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MRI‐derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis‐driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large‐scale meta‐ and mega‐analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large‐scale, collaborative studies of mental illness., This review discusses the major challenges facing neuroimaging research of bipolar disorder and highlights the major accomplishments, ongoing challenges and future goals of the ENIGMA Bipolar Disorder Working Group.

ObjectiveThe hippocampus is a heterogenous brain structure that differs between the sexes and has been implicated in the pathophysiology of psychiatric illnesses. Here, we explored sex and diagnostic group differences in hippocampal subfield volumes, in individuals with schizophrenia spectrum disorder (SZ), bipolar disorders (BD) and healthy controls.Methods1,521 participants underwent T1-weighted magnetic resonance imaging (SZ, n = 452, mean age 30.7 ± 9.2 [SD] years, males 59.1%; BD, n = 316, 33.7 ± 11.4, 41.5%; healthy controls, n = 753, 34.1 ± 9.1, 55.6%). Total hippocampal, subfield, and intracranial volumes were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple regression models were fitted to examine sex-by-diagnostic (sub)group interactions in volume. In SZ and BD, separately, associations between volumes and clinical as well as cognitive measures were examined between the sexes using regression models.ResultsSignificant sex-by-group interactions were found for the total hippocampus, dentate gyrus, molecular layer, presubiculum, fimbria, HATA, and CA4, indicating a larger volumetric deficit in male patients relative to female patients when compared with same-sex healthy controls. Subgroup analyses revealed that this interaction was driven by males with schizophrenia. Effect sizes were overall small (partial η2< 0.02). We found no significant sex differences in the associations between hippocampal volumes and clinical or cognitive measures in SZ and BD.ConclusionsUsing a well-powered sample, our findings indicate that the pattern of morphological sex differences in hippocampal subfields is altered in individuals with schizophrenia relative to healthy controls, due to higher volumetric deficits in males.

Young chronological age is one of the strongest predictors for antisocial behaviour in the general population and for violent offending in individuals with psychotic disorders. An individual's age can be predicted with high accuracy using neuroimaging and machine-learning. The deviation between predicted and chronological age, i.e., brain age gap (BAG) has been suggested to reflect brain health, likely relating partly to neurodevelopmental and aging-related processes and specific disease mechanisms. Higher BAG has been demonstrated in patients with psychotic disorders. However, little is known about the brain-age in violent offenders with psychosis and the possible associations with psychopathy traits. We estimated brain-age in 782 male individuals using T1-weighted MRI scans. Three machine learning models (random forest, extreme gradient boosting with and without hyper parameter tuning) were first trained and tested on healthy controls (HC, n = 586). The obtained BAGs were compared between HC and age matched violent offenders with psychosis (PSY-V, n = 38), violent offenders without psychosis (NPV, n = 20) and non-violent psychosis patients (PSY-NV, n = 138). We ran additional comparisons between BAG of PSY-V and PSY-NV and associations with Positive and Negative Syndrome Scale (PANSS) total score as a measure of psychosis symptoms. Psychopathy traits in the violence groups were assessed with Psychopathy Checklist-revised (PCL-R) and investigated for associations with BAG. We found significantly higher BAG in PSY-V compared with HC (4.9 years, Cohen's d = 0.87) and in PSY-NV compared with HC (2.7 years, d = 0.41). Total PCL-R scores were negatively associated with BAG in the violence groups (d = 1.17, p < 0.05). Additionally, there was a positive association between psychosis symptoms and BAG in the psychosis groups (d = 1.12, p < 0.05). While the significant BAG differences related to psychosis and not violence suggest larger BAG for psychosis, the negative associations between BAG and psychopathy suggest a complex interplay with psychopathy traits. This proof-of-concept application of brain age prediction in severe mental disorders with a history of violence and psychopathy traits should be tested and replicated in larger samples.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD., The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder.In the largest study of hippocampal subfields in bipolar disorder to date, from 23 sites worldwide, we report widespread reductions in nine of 12 subfields.The lack of differences between lithium users and healthy controls supports a possible protective role of lithium in bipolar disorder.

Objectives Cytomegalovirus (CMV) congenital infection and in immunodeficiency can have deleterious effects on human cortex. In immunocompetent adults, the putative association between CMV infection and cortical measures has not been explored. We hypothesized that CMV exposure is associated with smaller cortical surface area or cortical thinning mainly in patients with schizophrenia spectrum disorders. Study Design We included 67 adult patients with schizophrenia spectrum disorders and 262 adult healthy controls. We measured circulating CMV IgG antibody concentrations with solid-phase immunoassay techniques. We measured the total cortical surface area, regional cortical surface areas and the overall mean cortical thickness based on T1-weighted MRI scans processed in FreeSurfer v6.0. Study Results In the whole sample analysis, we found a significant diagnostic group-by-CMV status interaction on the total surface area (P = .020). Among patients, CMV antibody positivity was significantly associated with smaller total surface area (P = .002, partial eta2 = 0.138) whereas no such association was found in healthy controls (P = .059). Post hoc analysis among patients showed that higher CMV antibody concentrations were also significantly associated with smaller total surface area (P = .038), and that CMV antibody positivity was significantly inversely associated with 14 left and 16 right regional surface areas mainly in the frontal and temporal lobes. CMV infection was not associated with the overall mean cortical thickness. Conclusions The results are indicative of a cortical surface area vulnerability to CMV infection in patients with schizophrenia spectrum disorders but not in healthy controls. CMV infection may contribute to the established cortical surface area aberrations in schizophrenia.

Individuals with psychotic disorders have an increased risk of committing acts of violence. Neurobiological support for the extent to which violence in psychosis is driven by psychotic symptoms and/or antisocial traits could have clinical and legal implications. Neuroimaging studies have reported white matter (WM) abnormalities in individuals with psychosis and in those with antisocial traits. However, it is unknown whether WM abnormalities in psychosis patients with a history of violence (violent-PSY) resemble those found in nonviolent psychosis patients (nonviolent PSY), violent nonpsychotic individuals (violent non-PSY), or both. Diffusion tensor imaging scans from 301 males including violent-PSY (n = 28), violent non-PSY (n = 20), nonviolent PSY (n = 58), and healthy controls (HC, n = 195) were analyzed with tract-based spatial statistics. Fractional anisotropy (FA), mean, axial and radial (RD) diffusivity were compared between groups. Psychopathic traits in the violent groups were measured with Psychopathy Checklist-revisited (PCL-R). Violent-PSY had globally lower FA and higher RD, compared with nonviolent PSY. Both psychosis groups and violent non-PSY group had widespread disruptions in WM compared with HC. There were no significant WM differences between violent-PSY and violent non-PSY. PCL-R scores did not differ between the violence groups and were associated with higher RD in corpus callosum. Here we demonstrate a widespread pattern of reduced WM integrity in violent-PSY compared with nonviolent PSY. The lack of significant WM and PCL-R differences between the violence groups, together with the positive association between PCL-R and WM deficits in violent-PSY and violent non-PSY may indicate shared neurobiological underpinnings of trait violence.

This article provides a discussion about criminal insanity regulation in Norway, Sweden and the Netherlands, with a focus on the roles of legislators, judges and experts in the concretisation of the legal meaning of criminal insanity. The authors recognise that these three countries reflect different ideal type rule constructions that are interesting to study comparatively. The article addresses the following overall questions: To what extent and in what way do the different rule constructions also involve different views on the roles of legislators, judges and experts? And in case of competing models, which is the better solution? To investigate and eventually answer these questions, the authors analyse the content and legislative considerations of the relevant rules, how these rules are applied and understood by judges and experts, and how different understandings of insanity, of legislators, judges and experts, depend on each other. The authors show how the different rule constructions represent different considerations on the adequate roles of the legislator, judges and experts. They argue that what is important is not what precise division of roles that is settled, but that this interplay functions to secure clear and robust rules, and that each of the three countries has room for improvement in this regard.

Understanding complex body-brain processes and the interplay between adipose tissue and brain health is important for understanding comorbidity between psychiatric and cardiometabolic disorders. We investigated associations between brain structure and anthropometric and body composition measures using brain magnetic resonance imaging (MRI; n=24,728) and body MRI (n=4973) of generally healthy participants in the UK Biobank. We derived regional and global measures of brain morphometry using FreeSurfer and tested their association with (i) anthropometric measures, and (ii) adipose and muscle tissue measured from body MRI. We identified several significant associations with small effect sizes. Anthropometric measures showed negative, nonlinear, associations with cerebellar/cortical gray matter, and brain stem structures, and positive associations with ventricular volumes. Subcortical structures exhibited mixed effect directionality, with strongest positive association for accumbens. Adipose tissue measures, including liver fat and muscle fat infiltration, were negatively associated with cortical/cerebellum structures, while total thigh muscle volume was positively associated with brain stem and accumbens. Regional investigations of cortical area, thickness, and volume indicated widespread and largely negative associations with anthropometric and adipose tissue measures, with an opposite pattern for thigh muscle volume. Self-reported diabetes, hypertension, or hypercholesterolemia were associated with brain structure. The findings provide new insight into physiological body-brain associations suggestive of shared mechanisms between cardiometabolic risk factors and brain health. Whereas the causality needs to be determined, the observed patterns of body-brain relationships provide a foundation for understanding the underlying mechanisms linking psychiatric disorders with obesity and cardiovascular disease, with potential for the development of new prevention strategies. Funding Agencies|Research Council of NorwayResearch Council of Norway [223273, 276082]; South-Eastern Norway Regional Health Authority [2017112, 2020060]; Kristian Gerhard Jebsen Stiftelsen [SKGJ-MED-021]; European UnionEuropean Commission [847776]; European Research Council (ERC) StGEuropean Research Council (ERC) [802998]

BackgroundUnderstanding complex body-brain processes, and putative interplay between adipose tissue and brain health, is of vital importance for brain and somatic disease prevention in the general population. We studied the link between body composition and brain structure through large-scale investigation in a healthy population without secondary disease effects.MethodsWe processed brain magnetic resonance imaging (MRI) data and extracted measures of brain morphometry from 19,330 healthy UK Biobank participants, of which a subset (n=2,703) had body MRI. We investigated associations between brain structure and (i) anthropometric body composition measures, and (ii) regional/specific body MRI measures of abdominal fat and muscle tissue.FindingsWe identified highly significant body-brain associations (p-values≤0·0002). Anthropometric measures showed negative, nonlinear, associations with cerebellar/cortical gray matter, and brain stem structures, negative associations with white matter, and positive associations with ventricular volumes. Subcortical structures exhibited mixed effect directionality, with strongest positive association for accumbens. Among body MRI measures, liver fat was negatively associated with thinner/lower cortical gray matter thickness/volume, and thigh muscle volume positively associated with accumbens volume.InterpretationWe demonstrate significant body-brain associations, and map individual differences in body composition to brain morphology in healthy individuals. Common measures of body composition correlated negatively with cerebellar and cortical structures and positively with the accumbens, a dopamine rich structure involved in reward processing. These findings of a relationship between brain anatomy and body composition provide new insight into body-brain processes and suggest shared mechanisms of cardiometabolic risk factors and brain disorders. This may form the foundation for a new type of prevention studies, and provides a framework for studies of underlying mechanisms related to unhealthy lifestyle and obesity, with implications for public health and prevention.FundingThe Research Council of Norway, South-Eastern Norway Regional Health Authority, European Union’s Horizon 2020 Research and Innovation Programme & European Research Council.Research in contextEvidence before this studyPrior studies have indicated an association between brain structure and both obesity and fitness levels - of opposing directionality. Despite this, normal body-brain association patterns in healthy individuals have not been established, and the causal mechanisms are unclear. To enhance our understanding and establish the link between the body and the brain, we saw the need for large-scale investigations in healthy populations. For the study, we searched the PubMed database from March 12th, 2019, through February 25th, 2020, for scientific literature related to adipose tissue, body composition, brain morphology, and body and brain MRI. Search terms included: body fat, adipose tissue, subcutaneous/visceral adipose tissue, liver fat, body composition, anthropometric measures, body mass index, waist circumference, waist-to-hip ratio, adiposity, obesity, metabolic syndrome, cardiovascular, cardiometabolic, disease/disorder, muscle volume, fitness, brain structure, brain morphology, brain MRI, and body MRI. We based the scientific foundation on review studies, meta-analyses, and other larger studies, but generally excluded smaller studies, and thereby lowering the risk of evidential bias such as winner’s curse, although this does not eliminate the risk of publication bias.Added value of this studyIn the largest study, to date, including 19,330 healthy participants without secondary disease effects, we provide insight into normal body-brain processes by identifying body-brain associations that map normally varying body composition to brain morphology.Implications of all the available evidenceWe identified body-brain associations that give insight into normal physiological body-brain processes in healthy individuals, providing a reference point for studies of underlying mechanisms related to unhealthy lifestyle, obesity, and disorders of the body and the brain. Whereas the directionality and causal chain is unknown, these findings have potential implications for public health and disease prevention.

The hippocampus is a complex structure consisting of subregions with specialized cytoarchitecture and functions. Magnetic resonance imaging (MRI) studies in psychotic disorders show hippocampal subfield abnormalities, but affected regions differ between studies. We here present an overview of hippocampal anatomy and function relevant to psychosis, and the first systematic review and meta-analysis of MRI studies of hippocampal subfield morphology in schizophrenia and bipolar disorder. Twenty-one MRI studies assessing hippocampal subfield volumes or shape in schizophrenia or bipolar disorder were included (n 15–887 subjects). Nine volumetric group comparison studies (total n = 2593) were included in random effects meta-analyses of group differences. The review showed mixed results, with volume reductions reported in most subfields in schizophrenia and bipolar disorder. Volumetric studies using ex-vivo based image analysis templates corresponded best with the shape studies, with CA1 as the most affected region. The meta-analyses showed volume reductions in all subfields in schizophrenia and bipolar disorder compared to healthy controls (all p

The amygdala is involved in fear perception and aggression regulation, and smaller volumes have been associated with psychotic and non-psychotic violence. We explored the relationship between amygdala nuclei volumes in violent offenders with and without psychosis, and the association to psychopathy traits. 3T MRI scans (n=204, males, 18-66 years) were obtained from psychotic violent offenders (PSY-V, n=29), non-psychotic violent offenders (NPV, n=19), non-violent psychosis patients (PSY-NV, n=67), and healthy controls (HC, n=89). Total amygdala and 9 amygdala nuclei volumes were obtained with FreeSurfer. Psychopathy traits were measured with the Psychopathy Checklist-revised (PCL-R). Multivariate analyses explored diagnostic differences in amygdala nuclei volumes and associations to psychosis, violence, and psychopathy traits. PSY-V had a smaller basal nucleus, anterior amygdaloid area, and cortical amygdalar transition area (CATA), whereas PSY-NV had a smaller CATA than HC. Volumes in NPV did not differ from HC, and there were no associations between PCL-R total or factor scores and any of the nuclei or whole amygdala volumes. The lower volumes of amygdala nuclei involved in fear modulation, stress responses, and social interpretation may point towards some mechanisms of relevance to violence in psychosis, but the results warrant replication in larger subject samples.

Contains fulltext : 191289.pdf (Publisher’s version ) (Open Access) Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 x 10(-21)), left fusiform gyrus (d=-0.288; P=8.25 x 10(-21)) and left rostral middle frontal cortex (d=-0.276; P=2.99 x 10(-19)). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Background Substance use is one of many risk factors for schizophrenia, and substance use is also associated with violent offending. This study compared a group of individuals suffering from schizophrenia with a history of violent offending (SCZ-V) to a group of schizophrenia patients without any history of violent offending (SCZ-NV). We investigated whether there is a difference between the SCZ-V and SCZ-NV groups when it comes to lifetime use, and debut age for use, of alcohol, cannabis, and amphetamines. Methods This study examined the overall lifetime substance-use and the debut age of use of alcohol, cannabis and amphetamine among a selected group of patients with schizophrenia and a history of violent offending (SCZ-V n=25) recruited from psychiatric security wards in South-Eastern Norway, compared to a matched group of schizophrenia patients without violent offending (SCZ-NV n=34). Participants completed interviews and questionnaires to confirm diagnoses and to map the history of substance use. Results While we found no significant difference in lifetime use of alcohol and cannabis between the groups (alcohol: SCZ-V: 88%, SCZ-NV: 97%, cannabis: SCZ-V: 76%, SCZ-NV: 71%), the SCZ-V group reported significantly more lifetime use of amphetamines compared to the SCZ-NV group (SCZ-V: 76% vs SCZ-NV: 18%, p Discussion The SCZ-V group reported significantly more lifetime use of amphetamine and a significantly lower debut age for use of alcohol, cannabis, and amphetamines than the SCZ-NV group. According to the Norwegian Institute of Public Health, the average lifetime uses of cannabis for the general Norwegian population between 16 and 64 years old is 20.6%, while the average for the population between 16 and 34 years old when it comes to ever have used amphetamines is 4.7%. The numbers for both the SCZ-V and the SCZ-NV groups were noticeably higher than the population averages. What separates the groups are the significantly lower debut age of drug use in the SCZ-V group, and especially the higher number of lifetime amphetamines use. The findings point towards an association between the early debut of use of alcohol, cannabis, and amphetamines, and later violent offending in patients suffering from schizophrenia.

Objective Low total cholesterol has been linked with adverse mental symptoms such as aggression and impulsivity in severe mental disorders (SMDs). This putative association may affect the clinician's decision making about cholesterol lowering in this patient group. Here, we investigated the associations between cholesterol levels, aggression, and impulsivity in a large representative sample of in‐ and outpatients with SMD. Methods Patients with schizophrenia‐ or bipolar spectrum disorders (N = 1 001) underwent thorough clinical characterization and blood sampling (total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol). Aggression was characterized by the Positive and Negative Syndrome Scale Excited Component. Impulsivity was measured with the Barratt Impulsiveness Scale in a subsample of patients (N = 288). We used a multinomial logistic regression model to analyze the association between cholesterol and aggression and a multiple linear regression model to analyze the association between cholesterol and impulsivity, while controlling for confounders. Results We found no significant associations between cholesterol levels and aggression or impulsivity. There were no significant interactions between cholesterol and diagnostic group or inpatient versus outpatient status. Controlling for medication use, body mass index, alcohol or illicit substance use did not affect the results. Conclusion In this large sample of patients with schizophrenia‐ and bipolar spectrum disorders, we found no associations between cholesterol levels and aggression or impulsivity. This has clinical implications as patients with SMD are at increased CVD risk and currently undertreated with statins., In context of the urgent need to improve cardiovascular health of patients with severe mental disorders, we investigated the associations between cholesterol levels and aggression in a sample of in‐ and outpatients with schizophrenia‐ and bipolar spectrum disorders. This large representative sample of patients with severe mental disorders revealed no significant associations between cholesterol levels and aggression or impulsivity.

Schizophrenia (SCZ) is associated with an increased risk of violence compared to the general population. Previous studies have indicated smaller hippocampal and amygdala volumes in violent than non-violent psychotic patients. However, little is known about volumetric differences at the subdivision level of these structures. In the present study, hippocampal subfields and amygdala nuclei volumes were estimated with FreeSurfer from 3 T MRI of SCZ patients with (SCZ-V, n = 24) and without (SCZ-NV, n = 51) a history of severe violence and 90 healthy controls (HC). Volumetric differences between groups were explored with a general linear model covarying for confounders, in addition to follow-up analyses in patient groups controlling for clinical characteristics such as antipsychotic medication, duration of illness and illicit substance use. SCZ-V had smaller total hippocampal volume and smaller CA1, HATA, fimbria, and molecular layer of DG volumes compared to HC. Total amygdala volume together with basal nucleus, accessory basal nucleus, CTA, and paralaminar nucleus volumes were smaller in SCZ-V compared to HC. In SCZ-NV, compared to HC, the observed smaller volumes were limited to basal and paralaminar nucleus. There were no significant differences in hippocampal subfield and amygdala nuclei volumes between SCZ-V and SCZ-NV. Follow-up analyses showed that the results in patient groups were not affected by clinical characteristics. The results suggest that smaller hippocampal subfield and amygdala nuclei volumes may be relevant to violence risk in SCZ. However, the neurobiological signature of violence in SCZ should be further investigated in larger cohorts. Electronic supplementary material The online version of this article (10.1007/s00406-020-01098-y) contains supplementary material, which is available to authorized users.

BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts.METHODS: We trained 6 cross-validated models using different combinations of DTI data from 927 HC subjects (18-94 years of age) and applied the models to the test sets including 648 patients with SZ (18-66 years of age), 185 patients with BD (18-64 years of age), and 990 HC subjects (17-68 years of age), estimating the brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results.RESULTS: Tenfold cross-validation revealed high accuracy for all models. Compared with HC subjects, the model including all feature sets significantly overestimated the age of patients with SZ (Cohen's d = -20.29) and patients with BD (Cohen's d = 0.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy-based models showed larger group differences than the models based on other DTI-derived metrics.CONCLUSIONS: Brain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.

BackgroundWhether severe obstetric complications (OCs), which harm neural function in offspring, contribute to impaired cognition found in psychiatric disorders is currently unknown. Here, we sought to evaluate how a history of severe OCs is associated with cognitive functioning, indicated by Intelligence Quotient (IQ).MethodsWe evaluated the associations of a history of OCs and IQ in 622 healthy controls (HC) and 870 patients on the schizophrenia (SCZ) – bipolar disorder (BIP) spectrum from the ongoing Thematically Organized Psychosis study cohort, Oslo, Norway. Participants underwent assessments using the NART (premorbid IQ) and the WASI (current IQ). Information about OCs was obtained from the Medical Birth Registry of Norway. Multiple linear regression models were used for analysis.ResultsSevere OCs were equally common across groups. SCZ patients with OCs had lower performances on both premorbid and current IQ measures, compared to those without OCs. However, having experienced more than one co-occurring severe OC was associated with lower current IQ in all groups.ConclusionsSevere OCs were associated with lower IQ in the SCZ group and in the BIP and HC groups, but only if they had experienced more than one severe OC. Low IQ might be a neurodevelopmental marker for SCZ; wherein, severe OCs influence cognitive abilities and increase the risk of developing SCZ. Considering OCs as a variable of neurodevelopmental risk for severe mental illness may promote the development of neuroprotective interventions, improve outcome in vulnerable newborns and advance our ability to make clinical prognoses.

BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.MethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115;Mage=38.9±13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.ResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail (ß=−0.13) and CA1 (ß=−0.09) after adjusting for covariates and multiple testing (adjusted p’s (q)=0.028). A main effect of C-PTSD (n=1042 vs. control, n=1359) was not significant, but an interaction between C-PTSD and depression was significant in the CA1 (ß=−0.24, q=0.044). Pairwise comparisons revealed significantly smaller CA1 volumes in individuals with C-PTSD+Depression than controls (ß=−0.12, q=0.012), C-PTSD-only (ß=−0.17, q=0.001), and Depression-only (ß=−0.18, q=0.023). Follow-up analyses revealed sex effects in the hippocampal tail of depressed females, and an interaction effect of C-PTSD and depression in the fimbria of males.ConclusionsCollectively our results suggest that depression is a stronger predictor of hippocampal volumetry than PTSD, particularly in the CA1, and provide compelling evidence of more pronounced hippocampal phenotypes in comorbid PTSD and depression compared to either condition alone.

BackgroundSchizophrenia (SZ) and bipolar disorders (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, BD, and healthy controls across 10 cohorts.MethodsWe trained six cross-validated models using different combinations of DTI data from 927 healthy controls (HC, 18-94 years), and applied the models to the test sets including 648 SZ (18-66 years) patients, 185 BD patients (18-64 years), and 990 HC (17-68 years), estimating brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results.Results10-fold cross-validation revealed high accuracy for all models. Compared to controls, the model including all feature sets significantly over-estimated the age of patients with SZ (d=-.29) and BD (d=.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy (FA) based models showed larger group differences than the models based on other DTI-derived metrics.ConclusionsBrain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.

Objective The effect of antipsychotic medication on brain structure remains unclear. Given the prevalence of weight gain as a side-effect, body mass index (BMI) change could be a confounder. Method Patients with first-episode psychosis (n = 78) and healthy controls (n = 119) underwent two 1.5T MRI scans with a 1-year follow-up interval. siena (fsl 5.0) was used to measure whole-brain volume change. Weight and height were measured at both time points. Antipsychotic medication use at baseline and follow-up was converted into chlorpromazine equivalent dose and averaged. Results Patients did not show significantly larger brain volume loss compared with healthy controls. In the whole sample (n = 197), BMI change was negatively associated with brain volume change (β = −0.19, P = 0.008); there was no interaction effect of group. Among patients, higher antipsychotic medication dosage was associated with greater brain volume loss (β = −0.45, P < 0.001). This association was not affected by adjusting for BMI change. Conclusion Weight gain was related to brain volume reductions to a similar degree among patients and controls. Antipsychotic dosage-related reductions of brain volume were not confounded by BMI change. Generalizability to contexts involving severe weight gain needs to be established. Furthermore, disentangling effects of medication from illness severity remains a challenge.

BackgroundExcessive alcohol use is associated with brain damage but less is known about brain effects from moderate alcohol use. Previous findings indicate that patients with severe mental illness, particularly schizophrenia, are vulnerable to alcohol-related brain damage. We investigated the association between levels of alcohol consumption and cortical and subcortical brain structures in schizophrenia and bipolar disorder patients and healthy controls, and investigated for group differences for this association.Method1.5 T structural magnetic resonance images were acquired of 609 alcohol-using participants (165 schizophrenia patients, 172 bipolar disorder patients, 272 healthy controls), mean (s.d.) age 34.2 (9.9) years, 52% men. Past year alcohol use was assessed with the Alcohol Use Disorder Identification Test – Consumption part (AUDIT-C). General linear models were used to investigate associations between AUDIT-C score and cortical thickness, surface area, and total brain and subcortical volumes.ResultsIncreasing AUDIT-C score was linearly associated with thinner cortex in medial and dorsolateral frontal and parieto-occipital regions, and with larger left lateral ventricle volume. There was no significant interaction between AUDIT-C score and diagnostic group. The findings remained significant after controlling for substance use disorders, antipsychotic medication and illness severity.ConclusionThe results show a dose-dependent relationship between alcohol use and thinner cortex and ventricular expansion. The findings are present also at lower levels of alcohol consumption and do not differ between schizophrenia or bipolar disorder patients compared to healthy controls. Our results do not support previous findings of increased vulnerability for alcohol-related brain damage in severe mental illness.

Schizophrenia is associated with decreased life expectancy (15-25 y) compared to the general population, with comorbid somatic diseases and in particular cardiovascular diseases being a major cause. Life style and medication probably account for much of the increased mortality risk due to somatic diseases in schizophrenia, but the evidence implicating biological pathways potentially affecting both body and brain is increasing. This includes overlapping genes between schizophrenia and somatic diseases, prenatal risk factors such as hypoxia and infections, and increased cardiovascular disease risk in drug-naïve patients at illness onset. Although environmental bias increases throughout the disease course, there are also some studies on chronic schizophrenia and postmortem brain samples that warrant further attention. In the following, we will attempt to move beyond environmental impact and explore some of the shared pathophysiological mechanisms potentially underlying both schizophrenia and somatic diseases.

Clinical studies of patients with schizophrenia and a history of violence are challenging both from an ethical and practical perspective, and the neurobiological underpinnings remain largely unknown. We here present a comprehensive account of the brain cortical characteristics associated with violence in schizophrenia. We obtained 3T MRI scans and thorough clinical characterization of schizophrenia patients with a history of violence (murder, attempted murder, criminal assault, SCZ-V, n = 11), schizophrenia patients with no history of violence (SCZ-NV, n = 17), and healthy controls (HC, n = 19). Cortical thickness, area, and folding were analyzed vertex-wise across the cortical mantle (FreeSurfer). SCZ-V had significantly increased cortical folding in the visual and orbitofrontal cortex, and reduced cortical thickness within the precentral-, parietal-, temporal-, and fusiform cortex compared to SCZ-NV, as well as widespread regional thinning and increased folding compared to HC. There were no group differences in cortical area. A major limitation is the small subject sample. If replicated, the results from this pilot study suggest cortical abnormalities in areas involved in sensory processing, emotion recognition, and reward to be of importance to the neurobiology of violence in schizophrenia.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD);\ud however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical\ud heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with\ud BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered\ud individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean\ud fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and\ud meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD\ud compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and\ud cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to\ud higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities\ud in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD.\ud These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

How mental disorder relates to criminal insanity is a contested matter. Norway has a tradition of using a ‘medical model’ for the definition of criminal insanity that is unique in an international perspective. According to this model, insanity is determined only in relation to a medical criterion, so that all that is required is the presence of a qualifying mental disorder. Criminal insanity is, under the current rule, equated with psychosis, although this rule has recently been subject to a law reform. This article explains and discusses this medical model by gathering together legal, forensic, and clinical empirical perspectives on the legal meaning and relevance of psychosis. The article will provide an explanation of the background of the medical model in Norwegian law, and the justifications for tying criminal insanity to psychosis. It will also explain how criminal insanity is operationalised in forensic practice, and discuss the legal conceptualisation of psychosis from a medical perspective. A main conclusion is that the legal meaning of psychosis is unclear, and the authors describe several challenges in legal and forensic practice. The authors emphasise the need for further knowledge development in the intersection between law and medicine.

Supported by histological and genetic evidence implicating myelin, neuroinflammation and oligodendrocyte dysfunction in schizophrenia spectrum disorders (SZ), diffusion tensor imaging (DTI) studies have consistently shown white matter (WM) abnormalities when compared to healthy controls (HC). The diagnostic specificity remains unclear, with bipolar disorders (BD) frequently conceptualized as a less severe clinical manifestation along a psychotic spectrum. Further, the age-related dynamics and possible sex differences of WM abnormalities in SZ and BD are currently understudied.Using tract-based spatial statistics (TBSS) we compared DTI-based microstructural indices between SZ (n=128), BD (n=61), and HC (n=293). We tested for age-by-group and sex-by-group interactions, computed effect sizes within different age-bins and within genders.TBSS revealed global reductions in fractional anisotropy (FA) and increases in radial (RD) diffusivity in SZ compared to HC, with strongest effects in the body and splenium of the corpus callosum, and lower FA in SZ compared to BD in right inferior longitudinal fasciculus and right inferior fronto-occipital fasciculus, and no significant differences between BD and HC. The results were not strongly dependent on age or sex. Despite lack of significant group-by-age interactions, a sliding-window approach supported widespread WM involvement in SZ with most profound differences in FA from the late 20s.

Schizophrenia (SCZ) is associated with increased risk of violence compared to the general population. Neuroimaging research suggests SCZ to be a disorder of disrupted connectivity, with diffusion tensor imaging (DTI) indicating white matter (WM) abnormalities. It has been hypothesized that SCZ patients with a history of violence (SCZ-V) have brain abnormalities distinguishing them from SCZ patients with no history of violence (SCZ-NV). Yet, a thorough investigation of the neurobiological underpinnings of state and trait measures of violence and aggression in SCZ derived from DTI indices is lacking. Using tract-based spatial statistics, we compared DTI-derived microstructural indices: fractional anisotropy (FA), mean, axial (AD) and radial diffusivity across the brain; (1) between SCZ-V (history of murder, attempted murder, or severe assault towards other people, n = 24), SCZ-NV (n = 52) and healthy controls (HC, n = 94), and (2) associations with current aggression scores among both SCZ groups. Then, hypothesis-driven region of interest analyses of the uncinate fasciculus and clinical characteristics including medication use were performed. SCZ-V and SCZ-NV showed decreased FA and AD in widespread regions compared to HC. There were no significant differences on any DTI-based measures between SCZ-V and SCZ-NV, and no significant associations between state or trait measures of aggression and any of the DTI metrics in the ROI analyses. The DTI-derived WM differences between SCZ and HC are in line with previous findings, but the results do not support the hypothesis of specific brain WM microstructural correlates of violence or aggression in SCZ.

BackgroundFirst-episode psychosis (FEP) patients show structural brain abnormalities. Whether the changes are progressive or not remain under debate, and the results from longitudinal magnetic resonance imaging (MRI) studies are mixed. We investigated if FEP patients showed a different pattern of regional brain structural change over a 1-year period compared with healthy controls, and if putative changes correlated with clinical characteristics and outcome.MethodMRIs of 79 FEP patients [SCID-I-verified diagnoses: schizophrenia, psychotic bipolar disorder, or other psychoses, mean age 27.6 (s.d. = 7.7) years, 66% male] and 82 healthy controls [age 29.3 (s.d. = 7.2) years, 66% male] were acquired from the same 1.5 T scanner at baseline and 1-year follow-up as part of the Thematically Organized Psychosis (TOP) study, Oslo, Norway. Scans were automatically processed with the longitudinal stream in FreeSurfer that creates an unbiased within-subject template image. General linear models were used to analyse longitudinal change in a wide range of subcortical volumes and detailed thickness and surface area estimates across the entire cortex, and associations with clinical characteristics.ResultsFEP patients and controls did not differ significantly in annual percentage change in cortical thickness or area in any cortical region, or in any of the subcortical structures after adjustment for multiple comparisons. Within the FEP group, duration of untreated psychosis, age at illness onset, antipsychotic medication use and remission at follow-up were not related to longitudinal brain change.ConclusionsWe found no significant longitudinal brain changes over a 1-year period in FEP patients. Our results do not support early progressive brain changes in psychotic disorders.

Objectives Results from magnetic resonance imaging (MRI) studies are heterogeneous with regard to hippocampal and amygdala volume alterations in bipolar disorder (BD). Lithium treatment may influence both structures. It is unknown if lithium treatment has distinct effects on hippocampal subfield volumes and if subfield volumes change over the course of illness in BD. Methods MRI scans were obtained for 34 lithium-treated patients with BD (Li+), 147 patients with BD who were not treated with lithium (Non-Li), and 300 healthy controls. Hippocampal total and subfield volumes and amygdala volumes were automatically estimated using Freesurfer. General linear models were used to investigate volume differences between groups and the effects of illness course and lithium treatment. Results The Non-Li BD group displayed significantly smaller bilateral cornu ammonis (CA) 2/3 and CA4/dentate gyrus (DG) subfields, total hippocampal volumes, right CA1 and right subiculum subfields, and left amygdala volume compared to healthy controls. There were no differences between the Li+ BD and either the Non-Li BD or the healthy control groups. In patients with numerous affective episodes, Non-Li BD patients had smaller left CA1 and CA2/3 volumes compared to Li+ BD patients and healthy controls. There were positive associations between lithium treatment duration and left amygdala volume. Conclusions Hippocampal subfield and amygdala volumes were reduced in Non-Li BD patients compared to healthy controls, whereas the Li+ BD volumes were no different from those in Non-Li BD patients or healthy controls. Over the course of BD, lithium treatment might counteract reductions specifically in the left CA1 and CA2/3 hippocampal subfields and amygdala volumes, in accordance with the suggested neuroprotective effects of lithium.

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

BackgroundThe increased occurrence of obstetric complications (OCs) in patients with schizophrenia suggests that alterations in neurodevelopment may be of importance to the aetiology of the illness. Abnormal cortical folding may reflect subtle deviation from normal neurodevelopment during the foetal or neonatal period. In the present study, we hypothesized that OCs would be related to cortical folding abnormalities in schizophrenia patients corresponding to areas where patients with schizophrenia display altered cortical folding when compared with healthy controls.MethodIn total, 54 schizophrenia patients and 54 healthy control subjects underwent clinical examination and magnetic resonance image scanning on a 1.5 T scanner. Information on OCs was collected from original birth records. An automated algorithm was used to calculate a three-dimensional local gyrification index (lGI) at numerous points across the cortical mantle.ResultsIn both schizophrenia patients and healthy controls, an increasing number of OCs was significantly related to lowerlGI in the left pars triangularis (plGI were found in the right hemisphere and there were no significant case–control differences inlGI.ConclusionsThe reduced cortical folding in the left pars triangularis, associated with OCs in both patients and control subjects suggests that the cortical effect of OCs is caused by factors shared by schizophrenia patients and healthy controls rather than factors related to schizophrenia alone.

Cannabis is associated with increased risk for severe mental illness and is commonly used among individuals with schizophrenia or bipolar disorder. In this study we investigated associations between cannabis use and brain structures among patients with schizophrenia or bipolar disorders. Magnetic resonance imaging scans were obtained for 77 schizophrenia and 55 bipolar patients with a history of cannabis use (defined as lifetime use >10 times during one month or abuse/dependence), and 97 schizophrenia, 85 bipolar disorder patients and 277 healthy controls without any previous cannabis use. Cortical thickness, cortical surface area and subcortical volumes were compared between groups. Both hypothesis-driven region-of-interest analyses from 11 preselected brain regions in each hemisphere and exploratory point-by-point analyses were performed. We tested for diagnostic interactions and controlled for potential confounders. After controlling for confounders such as tobacco use and alcohol use disorders we found reduced cortical thickness in the caudal middle frontal gyrus compared to non-user patients and healthy controls. The findings were not significant when patients with co-morbid alcohol and illicit drug use were excluded from the analyses, but onset of cannabis use before illness onset was associated with cortical thinning in the caudal middle frontal gyrus. To conclude, we found no structural brain changes associated with cannabis use among patients with severe mental illness, but the findings indicate excess cortical thinning among those who use cannabis before illness onset. The present findings support the understanding that cannabis use is associated with limited brain effects in schizophrenia as well as bipolar disorder.

Background: Clinical studies in schizophrenia patients (SCZ) with a history of violence are practically and ethically challenging, hence the neurobiological underpinnings of violence in SCZ are largely unknown. Searching for cortical markers of violent SCZ, this is to the best of our knowledge the first complete cortical morphology (ie, folding, thickness, and area) study in violent SCZ.

Aims/hypothesis MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes. Methods Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic). Results We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3–5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p = 1.6 × 10−5). HNF1A showed the strongest enrichment of class 3–5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5. Conclusions/interpretation This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R

Objective Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood abuse, cognitive function, and brain abnormalities in psychoses. Method 249 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited to the TOP research study (mean ± age: 30.7 ± 10.9; gender: 49% males). History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Cognitive function was assessed through a standardized neuropsychological test battery. BDNF val66met was genotyped using standardized procedures. A sub-sample of n = 106 Caucasians with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder (mean ± age: 32.67 ± 10.85; 49% males) had data on sMRI. Results Carriers of the Methionine (met) allele exposed to high level of childhood abuse demonstrated significantly poorer cognitive functioning compared to homozygotic Valine (val/val) carriers. Taking in consideration multiple testing, using a more conservative p value, this was still shown for physical abuse and emotional abuse, as well as a trend level for sexual abuse. Further, met carriers exposed to high level of childhood sexual abuse showed reduced right hippocampal volume (r 2 = 0.43; p = 0.008), and larger right and left lateral ventricles (r 2 = 0.37; p = 0.002, and r 2 = 0.27; p = 0.009, respectively). Our findings were independent of age, gender, diagnosis and intracranial volume. Conclusion Our data demonstrate that in patients with psychoses, met carriers of the BDNF val66met with high level of childhood abuse have more cognitive and brain abnormalities than all other groups.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness., published version, peerReviewed