Familial risk for bipolar I disorder is associated with erythrocyte omega-3 polyunsaturated fatty acid deficits in youth with attention-deficit hyperactivity disorder.

Although attention-deficit/hyperactivity disorder (ADHD) and a family history of bipolar I disorder (BD) increase the risk for developing BD, associated pathoetiological mechanisms remain poorly understood. One candidate risk factor is a neurodevelopmental deficiency in omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This study investigated erythrocyte EPA+DHA biostatus in psychostimulant-free ADHD youth with ('high-risk', HR) and without ('low-risk', LR) a first-degree relative with BD, and healthy controls (HC). Erythrocyte EPA+DHA composition was determined by gas chromatography, and symptom ratings were performed. A total of n = 123 (HR, n = 41; LR, n = 42; HC, n = 40) youth (mean age: 14.4 ± 2.5 years) were included in the analysis. Compared with HC, erythrocyte EPA+DHA composition was significantly lower in HR (-13%) but not LR (-3%), and there was a trend for HR to be lower than LR (-11%). Both HR and LR differed significantly from HC on all symptom ratings. HR had greater ADHD hyperactivity/impulsive symptom severity, manic symptom severity, and higher parent-reported ratings of internalization, externalization, and dysregulation, compared with LR. ADHD youth with a BD family history exhibit erythrocyte EPA+DHA deficits and a more severe clinical profile, including greater manic and dysregulation symptoms, compared with ADHD youth without a BD family history.

Fish oil supplementation alters emotion-generated corticolimbic functional connectivity in depressed adolescents at high-risk for bipolar I disorder: A 12-week placebo-controlled fMRI trial.

OBJECTIVE: To evaluate the effects of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on emotion-generated corticolimbic functional connectivity in depressed youth at high risk for developing bipolar I disorder. METHODS: Thirty-nine antidepressant-free youth with a current depressive disorder diagnosis and a biological parent with bipolar I disorder were randomized to 12-week double-blind treatment with FO or placebo. At baseline and endpoint, fMRI (4 Tesla) scans were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Seed-to-voxel functional connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds. Measures of depression, mania, global symptom severity, and erythrocyte fatty acids were obtained. RESULTS: Erythrocyte EPA+DHA composition increased significantly in the FO group (+47%, p ≤ 0.0001) but not in the placebo group (-10%, p = 0.11). Significant group by time interactions were found for functional connectivity between the left OFC and the left superior temporal gyrus (STG) and between the right AMY and right inferior temporal gyrus (ITG). OFC-STG connectivity increased in the FO group (p = 0.0001) and decreased in the placebo group (p = 0.0019), and AMY-ITG connectivity decreased in the FO group (p = 0.0014) and increased in the placebo group (p < 0.0001). In the FO group, but not placebo group, the decrease in AMY-ITG functional connectivity correlated with decreases in Childhood Depression Rating Scale-Revised and Clinical Global Impression-Severity Scale scores. CONCLUSIONS: In depressed high-risk youth FO supplementation alters emotion-generated corticolimbic functional connectivity which correlates with changes in symptom severity ratings.

A preliminary study of the effects of mindfulness-based cognitive therapy on structural brain networks in mood-dysregulated youth with a familial risk for bipolar disorder.

BACKGROUND: Mindfulness-based cognitive therapy for children (MBCT-C), as a psychotherapeutic intervention, has been shown to be effective for treating mood dysregulation (MD). While previous neuroimaging studies of MD have reported both pre-treatment structural and functional alterations, the effects of MBCT-C on brain morphological network organisation has not been investigated. METHODS: We investigated brain morphological network organisation in 10 mood-dysregulated youth with familial risk for bipolar disorder and 15 matched healthy comparison youth (HC). Effects of 12 weeks of MBCT-C were examined in the mood-dysregulated youth. Topological properties of brain networks used for analyses were constructed based on morphological similarities in regional grey matter using a graph-theory approach using MRI data. RESULTS: At baseline, compared with the HC group, the mood-dysregulated group exhibited increased global efficiency (Eglob ), decreased path length (Lp ), and abnormal nodal properties, mainly in the limbic system. Right temporal pole alterations at baseline predicted change in Child and Adolescent Mindfulness Measure scores after treatment. The mood-dysregulated group showed significant decreases in both the Eglob and Lp metrics after MBCT-C, suggesting an improved capacity for optimal information processing. Changes in Lp were correlated with changes in Emotion Regulation Checklist scores. Our results show significant topological alterations in the mood-dysregulated group as compared to controls at baseline. After MBCT-C, disrupted topological properties in the mood-dysregulated group were significantly reduced. CONCLUSION: MBCT-C may facilitate clinically meaningful changes in the brain structural network in mood-dysregulated individuals.

Emotion-Related Network Reorganization Following Fish Oil Supplementation in Depressed Bipolar Offspring: An fMRI Graph-Based Connectome Analysis.

INTRODUCTION: Mood disorders are associated with fronto-limbic structural and functional abnormalities and deficits in omega-3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Emerging evidence also suggests that n-3 PUFA, which are enriched in fish oil, promote cortical plasticity and connectivity. The present study performed a graph-based connectome analysis to investigate the role of n-3 PUFA in emotion-related network organization in medication-free depressed adolescent bipolar offspring. METHODS: At baseline patients (n = 53) were compared with healthy controls (n = 53), and patients were then randomized to 12-week double-blind treatment with placebo or fish oil. At baseline and endpoint, erythrocyte EPA+DHA levels were measured and fMRI scans (4 Tesla) were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Graph-based analysis was used to characterize topological properties of large-scale brain network organization. RESULTS: Compared with healthy controls, patients exhibited lower erythrocyte EPA+DHA levels (p = 0.0001), lower network clustering coefficients (p = 0.029), global efficiency (p = 0.042), and lower node centrality and connectivity strengths in frontal-limbic regions (p<0.05). Compared with placebo, 12-week fish oil supplementation increased erythrocyte EPA+DHA levels (p<0.001), network clustering coefficient (p = 0.005), global (p = 0.047) and local (p = 0.023) efficiency, and node centralities mainly in temporal regions (p<0.05). LIMITATIONS: The duration of fish oil supplementation was relatively short and the sample size was relatively small. CONCLUSIONS: These findings provide preliminary evidence that abnormalities in emotion-related network organization observed in depressed high-risk youth may be amenable to modification through fish oil supplementation.

Network-level functional topological changes after mindfulness-based cognitive therapy in mood dysregulated adolescents at familial risk for bipolar disorder: a pilot study.

BACKGROUND: Given that psychopharmacological approaches routinely used to treat mood-related problems may result in adverse outcomes in mood dysregulated adolescents at familial risk for bipolar disorder (BD), Mindfulness-Based Cognitive Therapy for Children (MBCT-C) provides an alternative effective and safe option. However, little is known about the brain mechanisms of beneficial outcomes from this intervention. Herein, we aimed to investigate the network-level neurofunctional effects of MBCT-C in mood dysregulated adolescents. METHODS: Ten mood dysregulated adolescents at familial risk for BD underwent a 12-week MBCT-C intervention. Resting-state functional magnetic resonance imaging (fMRI) was performed prior to and following MBCT-C. Topological metrics of three intrinsic functional networks (default mode network (DMN), fronto-parietal network (FPN) and cingulo-opercular network (CON)) were investigated respectively using graph theory analysis. RESULTS: Following MBCT-C, mood dysregulated adolescents showed increased global efficiency and decreased characteristic path length within both CON and FPN. Enhanced functional connectivity strength of frontal and limbic areas were identified within the DMN and CON. Moreover, change in characteristic path length within the CON was suggested to be significantly related to change in the Emotion Regulation Checklist score. CONCLUSIONS: 12-week MBCT-C treatment in mood dysregulated adolescents at familial risk for BD yield network-level neurofunctional effects within the FPN and CON, suggesting enhanced functional integration of the dual-network. Decreased characteristic path length of the CON may be associated with the improvement of emotion regulation following mindfulness training. However, current findings derived from small sample size should be interpreted with caution. Future randomized controlled trials including larger samples are critical to validate our findings.