolescents: proposed chnges for the DSM-V. Eur Et Disord Rev 2010; 18:79 89 AJP in Advnce jp.psychitryonline.org 11