Establishing a training plan and estimating inter-rater reliability across the multi-site Texas childhood trauma research network.

OBJECTIVE: Minimal guidance is available in the literature to develop protocols for training non-clinician raters to administer semi-structured psychiatric interviews in large, multi-site studies. Previous work has not produced standardized methods for maintaining rater quality control or estimating interrater reliability (IRR) in such studies. Our objective is to describe the multi-site Texas Childhood Trauma Research Network (TX-CTRN) rater training protocol and activities used to maintain rater calibration and evaluate protocol effectiveness. METHODS: Rater training utilized synchronous and asynchronous didactic learning modules, and certification involved critique of videotaped mock scale administration. Certified raters attended monthly review meetings and completed ongoing scoring exercises for quality assurance purposes. Training protocol effectiveness was evaluated using individual measure and pooled estimated IRRs for three key study measures (TESI-C, CAPS-CA-5, MINI-KID [Major Depressive Episodes - MDE & Posttraumatic Stress Disorder - PTSD modules]). A random selection of video-recorded administrations of these measures was evaluated by three certified raters to estimate agreement statistics, with jackknife (on the videos) used for confidence interval estimation. Kappa, weighted kappa and intraclass correlations were calculated for study measure ratings. RESULTS: IRR agreement across all measures was strong (TESI-C median kappa 0.79, lower 95% CB 0.66; CAPS-CA-5 median weighted kappa 0.71 (0.62), MINI-MDE median kappa 0.71 (0.62), MINI-PTSD median kappa 0.91 (0.9). The combined estimated ICC was ≥0.86 (lower CBs ≥0.69). CONCLUSIONS: The protocol developed by TX-CTRN may serve as a model for other multi-site studies that require comprehensive non-clinician rater training, quality assurance guidelines, and a system for assessing and estimating IRR.

Brain functional activation and first mood episode in youth at risk for bipolar disorder.

BACKGROUND: In order to identify biomarkers of prodromal mood disorders, we examined functional brain activation in children and adolescent at familial risk for bipolar disorder. METHODS: Offspring of parents with bipolar I disorder (at-risk youth; N = 115, mean ± SD age: 13.6 ± 2.7; 54 % girls) and group-matched offspring of healthy parents (healthy controls; N = 58, mean ± SD age: 14.2 ± 3.0; 53 % girls) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional and neutral distracters. At baseline, at-risk youth had no history of mood episodes or psychotic disorders. Subjects were followed longitudinally until developing their first mood episode or being lost to follow-up. Standard event-related region-of-interest (ROI) analyses were performed to compare brain activation at baseline between groups and in survival analyses. RESULTS: At baseline, at-risk youth exhibited reduced activation to emotional distracters in the right ventrolateral prefrontal cortex (VLPFC) (p = 0.04). Activation was not significantly altered in additional ROIs, including left VLPFC, bilateral amygdala, caudate, or putamen. In those at-risk youth who developed their first mood episode during follow-up (n = 17), baseline increased activation in right VLPFC, right caudate, and right putamen activation predicted the development of a mood episode. LIMITATIONS: Sample size of converters, loss to follow-up, and number of statistical comparisons. CONCLUSIONS: We found preliminary evidence that a reduced activation in right VLPFC might be a marker of risk for or resilience to mood disorders in at-risk youth. Conversely, an increased activation in the right VLPFC, caudate, and putamen might indicate an increased risk for the later development of their first mood episode.

Neural functional connectivity changes to psychosocial stress in young adults with bipolar disorder and preliminary associations with clinical trajectories.

BACKGROUND: Stress-related mechanisms are implicated in the pathophysiology of bipolar disorder and may contribute to heterogeneity in illness course. Yet, there is a lack of study investigating the neural mechanisms underlying the stress response in this condition. This study investigated changes in amygdala activation and functional connectivity in response to acute psychosocial stress in young adults with bipolar disorder and explored relations with clinical phenotype and prospective mood symptoms. METHODS: 42 young adults [19 with bipolar disorder, agemean  ± SD =21.4 ± 2.2 years] completed a modified version of the Montreal Imaging Stress Task. Amygdala activation and functional connectivity with prefrontal cortex (PFC) regions of interest was calculated for control and stress conditions. Main effects of group, condition, and group by condition interaction on amygdala activation and connectivity were modeled. A subset of bipolar participants completed 1-year follow-up assessments. Relations between neural responses to stress with concurrent substance use and prospective mood symptoms were explored. RESULTS: There were no between-group differences in amygdala activation or functional connectivity during the control condition. Increased right amygdala-right rostral PFC (rPFC) functional connectivity to stress was observed in bipolar disorder, compared to typically developing controls. In bipolar disorder, greater increase in right amygdala-right rPFC functional connectivity to stress was associated with less frequent cannabis use, and prospectively with shorter duration and lower severity of depression symptoms over follow-up. CONCLUSION: Results from this preliminary study suggest differences in frontolimbic functional connectivity responses to stress in young adults with bipolar disorder and associations with cannabis use and prospective mood symptoms.

Recent Perceived Stress, Amygdala Reactivity to Acute Psychosocial Stress, and Alcohol and Cannabis Use in Adolescents and Young Adults With Bipolar Disorder.

Background: Psychosocial stress negatively affects the clinical course of bipolar disorder. Studies primarily focused on adults with bipolar disorder suggest the impact of stress is progressive, i.e., stress response sensitizes with age. Neural mechanisms underlying stress sensitization are unknown. As stress-related mechanisms contribute to alcohol/substance use disorders, variation in stress response in youth with bipolar disorder may contribute to development of co-occurring alcohol/substance use disorders. This study investigated relations between psychosocial stress, amygdala reactivity, and alcohol and cannabis use in youth with bipolar disorder, compared to typically developing youth. Methods: Forty-two adolescents/young adults [19 with bipolar disorder, 23 typically developing, 71% female, agemean ± SD = 21 ± 2 years] completed the Perceived Stress Scale (PSS), Daily Drinking Questionnaire modified for heaviest drinking week, and a modified Montreal Imaging Stress functional MRI Task. Amygdala activation was measured for both the control and stress conditions. Main effects of group, condition, total PSS, and their interactions on amygdala activation were modeled. Relationships between amygdala response to acute stress with recent alcohol/cannabis use were investigated. Results: Greater perceived stress related to increased right amygdala activation in response to the stress, compared to control, condition in bipolar disorder, but not in typically developing youth (group × condition × PSS interaction, p = 0.02). Greater amygdala reactivity to acute stress correlated with greater quantity and frequency of alcohol use and frequency of cannabis use in bipolar disorder. Conclusion: Recent perceived stress is associated with changes in amygdala activation during acute stress with amygdala reactivity related to alcohol/cannabis use in youth with bipolar disorder.

Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder

Objective: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). Methods: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. Results: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). Conclusions: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Childhood maltreatment, prefrontal-paralimbic gray matter volume, and substance use in young adults and interactions with risk for bipolar disorder.

Childhood maltreatment is associated with adverse effects on the brain, and an increased risk for psychopathology, including mood and substance use disorders. Individuals vary on the degree to which they exhibit neurobiological and clinical differences following maltreatment. Individuals with bipolar disorder exhibit greater magnitude of maltreatment-related prefrontal-paralimbic gray matter volume (GMV) deficits compared to typically developing individuals. It is unclear if greater structural differences stem from greater neural vulnerability to maltreatment in bipolar disorder, or if they relate to presence of other clinical features associated with childhood maltreatment, e.g., elevated prevalence of comorbid substance use disorders. To investigate this, we compared young adults with a family history of bipolar disorder (n = 21), but who did not fulfill diagnostic criteria for bipolar disorder, with typically developing young adults without a family history of bipolar disorder (n = 26). Participants completed structural neuroimaging, clinical and family history interviews, and assessment of childhood maltreatment and recent alcohol and cannabis use patterns. We examined relations between childhood maltreatment and prefrontal-paralimbic GMV by modeling main effects of maltreatment and family history group by maltreatment interactions on prefrontal-paralimbic GMV. We also examined relations between maltreatment and associated GMV changes with recent alcohol and cannabis use. Childhood maltreatment correlated with lower ventral, rostral and dorsolateral prefrontal and insular cortical GMV across all participants regardless of the presence or absence of familial history of bipolar disorder. However, exploratory analyses did reveal greater maltreatment-related GMV differences in individuals with prodromal symptoms of depression. Lower insula GMV was associated with greater frequency of cannabis use across all participants and greater quantity of alcohol use only in those with familial risk for bipolar disorder. Results suggest familial risk for bipolar disorder, and presumably genetic risk, may relate to outcomes following childhood maltreatment and should be considered in prevention/early intervention strategies.

Variation in rostral anterior cingulate functional connectivity with amygdala and caudate during first manic episode distinguish bipolar young adults who do not remit following treatment.

OBJECTIVES: Altered activity in the ventrolateral prefrontal and anterior cingulate cortices, as well as subcortical and amygdala projection sites, was previously reported during a first manic episode in youth with bipolar disorder and observed to be associated with treatment response. To extend these findings, we investigated functional connectivity among these regions in first-episode manic participants who remitted after 8 weeks of treatment compared to those who did not. METHODS: Forty-two participants with bipolar disorder (60% female) during their first manic episode were recruited and received 8 weeks of treatment. Twenty-one remitted following treatment. Participants completed fMRI scans, at baseline and following 8 weeks of treatment, while performing a continuous performance task with emotional and neutral distractors. A healthy comparison group (n = 41) received fMRI evaluations at the same intervals. Differences in functional connectivity of the amygdala and caudate with the rostral anterior cingulate and ventrolateral prefrontal cortices at baseline (and changes in functional connectivity following treatment) were modeled between groups. RESULTS: At baseline, non-remitters showed an increase in positive connectivity between right anterior cingulate and caudate and a loss of negative connectivity between right anterior cingulate and amygdala, compared to healthy participants. Individuals who remitted following treatment showed an increase in negative connectivity between amygdala and left anterior cingulate 8 weeks following treatment. CONCLUSIONS: Results provide evidence of alterations in anterior cingulate amygdala and caudate functional connectivity in bipolar disorder non-remitters during a first manic episode and changes in anterior cingulate functional connectivity associated with remission suggesting targets to predict treatment response. Registered at ClinicalTrials.Gov; Functional and Neurochemical Brain Changes in First-episode Bipolar Mania. NCT00609193. URL: https://clinicaltrials.gov/ct2/show/NCT00609193?term=strakowskirank=1.

Subjective response to alcohol: Associated alcohol use and orbitofrontal gray matter volume in bipolar disorder.

BACKGROUND: Alcohol use disorders (AUDs) are highly prevalent in bipolar disorder, however the developmental etiology of this comorbidity remains unknown. Structural differences in the orbitofrontal cortex (OFC) have been linked to problematic drinking in bipolar disorder and typically developing youth, with evidence implicating variations in OFC in differential subjective response to alcohol in typical development. METHODS: Subjective response to alcohol, recent alcohol use, impulsivity, and variation in OFC gray matter volume were investigated in 48 emerging adults (24 with bipolar disorder, 24 typically developing). On average 1.5 years later, drinking patterns were reassessed and relations between subjective response and changes in alcohol use were explored. RESULTS: Groups did not differ in baseline alcohol use or subjective response. At baseline, decreased subjective response to alcohol was associated with increased alcohol use in both groups. Lower gray matter volume in medial OFC in bipolar disorder was associated with increased subjective response to alcohol, whereas lower gray matter volume in OFC in typically developing participants was associated with decreased subjective response to alcohol. Increase in alcohol use (baseline to follow-up) was associated with increased baseline subjective response to alcohol in bipolar disorder, and decreased baseline subjective response in the typically developing group. LIMITATIONS: Preliminary study with a small sample size. CONCLUSION: Underlying OFC biology may contribute to differences in alcohol sensitivity in bipolar disorder which may also relate to prospective changes in alcohol use patterns. Future studies are needed to examine how these factors prospectively relate to development of AUDs in bipolar disorder.

Frontolimbic brain volume abnormalities in bipolar disorder with suicide attempts.

Over 2.3 million people in the United States live with bipolar disorder. Sixty percent of those with a bipolar disorder diagnosis attempt suicide at least once in their lifetime and up to 19% die by suicide. However, the neurobiology of suicide attempts in bipolar disorder remains unclear. We studied the gray matter volume (GMV) of 81 participants with a bipolar-I diagnosis (age-range: 14-34 years old) and 40 healthy participants (age-range 14.7-32 years old) to compare their neuroanatomy and histories of suicide attempt. In the bipolar group, 42 were manic with ages ranging from 14-30.6 years, and 39 were depressed with ages ranging from 14-34.3 years). Twenty three bipolar participants had a suicide attempt history, and 58 had no suicide attempt history. All participants completed behavioral/diagnostic assessments and MRI. We focused on a predefined frontolimbic circuitry in bipolar disorder versus controls to first identify diagnostic GMV correlates and to specifically identify GMV correlates for suicide attempt history. We found reduced GMV in bipolar diagnosis versus controls in the subgenual cingulate and dorsolateral prefrontal cortices. Our observed regional GMV reductions were associated with histories of suicide attempts and measures of individual variations in current suicidal ideation at the time of scanning.

Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder.

OBJECTIVE: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). METHODS: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. RESULTS: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). CONCLUSIONS: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Neurophysiological effects of multiple mood episodes in bipolar disorder.

OBJECTIVES: Bipolar disorder is marked by progressive symptomatic changes, which have been linked with episode-related structural findings-particularly in the prefrontal cortex. However, few studies have examined neurofunctional and neurochemical effects of disease burden. In this study, we compared first- and multi-episode bipolar individuals. We hypothesized that the latter would demonstrate evidence of neurophysiological differences consistent with a model of progressive functional degradation of these networks. METHODS: First- and multi-episode manic bipolar subjects participated in functional magnetic resonance imaging (fMRI) including a continuous performance task with emotional distractors, and in single-voxel (1 H) magnetic resonance spectroscopy (MRS). A priori fMRI regions-of-interest (ROI) included structures comprising prefrontal-striatal-amygdala networks; (1 H)MRS voxels were placed within bilateral ventrolateral prefrontal (VLPFC) and anterior cingulate cortex (ACC). Both ROI and voxel-based brain activation in response to emotional stimuli, and neurochemical concentrations derived from (1 H)MRS were compared across bipolar groups. RESULTS: Multi-episode bipolar subjects showed relatively lower regional activation across prefrontal-striatal-amygdala networks, including bilateral VLPFC, orbitofrontal cortex, ACC, putamen, caudate, and amygdala. Exploratory whole-brain, voxel-based analysis suggested additional areas of lower activation extending into Brodmann area 22, posterior parietal regions, and right thalamus. Glutamate and N-acetylaspartate (NAA) concentrations were also relatively lower in the ACC of multi-episode subjects. CONCLUSIONS: Disease burden, exemplified by multiple affective episodes is associated with evidence of widespread decrements in affective network activity. Lower ACC NAA concentration is similarly consistent with a model of progressive functional deficits. These findings support the functional significance of previously observed progressive structural changes throughout these regions.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode.

OBJECTIVES: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. METHODS: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. RESULTS: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. CONCLUSIONS: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.

Discrete patterns of cortical thickness in youth with bipolar disorder differentially predict treatment response to quetiapine but not lithium.

The need for treatment response predictive biomarkers is being increasingly recognized in children and adolescents with psychiatric disorders. Structural gray matter abnormalities as a predictor of treatment outcome in pediatric bipolar disorder have not been systematically investigated, especially early in the illness course. With a prospective longitudinal study design, the present study enrolled 52 bipolar adolescents with no history of treatment with mood stabilizers or a therapeutic dose of antipsychotic drugs and 31 healthy controls. Patients were randomly assigned to treatment with quetiapine or lithium after pretreatment data collection. A hierarchical cluster analysis was performed using pretreatment cortical thickness data that identified two discrete patient subgroups. Compared to healthy subjects, patients in subgroup 1 (n = 16) showed widespread greater cortical thickness mainly across heteromodal cortex but also involving some regions of unimodal cortex, while those in subgroup 2 (n = 36) showed regional cortical thinning mainly in superior temporal and superior parietal regions. Patients within subgroup 1 showed a significantly higher response rate to quetiapine than those in subgroup 2 (100% vs 53%). No statistically significant difference was found in lithium response rate between the patient subgroups (63% vs 53%). Pretreatment clinical ratings and neuropsychological data did not differ across subgroups. Our findings suggest the existence of distinct and clinically relevant subgroups of pediatric bipolar patients, as defined by pattern of cortical thickness. These groups appear to differentially respond to antipsychotic treatment-notably with greater cortical thickness relative to controls predicting better treatment response.

MRI Evidence of Neuropathic Changes in Former College Football Players.

OBJECTIVE: To examine effects of participating in collegiate football on neural health several years after retirement. We hypothesized that relative cortical thinning and loss of white matter integrity would be observed in former players. DESIGN: Former NCAA Division I football players were compared with demographically similar track-and-field athletes with regard to cortical thickness and white matter integrity. SETTING: Participants participated in MRI scans at the Center for Imaging Research at the University of Cincinnati. PARTICIPANTS: Eleven former football players and 10 demographically similar track-and-field athletes. MAIN OUTCOME MEASURES: Normalized cortical thickness was compared between groups using 2-tailed Student t test. As a secondary analysis, Spearman correlation coefficient was calculated between cortical thickness and number of concussions. Fractional anisotropy for regions-of-interest placed in frontal white matter tracts and internal capsule were compared between groups using 2-tailed Student t test. RESULTS: Football players showed significantly lower cortical thickness within portions of both the frontal and temporal cortex. Affected frontal regions included left frontal pole and right superior frontal gyrus. Affected temporal regions included portions of the superior temporal gyrus, left inferior temporal gyrus, and right middle and superior temporal gyri. Cortical thickness inversely correlated with number of reported concussions over most of these regions. In addition, fractional anisotropy was lower in the right internal capsule of former football players, relative to controls. CONCLUSIONS: These findings suggest that at least some consequences of high-level collegiate football play persist even after the cessation of regular head blows. Longer-term studies are warranted to examine potential cognitive and functional implications of sustained cortical atrophy.

White matter volumes in youth offspring of bipolar parents.

BACKGROUND: Studying youth at high risk of developing bipolar disorder may clarify neurobiological factors associated with vulnerability to this illness. We present here a baseline characterization of brain structure in youth at-risk for bipolar disorder. METHODS: Magnetic resonance images were obtained from 115 child and adolescent offspring of bipolar disorder type I subjects and 57 healthy child and adolescent offspring of healthy parents (healthy control offspring). Offspring of parents with bipolar disorder were divided into healthy bipolar offspring (n=47) or symptomatic bipolar offspring (n=68), according to presence or absence of childhood-onset psychopathology. All bipolar offspring were free of major mood and psychotic disorders. Gray (GM) and white matter (WM) volumes were compared between groups using voxel-based morphometry. RESULTS: No differences in GM volumes were found across groups. Healthy bipolar offspring presented with decreased WM volumes in areas of the right frontal, temporal and parietal lobes, and in the left temporal and parietal lobes compared to healthy control offspring. Symptomatic bipolar offspring did not present with any differences in WM volumes compared to either healthy bipolar offspring or healthy control offspring. LIMITATIONS: Cross-sectional design and heterogeneous sample of symptomatic bipolar offspring. CONCLUSIONS: WM volume decreases in areas of the frontal, occipital, and parietal lobes are present in bipolar offspring prior to the development of any psychiatric symptoms, and may be a correlate of familial risk to bipolar disorder. In this large cohort, we have not found evidence for regional GM volume abnormalities as an endophenotype for bipolar disorder.

Docosahexaenoic acid biostatus is associated with event-related functional connectivity in cortical attention networks of typically developing children.

OBJECTIVE: Although extant preclinical evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is important for neurodevelopment, little is known about its role in human cortical structural and functional maturation. In the present cross-sectional study, we investigated the relationship between DHA biostatus and functional connectivity in cortical attention networks of typically developing children. METHODS: Male children (aged 8-10 years, n = 36) were divided into 'low-DHA' (n = 18) and 'high-DHA' (n = 18) biostatus groups by a median split of erythrocyte DHA levels. Event-related functional connectivity during the performance of a sustained attention task (identical pairs continuous performance task (CPT-IP)) was conducted using functional magnetic resonance imaging. A voxelwise approach used the anterior cingulate cortex (ACC) as the seed-region. RESULTS: Erythrocyte DHA composition in the low-DHA group (2.6 ± 0.9%) was significantly lower than the high-DHA group (4.1 ± 1.1%, P ≤ 0.0001). Fish intake frequency was greater in the high-DHA group (P = 0.003) and was positively correlated with DHA levels among all subjects. The low-DHA group exhibited reduced functional connectivity between the ACC and the ventrolateral prefrontal cortex, insula, precuneus, superior parietal lobule, middle occipital gyrus, inferior temporal gyrus, and lingual gyrus compared with the high-DHA group (P < 0.05; corrected). The low-DHA group did not exhibit greater ACC functional connectivity with any region compared with the high-DHA group. On the CPT-IP task, the low-DHA group had slower reaction time (P = 0.03) which was inversely correlated with erythrocyte DHA among all subjects. DISCUSSION: These data suggest that low-DHA biostatus is associated with reduced event-related functional connectivity in cortical attention networks of typically developing children.

Neurofunctional Differences Among Youth With and at Varying Risk for Developing Mania.

OBJECTIVE: To examine prefrontal and amygdala activation during emotional processing in youth with or at varying risk for developing mania to identify candidate central prodromal risk biomarkers. METHOD: Four groups of medication-free adolescents (10-20 years old) participated: adolescents with first-episode bipolar I disorder (BP-I; n = 32), adolescents with a parent with bipolar disorder and a depressive disorder (at-risk depressed [ARD]; n = 32), healthy adolescents with a parent with bipolar disorder (at-risk healthy [ARH]; n = 32), and healthy adolescents with no personal or family history of psychiatric illness (healthy comparison [HC]; n = 32). Participants underwent functional magnetic resonance imaging while performing a continuous performance task with emotional and neutral distracters. Region-of-interest analyses were performed for the bilateral amygdala and for subregions of the ventrolateral prefrontal cortex and anterior cingulate cortex. RESULTS: Overall, no group differences in bilateral amygdala and ventrolateral prefrontal cortex (Brodmann area [BA] 45/47) activation during emotional or neutral stimuli were observed. The BP-I group exhibited lower right pregenual anterior cingulate cortex activation compared with the HC group, and activation in the left BA 44 was greater in the ARH and ARD groups compared with the HC group. BP-I and ARD groups exhibited blunted activation in the right BA 10 compared with the ARH group. CONCLUSION: During emotional processing, amygdala and ventrolateral prefrontal cortex (BA 45/47) activation does not differ in youth with or at increasing risk for BP-I. However, blunted pregenual anterior cingulate cortex activation in first-episode mania could represent an illness biomarker, and greater prefrontal BA 10 and BA 44 activations in at-risk youth could represent a biomarker of risk or resilience warranting additional investigation in prospective longitudinal studies.

fMRI brain activation changes following treatment of a first bipolar manic episode.

OBJECTIVES: We tested the hypothesis that, with treatment, functional magnetic resonance imaging (fMRI) regional brain activation in first-episode mania would normalize - i.e., that differences from healthy subjects would diminish over time, and would be associated with clinical remission status, potentially identifying neuroanatomic treatment response markers. METHODS: Forty-two participants with bipolar I disorder were recruited during their first manic episode, pseudo-randomized to open-label lithium or quetiapine, and followed for 8 weeks. fMRI scans were obtained at baseline and then after 1 and 8 weeks of treatment, while participants performed a continuous performance task with emotional distracters. Healthy participants received fMRI scans at these same intervals. Specific region-of-interest (ROI) activations within prefrontal emotional networks were assessed as potential measures of treatment response. RESULTS: ROI data were reduced using exploratory factor analysis, which identified five factors that were organizationally consistent with functional anatomic models of human emotion modulation. Half of the participants with bipolar disorder achieved remission by Week 8 and were contrasted with the other half that did not. Analyses demonstrated that, in the bipolar disorder group in general, treatment led to decreases in activation across brain regions toward healthy subject values. However, differences in activation changes were observed between subjects with bipolar disorder who did or did not achieve remission in subcortical and amygdala factors. CONCLUSIONS: These findings provide evidence for potential neuroanatomic treatment response markers in first-episode bipolar disorder.

Neural Function Before and After Mindfulness-Based Cognitive Therapy in Anxious Adolescents at Risk for Developing Bipolar Disorder.

OBJECTIVE: We sought to evaluate the neurophysiology of mindfulness-based cognitive therapy for children (MBCT-C) in youth with generalized, social, and/or separation anxiety disorder who were at risk for developing bipolar disorder. METHODS: Nine youth (mean age: 13 ± 2 years) with a generalized, social, and/or separation anxiety disorder and a parent with bipolar disorder completed functional magnetic resonance imaging (fMRI) while performing a continuous processing task with emotional and neutral distractors (CPT-END) prior to and following 12 weeks of MBCT-C. RESULTS: MBCT-C was associated with increases in activation of the bilateral insula, lentiform nucleus, and thalamus, as well as the left anterior cingulate while viewing emotional stimuli during the CPT-END, and decreases in anxiety were correlated with change in activation in the bilateral insula and anterior cingulate during the viewing of emotional stimuli (p < 0.05, uncorrected; p < 0.005 corrected; cluster size, 37 voxels). CONCLUSIONS: MBCT-C treatment in anxious youth with a familial history of bipolar disorder is associated with increased activation of brain structures that subserve interoception and the processing of internal stimuli-functions that are ostensibly improved by this treatment.

Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: a preliminary 1H MRS study.

OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H MRS) to investigate the effects of fish oil (FO) supplementation on cortical metabolite concentrations in adolescents with major depressive disorder (MDD). METHODS: Metabolite concentrations were determined by (1)H MRS in the anterior cingulate cortex and bilateral dorsolateral prefrontal cortex (DLPFC) of adolescents with MDD before and following 10-week open-label supplementation with low (2.4 g/day, n = 7) or high (16.2 g/day, n = 7) dose FO. Depressive symptom severity scores and erythrocyte fatty acid levels were also determined. RESULTS: Baseline erythrocyte eicosapentaenoic acid (EPA) composition was positively correlated, and arachidonic acid (AA) and the AA/EPA ratio were inversely correlated, with choline (Cho) concentrations in the right DLPFC. Docosahexaenoic acid (DHA) composition was inversely correlated with myo-inositol (mI) concentrations in the left DLPFC. Erythrocyte EPA and DHA composition increased, and AA decreased, significantly following low-dose and high-dose FO supplementation. In the intent-to-treat sample, depressive symptom severity scores decreased significantly in the high-dose group (-40%, P < 0.0001) and there was a trend in the low-dose group (-20%, P = 0.06). There were no significant baseline-endpoint changes in metabolite levels in each voxel. In the low-dose group there were changes with large effect sizes, including a decrease in mI in the left DLPFC (-12%, P = 0.18, d = 0.8) and increases in glutamate + glutamine (Glx) (+12%, P = 0.19, d = 0.8) and Cho (+15%, P = 0.08, d = 1.2) in the right DLPFC. In the high-dose group, there was a trend for increases in Cho in the right DLPFC (+10%, P = 0.09, d = 1.2). DISCUSSION: These preliminary data suggest that increasing the LCn-3 fatty acid status of adolescent MDD patients is associated with subtle changes in Glx, mI, and Cho concentrations in the DLPFC that warrant further evaluation in a larger controlled trial.