Development of superficial white matter and its structural interplay with cortical gray matter in children and adolescents.

Healthy human brain undergoes significant changes during development. The developmental trajectory of superficial white matter (SWM) is less understood relative to cortical gray matter (GM) and deep white matter. In this study, a multimodal imaging strategy was applied to vertexwise map SWM microstructure and cortical thickness to characterize their developmental pattern and elucidate SWM-GM associations in children and adolescents. Microscopic changes in SWM were evaluated with water diffusion parameters including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in 133 healthy subjects aged 10-18 years. Results demonstrated distinct maturational patterns in SWM and GM. SWM showed increasing FA and decreasing MD and RD underneath bilateral motor sensory cortices and superior temporal auditory cortex, suggesting increasing myelination. A second developmental pattern in SWM was increasing FA and AD in bilateral orbitofrontal regions and insula, suggesting improved axonal coherence. These SWM patterns diverge from the more widespread GM maturation, suggesting that cortical thickness changes in adolescence are not explained by the encroachment of SWM myelin into the GM-WM boundary. Interestingly, age-independent intrinsic association between SWM and cortical GM seems to follow functional organization of polymodal and unimodal brain regions. Unimodal sensory areas showed positive correlation between GM thickness and FA whereas polymodal regions showed negative correlation. Axonal coherence and differences in interstitial neuron composition between unimodal and polymodal regions may account for these SWM-GM association patterns. Intrinsic SWM-GM relationships unveiled by neuroimaging in vivo can be useful for examining psychiatric disorders with known WM/GM disturbances.

Altered affective, executive and sensorimotor resting state networks in patients with pediatric mania.

BACKGROUND: The aim of the present study was to map the pathophysiology of resting state functional connectivity accompanying structural and functional abnormalities in children with bipolar disorder. METHODS: Children with bipolar disorder and demographically matched healthy controls underwent resting-state functional magnetic resonance imaging. A model-free independent component analysis was performed to identify intrinsically interconnected networks. RESULTS: We included 34 children with bipolar disorder and 40 controls in our analysis. Three distinct resting state networks corresponding to affective, executive and sensorimotor functions emerged as being significantly different between the pediatric bipolar disorder (PBD) and control groups. All 3 networks showed hyperconnectivity in the PBD relative to the control group. Specifically, the connectivity of the dorsal anterior cingulate cortex (ACC) differentiated the PBD from the control group in both the affective and the executive networks. Exploratory analysis suggests that greater connectivity of the right amygdala within the affective network is associated with better executive function in children with bipolar disorder, but not in controls. LIMITATIONS: Unique clinical characteristics of the study sample allowed us to evaluate the pathophysiology of resting state connectivity at an early state of PBD, which led to the lack of generalizability in terms of comorbid disorders existing in a typical PBD population. CONCLUSION: Abnormally engaged resting state affective, executive and sensorimotor networks observed in children with bipolar disorder may reflect a biological context in which abnormal task-based brain activity can occur. Dual engagement of the dorsal ACC in affective and executive networks supports the neuroanatomical interface of these networks, and the amygdala's engagement in moderating executive function illustrates the intricate interplay of these neural operations at rest.

Negative emotion interference during a synonym matching task in pediatric bipolar disorder with and without attention deficit hyperactivity disorder.

This study examined whether processing of emotional words impairs cognitive performance in acutely ill patients with pediatric bipolar disorder (PBD), with or without comorbid attention-deficit hyperactivity disorder (ADHD), relative to healthy controls (HC). Forty youths with PBD without ADHD, 20 youths with PBD and ADHD, and 29 HC (mean age = 12.97 ± 3.13) performed a Synonym Matching task, where they decided which of two probe words was the synonym of a target word. The three words presented on each trial all had the same emotional valence, which could be negative, positive, or neutral. Relative to HC both PBD groups exhibited worse accuracy for emotional words relative to neutral ones. This effect was greater with negative words and observed regardless of whether PBD patients had comorbid ADHD. In the PBD group without ADHD, manic symptoms correlated negatively with accuracy for negative words, and positively with reaction time (RT) for all word types. Our findings suggest a greater disruptive effect of emotional valence in both PBD groups relative to HC, reflecting the adverse effect of altered emotion processing on cognitive function in PBD. Future studies including an ADHD group will help clarify how ADHD symptoms may affect emotional interference independently of PBD.

Maintaining force control despite changes in emotional context engages dorsomedial prefrontal and premotor cortex.

Viewing emotional as compared with neutral images results in an increase in force production. An emotion-driven increase in force production has been associated with increased brain activity in ventrolateral prefrontal cortex and primary motor cortex (M1). In many instances, however, force production must be held constant despite changes in emotional state and the neural circuits underlying this form of control are not well understood. To address this issue, we designed a task in which subjects viewed pleasant, unpleasant, and neutral images during a force production task. We measured brain activity using functional magnetic resonance imaging and examined functional connectivity between emotion and motor circuits. Despite similar force performance across conditions, increased brain activity was evidenced in dorsomedial prefrontal cortex (dmPFC) and left ventral premotor cortex (PMv) when force was produced during emotional as compared with neutral conditions. Connectivity analyses extended these findings by demonstrating a task-dependent functional circuit between dmPFC and ventral and dorsal portions of premotor cortex. Our findings show that when force production has to be consistent despite changes in emotional context, a functional circuit between dmPFC and PMv and dorsal premotor cortex is engaged.

Cognitive dysfunction is worse among pediatric patients with bipolar disorder Type I than Type II.

BACKGROUND: Impaired profiles of neurocognitive function have been consistently demonstrated among pediatric patients with bipolar disorder (BD), and may aid in the identification of endophenotypes across subtypes of the disorder. This study aims to determine phenotypic cognitive profiles of patients with BD Type I and II. METHODS: Subjects (N = 79) consisted of BD I (n = 27) and BD II (n = 19) patients and demographic and intellectually matched healthy controls (HC; n = 33) that completed a battery of neurocognitive tasks. RESULTS: Bipolar disorder Type I patients performed significantly more poorly compared to HC on all domains of cognitive function including attention, executive function, working memory, visual memory, and verbal learning and memory. BD I patients also performed more poorly compared to BD II patients on all domains of cognitive functioning with the exception of working memory, whereas BD II patients did poorly relative to HC only on verbal learning and memory. CONCLUSIONS: Findings from the current study indicate that BD I patients are characterized by more severe cognitive impairment relative to BD II patients who show an intermediate pattern of performance between BD I patients and HC. Verbal learning and memory may effectively differentiate pediatric BD patients and controls, regardless of the subtype of BD, and may serve as a cognitive endophenotype for the disorder. Additionally, these findings move us closer to developing effective cognitive interventions tailored to specific subtypes of pediatric BD patients.

Human reversal learning under conditions of certain versus uncertain outcomes.

Reversal learning tasks assess behavioral flexibility by requiring subjects to switch from one learned response choice to a different response choice when task contingencies change. This requires both the processing of negative feedback once a learned response is no longer reinforced, and the capacity for flexible response selection. In 2-choice reversal learning tasks, subjects switch between only two responses. Multiple choice reversal learning is qualitatively different in that at reversal, it requires subjects to respond to non-reinforcement of a learned response by selecting a new response from among several alternatives that have uncertain consequences. While activity in brain regions responsible for processing unexpected negative feedback is known to increase in relation to the hedonic value of the reward itself, it is not known whether the uncertainty of reinforcement for future response choices also modulates these responses. In an fMRI study, 15 participants performed 2- and 4-choice reversal learning tasks. Upon reversal in both tasks, activation was observed in brain regions associated with processing changing reinforcement contingencies (midbrain, ventral striatum, insula), as well as in neocortical regions that support cognitive control and behavioral planning (prefrontal, premotor, posterior parietal, and anterior cingulate cortices). Activation in both systems was greater in the 4- than in the 2-choice task. Therefore, reinforcement uncertainty for future responses enhanced activity in brain systems that process performance feedback, as well as in areas supporting behavioral planning of future response choices. A mutually facilitative integration of responses in motivational and cognitive brain systems might enhance behavioral flexibility and decision making in conditions for which outcomes for future response choices are uncertain.

Negative emotion impacts memory for verbal discourse in pediatric bipolar disorder.

OBJECTIVES: Cognitive and emotional deficits have been documented in youth with pediatric bipolar disorder (PBD); however, to date, a systematic evaluation of comprehension and memory for verbally presented information has not been conducted. The effect of emotion on comprehension and memory for verbally presented material also has not been examined. We examined whether youth with PBD have difficulty recalling the big picture (macrostructure) as well as the story details (microstructure). METHODS: A total of 35 youth with PBD and 25 healthy controls completed an Affective Story Task. A psychological processing model allowed for the examination of both the macrostructure and microstructure of language comprehension. RESULTS: Youth with PBD were capable of comprehending the gist of the stories and were not impaired by emotion when comprehending and remembering macrostructure. However, negative emotional material was found to proactively interfere with the encoding and recall of microstructure. Level of depression appeared to impact recall of microstructure, but not macrostructure. CONCLUSIONS: Negatively valenced material may impair subsequent comprehension and memory for details among youth with PBD. This deficit could impact the daily functioning of these youth, as the perception of negative affect may derail aspects of successful comprehension and learning.

Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder: fMRI outcomes.

The aim of this research was to determine the relative effects of risperidone and divalproex on brain function in pediatric mania. This is a double-blind 6-week functional magnetic resonance imaging trial with 24 unmedicated manic patients randomized to risperidone or divalproex, and 14 healthy controls (HCs) matched for IQ and demographic factors (mean age: 13.1±3.3years). A pediatric affective color matching task, in which subjects matched the color of a positive, negative or neutral word with one of two colored circles, was administered. The primary clinical measure was the Young Mania Rating Scale (YMRS). The risperidone group, relative to HC, showed an increase in activation from pre- to post-treatment in right pregenual and subgenual anterior cingulate cortex and decreased activation in bilateral middle frontal gyrus during the negative condition; and decreased activation in left inferior and medial, and right middle frontal gyri, left inferior parietal lobe, and right striatum with positive condition. In the divalproex group, relative to HC, there was an increased activation in right superior temporal gyrus in the negative condition; and in left medial frontal gyrus and right precuneus with the positive condition. Greater pre-treatment right amygdala activity with negative and positive condition in the risperidone group, and left amygdala activity with positive condition in divalproex group, predicted poor response on YMRS. Risperidone and divalproex yield differential patterns of prefrontal activity during an emotion processing task in pediatric mania. Increased amygdala activity at baseline is a potential biomarker predicting poor treatment response to both the risperidone and divalproex.

Individuals with the post-traumatic stress disorder process emotions in subcortical regions irrespective of cognitive engagement: a meta-analysis of cognitive and emotional interface.

Post-traumatic stress disorder (PTSD) manifests as emotional suffering and problem-solving impairments under extreme stress. This meta-analysis aimed to pool the findings from all the studies examining emotion and cognition in individuals with PTSD to develop a robust mechanistic understanding of the related brain dysfunction. We identified primary studies through a comprehensive literature search of the MEDLINE and PsychINFO databases. The GingerALE software (version 2.3.6) from the BrainMap Project was used to conduct activation likelihood estimation meta-analyses of the eligible studies for cognition, emotion and interface of both. Relative to the non-clinical (NC) group, the PTSD group showed greater activation during emotional tasks in the amygdala and parahippocampal gyrus. In contrast, the NC group showed significantly greater activation in the bilateral anterior cingulate cortex (ACC) than did the PTSD group in the emotional tasks. When both emotional and cognitive processing were evaluated, the PTSD group showed significantly greater activation in the striatum than did the NC group. No differences in activation between the PTSD and NC groups were noted when only the cognitive systems were examined. Individuals with PTSD exhibited overactivity in the subcortical regions, i.e., amygdala and striatum, when processing emotions. Underactivity in the emotional and cognitive processing intermediary cortex, i.e., the ACC, was especially prominent in individuals with PTSD relative to the NC population following exposure to emotional stimuli. These findings may explain the trauma-related fear, irritability, and negative effects as well as the concentration difficulties during cognitive distress associated with emotional arousal, that are commonly observed in individuals with PTSD.

Enhanced working and verbal memory after lamotrigine treatment in pediatric bipolar disorder.

OBJECTIVE: To examine the treatment impact of lamotrigine on the neurocognitive profile of patients with pediatric bipolar disorder (PBD). METHOD: Healthy controls (HC) (n = 24; mean age = 12.4 +/- 3.3 years) and unmedicated PBD patients with manic, mixed, or hypomanic episodes (n = 34; mean age = 13 +/- 3.1 years) were matched for IQ, age, sex, race, and socioeconomic status. A neurocognitive battery was administered at baseline and again after 14 weeks, during which PBD patients were treated with lamotrigine. RESULTS: Clinical symptoms improved with treatment in the patient group with significant change from baseline to follow-up on the Young Mania Rating Scale (p < 0.001) and the Children's Depression Rating Scale-Revised (p < 0.001). Global neurocognitive function improved with lamotrigine in PBD patients over time relative to that in HC, although overall performance remained impaired. Working memory and verbal memory significantly improved with treatment in patients, and deficits in these domains were no longer significantly impaired relative to HC at follow-up. Executive function significantly improved with treatment in the patient group but still lagged behind HC at follow-up. Performance on attention tests did not improve with treatment. CONCLUSIONS: There appears to be significant improvement in cognitive abilities in PBD patients treated with lamotrigine that is most prominent in the areas of working memory and verbal memory and that occurs along with mood stabilization.

Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder.

OBJECTIVE: To determine the relative effects of risperidone and divalproex in pediatric mania. METHODS: This is a double-blind, randomized, outpatient clinical trial with 66 children and adolescents (mean age= 10.9 ± 3.3 years; age range= 8-18 years) with mania who were randomly assigned to either risperidone (0.5-2 mg/day, n= 33) or divalproex (60-120 µg/mL, n= 33) for a six-week period. Measures included the Young Mania Rating Scale (YMRS) and Child Depression Rating Scale-Revised (CDRS-R). RESULTS: Mixed-effects regression models, with interaction between time and the active drug as predictors, found that the risperidone group had more rapid improvement than the divalproex group (p < 0.05), although final scores did not differ significantly between groups. Mixed models using only those subjects who completed the six-week study found similar results. The response rate on YMRS was 78.1% for risperidone and 45.5% for divalproex (p < 0.01). The remission rate for risperidone was 62.5%, compared with 33.3% for divalproex (p < 0.05). Improvement on the CDRS-R was significantly higher for the risperidone group relative to the divalproex group (p < 0.05). There were no significant differences between groups in safety, but subject retention was significantly higher at study endpoint in the risperidone group (p < 0.01). Dropout rate was 24% in the risperidone group and 48% in the divalproex group, with increased irritability being the most common reason for dropout in the latter. There was no significant weight gain in either group. CONCLUSION: Results suggest that risperidone was associated with more rapid improvement and greater reduction in manic symptoms compared to divalproex. Although the results suggest that both drugs are safe, risperidone's lower attrition rate and lower rate of adverse events may suggest better toleration. Clinical trials with larger samples are required to confirm these preliminary findings.

Differential engagement of cognitive and affective neural systems in pediatric bipolar disorder and attention deficit hyperactivity disorder.

This fMRI study investigates the neural bases of cognitive control of emotion processing in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). Seventeen un-medicated PBD patients, 15 un-medicated ADHD patients, and 14 healthy controls (HC) (mean age = 13.78 +/- 2.47) performed an emotional valence Stroop Task, requiring them to match the color of an emotionally valenced word to the color of either of two adjacent circles. Both patient groups responded significantly slower than HC, but there were no group differences in accuracy. A voxel-wise analysis of variance on brain activation revealed a significant interaction of group by word valence [F(2,41) = 4.44; p = .02]. Similar group differences were found for negative and positive words. For negative versus neutral words, both patient groups exhibited greater activation in dorsolateral prefrontal cortex (DLPFC) and parietal cortex relative to HC. The PBD group exhibited greater activation in ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) relative to HC. The ADHD group exhibited decreased VLPFC activation relative to HC and the PBD group. During cognitive control of emotion processing, PBD patients deployed the VLPFC to a greater extent than HC. The ADHD patients showed decreased VLPFC engagement relative to both HC and PBD patients.

Effects of early intervention on the course of bipolar disorder: theories and realities.

Given the severity and early onset of pediatric bipolar disorder, early intervention is important to bring about recovery and alter the course of the illness. There is a new and burgeoning body of literature on the biological basis of early signs of the illness and the mechanistic understanding of treatment interventions. Biological findings based on multimodal imaging, genomic studies of cellular proteins, and performance-based findings of neurocognitive studies are beginning to assemble a cohesive and interlinked model of systems neuroscience. This offers the promise of identifying biomarkers, predictors of illness, and treatment outcomes. In complement, at the tier of clinical application is a multitude of efficacy trials, yet neither a single medication nor a combination of choices seems to suffice in reality. The current review develops a point of view bridging scientific developments to where comprehensive, multipronged treatment strategies find their clinical application-a model that is similarly applicable in adult bipolar disorder.

Neural correlates of response inhibition in pediatric bipolar disorder and attention deficit hyperactivity disorder.

Impulsivity, inattention and poor behavioral inhibition are common deficits in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). This study aimed to identify similarities and differences in the neural substrate of response inhibition deficits that are associated with these disorders. A functional magnetic resonance imaging (fMRI) study was conducted on 15 unmedicated PBD patients (Type I, manic/mixed), 11 unmedicated ADHD patients, and 15 healthy controls (HC) (mean age = 13.5 years; S.D. = 3.5). A response inhibition task examined the ability to inhibit a motor response to a target when a stop cue appeared shortly after. The PBD and ADHD groups did not differ on behavioral performance, although both groups were less accurate than the HC group. fMRI findings showed that for trials requiring response inhibition, the ADHD group, relative to the PBD and HC groups, demonstrated reduced activation in both ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and increased bilateral caudate activation compared with HC. The PBD group, relative to HC, showed decreased activation in the left VLPFC, at the junction of the inferior and middle frontal gyri, and in the right anterior cingulate cortex (ACC). Prefrontal dysfunction was observed in both the ADHD and PBD groups relative to HC, although it was more extensive and accompanied by subcortical overactivity in ADHD.

Attentional engagement increases inferior frontal gyrus activity and mutes limbic activity in pediatric bipolar disorder: Meta-analyses of fMRI studies.

OBJECTIVES: Attention deficit has been shown to exist in adult and pediatric bipolar disorder across the life span. Given that emotion dysregulation is central to bipolar disorder, this study hypothesizes that emotional circuitry regions are altered along with anomalies in the attentional systems during cognitive deployment in bipolar disorder. METHODS: An activation likelihood estimation meta-analysis of attentional activities using GingerALE software was completed for adult and pediatric bipolar disorder populations in all published studies till December 2017. The meta-analysis of all fMRI studies included a total of ten pediatric studies (comprised of pediatric bipolar disorder (PBD) and typically developing (TD) groups) and nine adult patient studies (comprised of adult bipolar disorder (ABD) and healthy control (HC) groups). RESULTS: While engaged in attentional tasks, increased activation was seen in inferior frontal gyrus with decreased activation in limbic regions in subjects with PBD, relative to TD. Differential patterns of underactivity were also noted in the dorsal attentional system i.e., frontostriatal circuit (dorsolateral prefrontal cortex, anterior cingulate cortex, right lentiform nucleus and right globus pallidus) in PBD patients relative to the TD. However, we did not see any significant differences between the adult groups i.e., ABD vs. HC. CONCLUSIONS: In PBD, deploying attentional system potentially improves the fronto-limbic affective circuitry function, despite impaired dorsal attentional system i.e., fronto-striatal circuitry. In contrast, these neural correlates underlying attentional engagement appeared to be not significant in adult BD. LIMITATIONS: We examined the PBD vs. TD and the ABD vs. HC separately instead of four-way contrast (dual meta-analytic study). Also, attentional tasks were not unidimensional and tend to capture selective and sustained attention along with response inhibition, thereby recruiting multiple brain circuits.

Resting-state functional connectivity in medication-naïve adolescents with major depressive disorder.

Adolescence is a vulnerable period for major depressive disorder (MDD). The aim of our study was to investigate resting-state functional connectivity (RSFC) in first-episode, medication-naïve adolescent MDD patients. Twenty-three drug-naïve adolescents diagnosed with first-episode MDD and 27 healthy participants were enrolled. Seed-to-voxel RSFC analyses were performed. The frontolimbic circuit regions of interest included the amygdala, anterior cingulate cortex, insula, and hippocampus. A correlation analysis between the RSFC and Children's Depression Inventory, Hamilton depression rating scale, and duration of episodes was performed. The adolescents with MDD exhibited the following characteristics: a lower RSFC between the right amygdala and right superior frontal gyrus; a lower RSFC between the right hippocampus and clusters including the right insula and right middle frontal gyrus; a higher RSFC between the left insula and clusters including the bilateral middle frontal gyrus, right superior frontal gyrus, and right frontal pole; and a higher RSFC between the left dorsal anterior cingulate cortex and a cluster including the left insula. Medication-naïve adolescents with depression display lower connectivity of several brain regions implicated in processing, regulation, and memory of emotions. Higher connectivity was observed in brain regions that potentially explain rumination, impaired concentration, and physiological arousal.

Decreased protein kinase C (PKC) in platelets of pediatric bipolar patients: effect of treatment with mood stabilizing drugs.

Pediatric bipolar disorder (PBD) is a major public health concern, however, its neurobiology is poorly understood. We, therefore, studied the role of protein kinase C (PKC) in the pathophysiology of bipolar illness. We determined PKC activity and immunolabeling of various PKC isozymes (i.e., PKC alpha, PKC betaI, PKC betaII, and PKC delta) in the cytosol and membrane fractions of platelets obtained from PBD patients and normal control subjects. PKC activity and PKC isozymes were also determined after 8 weeks of pharmacotherapy of PBD patients (n=16) with mood stabilizers. PKC activity and the protein expression of PKC betaI and betaII, but not PKC alpha or PKC delta, were significantly decreased in both membrane as well as cytosol fractions of platelets obtained from medication-free PBD patients compared with normal control subjects. Eight weeks of pharmacotherapy resulted in significantly increased PKC activity but no significant changes in any of the PKC isozymes in PBD patients. These results indicate that decreases of specific PKC isozymes and decreased PKC activity may be associated with the pathophysiology of PBD and that pharmacotherapy with mood stabilizing drugs results in an increase and normalization of PKC activity along with improvement in clinical symptoms.

An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder.

The pathophysiology of pediatric bipolar disorder (PBD) impacts both affective and cognitive brain systems. Understanding disturbances in the neural circuits subserving these abilities is critical for characterizing developmental aberrations associated with the disorder and developing improved treatments. Our objective is to use functional neuroimaging with pediatric bipolar disorder patients employing a task that probes the functional integrity of attentional control and affect processing. Ten euthymic unmedicated pediatric bipolar patients and healthy controls matched for age, sex, race, socioeconomic status, and IQ were scanned using functional magnetic resonance imaging. In a pediatric color word matching paradigm, subjects were asked to match the color of a word with one of two colored circles below. Words had a positive, negative or neutral emotional valence, and were presented in 30-s blocks. In the negative affect condition, relative to the neutral condition, patients with bipolar disorder demonstrated greater activation of bilateral pregenual anterior cingulate cortex and left amygdala, and less activation in right rostral ventrolateral prefrontal cortex (PFC) and dorsolateral PFC at the junction of the middle frontal and inferior frontal gyri. In the positive affect condition, there was no reduced activation of PFC or increased amygdala activation. The pattern of reduced activation of ventrolateral PFC and greater amygdala activation in bipolar children in response to negative stimuli suggests both disinhibition of emotional reactivity in the limbic system and reduced function in PFC systems that regulate those responses. Higher cortical cognitive areas such as the dorsolateral PFC may also be adversely affected by exaggerated emotional responsivity to negative emotions. This pattern of functional alteration in affective and cognitive circuitry may contribute to the reduced capacity for affect regulation and behavioral self-control in pediatric bipolar disorder.

Affective neural circuitry during facial emotion processing in pediatric bipolar disorder.

BACKGROUND: Facial emotions are central to human interaction. Identifying pathophysiology in affect processing circuitry that supports the ability to assess facial emotions might facilitate understanding of affect regulation in pediatric bipolar disorder. METHODS: Ten euthymic, unmedicated pediatric bipolar patients and 10 healthy control subjects matched for age, gender, race, socioeconomic status, and IQ were scanned with functional magnetic resonance imaging. Angry, happy, and neutral faces were presented in 30-sec blocks, with a 20-sec rest period between blocks. Subjects were asked to press a button when each face appeared, to ensure that attention was maintained on-task. RESULTS: In bipolar patients, in response to both angry and happy faces relative to neutral faces, we observed reduced activation of right rostral ventrolateral prefrontal cortex together with increased activity in right pregenual anterior cingulate, amygdala, and paralimbic cortex. Bipolar patients also showed reduced activation of visual areas in occipital cortex together with greater activation in higher-order visual perceptual areas, including superior temporal sulcus and fusiform gyrus with angry faces and posterior parietal cortex with happy faces. CONCLUSIONS: Findings document a disturbance in affective neurocircuitry in pediatric bipolar disorder. Reduced activation in ventrolateral prefrontal cortex might reflect diminished top-down control that leads to the observed exaggerated activation in amygdala and paralimbic areas. Changes in occipital areas might represent an effort to gate sensory input when affective responses to the faces could not be successfully modulated. Disturbances in affect processing circuitry could contribute to emotional dysregulation and social cognitive difficulties in bipolar youth.