Fronto-limbic Dysfunction in Mania Pre-Treatment and Persistent Amygdala Over-activity Post-Treatment in Pediatric Bipolar Disorder

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 2-back fMRI 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 (SGAs) followed by 6 weeks of lamotrigine monotherapy. Results. At baseline, for the angry face condition, PBD, relative to HC, showed reduced activation in left ventrolateral prefrontal cortex (VLPFC) and right caudate; for the happy face condition, they 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 right VLPFC and amygdala, left subgenual anterior cingulated cortex (ACC) 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 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

Emotion Processing Influences Working Memory Circuits in Pediatric Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder

Objective. We 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. Also, 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 increased activation relative to HC in DLPFC, striatal and parietal regions, an 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 vs neutral 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

Oxotremorine treatment reduces repetitive behaviors in BTBR T+ tf/J mice

Repetitive behaviors with restricted interests is one of the core criteria for the diagnosis of autism spectrum disorder (ASD). Current pharmacotherapies that target the dopaminergic or serotonergic systems have limited effectiveness in treating repetitive behaviors. Previous research has demonstrated that administration of muscarinic cholinergic receptor (mAChR) antagonists can exacerbate motor stereotypies while mAChR agonists reduce stereotypies. The present study determined whether the mAChR agonist, oxotremorine affected repetitive behaviors in the BTBR T+ tf/J (BTBR) mouse model of autism. To test the effects of oxotremorine on repetitive behaviors, marble burying and grooming behavior were measured in BTBR mice and compared to that in C57BL/6J (B6) mice. The effects of oxotremorine on locomotor activity was also measured. Thirty minutes before each test, mice received an intraperitoneal injection of saline, 0.001mg or 0.01mg of oxotremorine methiodide. Saline treated BTBR mice exhibited increased marble burying and self-grooming behavior compared to that of saline-treated B6 mice. Oxotremorine significantly reduced marble burying and self48 grooming behavior in BTBR mice, but had no significant effect in B6 mice. In addition, oxotremorine did not affect locomotor activity in BTBR mice, but significantly reduced locomotor activity in B6 mice at the 0.01mg dose. These findings demonstrate that activation of mAChRs reduces repetitive behavior in the BTBR mouse and suggest that treatment with a mAChR agonist may be effective in reducing repetitive behaviors in ASD

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 fMRI 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±3.3 years). 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

Hemispheric Utilization of Alpha Oscillatory Dynamics as a Unique Biomarker of Neural Compensation in Females with Fragile X Syndrome

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide expansion on the FMR1 gene and characterized by intellectual disability, sensory hypersensitivity, executive function difficulties, and social anxiety. Recently, efforts to define neural biomarkers for FXS have highlighted disruptions to power in the alpha frequency band; however the dynamic mechanisms supporting these findings are poorly understood. The current study aimed to explore the temporal and hemispheric dynamics supporting alpha phenotypes in FXS and their relationship with neural phenotypes related to auditory processing using electroencephalography during an auditory evoked task. Adolescents and adults (N = 36) with FXS and age/sex matched typically developing controls (N = 40) completed an auditory chirp task. Frontal alpha power in the prestimulus period was decomposed into “bursts” using percentile thresholding, then assessed for number of bursts per second (burst count) and burst length. Data were compared across left and right hemispheres to assess lateralization of neural activity. Individuals with FXS showed more differences in alpha power compared to TDC primarily in the right hemisphere. Notably, alpha hemisphere outcomes in males with FXS were driven by the number of times they entered a dynamically relevant period of alpha (burst count) rather than length of time spent in alpha. Females with FXS showed reduced burst counts but remained in sustained high alpha states for longer periods of time. Length of time spent in alpha may reflect a modulatory or compensatory mechanism capable of recovering sensory processing abilities in females with FXS resulting in a less severe clinical presentation. Right hemisphere abnormalities may impact sensory processing differences between males and females with FXS. The relationship between alpha burst length, count, sex, and hemisphere may shed light on underlying mechanisms for previously observed alpha power abnormalities in FXS and their variation by sex

Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis

This study evaluated the ability to flexibly shift cognitive set and to consistently maintain a new response preference using the Penn Conditional Exclusion Test (PCET). The relationship of performance errors with catechol-O-methyltransferase (COMT) rs4680 (Val158Met) genotype (Met carriers vs. Val homozygotes) on test performance before and after antipsychotic treatment in 32 first episode psychosis (FEP) patients was examined. After treatment, patients demonstrated a mixture of beneficial and adverse cognitive outcomes that varied in relation to COMT genotype. Met carriers showed decreased perseverative and regressive errors, reflecting improved cognitive flexibility and enhanced stability of behavioral preferences, respectively. In contrast, Val homozygotes exhibited an increase in regressive errors after treatment. These findings suggest that Val homozygotes may be vulnerable to adverse effects of antipsychotic medication on cognitive processes that maintain consistent adaptive response preferences, an ability linked to the striatum in rodent models

Additional file 1 of Common and distinct cortical thickness alterations in youth with autism spectrum disorder and attention-deficit/hyperactivity disorder

Additional file 1. Supplementary methods of sensitivity, heterogeneity, publication bias, and meta-regression analyses. Table S1. PRISMA 2020 Checklist. Table S2. List of excluded studies that meet other inclusion criteria. Table S3. The checklist of imaging methodology quality assessment for all the articles included in the present meta-analysis. Table S4. Data sources of all public database studies included in the present meta-analysis. Table S5. Differences in cortical thickness between pure ADHD without comorbidity and TDC. Fig. S1. Results of cortical thickness differences between ASD and TDC. Fig. S2. Results of cortical thickness differences between ADHD and TDC