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Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

BackgroundBipolar disorder (BD) is a severe psychiatric disorder associated with structural and functional brain abnormalities, some of which have been found in unaffected relatives as well. In this study, we examined the potential role of decreased fractional anisotropy (FA) as a BD endophenotype, in adolescents at high risk for BD.MethodsWe included 15 offspring of patients with BD, 16 pediatric BD patients, and 16 matched controls. Diffusion weighted scans were obtained on a 3T scanner using an echo-planar sequence. Scans were segmented using FreeSurfer.ResultsOur results showed significantly decreased FA in six brain areas of offspring group; left superior temporal gyrus (LSTG; P P = .002), left banks of the superior temporal sulcus (LBSTS; P = .002), left anterior cingulum (LAC; P = .003), right temporal pole (RTP; P = .004) and left frontal pole (LFP; P = .017). On analysis, LSTG, LAC, and RTP demonstrated a potential to be an endophenotype when comparing all three groups. FA values in three regions, LBSTS, LTTG, and LFP were increased only in controls.ConclusionOur findings point at decreased FA as a possible endophenotype for BD, as they were found in children of patients with BD. Most of these areas were previously found to have morphological and functional changes in adult and pediatric BD, and are thought to play important roles in affected domains of functioning. Prospective follow up studies should be performed to detect reliability of decreased FA as an endophenotype and effects of treatment on FA.

In proton magnetic resonance spectroscopy (¹H MRS) studies, aberrant levels of choline-containing compounds that include glycerophosphocholine plus phosphocholine (GPC+PC), can signify alterations in the metabolism of cellular membrane phospholipids (MPLs) from a healthy baseline. In a recent ¹H MRS study, we reported increased GPC+PC in cortical and subcortical areas of adult patients with bipolar disorder I (BP-I). Post-traumatic stress disorder (PTSD) can worsen the severity of BP-I, but it is unclear whether the effect of a PTSD comorbidity in BP-I is associated with altered MPL metabolism. The purpose of this study was to re-investigate the ¹H MRS data to determine whether the regional extent of elevated GPC+PC was greater in BP-I patients with PTSD (BP-I/wPTSD) compared to BP-I without comorbid PTSD (BP-I/woPTSD) patients and healthy controls. GPC+PC levels from four brain areas [the anterior cingulate cortex (ACC), anterior-dorsal ACC, caudate, and putamen] were measured in 14 BP-I/wPTSD, 36 BP-I/woPTSD, and 44 healthy controls using a multi-voxel 1H MRS approach on a 3 Tesla system with high spatial resolution and absolute quantification. Results show a significant increase in GPC+PC levels from the caudate and putamen of BP-I/wPTSD patients compared to healthy controls (P

The neural mechanisms underlying the therapeutic effects of lamotrigine in bipolar depression are still unexplored. This preliminary study compares the effects of a 12-week treatment with lamotrigine on brain volumes in adults with bipolar disorder (BD).12 BD type II patients (age: 49.33 ± 9.95 years, 3 males, 9 females) and 12 age and gender-matched healthy controls (HC) (HC; age: 41 ± 8.60 years, 3 males, 9 females). BD patients were initially administered 25 mg/day of lamotrigine, which was progressively escalated to 200 mg/d. BD participants underwent brain imaging prior to and following lamotrigine treatment. A 50% reduction in depressive scores indicated “remission”. Bayesian general linear models controlled for age, gender and intracranial volume were used to examine changes in relevant brain region following treatment. A posterior probability > 0.90 indicated evidence that there was an effect of diagnosis or remission on brain volumes. Probability distributions of interaction effects between remission and time indicated that BD responders displayed decreased amygdala, cerebellum and nucleus accumbens volumes following lamotrigine treatment. No serious adverse side effects were reported. The antidepressant effects of lamotrigine may be linked to volumetric changes in brain regions involved in mood and emotional regulation. These findings are preliminary and replication in a larger sample is warranted.

Impulsivity is a well-established trait of bipolar disorder (BD) that persists across mood phases. It is, however, still unknown whether, in BD, impulsivity remains stable or varies in intensity over the lifespan. This cross-sectional study compared impulsive behavior in older euthymic BD patients and healthy individuals using a range of self-rating and behavioral measures of impulsivity.28 BD patients (56.07 ± 4.08 years, 16 women) and 15 healthy controls (HC; 55.1 ± 3.95 years, 6 women) were administered the Barratt Impulsivity Scale (BIS) and selected tasks of the Cambridge Neuropsychological Test Automated Batter (CANTAB) reflecting impulsivity. Multivariate analysis of variance controlled for age compared impulsivity measures across BD and HC.BD patients displayed poor decision making, risk taking, and increased delay aversion. Other measures of impulsivity such as response inhibition, sustained cognitive control, and BIS scores were, overall, comparable between BD and HC.These preliminary findings suggest that, in BD, aspects of impulsivity related to reward-based decision making persist into late adulthood. Large scale, longitudinal studies are needed to evaluate the relationship of age to impulsivity over time, and explore the link between impulsivity and illness progression in elderly individuals with BD.

Objective: Bipolar disorder (BD) is highly heritable. The present study aimed at identifying brain morphometric features that could represent markers of BD vulnerability in non-bipolar relatives of bipolar patients. Methods: In the present study, structural magnetic resonance imaging brain scans were acquired from a total of 93 subjects, including 31 patients with BD, 31 non-bipolar relatives of BD patients, and 31 healthy controls. Volumetric measurements of the anterior cingulate cortex (ACC), lateral ventricles, amygdala, and hippocampus were completed using the automated software FreeSurfer. Results: Analysis of covariance (with age, gender, and intracranial volume as covariates) indicated smaller left ACC volumes in unaffected relatives as compared to healthy controls and BD patients (p = 0.004 and p = 0.037, respectively). No additional statistically significant differences were detected for other brain structures. Conclusion: Our findings suggest smaller left ACC volume as a viable biomarker candidate for BD.

S100B is a calcium binding protein mainly produced by glial cells. Previous studies have shown elevated levels of S100B in patients with schizophrenia. We measured S100B levels in fasting plasma of 39 patients with schizophrenia and 19 adult healthy controls. We used linear regression to compare S100B between patients and controls. In patients only, we also investigated the relationship between S100B levels and psychotic symptoms (assessed by the Positive and Negative Syndrome Scale), and cognitive function (assessed by the NIH Toolbox Cognition Battery), respectively by calculating Pearson's correlation coefficients. Mean plasma S100B was significantly higher in the patient group than in the control group. There were no significant correlations between plasma S100B and psychotic symptoms or cognition.

OBJECTIVE To assess the global functioning and clinical outcomes of children and adolescents with bipolar disorder, children and adolescents with bipolar disorder and substance use disorder (SUD) comorbidity and healthy controls. METHODS This study had a cross-sectional design. Participants were children and adolescents aged between 6 and 17 years, and data were collected between 2003 and 2015. Psychiatric diagnosis was established according to DSM-IV criteria using the Kiddie-SADS-Present and Lifetime Version or the Mini-International Neuropsychiatric Interview for Children and Adolescents. Global functioning was assessed using the Children's Global Assessment Scale. Depressive symptoms were assessed using the Children's Depression Rating Scale. Manic symptoms were measured using the Young Mania Rating Scale, and the severity of anxious symptoms was assessed using the Screen for Child Anxiety Related Disorders. RESULTS The sample included 187 children and adolescents with bipolar disorder, 29 with BD and SUD comorbidity, and 115 healthy controls. Children and adolescents with BD and SUD comorbidity presented later onset of mood disorder (P < .001); higher rates of lifetime history of suicide attempt (P < .001), lifetime history of psychosis (trend toward significance: P = .076), and lifetime hospitalization (P < .001); and higher severity of depressive symptoms (trend toward significance: P = .080) as compared to those with BD without SUD comorbidity. In addition, both diagnosis groups presented higher rates of functional impairment when compared to controls (P < .001). Moreover, BD and SUD comorbidity presented higher functional impairment, as compared to BD without SUD comorbidity (P = .020). CONCLUSIONS Children and adolescents with bipolar disorder and substance use disorder comorbidity present a worse clinical course than those with bipolar disorder but without substance use disorder comorbidity.

Previous studies have found increased levels of choline-containing compounds (ie, glycerophosphocholine plus phosphocholine (GPC+PC)) in bipolar disorder using in vivo proton magnetic resonance spectroscopy (1H MRS), especially in bipolar I disorder (BD-I). Increased levels of GPC+PC suggest alterations in the membrane phospholipids metabolism in bipolar disorder. Rapid cycling (RC) bipolar disorder is considered as a severe course of bipolar disorder, but it is unclear whether rapid cycling bipolar disorder is linked to highly altered membrane phospholipid metabolism. The purpose of this study was to investigate whether the regional extent of elevated GPC+PC were greater in BD-I patients with rapid cycling compared to BD-I patients without rapid cycling and healthy controls. Using a multi-voxel 1H MRS approach at 3 Tesla with high spatial resolution and absolute quantification, GPC+PC levels from the anterior cingulate cortex (ACC), caudate and putamen of 16 RC BD-I, 34 non-RC BD-I and 44 healthy controls were assessed. We found significantly elevated GPC+PC levels in ACC, putamen and caudate of RC BD-I patients compared to healthy controls (P

To reduce patient anxiety caused by the MRI scanner acoustic noise.We developed a simple and low-cost system for patient distraction using visual computer animations that were synchronized to the MRI scanner's acoustic noise during the MRI exam. The system was implemented on a 3T MRI system and tested in 28 pediatric patients with bipolar disorder. The patients were randomized to receive noise-synchronized animations in the form of abstract animations in addition to music (n = 13, F/M = 6/7, age = 10.9 ± 2.5 years) or, as a control, receive only music (n = 15, F/M = 7/8, age = 11.6 ± 2.3 years). After completion of the scans, all subjects answered a questionnaire about their scan experience and the perceived scan duration.The scan duration with multisensory input (animations and music) was perceived to be ~15% shorter than in the control group (43 min vs. 50 min, P 0.05). However, the overall scan experience was scored less favorably (3.9 vs. 4.6 in the control group, P 0.04).This simple system provided patient distraction and entertainment leading to perceived shorter scan times, but the provided visualization with abstract animations was not favored by this patient cohort.

Objective Neuroinflammation has been implicated in the pathophysiology of bipolar disorder. Some evidence shows that nonsteroidal anti-inflammatory drugs (NSAIDs) have promising antidepressant effects. The antioxidant N-acetylcysteine (NAC) may enhance the effects of NSAIDs. No study has, however, tested the adjunctive therapeutic benefits of an NSAID and NAC in bipolar disorder. Methods The sample included 24 medicated patients diagnosed with DSM-IV-TR bipolar disorder who were aged 18-65 years and had a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20. Participants were randomly assigned to receive either aspirin (1,000 mg), NAC (1,000 mg), combined aspirin and NAC (1,000 mg each), or placebo. Data were collected between 2013 and 2017. The primary outcome was a ≥ 50% reduction in MADRS scores. Participants completed mood and global functioning questionnaires. They also underwent blood tests prior to and following 8 and 16 weeks of treatment. A Bayesian analytic method was adopted, and posterior probability distributions were calculated to determine the probability of treatment response. Results Following the first 8-week treatment phase, individuals on treatment with placebo and NAC + aspirin had a similar probability for successful treatment response (about 70%). Following a 16-week treatment period, NAC + aspirin was associated with higher probability of treatment response (67%) compared to placebo (55%), NAC (57%), and aspirin (33%). There was no treatment effect on interleukin-6 and C-reactive protein levels at either 8 or 16 weeks. Conclusions The coadministration of NAC and aspirin during a period of 16 weeks was associated with a reduction in depressive symptoms. The adverse effects were minimal. These preliminary findings may serve as a starting point for future studies assessing the efficacy, tolerability, and safety of anti-inflammatory and antioxidant agents in the treatment of bipolar depression. Trial registration ClinicalTrials.gov identifier: NCT01797575.

Background Previous proton magnetic resonance spectroscopy (1H MRS) studies have reported elevated glycerophosphocholine plus phosphocholine (GPC+PC) in the basal ganglia of patients with bipolar disorders (BD), which implicates an imbalance between synthesis and degradation activity of neuronal and glia membrane phospholipids (MPLs). However, the full extent of altered metabolites of MPLs in subareas within the basal ganglia, such as caudate and putamen, as well as anterior cingulate cortex (ACC) of BD patients is poorly understood. Methods Multi-voxel 1H MRS measurements were acquired in 50 type-one BD (BD-I) and 44 healthy controls (HC) on a 3-T MRI scanner. Four different anatomically defined voxels covering ACC, caudate and putamen were systematically extracted and quantified using LCModel. Group differences in absolute GPC+PC and other metabolites were tested with age and gender as covariates. Results BD-I patients had higher GPC+PC levels in the anterior-dorsal ACC (p = 0.037), caudate (p = 0.005) and putamen (p = 0.004) compared to HC. GPC+PC levels in the caudate were elevated most significantly in currently unmediated BD-I patients (p = 0.022) and were positively correlated with HAM-D scores (r = 0.51, p = 0.005). PCr+Cr and myo-inositol levels were also significantly higher in the caudate head (F(1,45) = 6.010, p = 0.018) of patients compared to HC. NAA and glutamate levels were not significantly different between BD-I and HC in these regions (p > 0.05). Conclusion The increased GPC+PC in BD-I patients may reflect an imbalance in the MPL metabolism. Caudate GPC+PC levels may be a potential biomarker for depressive symptoms in BD.

Background Cognitive impairment is a well-established feature of bipolar disorder (BD). Comorbid BD and substance use leads to poor psychosocial and clinical outcomes. However, knowledge on the neurocognitive functioning of individuals with dual diagnosis is limited. The aim of this study is to assess the cognitive performance of subjects with BD, BD with comorbid alcohol use disorder (AUD), and BD with comorbid illicit substance use disorders (SUD) as compared to healthy individuals. Methods We included 270 inpatients and outpatients with BD and 211 healthy controls. The diagnostic of BD and substance use disorder was assessed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders Axis I. Demographic and clinical information were also collected. The cognitive assessment included the Wechsler Test of Adult Reading (WTAR), and a revised version of the California Verbal Learning Test (CVLT) as part of the South Texas Assessment of Neurocognition (STAN). Results The STAN was administered to 134 BD patients (100 female, M±SD: 37.37±12.74 years), 72 BD patients with AUD (40 female, M±SD: 38.42±11.82), 64 BD patients with SUD (39 female, M±SD: 34.50±10.57), and 211 healthy controls with no lifetime history of mental illness and substance use (127 female, M±SD: 34.80±12.57 years). In terms of clinical characteristics, BD+SUD showed a marginally earlier onset of illness compared to BD. Compared to HC, BD performed poorly in the immediate recall and short-delay free tests of the CVLT, while BD patients with AUD and SUD showed significant memory deficits in both the immediate recall and recognition components of the CVLT. There were no differences in memory performance between BD and BD with either AUD or SUD. Conclusions A history of substance use disorders is associated with an earlier onset of BD. BD has marked effects on processes underlying the encoding of new information, while comorbid substance use in BD impairs more specifically the recognition of previously presented information. Future longitudinal studies should evaluate the effects of AUD and SUD on illness progression and therapeutic outcomes.

Background Cognitive deficits have been consistently reported in individuals with bipolar disorder (BD). The cognitive profile of siblings of individuals with BD is, however, less clearly established possibly due to the heterogeneity of neuropsychological measures used in previous studies. The aim of this exploratory study was to assess the cognitive function of siblings of individuals with BD and compare it with that of their first-degree relatives suffering with BD, and healthy controls (HC) using the Cambridge Neuropsychological Test Automated Battery (CANTAB) – a comprehensive and validated computerized cognitive battery. Methods We recruited 23 HC (33.52±10.29 years, 8 males), 27 individuals with BD (34.26±10.19 years, 9 males, 25 BDI, 1BDII and 1 BD-NOS), and 15 of their biologically related siblings (37.47±13.15 years, 4 males). Siblings had no current or lifetime history of mental disorders. Participants performed the CANTAB and completed questionnaires assessing mood and global functioning. Multivariate analyses compared CANTAB measures across the three participant groups. Results Individuals with BD and their siblings were less accurate in a task of sustained attention (Rapid Visual Processing) when compared to HC. Further, individuals with BD displayed pronounced deficits in affective processing (Affective Go/No-Go) compared to HC. There were no cognitive differences between siblings and individuals with BD. After correcting for current depressive symptoms, these results did not reach statistical significance. Conclusions Subthreshold depressive symptoms may be associated with reduced sustained attention in healthy siblings of BD patients. This preliminary result needs to be corroborated by large-scale, longitudinal studies assessing the relationship between cognition and mood in vulnerable individuals.

Studies about changes in hippocampal volumes in subjects with bipolar disorder (BD) have been contradictory. Since the number of manic episodes and hospitalization has been associated with brain changes and poor cognitive outcomes among BD patients, we have hypothesized that these variables could clarify this issue. We stratified subjects with BD in early (BD-Early), intermediate (BD-intermediate) and late (BD-Late) stages as a function of number of manic episodes and prior hospitalization. Then, we compared their hippocampal volumes and California Verbal Learning Test-II (CVLT-II) scores with healthy controls (HC) using the general linear model. A total of 173 subjects were included in the study (112 HC, 15 BD-Early, 30 BD-Intermediate, and 16 BD-Late). We found a significant group effect on hippocampus volume (F(3,167) = 3.227, p = 0.024). Post-hoc analysis showed that BD-Late subjects had smaller hippocampus than HC (p = 0.017). BD-Early and BD-Intermediate subjects showed no significant difference in hippocampus volume compared to HC and BD-Late subjects. The CVLT trial 1 to 5 scores were significantly different across the groups (F(3,167) = 6.371, p < 0.001). Post-hoc analysis showed that BD-Intermediate (p = 0.006) and BD-Late (p = 0.017) subjects had worse memory performance during immediate recall than HC, while the performance difference between BD-Early subjects and HC was not significant (p = 0.208). These findings add to the notion that BD is a neuroprogressive disorder with brain changes and cognitive impairment according to prior morbidity (number of manic episodes and hospitalization). Also, they suggest that hippocampus is a brain marker and a potential therapeutic target for patients at late stage.

Background Genetic and environmental factors are implicated in the onset and evolution of pediatric bipolar disorder, and may be associated to structural brain abnormalities. The aim of our study was to assess the impact of the interaction between the Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism and family functioning on hippocampal volumes of children and adolescents with bipolar disorder, and typically-developing controls. Methods: We evaluated the family functioning cohesion subscale using the Family Environment Scale-Revised, genotyped the BDNF rs6265 polymorphism, and performed structural brain imaging in 29 children and adolescents with bipolar disorder, and 22 healthy controls. Results: We did not find significant differences between patients with BD or controls in left or right hippocampus volume ( p =0.44, and p =0.71, respectively). However, we detected a significant interaction between low scores on the cohesion subscale and the presence of the Met allele at BNDF on left hippocampal volume of patients with bipolar disorder ( F =3.4, p =0.043). None of the factors independently (BDNF Val66Met, cohesion scores) was significantly associated with hippocampal volume differences. Limitations: small sample size, cross-sectional study. Conclusions: These results may lead to a better understanding of the impact of the interaction between genes and environment factors on brain structures associated to bipolar disorder and its manifestations.

Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.

BACKGROUND Increasing evidence shows that disruption of connectivity has been implicated as a central abnormality in schizophrenia, and the alterations in white matter may be the core basis for this disconnection. Diffusion tensor imaging (DTI) has shown white matter abnormalities in first-episode schizophrenia. However, few studies have examined the correlation between clinical symptoms and white matter abnormalities in drug-naive patients with first-episode schizophrenia. METHOD The white matter fractional anisotropy (FA) values of the whole-brain were determined by using voxel-based DTI in 39 drug-naive patients with first-episode schizophrenia (diagnosed according to DSM-IV) and 30 healthy controls matched for age and gender. The psychopathology of schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS). The study was conducted from April 2009 to March 2010. RESULTS The patients showed widespread FA reduction in several brain regions, including corpus callosum, brainstem, internal capsule, cingulate, and cerebellum in patients with first-episode schizophrenia when compared to healthy controls (all P values < .01 after adjusting for gender, age, and education). The correlation analysis showed a significant negative correlation between the FA value in the left cerebellum and positive symptoms (r38 = -0.32, P < .05) and a significant positive correlation between the FA values in the corpus callosum and both the PANSS general psychopathology subscore (r38 = 0.39, P < .01) and the PANSS total score (r38 = 0.33, P < .05). CONCLUSIONS Our results indicate that widespread disruption of white matter integrity occurs in an early stage of schizophrenic onset, suggesting an important role in pathogenesis and symptomatology of schizophrenia.

Accumulating evidence showed that interleukin-2 (IL-2) may be involved in the pathophysiology of schizophrenia. Increased IL-2 levels have been found in the serum of schizophrenia patients with mixed results. In the present study, we assessed serum IL-2 levels in a large group of 160 schizophrenia patients compared to 60 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum IL-2 levels were measured by sandwich ELISA. The results showed that IL-2 levels were significantly higher in chronic patients with schizophrenia than in healthy control subjects (p

Bipolar disorder (BD) is characterized by biased processing of emotional information. However, little research in this area has been conducted in youth with BD and at-risk individuals. The goal of this study was to determine whether children with BD displayed comparable or more severe manifestations of this bias relative to offspring of parents with BD.The sample (n = 57 children and adolescents) included 18 individuals with BD (age: 13.63 ± 2.99; 8 females), 16 offspring of parents with BD (age: 11.83 ± 2.96; 9 females) and 23 healthy controls (HC) (age: 12.789 ± 3.087; 8 females). All participants performed the Affective Go/No-Go (AGN) and the Rapid Visual Processing (RVP) tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB).Relative to HC, individuals with BD responded faster to correct trials and committed an elevated number of commission errors across all affective conditions of the AGN task. By contrast, BD offspring showed intact performance accuracy but quicker response times than HC. Post-hoc analyses revealed that this behavioral pattern was observed in BD offspring with mental health problems but not in healthy BD offspring. Overall, mean reaction times and total number of errors in the RVP task were comparable across groups.In line with previous findings, subjects with BD encountered difficulties in processing affective information. The tendency toward faster but accurate responses to affective stimuli observed in BD offspring may be a marker of attentional bias toward affective information and constitute a vulnerability marker for mood disorder.

Previous studies have reported abnormalities of white-matter diffusivity in pediatric bipolar disorder. However, it has not been established whether these abnormalities are able to distinguish individual subjects with pediatric bipolar disorder from healthy controls with a high specificity and sensitivity. Diffusion-weighted imaging scans were acquired from 16 youths diagnosed with DSM-IV bipolar disorder and 16 demographically matched healthy controls. Regional white matter tissue microstructural measurements such as fractional anisotropy, axial diffusivity and radial diffusivity were computed using an atlas-based approach. These measurements were used to `train' a support vector machine (SVM) algorithm to predict new or `unseen' subjects' diagnostic labels. The SVM algorithm predicted individual subjects with specificity = 87.5%, sensitivity = 68.75%, accuracy = 78.12%, positive predictive value = 84.62%, negative predictive value = 73.68%, area under receiver operating characteristic curve (AUROC) = 0.7812 and chi-square p-value = 0.0012. A pattern of reduced regional white matter fractional anisotropy was observed in pediatric bipolar disorder patients. These results suggest that atlas-based diffusion weighted imaging measurements can distinguish individual pediatric bipolar disorder patients from healthy controls. Notably, from a clinical perspective these findings will contribute to the pathophysiological understanding of pediatric bipolar disorder.

Background Major psychiatric disorders are increasingly being conceptualized as ‘neurodevelopmental’, because they are associated with aberrant brain maturation. Several studies have hypothesized that a brain maturation index integrating patterns of neuroanatomical measurements may reliably identify individual subjects deviating from a normative neurodevelopmental trajectory. However, while recent studies have shown great promise in developing accurate brain maturation indices using neuroimaging data and multivariate machine learning techniques, this approach has not been validated using a large sample of longitudinal data from children and adolescents. Methods T 1 -weighted scans from 303 healthy subjects aged 4.88 to 18.35 years were acquired from the National Institute of Health (NIH) pediatric repository ( http://www.pediatricmri.nih.gov ). Out of the 303 subjects, 115 subjects were re-scanned after 2 years. The least absolute shrinkage and selection operator algorithm (LASSO) was ‘trained’ to integrate neuroanatomical changes across chronological age and predict each individual 's brain maturity. The resulting brain maturation index was developed using first-visit scans only, and was validated using second-visit scans. Results We report a high correlation between the first-visit chronological age and brain maturation index (r = 0.82, mean absolute error or MAE = 1.69 years), and a high correlation between the second-visit chronological age and brain maturation index (r = 0.83, MAE = 1.71 years). The brain maturation index captured neuroanatomical volume changes between the first and second visits with an MAE of 0.27 years. Conclusions The brain maturation index developed in this study accurately predicted individual subjects' brain maturation longitudinally. Due to its strong clinical potentials in identifying individuals with an abnormal brain maturation trajectory, the brain maturation index may allow timely clinical interventions for individuals at risk for psychiatric disorders.

Background Impulsivity is a common feature shared by bipolar disorder (BD) and substance use disorder (SUD). SUD and recurrent mood episodes are considered to be risk factors for poor outcome in BD. However, the association between impulsivity, illness chronicity and SUD in BD remains unexplored. Methods 103 BD patients with and without a lifetime history of SUD (36.82±11.34 years, 40 males) were recruited. Participants completed the SCID interview and were administered measures of impulsivity including the Barratt Impulsivity Scale (BIS) and selected tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Hierarchical regression analyses explored the relationship between illness chronicity, SUD, and impulsivity. Results Variance in the BIS, number of false alarms on the Rapid Visual Processing task and other impulsivity indicators of the Cambridge Gambling Task (CGT) was not explained by the chosen variables. Only an increased number of commission errors in the negative condition of the Affective Go/No Go task was significantly associated with illness chronicity. Furthermore there was a trend suggesting a relationship between a lifetime history of SUD and increased propensity to risk-taking during the CGT. Limitations Potential limitations include medication and patients׳ remission status from SUD. Conclusions Contrary to our expectations impulsivity was generally not predicted by indicators of illness chronicity or SUD. While impulsivity could still be a marker of BD that is present before the onset of the disorder, the link between the number of mood episodes and specific indicators of impulsivity may be related to mechanisms of neuroprogression.

Recent evidence shows an important relationship between metabolic disturbances and bipolar disorder (BD). However, it is still unclear whether such metabolic disturbances are only a consequence or to some extent the precipitating factors for health problems and maladaptive behaviors observed in BD. Because both metabolic disturbances and BD are medical conditions sharing common alterations in multiple biomarkers, it is plausible to hypothesize that metabolic disturbances may be considered to some extent as a major vulnerability factor in the latent phase of BD for some young adults. In line with this hypothesis, obesity may be regarded as a major driving force for prevalent cardio-metabolic disorders encountered within the early stages of BD. Likewise, premorbid metabolic disturbances as a whole may be considered as a potential source for vulnerability to develop BD. In addition, a synergistic relationship between obesity and metabolic disturbances associated with a premorbid disruption of biological rhythms may also lead to BD. Therefore, we postulate that metabolic disturbances may serve as a specific marker of premorbid illness activity in some people at risk for BD. Future prospective studies should focus on validating metabolic disturbances as vulnerability factors within the staging model of BD.

Neurodegenerative processes may be involved in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF), the most widely distributed neurotrophin and oxidative stress (OS) may be critical for several pathological manifestations of neurodegenerative disorders. Accumulating evidence suggests that both BDNF and OS may be involved in the pathophysiology of schizophrenia. However, the possible interaction between BDNF and OS has been under-investigated. Serum BDNF, plasma malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were analyzed using established procedures in 164 chronic medicated schizophrenia and 50 healthy controls. Schizophrenic symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) with cognitive and depressive factors derived from the five factor model of the PANSS. Compared to the control group, the patients exhibited a significant decrease in BDNF levels, in the activities of SOD and GSH-Px but a significant increase in MDA levels. In patients, but not in controls, we observed a significant negative correlation between BDNF and SOD. Furthermore, the interaction between BDNF and CAT was associated with the PANSS cognitive factor, and the interaction between BDNF and GSH-Px with the PANSS depressive factor. Both decreased BDNF levels and OS may be implicated in the pathophysiology of chronic schizophrenia. Their inverse association only in the schizophrenia group may reflect a pathological mechanism involving an interaction of oxidative damage and neurotrophin dysfunction. Moreover, OS may interact with the BDNF system to influence the clinical symptoms and cognitive impairment in schizophrenia, which is line with the neurodevelopmental hypothesis of schizophrenia.

Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 ± 1.7 vs. Met/Val: 2.2 ± 1.7 vs. Val/Val: 2.0 ± 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smoker's response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors.

Bipolar disorder (BD) is a common disorder with high reoccurrence rate in general population. It is critical to have objective biomarkers to identify BD patients at an individual level. Neurocognitive signatures including affective Go/No-go task and Cambridge Gambling task showed the potential to distinguish BD patients from health controls as well as identify individual siblings of BD patients. Moreover, these neurocognitive signatures showed the ability to be replicated at two independent cohorts which indicates the possibility for generalization. Future studies will examine the possibility of combining neurocognitive data with other biological data to develop more accurate signatures. Electronic supplementary material The online version of this article (doi:10.1186/s40345-017-0101-9) contains supplementary material, which is available to authorized users.

Bipolar disorder (BD) is a common disorder with high reoccurrence rate in general population. It is critical to have objective biomarkers to identify BD patients at an individual level. Neurocognitive signatures including affective Go/No-go task and Cambridge Gambling task showed the potential to distinguish BD patients from health controls as well as identify individual siblings of BD patients. Moreover, these neurocognitive signatures showed the ability to be replicated at two independent cohorts which indicates the possibility for generalization. Future studies will examine the possibility of combining neurocognitive data with other biological data to develop more accurate signatures.

Cortical gyrification of the brain represents the folding characteristic of the cerebral cortex. How the brain cortical gyrification changes from childhood to old age in healthy human subjects is still unclear. Additionally, studies have shown regional gyrification alterations in patients with major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). However, whether the lifespan trajectory of gyrification over the brain is altered in patients diagnosed with major psychiatric disorders is still unknown. In this study, we investigated the trajectories of gyrification in three independent cohorts based on structural brain images of 881 subjects from age 4 to 83. We discovered that the trajectory of gyrification during normal development and aging was not linear and could be modeled with a logarithmic function. We also found that the gyrification trajectories of patients with MDD, BD and SCZ were deviated from the healthy one during adulthood, indicating altered aging in the brain of these patients.

Immune dysfunction has been implicated in the pathophysiology of schizophrenia. Leukocyte migration to the site of inflammation is a fundamental step of immune response which involves P-, E-, and L-selectins. Elevated selectin levels have been reported in un-medicated first-episode patients with schizophrenia but not in medicated patients with multi-episode schizophrenia. We measured fasting plasma soluble P-, E-, and L-selectin in 39 medicated patients with multi-episode schizophrenia and 19 healthy controls. In patients, psychotic symptom severity and cognitive function were assessed with the Positive and Negative Syndrome Scale (PANSS) and the NIH Toolbox Cognitive Test Battery respectively. C-reactive protein (CRP) and Body Mass Index (BMI) were measured in patients and controls. Comparison of selectin levels between patients and controls was done with t-tests and linear regression. Pearson correlation coefficients between plasma selectins and PANSS and cognitive measures were calculated. Geometric mean plasma soluble L-selectin level was lower in patients compared to controls from unadjusted (606.7 ± 1.2 ng/ml vs. 937.7 ± 1.15 ng/ml, p < 0.001) and adjusted analyses (β = 0.59; CI 0.41 to 0.88, p = 0.011). There was a trend towards higher plasma soluble P-selectin in patients compared to controls (90.4 ± 1.2ng/ml vs. 71.8 ± 1.2ng/ml, p = 0.059) in the unadjusted analysis. There was no association between the selectins and psychotic symptoms or cognitive function in the patients. In addition, the selectins were not significantly associated with CRP or BMI. The limitations of this study include small sample size and unavailability of information on medications and blood cell counts. The potential utility of soluble L-selectin as a biomarker of antipsychotic exposure in patients with schizophrenia and the concomitant change in immune response with the use of antipsychotics should be further evaluated.

Objective: Increased impulsivity seems to be present across all phases of bipolar disorder (BD). Impulsivity may therefore represent an endophenotype for BD, if it is also found among normal individuals at high genetic risk for mood disorders. In this study, we assessed impulsivity across four different groups of children and adolescents: patients with BD, major depressive disorder (MDD) patients, unaffected offspring of bipolar parents (UO), and healthy controls (HC). Subjects and Methods: 52 patients with BD, 31 with MDD, 20 UO, and 45 HC completed the Barratt Impulsiveness Scale (BIS-11), an instrument designed to measure trait impulsivity. Results: UO displayed significantly higher total BIS-11 impulsivity scores than HC (p = 0.02) but lower scores than BD patients (F = 27.12, p

Background Four of the most consistently replicated variants associated with mood disorder occur in genes important for synaptic function: ANK3 (rs10994336), BDNF (rs6265), CACNA1C (rs1006737), and DGKH (rs1170191). Aims The present study examined associations between these candidates, mood disorder diagnoses, cognition, and fronto-limbic regions implicated in affect regulation. Methods and materials Participants included 128 individuals with bipolar disorder (33% male, Mean age = 38.5), 48 with major depressive disorder (29% male, Mean age = 40.4), and 149 healthy controls (35% male, Mean age = 36.5). Genotypes were determined by 5′-fluorogenic exonuclease assays (TaqMan®). Fronto-limbic volumes were obtained from high resolution brain images using Freesurfer. Chi-square analyses, bivariate correlations, and mediational models examined relationships between genetic variants, mood diagnoses, cognitive measures, and brain volumes. Results Carriers of the minor BDNF and ANK3 alleles showed nonsignificant trends toward protective association in controls relative to mood disorder patients (P = 0.047). CACNA1C minor allele carriers had larger bilateral caudate, insula, globus pallidus, frontal pole, and nucleus accumbens volumes (smallest r = 0.13, P = 0.043), and increased IQ (r = 0.18, P

Objectives To evaluate temperament and character traits using the Junior Temperament and Character Inventory (JTCI) in children and adolescents with major depressive disorder (MDD) in comparison with healthy control subjects (HC), and to verify if comorbidity with disruptive behavioral disorders and being currently depressed influence JTCI scores. Methods A case–control study comprising 41 MDD children/adolescents matched to 40 HC by gender and age (8–17 years). All participants were assessed diagnostically with the Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime (K-SADS-PL). Temperament and character traits were measured with the parent and child versions of JTCI, and depression was evaluated with the Children's Depression Rating Scale (CDRS). Results According to child and parent data, MDD subjects had significantly higher scores on harm avoidance and novelty seeking, and lower scores on reward dependence, persistence, self-directedness and cooperativeness compared with HC. According to parent data only, MDD subjects significantly differed from HC on self-transcendence (lower spirituality scores and higher fantasy scores). Comorbidity with disruptive behavioral disorders exerted influence on almost all dimensions, in general increasing the mean differences between MDD and HC subjects. Also, being currently depressed did not influence the results, except for reward dependence according to parent data. Limitations The cross-sectional nature of the study and its limited sample size. Conclusions MDD children/adolescents have a different temperament and character profile compared to HC subjects. This study supports previous findings of trait-like characteristics of harm avoidance and self-directedness.

Bipolar disorder (BD) is commonly associated with increased impulsivity, particularly during manic and depressed episodes (1, 2), and unipolar depressive disorder (UP) is also associated with increased impulsivity during depressive episodes (3). In BD, impulsivity also remains elevated during euthymic phases, suggesting that it is a trait-like personality characteristic (4). Increased impulsivity adversely affects the illness course of BD and UP by increasing suicide risk (1, 3, 5, 6) and mood instability (7). In BD, elevated impulsivity during euthymic periods contributes to disruptive behaviors such as reckless driving (8), substance abuse disorder (9), and poor adherence to treatment (10). However, there is a lack of studies assessing impulsivity in euthymic UP patients, so it is not known whether impulsivity is related to poor illness course and risk of substance abuse as with BD. Increased impulsivity in BD and UP during illness episodes as well as in euthymic states supports the suggestion that impulsivity is related to mood disorders in general (4, 7). If this is confirmed, then therapies targeting impulsivity could represent novel interventions for mental disorders with impulsivity at their core, as suggested by Pattij and Vanderschuren (11). In this study, we compared questionnaire-measured impulsivity in euthymic BD and UP patients, healthy controls (HC), and a group of unaffected relatives (NAR) of BD patients. The NAR were included because impulsivity may be an inherited trait that could predispose vulnerable individuals to affective disorders in general (12). We also compared impulsivity in patients with and without history of suicide attempts and substance abuse to determine whether impulsivity during the euthymic interval predicts these outcomes. We hypothesized that: (i) euthymic BD and UP subjects have higher impulsivity than NAR and HC; (ii) NAR have higher impulsivity than HC; and (iii) euthymic BD and UP patients with past suicide attempts and substance abuse history have higher impulsivity than BD and UP subjects without such histories.

Neuroanatomical abnormalities in Bipolar disorder (BD) have previously been reported. However, the utility of these abnormalities in distinguishing individual BD patients from Healthy controls and stratify patients based on overall illness burden has not been investigated in a large cohort.In this study, we examined whether structural neuroimaging scans coupled with a machine learning algorithm are able to distinguish individual BD patients from Healthy controls in a large cohort of 256 subjects. Additionally, we investigated the relationship between machine learning predicted probability scores and subjects' clinical characteristics such as illness duration and clinical stages. Neuroimaging scans were acquired from 128 BD patients and 128 Healthy controls. Gray and white matter density maps were obtained and used to 'train' a relevance vector machine (RVM) learning algorithm which was used to distinguish individual patients from Healthy controls.The RVM algorithm distinguished patients from Healthy controls with 70.3 % accuracy (74.2 % specificity, 66.4 % sensitivity, chi-square p0.005) using white matter density data and 64.9 % accuracy (71.1 % specificity, 58.6 % sensitivity, chi-square p0.005) with gray matter density. Multiple brain regions - largely covering the fronto - limbic system were identified as 'most relevant' in distinguishing both groups. Patients identified by the algorithm with high certainty (a high probability score) - belonged to a subgroup with more than ten total lifetime manic episodes including hospitalizations (late stage).These results indicate the presence of widespread structural brain abnormalities in BD which are associated with higher illness burden - which points to neuroprogression.

Up to 50% of bipolar disorder (BD) patients present a lifetime diagnosis of alcohol use disorders (AUD). BD patients with comorbid AUD, even when in remission from the AUD, have a poorer outcome and functional impairment than patients with BD alone. The neurobiological abnormalities that potentially characterize this severe subgroup of BD patients are unknown. Our goal was to investigate gray matter (GM) volume abnormalities in BD I patients with comorbid AUD. Twenty-one BD-AUD patients, 21 BD-nonAUD BD patients, and 25 healthy controls (HC), matched by age, gender, and handedness were studied. The BD-AUD patients were in remission from AUD on average for 6.8 years. 3D SPGR MRIs (TR=25 ms, TE=5 ms, slice thickness=1.5 mm) were acquired from all subjects using a 1.5 T GE Signa Imaging System. We used an optimized voxel-based morphometry protocol to compare GM volumes among the groups. BD-AUD patients presented smaller GM volumes in the left medial frontal and the right anterior cingulate gyri compared to BD-nonAUD patients. BDnon-AUD patients did not present GM volume differences compared to HC. These findings provide evidence for an effect of comorbid AUD on regional brain structure of BD I patients and warrant further research on neurobiological aspects of this prevalent and severe comorbidity.