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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.

Schizophrenia and bipolar disorder are severe mental illnesses (SMI) linked to both genetic and environmental factors. Herpes simplex virus 1 (HSV1) is a common neurotropic pathogen which after the primary infection establishes latency with periodic reactivations. We hypothesized that the latent HSV1 infection is associated with brain structural abnormalities and cognitive impairment, especially in SMI. We included 420 adult patients with SMI (schizophrenia or bipolar spectrum) and 481 healthy controls. Circulating HSV1 immunoglobulin G concentrations were measured with immunoassays. We measured the total grey matter volume (TGMV), cortical, subcortical, cerebellar and regional cortical volumes based on T1-weighted MRI scans processed in FreeSurfer v6.0.0. Intelligence quotient (IQ) was assessed with the Wechsler Abbreviated Scale of Intelligence. Seropositive patients had significantly smaller TGMV than seronegative patients (642 cm3 and 654 cm3, respectively; p = 0.019) and lower IQ (104 and 107, respectively; p = 0.018). No TGMV or IQ differences were found between seropositive and seronegative healthy controls. Post-hoc analysis showed that (a) in both schizophrenia and bipolar spectrum, seropositive patients had similarly smaller TGMV than seronegative patients, whereas the HSV1-IQ association was driven by the schizophrenia spectrum group, and (b) among all patients, seropositivity was associated with smaller total cortical (p = 0.016), but not subcortical or cerebellar grey matter volumes, and with smaller left caudal middle frontal, precentral, lingual, middle temporal and banks of superior temporal sulcus regional cortical grey matter volumes. The results of this cross-sectional study indicate that HSV1 may be an environmental factor associated with brain structural abnormalities and cognitive impairment in SMI.

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.

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.

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]

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.

Schizophrenia is a severe mental disorder with often a chronic course. Neuroimaging studies report brain abnormalities in both white and gray matter structures. However, the relationship between microstructural white matter differences and volumetric subcortical structures is not known.We investigated 30 long-term treated patients with schizophrenia (mean age 51.1±7.9 years, illness duration 27.6±8.0 years) and 42 healthy controls (mean age 54.1±9.1 years) using 3 T diffusion and structural magnetic resonance imaging. The free-water imaging method was used to model the diffusion signal, and subcortical volumes were obtained from FreeSurfer. We applied multiple linear regression to investigate associations between (i) patient status and regional white matter microstructure, (ii) medication dose or clinical symptoms on white matter microstructure in patients, and (iii) for interactions between subcortical volumes and diagnosis for microstructural white matter regions showing significant patient-control differences.The patients had significantly decreased free-water corrected fractional anisotropy (FAt), explained by decreased axial diffusivity and increased radial diffusivity (RDt) bilaterally in the anterior corona radiata (ACR) and the left anterior limb of the internal capsule (ALIC) compared to controls. In the fornix, the patients had significantly increased RDt. In patients, positive symptoms were associated with localized increased free-water and negative symptoms with localized decreased FAt and increased RDt. There were significant interactions between patient status and several subcortical structures on white matter microstructure and the free-water compartment for left ACR and fornix, and limited to the free-water compartment for right ACR and left ALIC. The Cohen’s d effect sizes were medium to large (0.61 to 1.20, absolute values).The results suggest a specific pattern of frontal white matter axonal degeneration and demyelination and fornix demyelination that is attenuated in the presence of larger structures of the limbic system in patients with chronic schizophrenia. Findings warrants replication in larger samples.

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.

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.

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.

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.

Background:Persons with schizophrenia have a small but significant increase in risk of violence, which remains after controlling for known environmental risk factors.In vivoMRI-studies may point toward the biological underpinnings of psychotic violence, and neuroimaging has increasingly been used in forensic and legal settings despite unclear relevance. Objectives:(1) To present the first systematic review, following standardized guidelines, of MRI studies of violence with schizophrenia. (2) To critically discuss the promises and pitfalls of using this literature to understand violence in schizophrenia in clinical, forensic, and legal settings. Methods:Following the PRISMA guidelines and literature searches until January 2018, we found 21 original studies that fulfilled the inclusion criteria: (1) Studies of persons with schizophrenia, (2) a history of violence or aggressive behavior, (3) the use of one or more MRI-modalities (sMRI, DTI, fMRI). Results:The most consistent findings from the structural studies were reduced volumes of the hippocampus and the frontal lobe (in particular the orbitofrontal and anterior cingulate cortex) in schizophrenia patients with a history of violence or higher aggression scores. The functional studies mainly showed differences and aggression correlates in the frontal lobe and amygdala. However, the studies were methodologically heterogeneous, with four particular areas of concern: different definitions of violence, region of interest vs. whole-brain studies, small subject samples, and group comparisons in a heterogeneous diagnostic category (schizophrenia). Conclusion:The literature reports subtle, but inconsistent group level differences in brain structure and function associated with violence and aggression with schizophrenia, in particular in areas involved in the formation of psychosis symptoms and affective regulation. Due to methodological challenges the results should be interpreted with caution. In order to come closer to the neurobiological underpinnings of violence in schizophrenia future studies could: (1) address the neurobiological differences of premeditated and reactive violence, (2) use RDoC criteria, for example, or other symptom-based systems to categorize psychosis patients, (3) increase subject cohorts and apply new data driven methods. In this perspective, MRI-studies of violence in schizophrenia have the potential to inform clinical violence prediction and legal evaluationsin the future. publishedVersion

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.

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.

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.

BACKGROUND Schizophrenia is a serious mental disorder that affects several brain functions. MRI technology has enabled in vivo studies of brain anatomy in patients with schizophrenia aimed at understanding more about the disorder. METHOD This article is based on a search in PubMed on «schizophrenia MRI» and on the authors' own research and experience. We included structural MRI studies, carried out on humans, written in English. Here we present a selection of studies that we believe are representative of the field. RESULTS In patients with schizophrenia, MR imaging shows a smaller total brain volume and enlarged ventricles. Specific subcortical regions are affected, with reduced hippocampal and thalamic volumes, and an increase in the volume of the globus pallidus. In the cortex can be seen changes in folding patterns and a reduction in cortical volume and thickness, most pronounced in the frontal and temporal lobes. These findings are at group level--there is a high degree of overlap between sick and healthy individuals, and the effect sizes are medium to small. Several of the changes are present at onset of the disorder; this supports the theory that schizophrenia may be related to abnormal neurodevelopment. Longitudinal anatomical changes are reported, but it is uncertain what these changes represent. INTERPRETATION The research literature shows that schizophrenia has neuroanatomical correlates that can be seen at group level by studying MR images. Structural MRI cannot currently be used to identify schizophrenia at the level of the individual.

Background Magnetic resonance imaging studies have demonstrated that patients with schizophrenia have thinner cortex in prefrontal and temporal brain regions, and enlarged lateral ventricles, compared to healthy subjects. Longitudinal studies have shown progressive brain tissue loss and ventricular dilatation among patients, predominantly in the early phase of the illness. Evidence for progression in more chronic phases of schizophrenia is less established. Methods Measurements of cortical thickness, cortical volume and subcortical volumes were obtained from 52 patients with long-term treated schizophrenia and 63 healthy subjects who were scanned twice over five years. Differences in brain measurements across time and group were investigated using general linear models. Results Compared to controls, patients had similar patterns of thinner cortex and smaller cortical volumes in prefrontal and temporal regions at both time points. In the follow-up interval regional cortical volumes decreased and lateral ventricle volumes increased in both groups. There was a trend level interaction effect of group and time for the right lateral ventricle, but not for cortical measurements. This effect was related to higher degree of negative symptoms at follow-up. Conclusions Regional differences in cortical thickness and volume between long-term treated patients with schizophrenia and healthy subjects are stable across five years, while right lateral ventricle volumes tend to increase more in the patients. The findings indicate that brain structure abnormalities found in schizophrenia are not progressive in the chronic stage of the disease, but that some progression in subcortical structures may be present in patients with poor outcome.

Background Similar patterns of subcortical brain abnormalities and neurocognitive dysfunction have been demonstrated in schizophrenia and bipolar disorder, with more extensive findings in schizophrenia. It is unknown whether relationships between subcortical volumes and neurocognitive performance are similar or different between schizophrenia and bipolar disorder. Methods MRI scans and neuropsychological test performance were obtained from 117 schizophrenia or 121 bipolar spectrum disorder patients and 192 healthy control subjects. Using the FreeSurfer software, volumes of 18 selected subcortical structures were automatically segmented and analyzed for relationships with results from 7 neurocognitive tests. Results In schizophrenia, larger left ventricular volumes were related to poorer motor speed, and bilateral putamen volumes were related to poorer verbal learning, executive functioning and working memory performance. In bipolar disorder, larger left ventricular volumes were related to poorer motor speed and executive functioning. The relationship between left putamen volume and working memory was specific to schizophrenia. The relationships between left inferior lateral ventricles and motor speed and between right putamen volumes and executive functioning were similar in schizophrenia and bipolar disorder, and different from healthy controls. The results remained significant after corrections for use of antipsychotic medication. Significant structure–function relationships were also found when all subjects were combined into one group. Conclusion The present findings suggest that there are differences as well as similarities in subcortical structure/function relationships between patients with schizophrenia or bipolar disorder and healthy individuals. The observed differences further suggest that ventricular and putamen volume sizes may reflect severity of cognitive dysfunction in these disorders.

Background Smaller hippocampal volume has repeatedly been reported in schizophrenia patients Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls. Methods Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects Information on obstetric complications was collected from original birth records Results Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume. Conclusions. The findings suggest a gene-environment (G x E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia Due to the modest sample size, the results must be considered preliminary and require replication in independent samples. (C) 2010 Elsevier Inc All rights reserved (Less)

Background Heterogeneous findings have been reported in studies of basal ganglia volumes in schizophrenia patients as compared to healthy controls. The basal ganglia contain dopamine receptors that are known to be involved in schizophrenia pathology and to be vulnerable to pre- and perinatal hypoxic insults. Altered volumes of other brain structures (e.g. hippocampus and lateral ventricles) have been reported in schizophrenia patients with a history of obstetric complications (OCs). This is the first study to explore if there is a relationship between OCs and basal ganglia volume in schizophrenia. Methods Thorough clinical investigation (including information on medication) of 54 schizophrenia patients and 54 healthy control subjects was undertaken. MR images were obtained on a 1.5 T scanner, and volumes of nucleus caudatus, globus pallidum, putamen, and nucleus accumbens were quantified automatically. Information on OCs was blindly collected from original birth records. Results Unadjusted estimates demonstrated a relationship between increasing number of OCs and larger volume of nucleus accumbens in schizophrenia patients and healthy controls. No statistically significant relationships were found between OCs and the basal ganglia volumes when controlled for intracranial volume, age, and multiple comparisons. There were no effects of typical versus atypical medication on the basal ganglia volumes. The patients with schizophrenia had larger globus pallidum volumes as compared to healthy controls, but there were no case–control differences for accumbens, putamen, or caudate volumes. Conclusion The present results do not support the hypothesis that OCs are related to alterations in basal ganglia volume in chronic schizophrenia.

One of the medical sequelae that chemo- and radiotherapy may cause is premature ovarian failure (POF). The scope of this study was to investigate the risk of developing POF as a long-term complication in young women treated for Hodgkin's lymphoma.The 99 women included in the study were treated between 1975 and 1992 at the Norwegian Radium Hospital. All patients received radiotherapy and 67 of the women also received chemotherapy.POF was found in 37.4% of the patients. The risk of developing POF was significantly higher if the patient received chemotherapy in addition to radiotherapy. Furthermore, the risk increased if chemotherapy included alkylating agents. Long-term follow-up revealed that women who at the time of treatment were under 30 years of age developed POF later, but with the same cumulative risk as women above 30 years of age.The risk of developing POF after radio- and chemotherapy is higher than earlier estimates suggest. After an observation time of 15 years the cumulative risk is 38% independent of age at the time of treatment. Age below 30 years at the time of treatment delays the development of POF, but does not decrease the life-time risk.

Objective We investigated whether elevated plasma levels of immune markers were associated with verbal memory and hippocampal subfield volumes in patients with severe mental illnesses and in healthy controls. Method In total, 230 patients with a broad DSM-IV schizophrenia spectrum illness or bipolar disorder and 236 healthy controls were recruited. Memory was assessed using the Wechsler Memory Scale-Third Edition (WMS-III) Logical Memory immediate and delayed recall, and the California Verbal Learning Test summed recall over learning list (CVLT learning) and delayed free recall. We measured plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist, interleukin-6, von Willebrand factor, osteoprotegerin, high-sensitivity C-reactive protein and sCD40 ligand. Hippocampal subfield estimates were obtained using FreeSurfer. Results We found a moderate negative association between sTNF-R1 and performance on verbal memory learning and recall tests as measured by the WMS-III Logical Memory after controlling for age, sex and diagnosis. We observed no interaction effect of diagnosis and sTNF-R1 on memory scores. We also found a nominally significant positive association between CVLT learning and hippocampal volumes. Conclusion The findings suggest a role for immune involvement in memory independent of severe mental disorders and may support the 'bigger is better' hypothesis of hippocampal subfield volumes.

Objective Here we investigated a two hit gene environment model in relation to functional genomic factors (BDNF mRNA), and volume of hippocampal subfields in schizophrenia spectrum and bipolar disorders, focusing on both an environmental (childhood trauma) and genetic risk factor (BDNF val66met). Method A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF DNA and RNA were analyzed using standardized procedures. A subsample of n = 108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. All MRI data were corrected for age and gender, with post-hoc analysis correcting for ICV. Results A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus. Conclusion The current findings demonstrate that the reduced BDNF mRNA levels found in psychosis may be associated with both a history of childhood trauma and BDNF val66met variants. Further, our study supports a two hit model including a history of childhood trauma as well as genetic vulnerability (met carriers of the BDNF val66met) behind reduced volume of hippocampal subfields in psychosis. This was specifically found for areas important for neurogenesis, the CA2/3and the CA4 DG.

Background Schizophrenia is a serious mental disease of unknown aetiology. Genetic liability is the most important risk factor. Several studies have demonstrated that pre and perinatal complications/traumas are associated with an increased risk of developing schizophrenia in adult age. The purpose of this article is to provide an overview of research on obstetric complications as risk factors for schizophrenia. Material and methods The article is based on literature identified through non-systematic searches in the databases PubMed and Embase. Results The putative association between obstetric complications and schizophrenia has been investigated for almost 80 years. Numerous controlled studies have found that maternal infection (influenza, rubella, toxoplasmosis), prenatal malnutrition and birth-associated complications (such as low birth weight and asphyxia) are associated with an increased risk of developing schizophrenia. Experiments in animal models suggest that foetal hypoxia and maternal inflammatory responses may affect neuronal development. However, underlying pathophysiological mechanisms and modes of interaction with schizophrenia susceptibility genes are unknown. Interpretation An association between obstetric complications and an increased risk of schizophrenia is strongly supported by scientific evidence.

Background Hippocampal dysfunction and volume reductions have been reported in patients with schizophrenia and bipolar disorder. The hippocampus consists of anatomically distinct subfields. We investigated to determine whether in vivo volumes of hippocampal subfields differ between clinical groups and healthy control subjects. Methods Clinical examination and magnetic resonance imaging were performed in 702 subjects (patients with schizophrenia spectrum [ n = 210; mean age, 32.0 ± 9.3 (SD) years; 59% male], patients with bipolar spectrum [ n = 192; mean age, 35.5 ± 11.5 years; 40% male] and healthy control subjects [ n = 300; mean age, 35.3 ± 9.9 years; 53% male]). Hippocampal subfield volumes were estimated with FreeSurfer. General linear models were used to explore diagnostic differences in hippocampal subfield volumes, covarying for age, intracranial volume, and medication. Post hoc analyses of associations to psychosis symptoms (Positive and Negative Syndrome Scale) and cognitive function (verbal memory [California Verbal Learning Test, second edition] and IQ [Wechsler Abbreviated Scale of Intelligence]) were performed. Results Patient groups had smaller cornu ammonis (CA) subfields CA2/3 (left, p = 7.2 × 10 −6 ; right, p = 2.3 × 10 −6 ), CA4/dentate gyrus (left, p = 1.4 × 10 −5 ; right, p = 2.3 × 10 −6 ), subiculum (left, p = 3.7 × 10 −6 ; right, p = 2.8 × 10 −8 ), and right CA1 ( p = .006) volumes than healthy control subjects, but smaller presubiculum volumes were found only in patients with schizophrenia (left, p = 6.7 × 10 −5 ; right, p = 1.6 × 10 −7 ). Patients with schizophrenia had smaller subiculum (left, p = .035; right, p = .031) and right presubiculum ( p = .002) volumes than patients with bipolar disorder. Smaller subiculum volumes were related to poorer verbal memory in patients with bipolar disorder and healthy control subjects and to negative symptoms in patients with schizophrenia. Conclusions Hippocampal subfield volume reductions are found in patients with schizophrenia and bipolar disorder. The magnitude of reduction is greater in patients with schizophrenia, particularly in the hippocampal outflow regions presubiculum and subiculum.

BackgroundPre- and perinatal adversities may increase the risk for schizophrenia and bipolar disorder. Hypoxia-related obstetric complications (OCs) are associated with brain anatomical abnormalities in schizophrenia, but their association with brain anatomy variation in bipolar disorder is unknown.MethodMagnetic resonance imaging brain scans, clinical examinations and data from the Medical Birth Registry of Norway were obtained for 219 adults, including 79 patients with a DSM-IV diagnosis of bipolar disorder (age 29.4 years,s.d. = 11.8 years, 39% male) and 140 healthy controls (age 30.8 years,s.d. = 12.0 years, 53% male). Severe hypoxia-related OCs throughout pregnancy/birth and perinatal asphyxia were each studied in relation toa prioriselected brain volumes (hippocampus, lateral ventricles and amygdala, obtained with FreeSurfer), using linear regression models covarying for age, sex, medication use and intracranial volume. Multiple comparison adjustment was applied.ResultsPerinatal asphyxia was associated with smaller left amygdala volume (t = −2.59,p = 0.012) in bipolar disorder patients, but not in healthy controls. Patients with psychotic bipolar disorder showed distinct associations between perinatal asphyxia and smaller left amygdala volume (t = −2.69,p = 0.010), whereas patients with non-psychotic bipolar disorder showed smaller right hippocampal volumes related to both perinatal asphyxia (t = −2.60,p = 0.015) and severe OCs (t = −3.25,p = 0.003). No associations between asphyxia or severe OCs and the lateral ventricles were found.ConclusionsPre- and perinatal hypoxia-related OCs are related to brain morphometry in bipolar disorder in adulthood, with specific patterns in patients with psychoticversusnon-psychotic illness.

Longitudinal studies on first-episode psychosis (FEP) patients have shown a decrease of substance use disorders (SUDs) over the first years of illness, but there has been less focus on the gender aspect. The present study examines stability of alcohol and illicit substance use, with specific focus on gender, in a one year follow-up investigation of 154 FEP patients (91 men, 63 women) in Oslo, Norway, using criteria for DSM-IV substance use disorder diagnosis, the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Use Disorders Identification Test (DUDIT). The results show that cannabis was the most frequently used illicit substance at both times. Significantly more men (34%) than women (13%) had a current illicit SUD at baseline. At follow-up, the rate of illicit SUDs was significantly reduced in men (18%) but not in women (11%). There were no significant gender differences in the rate of current alcohol use disorders (AUD) (men 14%; women 8%) at baseline, and no significant reduction in AUD in any of the genders at follow-up. At follow-up, total AUDIT and DUDIT scores were reduced in men only. In conclusion, the high and persistent rate of SUDs, particularly of cannabis, among men and women during the first year of treatment for psychosis should be addressed in the clinical management of the patients. Female FEP patients who are also substance users may be particularly vulnerable in this regard and warrant closer attention.

Background Normal birth weight variation affects schizophrenia risk and cognitive performance in schizophrenia patients and healthy controls. Brain cortical anatomy is altered in psychotic disorders and in low birth weight subjects, but if birth weight variation relates to cortical morphology across the psychosis spectrum is not known. Methods Magnetic Resonance Imaging brain scans and clinical-, neurocognitive-, and medical birth registry data were collected from 359 adults including patients with a DSM-IV diagnosis of schizophrenia (n = 90, mean age 29.4±10.2 [95% CI], 62% male), bipolar disorder (n = 79, age 29.4±11.8, 39% male) or other psychosis (n = 40, age 26.3±10.0, 56% male), and healthy controls (n = 140, age 30.8±12.0,53% male). We explored the relationship between whole-range birth weight variation and cortical surface area and thickness and their possible associations to cognitive performance. Results Across all groups, lower birth weight was associated with smaller total surface area (t = 3.87, P = .0001), within specific regions of the temporal, parietal, and frontal cortex bilaterally. There were no associations between birth weight and cortical thickness, and no diagnosis by birth weight interaction effects on cortical thickness or surface area. Smaller cortical area (t = 2.50, P = .013) and lower birth weight (t = 2.53, P = .012) were significantly related to poorer working memory performance in all diagnostic groups except schizophrenia. Conclusion Birth weight relates to adult cortical surface area, but not cortical thickness, in patients across the psychosis spectrum and in healthy controls. Cortical area appears to be a diagnosis-independent general marker of early neurodevelopment, with a dose-response association to normal birth weight variation.

While recent genome-wide association studies have identified several new bipolar disorder (BD) risk variants, structural imaging studies have reported enlarged ventricles and volumetric reductions among the most consistent findings. We investigated whether these genetic risk variants could explain some of the structural brain abnormalities in BD.In a sample of 517 individuals (N=121 BD cases, 116 SZ cases, 61 other psychosis cases and 219 healthy controls), we tested the potential association between nine SNPs in the genes CACNA1C, ANK3, ODZ4 and SYNE1 and eight brain structural measures found to be altered in BD, and if these were specifically affecting the BD sample. We also assessed the polygenic effect of all these 9 SNPs on the brain phenotypes.Our most significant result was an association between the risk allele A in CACNA1C SNP rs4775913 and decreased cerebellar volume (pnom.=0.0075) in the total sample, which did not remain significant after multiple testing correction (pthreshold0.0064). There was no evidence for diagnostic specificity for this association in the BD group. Further, no polygenic effect of these 9 SNPs was observed.Low statistical power might increase our type II error rate.The present findings indicate that these risk SNPs do not explain a large proportion of the structural brain alterations in BD. Thus, these genes which are all related to neuronal functions must be involved in other pathophysiological aspects of BD development.

ZNF804A SNP rs1344706 confers genome-wide risk for schizophrenia and bipolar disorder. Both disorders affect cortical thickness. To determine if single nucleotide polymorphisms (SNPs) across ZNF804A are associated with cortical thinning, we investigated 63 SNPs (including rs1344706) in 365 psychosis patients and healthy controls. Results show no significant associations.

Relationships between cortical brain structure and neurocognitive functioning have been reported in schizophrenia, but findings are inconclusive, and only a few studies in bipolar disorder have addressed this issue. This is the first study to directly compare relationships between cortical thickness and surface area with neurocognitive functioning in patients with schizophrenia (n = 117) and bipolar disorder (n = 121) and healthy controls (n = 192). MRI scans were obtained, and regional cortical thickness and surface area measurements were analyzed for relationships with test scores from 6 neurocognitive domains. In the combined sample, cortical thickness in the right rostral anterior cingulate was inversely related to working memory, and cortical surface area in four frontal and temporal regions were positively related to neurocognitive functioning. A positive relationship between left transverse temporal thickness and processing speed was specific to schizophrenia. A negative relationship between right temporal pole thickness and working memory was specific to bipolar disorder. In conclusion, significant cortical structure/function relationships were found in a large sample of healthy controls and patients with schizophrenia or bipolar disorder. The differences that were found between schizophrenia and bipolar may indicate differential relationship patterns in the two disorders, which may be of relevance for understanding the underlying pathophysiology. (JINS, 2011, 17, 1080–1093)

Background Magnetic resonance imaging studies have shown that structural brain abnormalities are present in both schizophrenia and bipolar disorder. Most previous studies have focused on brain tissue volumes, but advances in neuroimaging data processing have made it possible to separate cortical area and cortical thickness. The purpose of the present study was to provide a more complete picture of cortical morphometric differences in schizophrenia and bipolar disorder, decomposing cortical volume into its constituent parts, cortical thickness and cortical area. Methods We analyzed magnetic resonance imaging images from a sample of 173 patients with schizophrenia, 139 patients with bipolar disorder, and 207 healthy control subjects. Maps of cortical volume, area, and thickness across the continuous cortical surface were generated within groups and compared between the groups. Results There were widespread reductions in cortical volume in schizophrenia relative to healthy control subjects and patients with bipolar disorder type I. These reductions were mainly driven by cortical thinning, but there were also cortical area reductions in more circumscribed regions, which contributed to the observed volume reductions. Conclusions The current surface-based methodology allows for a distinction between cortical thinning and reduction in cortical area and reveals that cortical thinning is the most important factor in volume reduction in schizophrenia. Cortical area reduction was not observed in bipolar disorder type I and may be unique to schizophrenia.

Background Schizophrenia and bipolar disorder are severe psychiatric diseases with overlapping symptomatology. Widespread brain morphologic abnormalities, including cortical thinning and subcortical volume reductions, have been demonstrated in schizophrenia but it is unclear whether similar abnormalities are present in bipolar disorder. The purpose of this study was to compare cortical thickness and subcortical volumes in schizophrenia and bipolar disorder, to assess differences and similarities in cortical and subcortical brain structure. Methods We analyzed magnetic resonance images from a sample of 173 patients with schizophrenia spectrum disorder, 139 patients with bipolar disorder, and 207 healthy control subjects. Cortical thickness was compared between the groups in multiple locations across the continuous cortical surface. Subcortical volumes were compared on a structure-by-structure basis. Results There was widespread cortical thinning in schizophrenia compared with control subjects, in frontal, temporal, occipital, and smaller parietal regions. There was no cortical thinning in bipolar disorder compared with control subjects or in schizophrenia compared with bipolar disorder. However, the subgroup of patients with bipolar disorder Type 1 showed cortical thinning, primarily in the frontal lobes and superior temporal and temporoparietal regions. Both patient groups showed substantial subcortical volume reductions bilaterally in the hippocampus, the left thalamus, the right nucleus accumbens, the left cerebellar cortex, and the brainstem, along with substantial ventricular enlargements. Conclusions We found substantial overlap in the underlying brain morphologic abnormalities in schizophrenia and bipolar disorder in subcortical structures, and between schizophrenia and bipolar disorder Type 1 in the cerebral cortex.