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NEW RESEARCH|
Reward Processing in AdolescentsWith Bipolar I Disorder
Manpreet K. Singh, M.D., Kiki D. Chang, M.D., Ryan G. Kelley, B.S., Xu Cui, Ph.D.,Lindsey Sherdell, M.A., Meghan E. Howe, L.C.S.W., Ian H. Gotlib, Ph.D., Allan L. Reiss, M.D.
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Objective: Bipolar disorder (BD) is a debilitating psychiatric condition that commonly begins inadolescence, a developmental period that has been associated with increased reward seeking.Because youth with BD are especially vulnerable to negative risk-taking behaviors, under-standing the neural mechanisms by which dysregulated affect interacts with the neurobeha-vioral processing of reward is clearly important. One way to clarify how manic symptomsevolve in BD is to ‘‘prime’’ the affect before presenting rewarding stimuli. The objective of thisstudy was to investigate the neural effects of an affective priming task designed to positivelyinduce mood before reward processing in adolescents with and without BD. Method: Neuralactivity and behaviors during the anticipation of and response to monetary reward and loss afteran affective prime were compared using functional magnetic resonance imaging in 13- to 18-year-old adolescents with a recent onset of BD-I (n¼ 24) and demographically matched healthycomparison youth (n ¼ 24). Results: Compared with the healthy control youth, youth withBD had speeded reaction times and showed decreased activation in the thalamus and inferiortemporal gyrus while anticipating gains after priming but increased activations in the middlefrontal gyrus and parietal cortices while anticipating losses after priming. Youth with BD alsoshowed less activation in the inferior parietal lobule, thalamus, and superior frontal gyrus whilereceiving losses after priming. Conclusions: Aberrant prefrontal and subcortical activationsduring reward processing suggest mechanisms that may underlie disordered self-awarenessduring goal pursuit and motivation in BD. Longitudinal studies are needed to examine whetherthis pattern of neural activation predicts a poorer long-term outcome. J. Am. Acad. ChildAdolesc. Psychiatry; 2012;52(1):68–83. Key Words: reward processing, functional magneticresonance imaging, adolescent, bipolar disorder, affective prime
B ipolar disorder (BD) is a debilitating, recur-rent psychiatric condition with an onsettypically during adolescence,1 a develop-
mental period that has been associated withincreased risk-taking and reward-seeking.2 Clini-cally, BD is characterized by aberrations in emo-tion and motivation that may lead to risk-takingbehaviors that have maladaptive consequences.Specifically, individuals with BD experiencehyperhedonia (e.g., excessive pleasure-seekingand goal-directed activity) during manic statesand anhedonia (i.e., decreased pleasure inresponse to hedonic stimuli or experiences)
ical guidance is available at the end of this article.
article is discussed in an editorial by Dr. Tonya J.H. White one 9.
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during depressive episodes.3 These disturbancesin core emotional and motivational functionsmay provide a basis for understanding theorigins of symptom manifestations associatedwith BD. Surprisingly, however, few studies haveexamined the precise nature of, and neuralaspects associated with, these aberrations,particularly in adolescents with BD who aretemporally close to the onset of illness and,consequently, are likely to be symptomatic atthe time of assessment and to have minimallifetime exposure to psychotropic medicationsor many previous mood episodes.
Studies to date have examined different aspectsof reward processing in individuals with BD,including responses to various types of positivestimuli (e.g., money, faces), affective responsesto rewards, and aspects of decision making
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REWARD PROCESSING IN ADOLESCENT BD
(e.g., reversal learning) or judgments, whichtarget similar regions of the brain. These studieshave found that adults4 and youth5,6 with BDhave decreased reward learning, even when theyare euthymic.4 However, happy mood states canbe induced in euthymic adults with BD while theyare engaging in a reward paradigm, suggestingpotentially important interactions between cog-nitive and emotional responses to rewardingstimuli.7 Other investigators have found thatyouth with BD compared with typically develop-ing controls report increased reward reactivityand greater arousal in reward conditions8 andgreater satisfaction with winning.9 The first offour neuroimaging studies examining rewardprocessing in BD used a monetary incentive delay(MID) task in acutely manic and medicated adultswith BD.10 In this study, adults with BD did notactivate the ventral tegmentum as did healthy andschizophrenic comparison adults while anticipat-ing high versus no reward outcomes and had alower differential signal in the nucleus accumbens(NAcc) upon receipt of rewards compared withhealthy control subjects. In the second study,adults with mania did not differ from healthycontrols in the ventral striatal response to cuedincentives.11 However, adults with mania didshow significant increases in activation in the leftlateral orbitofrontal cortex (Brodmann areas [BAs]11 and 47) while anticipating increasing gains anddecreased activation in this region during anexpectation of increasing loss, whereas healthysubjects tended to show the opposite effect. In athird study that used a card-guessing paradigm,whole-brain analyses found adults with BD tohave increased left-sided lateral orbitofrontalactivation during reward anticipation. Region-of-interest (ROI) analyses in this study showedthat adults with BD compared with healthycontrols exhibited greater ventral striatal andright-sided orbitofrontal (BA 11) activity duringthe anticipation, but not during the outcome,of monetary reward.12 A recent study relatedincreased activity in the amygdala and theorbitofrontal cortex to heightened sensitivityin response to reward and reward reversal andto deficient prediction error signaling in indi-viduals with BD and their relatives.13 Thesestudies highlight the aberrant neural function-ing in BD that may be related to an increasedmotivation for seeking rewards and to an under-estimation of associated risks and potentialpunishments.
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It is not clear, however, whether these patternsof behavioral and neural functioning reflect adevelopmental process typical of adolescentsversus adults, play an etiologic role in BD, orare a consequence of chronic exposure to multiplemood episodes or psychotropic medications.Moreover, neither the specific neural features thatare associated with aberrant reward processing inadolescents nor the mechanisms by which rewardprocessing interacts with mood state are currentlyknown. In addition, findings across studies areinconsistent, showing different regions and oppo-site directions of activations during gain and lossconditions, possibly due to type I error or smallsamples. Therefore, to gain a better understandingof the precise nature and origins of the aberrantemotion and motivation associated with BD, it isimportant to compare neural correlates of rewardprocessing in a large sample of typically developingadolescents and youth who are close to the onset oftheir first manic episode, to experimentally manip-ulate mood state while participants are processingrewards by priming their affect before the presen-tation of rewarding stimuli, and to model analysesto explore the regions and directions of neuralactivations associated with reward (gain) versusrisk (loss). Such an approach would advanceresearchers’ understanding of the neural basis ofhow dysregulated mood might lead to the intensi-fication of goal pursuit and motivation in BD.
The first aim of the present study was to examineneural activations associated with reward proces-sing after an affective prime by scanning adolescentswith BD-I who experienced only a single episode ofmania in their lifetime. Because the authors wereinterested in the interaction of cognitive and emo-tional processes in BD, they predicted that com-pared with healthy control (HC) youth, youth withBD would exhibit significant aberrations in frontos-triatal activation associated with the MID task thatwould be more pronounced when the task waspreceded by an affective prime, which the authorsposited would intensify emotional and neuralresponses to rewarding stimuli (similar to the effectsof a positive mood induction7) than when it waspreceded by a nonaffective control task. Drawing onprevious reports showing differential brain functionand behavior during anticipation and receipt ofrewards versus punishments in adults with BD,10–13
the second aim was to explore neural activations asa function of the interaction of group and primewithin gain and loss conditions separately. In thesesecondary analyses, the authors predicted that
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SINGH et al.
compared with HC participants, adolescents withBD would exhibit increased activation in the ventralstriatum (i.e., NAcc) and orbitofrontal cortex (inclu-sive of BA 10, 11, or 47) while anticipating gains onthe MID task and increased activation in theamygdala while receiving gains. They also pre-dicted that while anticipating and receiving losses,youth with BD would show decreased activa-tion in the ventral striatum and orbitofrontalcortex but not in the amygdala. Third, given thelikely relation between symptoms of dysregu-lated motivation in mania and reward proces-sing, the authors predicted that the manic moodstate would intensify emotional and neuralresponses such that those participants withhigher levels of mania on the day of scanningwould show relatively greater activations in theorbitofrontal and striatal regions during rewardanticipation and receipt and lower orbitofrontaland striatal activations during the anticipationand receipt of losses.
METHODParticipants
The university panel of medical research in humansubjects approved this research protocol. After hearing acomplete description of the study, parents and youthyounger than 18 years gave written informed consentand assent, respectively. Adolescents (13–18 years old)with BD-I (n ¼ 24) diagnosed as having their first manicepisode within the previous 12 months (mean intervalfrom the onset of mania to the scan ¼ 5 months) wererecruited by referral to a pediatric BD clinic or from thesurrounding community. HC adolescents (n ¼ 24)without any personal or family history of psychiatricdiagnoses or psychotropic medication exposure wererecruited through local community advertisements. Atelephone screening with a parent established that allparticipants had English fluency and did not have anymetal in their body, a history of head injury (with loss ofconsciousness 45 minutes), seizures, or developmentaldisorders. Youth with BD who were prescribed stimu-lants did not take them 24 hours before neuroimagingand were required to not have used recreational drugs forat least 30 days before the magnetic resonance imaging(MRI) scan. To avoid the risk of mood destabilization,subjects with BD were allowed to continue any otherpsychotropic medications, including mood stabilizers,atypical antipsychotics, or antidepressants.
Diagnostic and Clinical AssessmentsAll participants were evaluated for current and
lifetime psychiatric disorders using the WashingtonUniversity in St. Louis Schedule for Affective Disorders
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and Schizophrenia14 for affective disorders and theSchedule for Affective Disorders and SchizophreniaPresent and Lifetime version15 for other psychopathology,which were administered separately to parents andchildren by the interviewers, with established symptomand diagnostic inter-rater reliability (k 40.9). A manicepisode was defined by DSM-IV-TR criteria, lasted at least1 week, and could not have been precipitated by exposureto recreational drugs, antidepressants, psychostimulants,or other medications or medical conditions. Symptomseverity was assessed on the day of scan using the YoungMania Rating Scale (YMRS),16 the Children’s DepressionRating Scale–Revised Version,17 and the Childhood Glo-bal Assessment Scale18 by raters with established reli-abilities (intra-rater intercorrelation coefficients 40.9).Active symptoms on the day of scanning were summar-ized for the imaging analyses using the following cutoffs:a YMRS score higher than 20 for active manic symptomsand a Children’s Depression Rating Scale score higherthan 40 for active depression. All participants completedthe Barratt Impulsiveness Scale 11, which yielded sub-scale scores on the dimensions of attentional, motor, andnonplanning trait impulsivity.19 Age, sex, socioeconomicstatus (Hollingshead Four Factor Index),20 pubertal stage(Pubertal Development Scale),21 IQ (Wechsler Abbre-viated Scale of Intelligence),22 and handedness (CrovitzHandedness Questionnaire)23 were also assessed.
MID TaskAll participants practiced and were tested for their
comprehension of explicit cues presented in the MIDtask.24 They were shown cash that they could win duringthe task before entering the scanner. The MID task wasdesigned to probe neural responses to the anticipationand receipt of gain and loss outcomes by using a set ofcues to indicate whether the participants could win oravoid losing money if they responded quickly enough toa target (represented by a triangle) that followed a cueand anticipation period. In each trial the participantswere presented with a cue indicating that they had achance to win or lose $0, $1, or $2. Circle cues indicatedtrials with the opportunity to win money, square cuesindicated trials when money could be lost, and lineswithin those shapes defined the amount of moneypresented for that trial. Immediately after each trial,the participants were shown feedback (how much moneythey won or lost on that trial and a running total).
Each of these six trial types appeared nine times for6 seconds and was pseudorandomly distributed, for atotal of 54 trials per run (approximately 6 minutes � 2runs). Cues were displayed for 250 ms, followed by ajittered anticipatory period (2,000–2,500 ms). The targetwas displayed for different durations (250–350 ms)determined from reaction times collected during apractice session before scanning and set such that theparticipants would succeed on approximately 66% oftheir target responses. A jittered delay period separated
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REWARD PROCESSING IN ADOLESCENT BD
the offset of the target stimulus from the onset of thefeedback stimulus, so that the length of the entire trial wasexactly 6 seconds. After the scan, participants wereretested on their comprehension of the cues.
Affective Priming TaskTo examine the interaction between emotion and
motivation, and because participants with BD were indifferent mood states on the day of their scan, a newfunctional MRI (fMRI) task was designed to experi-mentally induce an elevated state of arousal in allparticipants. Positive mood inductions during rewardprocessing have been described previously in adultswith BD7 and provide a relevant context for thisapproach; however, in the present study, the moodinduction could yield a positive or negative affect. Tworuns of the MID task, with each run preceded by cardgames using a traditional 52-card deck, were designed toenhance engagement, motivation, confidence, and driveto perform in the MID task. Using a button box, theparticipants were instructed to press a button corre-sponding to one of four card piles that would move a cardof adjacent value to a deposit pile, creating a sequence.Two versions of the card game were presented to theparticipants in each group in counterbalanced order: inone version (affective priming), they played against thecomputer and, during the last minute of the game, weregiven feedback that they had won the game; in the otherversion (control task), the participants played by them-selves without any feedback (Figure 1). The participantsrated their levels of happiness, distraction, excitement,
FIGURE 1 Experimental paradigm of tasks presented duringtask or the affective priming task was counterbalanced to prec
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anxiety, and confidence about winning money in thesubsequent MID task (1 ¼ not at all, 2 ¼ somewhat, 3 ¼very, 4 ¼ extremely) at the beginning and end of eachcard game.
MRI Data Collection and PreprocessingAfter being trained on the fMRI tasks and desen-
sitized to the scanning environment by an MRIsimulator, imaging-related procedures were performedusing a 3-T Signa Excite scanner (GE Medical Systems,Milwaukee WI) equipped with echo-speed gradientsusing a standard whole-head coil (General Electric,Milwaukee, WI) and high-resolution, T1-weighted,spoiled Gradient Recall Acquisition in Steady State(GRASS) images. Functional images were collectedwith a T2*-weighted spiral pulse sequence with arecovery time of 2,000 ms, an echo time of 30 ms, aflip angle of 801, a field of view of 22 cm, a matrix of64 � 64, a voxel size of 3.4375 � 3.4375 mm, and a slicethickness of 4 mm with 1-mm spacing. An automatedhigh-order shimming method was used before acquir-ing fMRI data to decrease field inhomogeneities.Structural images were collected to aid in the localiza-tion of the functional data using high-resolution, T1-weighted, spoiled gradient-recalled acquisition, three-dimensional MRI sequences with a recovery time of6.4 ms, an echo time of 2.0 ms, an inversion recoverypreparation pulse of 300 ms, a flip angle of 151, a field ofview of 22 cm, a matrix of 256 � 256, three excitations,124 slices in the coronal plane, and 1.5-mm slice thick-ness. Seven participants (six with BD and one HC youth)
functional magnetic resonance imaging. Note: The controlede two runs of the monetary incentive delay paradigm.
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SINGH et al.
originally recruited were excluded from analysis owingto motion artifacts or poor behavioral performance,resulting in a sample size of 24 per group.
Functional images were processed with SPM 8(Wellcome Department of Cognitive Neurology, London,United Kingdom), including realignment, slice timecorrection, coregistration, normalization into MontrealNeurological Institute (MNI) space with 2-mm voxelresampling, and spatial smoothing. Images wererepaired by interpolation from the nearest unaffectedvolumes using the ArtRepair software toolbox for SPM(http://cibsr.stanford.edu/tools/methods/artrepair-software.html) if the motion exceeded a 0.5-mm/recov-ery time threshold or if the global signal was greater than3% from the mean global signal of all images. Data werecoregistered and spatially normalized into standardstereotactic space using an adolescent template(https://irc.cchmc.org/software/pedbrain.php). Nor-malized images were then smoothed with a 7-mm full-width half-maximum Gaussian filter.
Statistical AnalysisReaction time and accuracy were recorded for
each trial of the MID task. Three-way (group [BD, HC]repeated over priming condition [prime, control] andvalence [gain, loss]) analyses of variance (ANOVAs)were conducted on individual hit rates, mean reactiontimes, and total money gained across anticipation andfeedback conditions. These were followed by two-wayANOVAs to examine the behavioral differences occur-ring during the gain and loss conditions.
Statistical contrasts were conducted separately fromanticipation and feedback event onsets. Because reac-tion times did not differ as a function of incentive level,trials presenting anticipation of gain cues (i.e., $1 and$2) were combined to increase statistical power, as weretrials presenting anticipation of loss cues. For theanticipation phase, trials with gain or loss cues werecompared with their corresponding nongain and non-loss trials. For the feedback phase, trials in whichparticipants gained money were compared with non-gain feedback trials, and trials in which participants lostmoney were compared with nonloss trials. Statisticsconducted at the individual level used a fixed effectsmodel to define experimental (anticipation gain andloss, gain and loss outcomes) and control (nongain andnonloss outcomes) conditions using SPM 8. A high-passfilter of 120 seconds was applied and six motionregressor nuisance covariates were included in themodel.
To investigate group differences in reward proces-sing after an affective prime, a three-way (group [BD,HC] by prime [affective priming, control] by valence[gain, loss]) ANOVA was conducted as the primaryanalysis. In a secondary analysis, a two-way (group[BD, HC] by prime [affective priming, control])ANOVA was conducted for each MID condition (gain,
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loss). Significant activations associated with the maineffect of group, the main effect of priming, and theinteraction of these terms were identified for thecomparison of anticipated and received gains versusnongains and of anticipated and received losses versusnonlosses. Activation foci were superimposed on high-resolution, T1-weighted images in MNI space, and theirlocations were interpreted using the Talairach atlasand known neuroanatomic landmarks. The voxel levelsignificance (p ¼ .01) and cluster size (k ¼ 194) criteriaused to hold the family-wise error at a p value equal to.05 were calculated with AlphaSim (AFNI, Bethesda,MD)25 based on parameters for a matrix size of91 � 109 � 91, voxel dimensions of 2 mm3, 7-mmfull-width half-maximum smoothing kernel, and10,000 Monte Carlo simulations. This program gener-ates null hypothesis distributions and correspondingstatistical criterion values through the use of MonteCarlo simulation. Parameters known to affect the shapeof null hypothesis distributions of fMRI data, such asthe number of voxels compared and their effective size,the per-voxel statistical criterion, and the definition ofvoxel clustering used, are modeled in these MonteCarlo simulations.26
Exploratory ROI analyses were conducted withinthe BD group to examine the effects of priming on thereward processing associated with the presence of highversus low manic symptoms on scan day. ROIs weredefined by the Automated Anatomical Labeling atlas27
and were selected based on findings from the presentwhole-brain analysis and from the extant rewardliterature12,28–30: anterior cingulate cortex (ACC), amyg-dala, insula, and portions of the striatum including thecaudate, putamen, NAcc, and globus pallidus. MeanZ-score values were extracted using MarsBar (http://marsbar.sourceforge.net/) and imported into SPSS 18(http://www.spss.com/) for analysis. ROI significancelevels were corrected for multiple comparisons using aBonferroni correction (0.05/n ROIs ¼ 0.007).
RESULTSParticipant CharacteristicsDemographic and clinical characteristics of thetwo participant groups are presented in Table 1.The BD and HC groups did not differ significantlywith respect to age (t46 ¼ 1.51), gender (n ¼ 48,w2¼ 1.34), handedness (n ¼ 48, w2
¼ 2.10),Wechsler Abbreviated Scale of Intelligence IQscores (t46 ¼ 1.73), socioeconomic status (t46 ¼
0.32), Tanner stage (t46¼ 1.08), or ethnicity (n¼ 48,w2¼ 8.74, p 4 .05 for all comparisons). Adoles-
cents with BD reported significantly higher YMRS(t46 ¼ 10.7, p o .0001), Children’s DepressionRating Scale (t46 ¼ 8.6, p o .0001), and TraitImpulsivity subscale scores in attention (t41 ¼
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TABLE 1 Participant Demographic and Clinical Variables
Variable BD (n ¼ 24) HC (n ¼ 24)
Age (y), mean (SD) 15.7 (1.7) 15.0 (1.4)Female, n (%) 11 (46) 15 (63)Caucasian, n (%) 13 (54) 14 (58)Right handedness, n (%) 19 (79) 21 (88)Tanner stage, mean (SD) 3.30 (0.40) 3.16 (0.53)Socioeconomic status, mean (SD) 4.7 (0.56) 4.61 (0.65)Full-Scale IQ, mean (SD) 107 (10.2) 113 (10.8)YMRS, mean (SD)* 17.8 (8.1) 0.13 (0.34)CDRS, mean (SD)* 44.0 (14.8) 17.9 (1.4)CGAS, mean (SD)* 58.3 (11.0) 93.7 (3.2)BIS—attentional impulsivity, mean (SD)* 20.8 (4.9) 14.0 (3.3)BIS—motor impulsivity, mean (SD)* 25.1 (3.9) 20.4 (3.4)BIS—nonplanning impulsivity, mean (SD)* 28.9 (6.2) 24.1 (4.2)Mood state on day of scan, n (%)*
Manic 6 (25) 0 (0)Mixed (manic þ depressed) 5 (21) 0 (0)Depressed 9 (38) 0 (0)Euthymic 4 (17) 24 (100)
Other lifetime psychiatric diagnoses, n (%)*ADHD 9 (38) 0 (0)Any anxiety disorder 5 (21) 0 (0)Oppositional-defiant disorder 4 (17) 0 (0)Conduct disorder 1 (4) 0 (0)Marijuana abuse 9 (38) 0 (0)
Lifetime medication exposure, n (%) 20 (83) 0 (0)Weeks on medication on scan day, mean (SD) 15.5 (25) 0 (0)Depressive episode before mania, n (%) 14 (58) 0 (0)Months to scan after manic episode, mean (SD) 5.57 (3.4) 0 (0)Lifetime medication exposure, n (mean exposure in wk)*
Lithium 8 (1.25) 0 (0)Atypical antipsychotics 17 (4.6) 0 (0)Antidepressants 12 (4.2) 0 (0)Psychostimulants 7 (5) 0 (0)Any medication 20 (16) 0 (0)
Note: ADHD¼ attention-deficit/hyperactivity disorder; BD¼ adolescents with bipolar I disorder; BIS¼ Barratt Impulsiveness Scale; CGAS¼Clinical GlobalAssessment Scale; CDRS ¼ Childhood Depression Rating Scale; HC ¼ healthy control adolescents; YMRS ¼ Young Mania Rating Scale.
*p o .05.
REWARD PROCESSING IN ADOLESCENT BD
5.4, p o .0001), motor (t41 ¼ 4.2, p o .0001), andnonplanning (t41 ¼ 3.1, p o .004) compared withthe HC group. The BD group had lower scores onthe Childhood Global Assessment Scale (t46 ¼
14.8, p o .0001) compared with the HC group,indicating greater functional impairment.
Behavioral ResultsA three-way (group by prime by valence)ANOVA conducted on reaction times yielded asignificant interaction of group and valence (F1,48
¼ 3.99, p ¼ .05). Subsequent two-way (group by
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prime) ANOVAs indicated that adolescents withBD had significantly faster reaction times than didHC adolescents for anticipation of gain and gaincontrol trials during the MID task after theaffective prime (F1,48 ¼ 5.734, p ¼ .021); analysesof hit rates and reaction times for anticipation ofloss trials yielded no significant main effects orinteractions, indicating comparable performanceof the two groups on the task. Three-way (groupby prime by order [i.e., pre-/post-task rating])ANOVAs conducted on self-report measurementsyielded significant interactions of prime andorder for positive affect (F ¼ 34.71, p o .001),
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TABL
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1.1
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gro
up�
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nce,
F¼
3.9
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p¼
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203.8
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207.3
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223.9
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225.9
6(2
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0.7
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0.6
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0.6
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9(0
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0.6
6(0
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2.1
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prim
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1.7
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excitability (F ¼ 5.35, p ¼ .025), and confidence(F ¼ 6.686, p ¼ .013). Subsequent paired t testsshowed significant increases across the primingtask from before to after the priming task forpositive affect (t¼ 5.38, p o .001), excitability (t¼2.12, p ¼ .04), and confidence (t ¼ 4.23, p o .001);there were no significant pre-/post-task differ-ences across the control task for these measure-ments (p 4 .05 for all comparisons; Table 2).
Neuroimaging ResultsPrimary Three-Way ANOVA Results With Post HocAnalyses. A three-way (group by prime byvalence) ANOVA during the anticipation condi-tion yielded a significant three-way interaction;activations in this interaction included the leftmiddle frontal gyrus (BA 10), left and rightinferior parietal lobules (BA 40), right inferiortemporal gyrus (BA 20), and left thalamus(Table 3, Figure 2). Post hoc tests in these regionsindicated that, compared with the HC group, theBD group showed decreased activation in thethalamus and inferior temporal gyrus whileanticipating gains after priming but increasedactivations in the middle frontal gyrus andparietal cortices while anticipating losses afterpriming.
During the feedback phase of the task, the three-way ANOVA also yielded a significant three-wayinteraction, with activations in the right inferiorparietal lobule (BA 40), thalamus, and right super-ior frontal gyrus (BA 8; Table 3). Post hoc t testsshowed that, compared with the HC group, the BDgroup showed less activation in these three regionswhile receiving losses after priming.
Secondary Whole-Brain Two-Way ANOVAResults. A significant main effect of valence fromthe three-way ANOVA showed that the ventralstriatum was significantly more activated duringthe anticipation of gain than during the anticipa-tion of loss. To pursue the hypotheses aboutdifferential prefrontal and subcortical dysfunc-tions during gain and loss conditions as shown inprevious studies using the MID task,24,26,29 theauthors conducted exploratory two-way whole-brain ANOVAs comparing the BD with HC groupin gain and loss conditions. These secondaryanalyses were not derived from the three-wayANOVA and thus should be viewed with cautionas exploratory and yielded the following results(p ¼ .05, family-wise error -corrected; Table 4,Figure 3).
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TABLE 3 Significant Clusters of Activation Using Three-Way Analysis of Variance (ANOVA)
ANOVA Cluster Location BA Extent F
PrimaryPeak (x, y, z) Direction of Significant Post Hoc Analyses
Anticipation: group � prime �valence 3-way ANOVA
Group � prime � valence right superiorparietal lobule
7 632 11.38 56, �42, 50 group � prime, F46 ¼ 4.17, p ¼ .047; prime � valence,F46 ¼ 9.49, p ¼ .003
group differences: loss after prime, BD 4 HC, p ¼ .006; loss after control,HC 4 BD, p ¼ .006
prime differences: HC, gain, prime 4 control, p ¼ .021; HC, loss,control 4 prime, p ¼ .001; BD, loss, prime 4 control, p ¼ .013
valence differences: HC, prime, gain 4 loss, p ¼ .001; HC, control,loss 4 gain, p ¼ .015
left inferior parietallobule
40 445 9.28 �50, �48, 56 main effect of prime: prime 4 control, F46 ¼ 8.76, p ¼ .005
group differences: loss after prime, BD 4 HC, p ¼ .016; loss after control,HC 4 BD, p ¼ .014
prime differences: HC, gain, prime 4 control, p ¼ .005; BD, loss,prime 4 control, p ¼ .006
valence differences: HC, prime, gain 4 loss, p ¼ .009; HC, control,loss 4 gain, p ¼ .022
left middle frontalgyrus
10 617 12.01 �43, 56, �3 group differences: loss after control, HC 4 BD, p ¼ .003 prime differences:HC, loss, control 4 prime, p ¼ .039; BD, loss, prime 4 control, p ¼ .015
valence differences: HC, control, loss 4 gain, p ¼ .002; BD, control,gain 4 loss, p ¼ .013
thalamus 226 11.46 �3, 31, 2 main effect of valence, prime 4 control, F46 ¼ 5.04, p ¼ .030 groupdifferences: gain after prime, HC 4 BD, p ¼ .009
prime differences: BD, gain, control 4 prime, p ¼ .012valence differences: HC, control, gain 4 loss, p ¼ .004; BD, control,
gain 4 loss, p ¼ .010right inferior
temporal gyrus20 197 10.26 58, �36, �15 main effect of prime: prime 4 control, F46 ¼ 4.17, p ¼ .048; main
effect of valence: gain 4 loss, F46 ¼ 4.43, p ¼ .041; prime � valence,F46 ¼ 3.87, p ¼ .055
group differences: gain after control, BD 4 HC, p ¼ 0.016prime differences: HC, gain, prime 4 control, p ¼ .013valence differences: HC, prime, gain 4 loss, p¼ .019; BD, control, gain 4 loss, p¼ .050
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TABLE 3 Continued
ANOVA Cluster Location BA Extent F
PrimaryPeak (x, y, z) Direction of Significant Post Hoc Analyses
Feedback: group � prime �valence 3-way ANOVA
Group � prime � valence right inferiorparietal lobule
40 409 17.52 49, �43, 28 group differences: loss after prime, HC 4 BD, p ¼ .006; loss aftercontrol, HC 4 BD, p ¼ .035
prime differences: HC, gain, prime 4 control, p ¼ .035; BD, loss,control 4 prime, p ¼ .008
valence differences: HC, control, gain 4 loss, p ¼ .012; BD, prime,gain 4 loss, p ¼ .008
right superiorfrontal gyrus
8 1,101 13.79 7, 24, 49 main effect of valence: gain 4 loss, F46 ¼ 8.75, p ¼ .005
group differences: loss after control, BD 4 HC, p ¼ .003prime differences: HC, gain, control 4 prime, p ¼ .024; HC, loss,
prime 4 control, p ¼ .035valence differences: HC, control, gain 4 loss, p o .001; BD, prime,
gain 4 loss, p ¼ .028thalamus 377 11.75 �3, �13, 4 main effect of group: HC 4 BD, F46 ¼ 4.10, p ¼ .049; main effect of valence:
gain 4 loss, F46 ¼ 4.48, p ¼ .04group differences: loss after prime, HC 4 BD, p 4 .001prime differences: BD, loss, control 4 prime, p ¼ .019valence differences: BD, prime, gain 4 loss, p ¼ .001
Note: BA ¼ Brodmann area; BD ¼ adolescents with bipolar I disorder; HC ¼ healthy controls.
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FIGURE 2 Significant neural activations from whole-brain three-way analysis of variance (ANOVA; threshold of p¼ .05,k Z194 voxels). Note: IPL¼ inferior parietal lobule; ITG¼ inferior temporal gyrus; L¼ left; MFG¼middle frontal gyrus; R¼right; SFG ¼ superior frontal gyrus; SPL ¼ superior parietal lobule; Thal ¼ thalamus.
REWARD PROCESSING IN ADOLESCENT BD
Anticipation of Gain Minus Nongain. The maineffect of group showed that the BD group hadincreased orbitomedial frontal cortex (OMFC) acti-vation compared with the controls, whereas the HCgroup had increased bilateral angular gyrus activa-tion compared with the BD group during thiscontrast. The main effect of priming while antici-pating gains showed significant activationsthroughout the brain compared with the controlcondition (Table 3). In the two-way interaction ofgroup and prime, the HC group had significantlygreater activation in the subgenual ACC than didthe BD group after affective priming.
Anticipation of Loss Minus Nonloss. The maineffect of group yielded no significant clusters ofactivation during this contrast. The main effect ofpriming during the anticipation of loss showedsignificant activations in the right posterior cin-gulate, inferior parietal lobe, and caudate com-pared with the control condition. In the interactionof group and prime, the BD group showed greateractivation than the HC group in the bilateralinferior parietal lobules, bilateral middle frontalgyrus, and left middle temporal gyrus, whereas theHC group showed greater activation in the leftparahippocampal gyrus compared with the BDgroup after affective priming.
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Gain Minus Nongain Outcomes. This contrastyielded no significant main effects or interactions.
Loss Minus Nonloss Outcomes. The main effect ofgroup showed that the BD group had greateractivation than the HC group in the right superiorand orbitofrontal gyri. The main effect of primingshowed significant activations in the left parahippo-campal gyrus compared with the control condition.In the interaction of group and prime, the HC grouphad greater activation in the right superior frontalgyrus than did the BD group after affective priming.
Exploratory ROI analysis from the two-wayANOVAs showed that during the anticipation ofgain after affective priming, youth with BD withhigh levels of mania at the scan (YMRS score 420,n ¼ 11) exhibited less activation in the NAccbilaterally than did youth with BD and low levelsof mania (YMRS score r20, n ¼ 13, p ¼ .003,uncorrected). Levels of depression were notassociated with a priming effect.
DISCUSSIONThe present study is the first to compare neuralactivation during reward processing after affec-tive priming in adolescents with BD and healthyadolescents. Youth with BD were found to show
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TABLE 4 Significant Clusters of Activation Using Two-Way Analysis of Variance (ANOVA)
ANOVA Cluster Location BA Extent Direction of Post Hoc t-Test Post Hoc t-Test (p) F
Primary Peakx y z
Anticipation gain ANOVAMain effect of group right orbitomedial frontal cortex 10 403 BD 4 HC .003 9.94 11 55 14
right angular gyrus 39 202 HC 4 BD .001 11.88 31 �65 27prime 4 control .02 5.53
left angular gyrus 39 233 HC 4 BD .005 8.92 �31 �63 18prime 4 control .013 6.73
Main effect of prime left middle frontal gyrus 6 1,363 prime 4 control o.001 20.45 �37 11 57left inferior parietal lobule 40 1,271 prime 4 control o.001 14.67 �52 �44 43right superior parietal lobule 7 808 prime 4 control .002 10.44 29 �69 55right superior frontal gyrus 8 454 prime 4 control .001 12.93 41 24 49right middle temporal gyrus 21 371 prime 4 control .001 12.02 66 �28 �14left inferior occipital gyrus 18 223 prime 4 control .001 12.39 �43 �84 �3right parahippocampal gyrus 30 207 prime 4 control .002 10.45 29 �54 58right precentral gyrus 6 205 prime 4 control .001 11.98 60 5 31left orbitofrontal gyrus 11 203 prime 4 control .001 12.53 �29 34 �17
Group � prime subgenual cingulate 25 213 HC 4 BD o.001 14.97 �13 22 �14Anticipation loss ANOVA
Main effect of group no significant clusters identified 4.05Main effect of prime right posterior cingulate 31 408 control 4 prime .002 10.34 1 �39 31
right inferior parietal lobule 40 491 prime 4 control o.001 14.38 62 �29 46right caudate 249 prime 4 control .002 11.19 15 16 16
Group � prime right inferior parietal lobule 40 1,083 BD 4 HC o.001 17.30 54 �42 52right middle frontal gyrus 10 894 BD 4 HC o.001 15.54 41 44 16left inferior parietal lobule 40 823 BD 4 HC .001 11.98 �49 �50 56left parahippocampal gyrus 19 381 HC 4 BD o.001 18.47 �35 �43 �3left middle frontal gyrus 46 372 BD 4 HC .001 13.71 �43 42 15right middle frontal gyrus 6 223 BD 4 HC .002 10.40 50 1 52left middle temporal gyrus 20 195 BD 4 HC .002 11.38 �60 �45 �11
Feedback gain ANOVAMain effects and interactions no significant clusters identified 4.05
Feedback loss ANOVAMain effect of group right superior frontal gyrus 6 446 BD 4 HC o.001 15.08 7 30 55
prime 4 control .042 4.39right orbitofrontal gyrus 47 355 BD 4 HC o.001 17.81 43 28 �7
Main effect of prime left parahippocampal gyrus 30 211 control 4 prime o.001 27.11 �21 �48 6Group � prime right superior frontal gyrus 6 214 HC 4 BD .001 11.95 5 12 53
Note: BA ¼ Brodmann area; BD ¼ adolescents with bipolar I disorder; HC ¼ healthy controls.
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FIGURE 3 Significant neural activations from secondary two-way whole-brain analysis of variance (ANOVA; threshold ofp ¼ .05, Z194 voxels) depicted in red and blue. Note: No significant activations during the feedback gain ANOVA wereidentified. AngG¼ angular gyrus; BD¼ bipolar disorder; Caud¼ caudate; HC¼ healthy controls; L¼ left; MFG¼middlefrontal gyrus; OFC¼ orbitofrontal cortex; OMFC¼ orbitomedial frontal cortex; PCC¼ posterior cingulate cortex; Phipp¼parahippocampal gyrus; R ¼ right; sACC ¼ subgenual anterior cingulate cortex; SFG ¼ superior frontal gyrus.
REWARD PROCESSING IN ADOLESCENT BD
aberrant neurobehavioral responses during antici-pation and receipt of reward and loss with affectivepriming. The present results point to anomalousmechanisms of reward processing in youth withBD that may be related to aberrant goal pursuit andmotivation. Specifically, compared with their HCpeers, youth with BD showed decreased activationin the thalamus and inferior temporal gyrus whileanticipating gains after priming, but increasedactivations in the middle frontal gyrus and parietalcortices while anticipating losses after priming.Youth with BD also showed less activation in theinferior parietal lobule, thalamus, and superiorfrontal gyrus while receiving losses after priming.Given the significant effect of valence, the authorsconducted an exploratory examination of gain andloss conditions separately in a secondary analysis.This analysis yielded increased activation in pre-frontal and subcortical regions that has beendocumented to subserve functions related toreward processing, such as motivation, goal pursuit(caudate, OMFC), and emotion regulation (OMFC,ACC). The increased orbitomedial frontal activa-tion (BA 10) in the BD compared with the HC groupduring reward anticipation was consistent with the
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authors’ prediction. It is noteworthy, however, thatthe BD group also showed decreases in subgenualACC activation after affective priming, suggestinginterference in cognitive control over reward pro-cessing during primed reward anticipation. Inaddition, compared with HC adolescents, youthwith BD showed speeded reaction times anddecreases in activation in the parahippocampalgyrus during loss anticipation after affective prim-ing. In summary, the profile of aberrant activationobserved in the present adolescent BD sampleprovides an initial picture of developmental braindysfunction that may underlie disordered goalpursuit and motivation in individuals at the earlieststages of this serious neuropsychiatric disorder.
The present study showed that, in BD youth,the processing of reward after affective primingresults in aberrant activations in regions impor-tant in information relay to the prefrontal cortex(thalamus), visuospatial processing (parietal cor-tex, inferior temporal gyrus), and uncertainty andself-awareness (superior frontal and middle fron-tal gyrus). These regions have been previouslyimplicated in individuals with BD while theyare performing tasks assessing visuospatial
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emotion processing and reactivity,31 workingmemory,32 sustained attention with emotionaland neutral distracters,33–35 response inhibition,36
and reversal learning.37 Most relevant to bipolarsymptomatology, however, particularly in thecontext of hedonic drive, grandiosity, and poorinsight, were the findings of prefrontal activationin the middle and superior frontal gyri. Contraryto the authors’ prediction, increased activationwas observed in the middle frontal gyrus inthe BD group during the primed loss comparedwith the primed gain condition, suggesting thatpriming has differential effects on gain and lossconditions in pediatric BD. It is noteworthy,however, that decreased activation in the superiorfrontal gyrus after primed loss receipt is consis-tent with prior studies that have associatedthis region with aberrant attention to negativeemotional information38 and decreased top-downcontrol of emotional reactivity31 in youth withbipolar symptoms. The present results point topotential neural mechanisms that may underliedisordered self-awareness or insight during goalpursuit and motivation in BD.39 That similaractivation patterns have been observed in youthwith BD across different cognitive tasks40 sug-gests that these candidate neural regions are likelyinvolved in the pathophysiology of BD.
Although exploratory and not derived fromthe primary three-way analysis, the findings fromthe secondary two-way whole-brain ANOVAsexamining activations within each condition,combined with the literature on reward proces-sing, provide a relevant context within which tounderstand the role of the medial prefrontalcortex in the processing of rewarding stimuli inyouth with BD.13 Prior research has suggestedthat mesocorticolimbic brain regions subserve ahierarchical model of reward processing that maybe relevant to several possible pathways leadingto dysregulated goal pursuit and motivation inBD. Although striatal regions represent an affec-tive component expressed as arousal and action,cortical regions represent a probabilistic compo-nent that may be related to confidence in goalattainment and may manifest in BD as grandiosityand dysregulated goal pursuit.28 In the secondarytwo-way ANOVA, the main effect of groupsuggests that the typical mechanisms of rewardprocessing are altered in BD. Although youth withBD showed increased OMFC activation, HCyouth exhibited activation of the angular gyrusbilaterally during reward anticipation. OMFC
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activation may be related to the perceivedlikelihood of attaining a reward,26 whereas theangular gyrus has been found to be involved incalculations concerning arithmetic fact retrieval.41
Although the probability of reward in the MIDtask is titrated individually to be held constantacross all participants,28 the subjective perceptionof a higher probability of reward outcomes mayunderlie illness-associated characteristics such asunrealistic outcome expectations3,42 and impaireddecision making43 that may make individuals withBD particularly vulnerable to increased rewardreactivity during reward anticipation. For example,when youth with BD received feedback about losingmoney after priming, the primary and secondaryanalyses yielded deficits in the recruitment ofsuperior frontal regions compared with the HCgroup, putatively indicating a lack of self-awarenessthat would otherwise strengthen executive controlto improve performance. Importantly, the BD andHC groups did not differ in ventrostriatal activationduring reward anticipation in the primary orsecondary analysis, suggesting a lack of differentialregard for reward magnitude during this condi-tion.10,11,28 Together, these findings suggest thatreward magnitude is less salient for youth withBD than is OMFC-mediated reward probability, andthat youth with BD have aberrant prefrontal execu-tive control when primed to process rewards.
This study was also a proof-of-concept inves-tigation to examine whether an affective primehas neurobehavioral effects. Behaviorally, theauthors found that affective priming resulted inincreased reaction times in the BD compared withthe HC group, particularly during reward antici-pation followed by affective priming. Self-reportratings of increased happiness, excitability, andconfidence were observed after priming acrossall participants, permitting neural comparisonswithout the confound of heterogeneous moodstates within the BD group. Regarding the neuralactivation effects associated with priming, whichhave not previously been studied, the authorsobtained the main effects of priming that includedincreased frontostriatal activation during antici-pation of reward and loss. Decreases in activationafter priming were found in the thalamus andinferior temporal gyrus during gain anticipationand in the thalamus, inferior parietal lobule, andsuperior frontal gyrus during loss feedback,suggesting task condition-specific effects thatmight aid in understanding how different moodstates (versus traits) influence reward processing.
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REWARD PROCESSING IN ADOLESCENT BD
In a previous study using positive mood induc-tions to examine mood state and trait factorsthat mediate cognitive changes associated withemotional processing in BD, the investigatorsreported that positive mood inductions weremore effective in individuals with BD than incontrols.44 In that study, individuals with BDshowed a positive emotional bias on an affectivego/no-go task and performed more slowly thandid controls on a Cambridge Gambling Task,especially while making more difficult decisions.That study was limited, however, by the lack of aneutral control condition, so latency differenceson the Cambridge Gambling Task could not beexplained as being due to state or trait effects inBD. Together, these data underscore the strengthsof the present experimental design.
In the present study, speeded reaction times andneural interactions of group and priming support thenotion that an affective prime interferes with thetypical processing of reward stimuli. The fact that theinteraction of group and prime in self-report ratingswas not significant suggests that neural differencesbetween the BD and HC groups are unlikely to beexplained by any state-related positive affect that wasinduced with priming. Significant decreases in tha-lamic and inferior temporal activations after affectivepriming in the BD versus HC group duringreward anticipation and greater NAcc deactiva-tion during reward anticipation after affectivepriming in youth with BD with higher levels ofmanic symptoms provide supporting evidencethat errors in reward prediction signaling maybe due to desensitization or downregulation ofthe NAcc during reward activation.10 Thus,deficits in thalamic, temporal, and striatal acti-vation may be due to the interference of typicalreward processing by trait affective symptomsor may reflect abnormal top-down modulationof these regions by higher cortical regions, aphenomenon that has been documented withother emotion-processing31,32,45–47 and reversal-learning48 tasks in youth with BD.
Some limitations of this study should be noted.First, to minimize motion artifact and limit thestrain of scanning teenagers with significantmood symptoms, in the MID task, only ninereplications of each trial type were administered,which may have decreased power to obtainsignificant effects. Second, the cross-sectionaldesign does not permit a separation of mania-versus depression-dependent contributions tothese findings that may center on state-
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dependent enhanced arousal to reward duringmania and on the avoidance of punishment or lossduring depressed and euthymic states. Indeed,although the affective priming task influencedself-reported affect and neural activation, it didnot intensify activation in reward- or emotion-related regions across conditions. Importantly,however, an advantage of adding an affectiveprime is that it may have neutralized any con-found of heterogeneity of opposing mood stateson the day of scanning by inducing a comparableaffective state in all participants; moreover, acontrol condition that counterbalanced the affec-tive prime permitted the authors to make infer-ences about the trait versus state features of BD.Third, although the authors attempted to mini-mize heterogeneity in this sample, variationsremained in the levels of medication and sub-stance exposure and in the time elapsed since thefirst episode of mania. Although group differ-ences in neural responses may have been due to adifferential exposure to medications, this is unli-kely in the present sample in which participantshad an average of only 16 weeks of lifetimemedication exposure and in which the length oflifetime exposure to atypical antipsychotics, lithium,antidepressants, or psychostimulants did not cor-relate with any significant activations within the BDgroup. Fourth, although not within the scope orgoals of the present study, further investigation isneeded to relate these findings to the true traitfeatures of BD that could be evaluated in ado-lescents at risk for BD preceding the onset ofillness, to examine the specificity of these find-ings to adolescent-onset BD as opposed toother psychiatric disorders in this age group,and to determine whether these characteristicspredict long-term clinical outcome. Nevertheless,the authors found group differences in key brainregions involved in cognition, self-awareness,motivation, and affect in adolescents with andwithout mania, providing an initial step in under-standing the role of reward processing in theneurophysiology of pediatric BD.
In summary, mania affects the neural mech-anisms underlying the anticipation and receipt ofreward. This study presents evidence that earlyafter the onset of mania, adolescents with BD exhibitanomalies in prefrontal and subcortical regionsduring reward processing. These regions maybe promising candidates for biological markersfor the development and progression of BD intoadulthood. Future research is needed to examine
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the longitudinal trajectories of these characteristicsand their ability to predict the clinical progression ofthis disorder over time. &
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Clinical Guidance
� Youth with BD showed aberrant neurobehavioralresponses during the anticipation and receipt ofreward and loss with affective priming.� Compared with typically developing adolescents,
youth with BD had speeded reaction times whileanticipating primed rewards and showed aberrantpatterns of activation in regions important forinformation relay to the prefrontal cortex (thalamus),visuospatial processing (parietal cortex, inferiortemporal gyrus), and self-awareness (superiorfrontal and middle frontal gyrus).� Youth with BD who had higher levels of manic
symptoms showed decreases in NAcc activationcompared with those with lower levels of manicsymptoms.� Together, these patterns of activation may clinically
manifest in BD as grandiosity and dysregulated goalpursuit and distinguish psychopathology from theprocesses associated with typical adolescence.
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Accepted October 9, 2012.
Drs. Singh, Chang, Cui, Gotlib, and Reiss, Mr. Kelley, Ms. Sherdell,and Ms. Howe are with Stanford University School of Medicine,Stanford, CA.
This research was supported by the Klingenstein Third GenerationFoundation Depression Fellowship and National Institute of MentalHealth (NIMH) grant MH085919 (M.K.S.).
This paper was presented as a poster at the annual meeting for theAmerican College of Neuropsychopharmacology; Hollywood, FL;December 9, 2009.
The authors thank Melissa Pease, Erica Weitz, Elizabeth Adams, TenahAcquaye, and Layla Bararpour of Stanford University for theirassistance with recruitment and data collection, and Allison Libby ofPalo Alto University for help with data entry.
Disclosure: Dr. Chang has served as a consultant for GlaxoSmithKline,Eli Lilly and Co., Merck, and Bristol-Myers Squibb. He has receivedresearch support from GlaxoSmithKline, Merck, the NIMH, and theNational Alliance for Research in Schizophrenia and Depression. Dr.Reiss has served as a consultant for Novartis for the development ofneuroimaging biomarkers in fragile X syndrome. Drs. Singh, Cui, andGotlib, Mr. Kelley, Ms. Sherdell, and Ms. Howe report no biomedicalfinancial interests or potential conflicts of interest.
Correspondence to Manpreet Kaur Singh, M.D., M.S., StanfordUniversity School of Medicine, Division of Child and AdolescentPsychiatry, 401 Quarry Road, Stanford, CA 94305-5795; e-mail:[email protected]
0890-8567/$36.00/C 2013 American Academy of Child andAdolescent Psychiatry
http://dx.doi.org/10.1016/j.jaac.2012.10.004
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