OBJECTIVE The aim of the current study was to determine the influence of implicated affective circuitry disturbance in pediatric bipolar disorder (PBD) on behavioral inhibition. The differential influence of an antipsychotic and an anti-epileptic medication on the functional connectivity across affective and cognitive neural operations in PBD was examined.. METHODS This was a six-week double blind randomized fMRI trial of risperidone plus placebo vs. divalproex plus placebo for patients with mania (n=22; 13.6±2.5 years). Healthy controls (HC; n=14, 14.5±2.8 years) were also scanned for normative comparison. Participants performed a response inhibition fMRI task where a motor response, already ‘on the way’ to execution, had to be voluntarily inhibited on trials where a stop signal was presented. Independent component analysis was used to map functional connectivity across the whole brain. RESULTS While there were no behavioral differences between the groups at pre- or post-drug trial, there was significant improvement on manic symptoms in the patient groups. All participants engaged an Evaluative Affective Circuit (EAC: bilateral inferior frontal gyrus, middle frontal gyrus, anterior cingulate cortex (ACC), middle temporal gyrus, insulae, caudate and putamen) and a Reactive Affective Circuit (RAC: bilateral occipital cortex, amygdala, medial frontal gyrus and insula) during task performance. Within the EAC, post treatment and relative to HC, greater engagement was seen in left insula in risperidone group and left subgenual ACC in divalproex group. Within the RAC, greater baseline amygdala connectivity in patients did not alter with treatment. CONCLUSION EAC and RAC are two key circuits that moderate emotional influence on response inhibition in PBD. Risperidone and divalproex differentially engage the EAC. Limited change in amygdala activity with treatment in all patients indicates a likely trait deficit in PBD.

The aim of this study was to determine functional connectivity among patients with pediatric bipolar disorder (PBD) who are responders to pharmacotherapy and those who are nonresponders, and learn how they differ from healthy controls (HC) while performing a task that engages affective and cognitive neural systems. PBD participants (n = 34; 13.4 -2.3 years) were defined as responders if there was ‡ 50% improvement in Young Mania Rating Scale (YMRS) scores (n = 22) versus nonresponders with < 50% improvement (n = 12) with one of three mood stabilizing medications (divalproex, risperidone, or lamotrigine). HC (n = 14; 14.2 -3.1 years) participants also were scanned at baseline and follow-up. During functional magnetic resonance imaging, participants performed a color-matching task in which they had to match the color of positive, negative, or neutral words with colored dots. Independent component analysis was used to identify functionally connected networks across the whole brain, which were subsequently interrogated using region-of-interest analyses to test for group differences. A frontolimbic network was identified that showed impaired functional integration in PBD relative to HC when participants viewed negatively valenced words. PBD medication responders showed greater connectivity of the amygdala into the network before and after treatment compared with nonresponders, with responders showing a pattern more similar to HC than to nonresponders. Regardless of medication type, the degree of amygdala functional connectivity predicted medication response as well as the improvement in YMRS scores across responders and nonresponders. These findings suggest that increased functional integration of the amygdala within the frontolimbic network might be a biomarker of general mood stabilizer medication responsivity in bipolar disorder.

This study examined whether adolescents with pediatric bipolar disorder (PBD) have abnormal regional functional connectivity in distributed brain networks during an affective working memory task. Adolescents with PBD (n=41) and healthy controls (HC; n=16) performed a two-back functional magnetic resonance imaging working memory task with blocks of either angry or neutral faces. Independent component analysis methodology identified two temporally independent and functionally connected brain networks that showed differential functional connectivity in PBD and HC. Within a network for "affect evaluation and regulation," PBD showed decreased functional connectivity relative to HC in regions involved in emotion processing such as the right amygdala, and in emotion regulation regions such as the right ventrolateral prefrontal cortex (VLPFC), while functional connectivity was increased in emotion evaluation regions such as the bilateral medial PFC. Furthermore, in an "Affective Working Memory Network," PBD exhibited greater connectivity relative to HC in left dorsolateral PFC (DLPFC), caudate, and right VLPFC; and simultaneously reduced connectivity in emotion processing regions, such as the right amygdala, bilateral temporal regions, and the junction of DLPFC/VLPFC, which interfaces affective and cognitive processes. Dysfunction in network engagement in PBD patients illustrates that they are expending greater effort in face emotion evaluation, while being less able to engage affect regulation regions.

Background In response to emotional faces, patients with adolescent bipolar disorder (ABD) exhibit increased neural activity in subcortical emotional processing regions (e.g. amygdala, ventral striatum) and variable prefrontal activity. We extend previous research by identifying cortical and subcortical regions showing altered hemodynamic response shapes in ABD relative to healthy controls (HC). Methods ABD (N = 65) and matched HC (N= 79) completed a slow event-related affective hemodynamic probe task that required indicating the gender of fearful and neutral faces. An informed basis set in SPM8 evaluated shape variations of the hemodynamic responses to these faces. Results Patients with ABD showed higher activity for fearful relative to neutral faces in the amygdala and prefrontal cortex and a delayed hemodynamic response to fearful faces in dorsolateral and ventrolateral prefrontal cortices (PFC), as well as bilateral amygdala and caudate. Furthermore, the ABD group, relative to HC, showed a prolonged response to fearful faces in right dorsolateral PFC. Clinical measures of mania and depression severity correlated with increased processing delays in the amygdala and striatum. Limitations By design, the task contained fewer, more widely-spaced stimuli, possibly reducing its power to detect group differences. The use of fearful faces makes comparisons with prior literature in ABD somewhat more difficult. Conclusions The ABD group engaged in enhanced neural processing of the fearful faces which was associated with increasingly severe manic/mixed mood states. These exploratory findings could help elucidate a “biosignature” of emotion-attention interactions in ABD and present a potential target for reversal with medication treatment.