Effect of non-invasive spinal cord stimulation in unmedicated adults with major depressive disorder: a pilot randomized controlled trial and induced current flow pattern.

Converging theoretical frameworks suggest a role and a therapeutic potential for spinal interoceptive pathways in major depressive disorder (MDD). Here, we aimed to evaluate the antidepressant effects and tolerability of transcutaneous spinal direct current stimulation (tsDCS) in MDD. This was a double-blind, randomized, sham-controlled, parallel group, pilot clinical trial in unmedicated adults with moderate MDD. Twenty participants were randomly allocated (1:1 ratio) to receive "active" 2.5 mA or "sham" anodal tsDCS sessions with a thoracic (anode; T10)/right shoulder (cathode) electrode montage 3 times/week for 8 weeks. Change in depression severity (MADRS) scores (prespecified primary outcome) and secondary clinical outcomes were analyzed with ANOVA models. An E-Field model was generated using the active tsDCS parameters. Compared to sham (n = 9), the active tsDCS group (n = 10) showed a greater baseline to endpoint decrease in MADRS score with a large effect size (-14.6 ± 2.5 vs. -21.7 ± 2.3, p = 0.040, d = 0.86). Additionally, compared to sham, active tsDCS induced a greater decrease in MADRS "reported sadness" item (-1.8 ± 0.4 vs. -3.2 ± 0.4, p = 0.012), and a greater cumulative decrease in pre/post tsDCS session diastolic blood pressure change from baseline to endpoint (group difference: 7.9 ± 3.7 mmHg, p = 0.039). Statistical trends in the same direction were observed for MADRS "pessimistic thoughts" item and week-8 CGI-I scores. No group differences were observed in adverse events (AEs) and no serious AEs occurred. The current flow simulation showed electric field at strength within the neuromodulation range (max. ~0.45 V/m) reaching the thoracic spinal gray matter. The results from this pilot study suggest that tsDCS is feasible, well-tolerated, and shows therapeutic potential in MDD. This work also provides the initial framework for the cautious exploration of non-invasive spinal cord neuromodulation in the context of mental health research and therapeutics. The underlying mechanisms warrant further investigation. Clinicaltrials.gov registration: NCT03433339 URL: https://clinicaltrials.gov/ct2/show/NCT03433339 .

Common and distinct cortical thickness alterations in youth with autism spectrum disorder and attention-deficit/hyperactivity disorder.

BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with overlapping behavioral features and genetic etiology. While brain cortical thickness (CTh) alterations have been reported in ASD and ADHD separately, the degree to which ASD and ADHD are associated with common and distinct patterns of CTh changes is unclear. METHODS: We searched PubMed, Web of Science, Embase, and Science Direct from inception to 8 December 2023 and included studies of cortical thickness comparing youth (age less than 18) with ASD or ADHD with typically developing controls (TDC). We conducted a comparative meta-analysis of vertex-based studies to identify common and distinct CTh alterations in ASD and ADHD. RESULTS: Twelve ASD datasets involving 458 individuals with ASD and 10 ADHD datasets involving 383 individuals with ADHD were included in the analysis. Compared to TDC, ASD showed increased CTh in bilateral superior frontal gyrus, left middle temporal gyrus, and right superior parietal lobule (SPL) and decreased CTh in right temporoparietal junction (TPJ). ADHD showed decreased CTh in bilateral precentral gyri, right postcentral gyrus, and right TPJ relative to TDC. Conjunction analysis showed both disorders shared reduced TPJ CTh located in default mode network (DMN). Comparative analyses indicated ASD had greater CTh in right SPL and TPJ located in dorsal attention network and thinner CTh in right TPJ located in ventral attention network than ADHD. CONCLUSIONS: These results suggest shared thinner TPJ located in DMN is an overlapping neurobiological feature of ASD and ADHD. This alteration together with SPL alterations might be related to altered biological motion processing in ASD, while abnormalities in sensorimotor systems may contribute to behavioral control problems in ADHD. The disorder-specific thinner TPJ located in disparate attention networks provides novel insight into distinct symptoms of attentional deficits associated with the two neurodevelopmental disorders. TRIAL REGISTRATION: PROSPERO CRD42022370620. Registered on November 9, 2022.

Aberrant brain network topology in youth with a familial risk for bipolar disorder: a task-based fMRI connectome study.

BACKGROUND: Youth with a family history of bipolar disorder (BD) may be at increased risk for mood disorders and for developing side effects after antidepressant exposure. The neurobiological basis of these risks remains poorly understood. We aimed to identify biomarkers underlying risk by characterizing abnormalities in the brain connectome of symptomatic youth at familial risk for BD. METHODS: Depressed and/or anxious youth (n = 119, age = 14.9 ± 1.6 years) with a family history of BD but no prior antidepressant exposure and typically developing controls (n = 57, age = 14.8 ± 1.7 years) received functional magnetic resonance imaging (fMRI) during an emotional continuous performance task. A generalized psychophysiological interaction (gPPI) analysis was performed to compare their brain connectome patterns, followed by machine learning of topological metrics. RESULTS: High-risk youth showed weaker connectivity patterns that were mainly located in the default mode network (DMN) (network weight = 50.1%) relative to controls, and connectivity patterns derived from the visual network (VN) constituted the largest proportion of aberrant stronger pairs (network weight = 54.9%). Global local efficiency (Elocal , p = .022) and clustering coefficient (Cp , p = .029) and nodal metrics of the right superior frontal gyrus (SFG) (Elocal : p < .001; Cp : p = .001) in the high-risk group were significantly higher than those in healthy subjects, and similar patterns were also found in the left insula (degree: p = .004; betweenness: p = .005; age-by-group interaction, p = .038) and right hippocampus (degree: p = .003; betweenness: p = .003). The case-control classifier achieved a cross-validation accuracy of 78.4%. CONCLUSIONS: Our findings of abnormal connectome organization in the DMN and VN may advance mechanistic understanding of risk for BD. Neuroimaging biomarkers of increased network segregation in the SFG and altered topological centrality in the insula and hippocampus in broader limbic systems may be used to target interventions tailored to mitigate the underlying risk of brain abnormalities in these at-risk youth.

Brain morphometric features predict medication response in youth with bipolar disorder: a prospective randomized clinical trial.

BACKGROUND: Identification of treatment-specific predictors of drug therapies for bipolar disorder (BD) is important because only about half of individuals respond to any specific medication. However, medication response in pediatric BD is variable and not well predicted by clinical characteristics. METHODS: A total of 121 youth with early course BD (acute manic/mixed episode) were prospectively recruited and randomized to 6 weeks of double-blind treatment with quetiapine (n = 71) or lithium (n = 50). Participants completed structural magnetic resonance imaging (MRI) at baseline before treatment and 1 week after treatment initiation, and brain morphometric features were extracted for each individual based on MRI scans. Positive antimanic treatment response at week 6 was defined as an over 50% reduction of Young Mania Rating Scale scores from baseline. Two-stage deep learning prediction model was established to distinguish responders and non-responders based on different feature sets. RESULTS: Pre-treatment morphometry and morphometric changes occurring during the first week can both independently predict treatment outcome of quetiapine and lithium with balanced accuracy over 75% (all p < 0.05). Combining brain morphometry at baseline and week 1 allows prediction with the highest balanced accuracy (quetiapine: 83.2% and lithium: 83.5%). Predictions in the quetiapine and lithium group were found to be driven by different morphometric patterns. CONCLUSIONS: These findings demonstrate that pre-treatment morphometric measures and acute brain morphometric changes can serve as medication response predictors in pediatric BD. Brain morphometric features may provide promising biomarkers for developing biologically-informed treatment outcome prediction and patient stratification tools for BD treatment development.

Brain network structural connectome abnormalities among youth with attention-deficit/hyperactivity disorder at varying risk for bipolar I disorder: a cross-sectional graph-based magnetic resonance imaging study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent among youth with or at familial risk for bipolar-I disorder (BD-I), and ADHD symptoms commonly precede and may increase the risk for BD-I; however, associated neuropathophysiological mechanisms are not known. In this cross-sectional study, we sought to investigate brain structural network topology among youth with ADHD, with and without familial risk of BD-I. METHODS: We recruited 3 groups of psychostimulant-free youth (aged 10-18 yr), namely youth with ADHD and at least 1 biological parent or sibling with BD-I (high-risk group), youth with ADHD who did not have a first- or second-degree relative with a mood or psychotic disorder (low-risk group) and healthy controls. We used graph-based network analysis of structural magnetic resonance imaging data to investigate topological properties of brain networks. We also evaluated relationships between topological metrics and mood and ADHD symptom ratings. RESULTS: A total of 149 youth were included in the analysis (49 healthy controls, 50 low-risk youth, 50 high-risk youth). Low-risk and high-risk ADHD groups exhibited similar differences from healthy controls, mainly in the default mode network and central executive network. We found topological alterations in the salience network of the high-risk group, relative to both low-risk and control groups. We found significant abnormalities in global network properties in the high-risk group only, compared with healthy controls. Among both low-risk and high-risk ADHD groups, nodal metrics in the right triangular inferior frontal gyrus correlated positively with ADHD total and hyperactivity/impulsivity subscale scores. LIMITATIONS: The cross-sectional design of this study could not determine the relevance of these findings to BD-I risk progression. CONCLUSION: Youth with ADHD, with and without familial risk for BD-I, exhibit common regional abnormalities in the brain connectome compared with healthy youth, whereas alterations in the salience network distinguish these groups and may represent a prodromal feature relevant to BD-I risk.

Different brain functional network abnormalities between attention-deficit/hyperactivity disorder youth with and without familial risk for bipolar disorder.

Attention-deficit/hyperactivity disorder (ADHD) commonly precedes the initial onset of mania in youth with familial risk for bipolar disorder (BD). Although ADHD youth with and without BD familial risk exhibit different clinical features, associated neuropathophysiological mechanisms remain poorly understood. This study aimed to identify brain functional network abnormalities associated with ADHD in youth with and without familial risk for BD. Resting-state functional magnetic resonance imaging scans were acquired from 37 ADHD youth with a family history of BD (high-risk), 45 ADHD youth without a family history of BD (low-risk), and 32 healthy controls (HC). Individual whole-brain functional networks were constructed, and graph theory analysis was applied to estimate network topological metrics. Topological metrics, including network efficiency, small-worldness and nodal centrality, were compared across groups, and associations between topological metrics and clinical ratings were evaluated. Compared to HC, low-risk ADHD youth exhibited weaker global integration (i.e., decreased global efficiency and increased characteristic path length), while high-risk ADHD youth showed a disruption of localized network components with decreased frontoparietal and frontolimbic connectivity. Common topological deficits were observed in the medial superior frontal gyrus between low- and high-risk ADHD. Distinct network deficits were found in the inferior parietal lobule and corticostriatal circuitry. Associations between global topological metrics and externalizing symptoms differed significantly between the two ADHD groups. Different patterns of functional network topological abnormalities were found in high- as compared to low-risk ADHD, suggesting that ADHD in youth with BD familial risk may represent a phenotype that is different from ADHD alone.

Structural connectivity associated with familial risk for mental illness: A meta-analysis of diffusion tensor imaging studies in relatives of patients with severe mental disorders.

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder-specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta-analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed-based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder-specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta-analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack-knife analysis and subgroup analyses. In disorder-specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.

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.

Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism.

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications.The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism.The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs.The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur.Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism.

N-acetylcysteine as an adjunctive treatment for bipolar depression: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Previous studies and meta-analyses suggested that N-acetylcysteine (NAC) was superior to placebo in improving depression in bipolar disorder. However, more recent data, including two larger trials, found that NAC was no more effective than placebo. We conducted a meta-analysis to appraise the possible efficacy of NAC in treating bipolar depression. METHODS: A systematic review and meta-analysis of double-blind, placebo-controlled trials of NAC as a treatment augmentation strategy for bipolar depression was carried out in PubMed (1966-2020). We utilized random-effect analysis to evaluate improvement in depressive symptoms from baseline to endpoint as the primary efficacy measure. RESULTS: Six trials including 248 patients were included. Treatment augmentation with NAC showed a moderate effect size favoring NAC over placebo (d = 0.45, 95% C.I.: 0.06-0.84). There was substantial heterogeneity (I2  = 49%). Meta-regression analyses did not identify any moderator that might explain variation in heterogeneity, including baseline depressive symptom scores, mean NAC dose, or duration of study. CONCLUSIONS: Results from six clinical trials suggest that treatment augmentation with NAC for bipolar depression appears to be superior to placebo, with a moderate effect size, but a large confidence interval. Larger clinical trials, investigating possible moderating factors, such as NAC dose, treatment duration, baseline depression severity, or chronicity of illness, are warranted.

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.

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.

Individual prediction of symptomatic converters in youth offspring of bipolar parents using proton magnetic resonance spectroscopy.

Children of individuals with bipolar disorder (bipolar offspring) are at increased risk for developing mood disorders, but strategies to predict mood episodes are unavailable. In this study, we used support vector machine (SVM) to characterize the potential of proton magnetic resonance spectroscopy (1H-MRS) in predicting the first mood episode in youth bipolar offspring. From a longitudinal neuroimaging study, 19 at-risk youth who developed their first mood episode (converters), and 19 without mood episodes during follow-up (non-converters) were selected and matched for age, sex and follow-up time. Baseline 1H-MRS data were obtained from anterior cingulate cortex (ACC) and bilateral ventrolateral prefrontal cortex (VLPFC). Glutamate (Glu), myo-inositol (mI), choline (Cho), N-acetyl aspartate (NAA), and phosphocreatine plus creatine (PCr + Cr) levels were calculated. SVM with a linear kernel was adopted to classify converters and non-converters based on their baseline metabolites. SVM allowed the significant classification of converters and non-converters across all regions for Cho (accuracy = 76.0%), but not for other metabolites. Considering all metabolites within each region, SVM allowed the significant classification of converters and non-converters for left VLPFC (accuracy = 76.5%), but not for right VLPFC or ACC. The combined mI, PCr + Cr, and Cho from left VLPFC achieved the highest accuracy differentiating converters from non-converters (79.0%). Our findings from this exploratory study suggested that 1H-MRS levels of mI, Cho, and PCr + Cr from left VLPFC might be useful to predict the development of first mood episode in youth bipolar offspring using machine learning. Future studies that prospectively examine and validate these metabolites as predictors of mood episodes in high-risk individuals are necessary.

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.

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.

An International Society of Bipolar Disorders task force report: Precursors and prodromes of bipolar disorder.

OBJECTIVES: To clarify the clinical features preceding the onset of bipolar disorder (BD) has become a public health priority for the prevention of high morbidity and mortality. BD remains frequently under- or misdiagnosed, and under- or mistreated, often for years. METHODS: We assessed the predictive value of precursors and prodromes of BD. We assessed precursors of first-lifetime manic or hypomanic episodes with/without mixed features in retrospective and prospective studies. The task force evaluated and summarized separately assessments of familial risk, premorbid personality traits, retrospective, and prospective studies. RESULTS: Cyclothymic features, a family history of BD, retrospectively reported attenuated manic symptoms, prospectively identified subthreshold symptoms of hypomania, recurrence of depression, panic anxiety and psychotic features, have been identified as clinical precursors of BD. The prodromal symptoms like [hypo]mania often appears to be long enough to encourage early identification and timely intervention. CONCLUSIONS: The predictive value of any risk factor identified remains largely unknown. Prospective controlled studies are urgently needed for prevention and effective treatment.

Cardiometabolic risks and omega-3 index in recent-onset bipolar I disorder.

OBJECTIVES: The aims of the present study were to characterize cardiometabolic risk factors in a cohort of bipolar disorder patients with limited exposure to psychotropic medications, and to evaluate their associations with mood symptoms and omega-3 polyunsaturated fatty acid (PUFA) blood levels. METHODS: Cardiometabolic risk assessments were compared in individuals with bipolar I disorder experiencing a first manic or mixed episode or an early depressive episode (n=117) and healthy subjects (n=56). Patients were medication free at assessment and had no or limited exposure to mood-stabilizer or antipsychotic medications prior to the current admission. Associations among cardiometabolic parameters and Clinical Global Impression-Severity scale (CGI-S), manic (Young Mania Rating Scale [YMRS]), and depressive (Hamilton Depression Rating Scale [HDRS]) symptom ratings were evaluated within the bipolar group. RESULTS: Following adjustment for demographic variables (i.e., age, gender, and parental education), significantly higher fasting triglyceride levels were observed in the bipolar group compared to the healthy group (121.7 mg/dL vs 87.0 mg/dL; P<.01). There were no clear trends for other metabolic indicators, including blood pressure, body mass index, and fasting glucose. Nineteen percent of the bipolar group and 6% of the healthy group met the criteria for metabolic syndrome (P=.23). The omega-3 index was lower in the bipolar group (3.4% vs 3.9%; P<.01). Within the bipolar group, no associations were found between the cardiometabolic parameters and CGI-S, YMRS, and HDRS symptom ratings. CONCLUSIONS: Recent-onset medication-free bipolar disorder is associated with higher triglyceride levels. These findings are suggestive of early metabolic dysregulation prior to long-term psychotropic medication exposure. Lower omega-3 PUFA levels in individuals with bipolar I disorder represent a potential therapeutic target for additional investigation.

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.

Prediction of lithium response in first-episode mania using the LITHium Intelligent Agent (LITHIA): Pilot data and proof-of-concept.

OBJECTIVES: Individualized treatment for bipolar disorder based on neuroimaging treatment targets remains elusive. To address this shortcoming, we developed a linguistic machine learning system based on a cascading genetic fuzzy tree (GFT) design called the LITHium Intelligent Agent (LITHIA). Using multiple objectively defined functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1 H-MRS) inputs, we tested whether LITHIA could accurately predict the lithium response in participants with first-episode bipolar mania. METHODS: We identified 20 subjects with first-episode bipolar mania who received an adequate trial of lithium over 8 weeks and both fMRI and 1 H-MRS scans at baseline pre-treatment. We trained LITHIA using 18 1 H-MRS and 90 fMRI inputs over four training runs to classify treatment response and predict symptom reductions. Each training run contained a randomly selected 80% of the total sample and was followed by a 20% validation run. Over a different randomly selected distribution of the sample, we then compared LITHIA to eight common classification methods. RESULTS: LITHIA demonstrated nearly perfect classification accuracy and was able to predict post-treatment symptom reductions at 8 weeks with at least 88% accuracy in training and 80% accuracy in validation. Moreover, LITHIA exceeded the predictive capacity of the eight comparator methods and showed little tendency towards overfitting. CONCLUSIONS: The results provided proof-of-concept that a novel GFT is capable of providing control to a multidimensional bioinformatics problem-namely, prediction of the lithium response-in a pilot data set. Future work on this, and similar machine learning systems, could help assign psychiatric treatments more efficiently, thereby optimizing outcomes and limiting unnecessary treatment.