Objective-To investigate microstructure of white matter fiber tracts in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD).Methods-A diffusion tensor imaging (DTI) study was conducted at 3 Tesla on age and IQ-matched children and adolescents with PBD (n=13), ADHD (n=13), and healthy controls (HC) (n=15). Three DTI parameters, fractional anisotropy (FA), apparent diffusion coefficient (ADC), and regional fiber coherence index (r-FCI), were examined in eight fiber tracts: Anterior corona radiata (ACR); anterior limb of the internal capsule (ALIC); superior region of the internal capsule (SRI); posterior limb of the internal capsule (PLIC); superior longitudinal fasciculus (SLF); inferior longitudinal fasciculus (ILF); cingulum (CG); splenium (SP).Results-Significantly lower FA was observed in ACR in both PBD and ADHD relative to HC. In addition, FA and r-FCI values were significantly lower in ADHD relative to PBD and HC in both the ALIC and the SRI. Further, ADC was significantly greater in ADHD relative to both the PBD and HC in ACR, ALIC, PLIC, SRI, CG, ILF, and SLF. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conclusions-Decreased FA in ACR implies an impaired fiber density or reduced myelination in both PBD and ADHD in this prefrontal tract. These abnormalities, together with the reduced fiber coherence, extended to cortico-bulbar tracts in ADHD. Increased ADC across multiple white matter tracts in ADHD indicates extensive cellular abnormalities with less diffusion restriction in ADHD relative to PBD. NIH Public Access

Objective-This fMRI study examined how working memory circuits are affected by face emotion processing in pediatric bipolar disorder (PBD) and attention-deficit hyperactivity disorder (ADHD).Methods-Twenty-three patients with bipolar disorder, 14 patients with ADHD and 19 healthy controls (HC) (mean age = 13.36 ± 2.55) underwent an affective 2-back fMRI task with blocks of happy, angry and neutral faces.Results-For angry vs neutral faces PBD patients, relative to ADHD patients, exhibited increased activation in subgenual anterior cingulate cortex (ACC) and orbitofrontal cortex, and reduced activation in dorsolateral prefrontal cortex (DLPFC) and premotor cortex. Relative to HC the PBD group showed no increased activation and reduced activation at the junction of DLPFC and ventrolateral prefrontal cortex (VLPFC). Relative to HC the ADHD patients exhibited greater activation in DLPFC and reduced activation in ventral and medial PFC, pregenual ACC, striatum and temporo-parietal regions. For happy vs neutral faces, relative to ADHD the PBD group exhibited greater activation in bilateral caudate, and relative to HC it showed increased activation in DLPFC, striatal and parietal regions, and no reduced activation. The ADHD group, compared to HC, showed no reduced activation and increased activation in regions that were under-active for the angry face condition.Conclusions-Relative to the ADHD group the PBD group exhibited greater deployment of the emotion processing circuitry and reduced deployment of working memory circuitry. Commonalities across PBD and ADHD patients, relative to HC, entailed cortico-subcortical activity that is reduced under negative emotional challenge, and increased under positive emotional challenge.

Impulsivity, inattention and poor behavioral inhibition are common deficits in PBD (Pediatric Bipolar Disorder) and ADHD (Attention Deficit Hyperactivity Disorder). 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 un-medicated PBD patients (Type I, manic/mixed), 11 un-medicated 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 group 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 to HC. The PBD group, relative to HC, showed decreased activation in left VLPFC, at the junction of inferior and middle frontal gyri, and in 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 sub-cortical over activity in ADHD.

Although a few developmental fMRI studies have shed some light on the neurological development of either object or spatial processing we still know very little about the development of the 'what' and 'where' processing systems. The present study is the first to address this issue by comparing, concurrently and within the same behavioral paradigm, patterns of functional activation for face processing and location processing in 12 children (10-12 years old) and 16 adults. For both tasks this study found a developmental shift from a more distributed pattern of activation in children to a more focused pattern of activation in adults. Furthermore, the type of developmental redistribution of activation in children varied depending on the task. The present findings have important implications for theories of visuospatial development. They suggest that the neural systems involved in face and location processing may undergo development and fine-tuning well into late childhood.

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.

Objective To use functional neuroimaging to probe the affective circuitry dysfunctions underlying disturbances in emotion processing and emotional reactivity in pediatric bipolar disorder (PBD). Method Equal numbers of controls (HC) and unmedicated patients with euthymia and PBD were matched for age, sex, race, socioeconomic status, and IQ (n = 10 per group; mean age 14.2 years [SD 2.0 years]). The task consisted of a “directed” emotion processing condition where subjects judged whether emotion in facial expression was positive or negative and an “incidental” condition where subjects judged whether faces expressing similar affect were older or younger than 35 years. Results Relative to the directed condition, the incidental condition elicited greater activation in the right amygdala and the right insula, the left middle frontal gyrus, and the left posterior cingulate cortex in patients with PBD, in contrast to the HC that showed greater activation in the right superior frontal gyrus. In both incidental and directed conditions, relative to visual fixation, patients with PBD showed less activation in the right prefrontal cortex (superior, middle, and inferior frontal gyri) and the pregenual anterior cingulate cortex and greater activation in the posterior visual and face-processing regions (i.e., right precuneus/cuneus, fusiform gyrus). Conclusions Increased amygdala activation observed in patients with PBD elicited by incidental emotional processing relative to directed emotional processing may indicate more intense automatic emotional reactivity. Furthermore, the right prefrontal systems that are believed to modulate affect seem to be less engaged in patients with PBD regardless of whether the emotion processing is incidental or directed, which may signify reduced top-down control of emotional reactivity in PBD.

Rationale Neural deficits at the interface of affect and cognition may improve with pharmacotherapy in pediatric bipolar disorder (PBD). Objectives We examined lamotrigine treatment impact on the neural interface of working memory and affect in PBD. Methods Un-medicated, acutely ill, patients with mania and hypomania (n=17), and healthy controls (HC; n=13; mean age=13.36±2.55) performed an affective two-back functional magnetic resonance imaging task with blocks of angry vs neutral faces (i.e., angry face condition) or happy vs neutral faces (i.e., happy face condition) before treatment and at follow-up, after 8-week treatment with second-generation antipsychotics followed by 6 weeks of lamotrigine monotherapy. Results At baseline, for the angry face condition, PBD, relative to HC, showed reduced activation in the left ventrolateral prefrontal cortex (VLPFC) and right caudate; for the happy face condition, PBD showed increased activation in bilateral PFC and right amygdala and middle temporal gyrus. Post-treatment, PBD showed greater activation in right amygdala relative to HC for both conditions. Patients, relative to HC, exhibited greater changes over time in the right VLPFC and amygdala, left subgenual anterior cingulate cortex and left caudate for the angry face condition, and in right middle temporal gyrus for the happy face condition. Conclusions Pharmacotherapy resulted in symptom improvement and normalization of higher cortical emotional and cognitive regions in patients relative to HC, suggesting that the VLPFC dysfunction may be state-specific in PBD. Amygdala was overactive in PBD, relative to HC, regardless of reduction in manic symptoms, and may be a trait marker of PBD.

Objective-The aim of the current study is to determine whether pharmacotherapy normalizes cognitive circuitry function supporting voluntary behavioral inhibition in adolescent bipolar disorder (ABD).Method-Healthy controls (HC) and unmedicated patients with ABD in manic, mixed or hypomanic episodes are matched on demographics and IQ (n=13 per group; Mean age=14.4 ±2.4 years). fMRI studies are performed at baseline and after 14 weeks, during which time patients with ABD are treated initially with second generation antipsychotics (SGAs) followed by lamotrigine monotherapy. A Response Inhibition Task is administered in which a planned motor response, already on the way' to execution, has to be voluntarily inhibited on the trials where a stop signal is presented at varying delays between the cue to respond and response initiation. There are six blocks, each with a predominant rate of "Go" or "Stop" trials and separated by a 10 sec rest/ fixation period.Results-All patients showed significant improvement in both the manic and depressive symptoms from baseline (p<.001). Behavioral data showed that accuracy improved over 14 weeks in patients and HC. Significant time by group interaction effects [F(1, 24) =5.34, p<.03] for the difference between Stop vs. Go blocks showed greater increases of activation in prefrontal (left inferior and middle frontal gyri and medial frontal gyrus bilaterally) and temporal (left superior temporal gyrus and right middle temporal gyrus) regions, and greater decreases in activation in right putamen and bilateral thalamus at follow-up in the ABD group. Increased ventrolateral prefrontal cortex function was related to clinical treatment response.Conclusions-Treatment with SGAs followed by lamotrigine monotherapy enhances prefrontal and temporal lobe activity during a Response Inhibition Task demonstrating the reversal of disorder-relevant neural circuitry dysfunction in patients with ABD. Patients are not slowed down in performance with this treatment regime. Keywordsfrontal; striatum; bipolar; child; fMRI; cognition In adolescent bipolar disorder (ABD), inattention, impulsivity and behavioral dis-inhibition are prominent and persist even after achieving mood stability. 4 The frontostriatal circuitry that supports motor response inhibition has been shown to be affected in ABD. 5 Appropriate goals of treatment, therefore, are to aim for mood stabilization, reducing motor response inhibition problems, and reversing the related frontostriatal deficits in ABD. Lamotrigine is one such medication that is used to stabilize mood in ABD 6 and adult bipolar disorder (BD) 7;8 due to its glutamatergic attenuating function that is believed to have the potential to improve cognitive function related to motor response inhibition problems. [9][10][11] There is preliminary evidence from two fMRI studies indicating that lamotrigine may enhance brain circuitry function in bipolar disorder. 6;12 In a study of patients with ABD performing an affective task requiring the rating of emotions in pictures, re...