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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 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 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.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

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.

Purpose: Cardiometabolic disease in patients with severe mental illness is a major cause of shortened life expectancy. There is sparse evidence of real-world clinical risk prevention practice. We investigated levels of assessments of cardiometabolic risk factors and risk management interventions in patients with severe mental illness in the Norwegian mental health service according to an acknowledged international standard., Methods: We collected data from 264 patients residing in six country-wide health trusts for: (a) assessments of cardiometabolic risk and (b) assessments of levels of risk reducing interventions. Logistic regressions were employed to investigate associations between risk and interventions., Results: Complete assessments of all cardiometabolic risk variables were performed in 50% of the participants and 88% thereof had risk levels requiring intervention according to the standard. Smoking cessation advice was provided to 45% of daily smokers and 4% were referred to an intervention program. Obesity was identified in 62% and was associated with lifestyle interventions. Reassessment of psychotropic medication was done in 28% of the obese patients. Women with obesity were less likely to receive dietary advice, and use of clozapine or olanzapine reduced the chances for patients with obesity of getting weight reducing interventions., Conclusions: Nearly nine out of the ten participants were identified as being at cardiometabolic high risk and only half of the participants were adequately screened. Women with obesity and patients using antipsychotics with higher levels of cardiometabolic side effects had fewer adequate interventions. The findings underscore the need for standardized recommendations for identification and provision of cardiometabolic risk reducing interventions in all patients with severe mental illness.

Background: Older patients with mental disorders are particularly likely to be affected by negative consequences of the infection control measures that have been implemented as a result of the COVID-19 pandemic., Material and Method: A questionnaire survey was sent to 18 departments of geriatric psychiatry from all four health regions in Norway., Results: Altogether 83 therapists from various occupational groups responded, with representatives from all the health regions. Almost one-half (45.8 %) reported an exacerbation of patients' mental condition to a large or very large degree due to social isolation, and an equal proportion (48.2 %) reported that normal follow-up was limited. The contact between the specialist and primary health services was reduced, and 15.6 % reported that patients had failed to receive the necessary somatic medical assistance to a large or very large degree., Interpretation: The service for older patients with mental disorders in the specialist health service was reduced as a result of the COVID-19 pandemic, while coordination with the primary health service was also curtailed, and many patients deteriorated mentally as a result of the infection control measures. Collaboration between the specialist and primary health services may be an important focus area for this patient group.

Background: To bridge the gap between symptoms and treatment, constructing case formulations is essential for clinicians. Limited scientific value has been attributed to case formulations because of problems with quality, reliability, and validity. For understanding, communication, and treatment planning beyond each specific clinician-patient dyad, a case formulation must convey valid information concerning the patient, as well as being a reliable source of information regardless of the clinician's theoretical orientation. The first aim of the present study is to explore the completeness of unstructured psychodynamic formulations, according to four components outlined in the Case Formulation Content Coding Method (CFCCM). The second aim is to estimate the reliability of independent formulations and their components, using similarity ratings of matched versus mismatched cases., Methods: This study explores psychodynamic case formulations as made by two or more experienced clinicians after listening to an evaluation interview. The clinicians structured the formulations freely, with the sole constraint that technical, theory-laden terminology should be avoided. The formulations were decomposed into components after all formulations had been written., Results: The results indicated that most formulations were adequately comprehensive, and that overall reliability of the formulations was high (> 0.70) for both experienced and inexperienced clinician raters, although the lower bound reliability estimate of the formulation component deemed most difficult to rate - inferred mechanisms - was marginal, 0.61., Conclusions: These results were achieved on case formulations made by experienced clinicians using simple experience-near language and minimizing technical concepts, which indicate a communicative quality in the formulations that make them clinically sound., Trial Registration: linicalTrials.gov Identifier: NCT00423462 . https://doi.org/10.1007/s00432-018-2781-7 ., January 18, 2007.

Objective: Anxiety symptoms are common in old age and have been suggested as risk factors for development of cognitive impairment and mortality. The objective of the present study was to investigate whether anxiety symptoms among older adults with a mental health diagnosis are persistent, and severity of anxiety predicts cognitive decline and mortality., Methods: We collected data from 201 patients referred to specialist mental health service in a department of geriatric psychiatry. Of these, 150 were reexamined after 33 months, while 51 patients died before follow-up. Mean age (SD) at baseline among the patients that were reexamined was 73.4 (7.3) years, and 67% were women. The Geriatric Anxiety Inventory (GAI) was used to measure anxiety symptoms at baseline and follow-up. We investigated whether higher GAI scores at baseline were associated with persistence of anxiety. Associations with cognitive decline or mortality were also explored. The associations were estimated by use of trajectory analysis and regression models., Results: Seventy-four percentages had the same level of anxiety symptoms, and 29% had a high level of anxiety at baseline and follow-up. GAI score at baseline was not associated with cognitive decline or mortality at 33-month follow-up., Conclusion: In a longitudinal study of anxiety symptoms among older adults in specialist mental health services, we demonstrate persistent high or low levels of anxiety symptoms. Anxiety trajectories over time were not predicted by patient characteristics. Also the level of anxiety cannot be used as predictor for future cognitive decline or mortality in a clinical population., (© 2019 John Wiley & Sons, Ltd.)

Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group., Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide., Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset., Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to investigate morphometric correlates of auditory hallucinations in bipolar disorder (BD) by comparing cortical thickness and cortical surface area in bipolar disorder patients with (BD+) and without (BD-) a lifetime history of auditory hallucinations. Based on previous findings in schizophrenia patients, we hypothesized that the cortex would be thinner in the auditory cortex in BD+ compared to BD-., Methods: Bipolar disorder spectrum (n = 157) patients and healthy controls (n = 279) underwent 1.5T magnetic resonance imaging (MRI) scanning. Hypothesis-driven analyses of cortical thickness and surface area in regions of the auditory cortex (Heschl's gyrus [HG], planum temporale and superior temporal gyrus) were conducted comparing BD+ (n = 49) and BD- (n = 108) using linear regression models, covaried for age and sex. Furthermore, we explored vertex-wise group differences in thickness and surface area across the whole cerebral cortex., Results: Hypothesis-driven analyses:BD+ had significantly thicker cortex in the left HG compared to BD- (B = 0.128, P = .0046). The finding was not explained by duration of illness, global functioning, bipolar subtype, IQ or use of antipsychotic, antidepressant or antiepileptic medication, or by lithium. Exploratory analyses: A small region of thicker cortex in BD+ compared to BD- was seen in the left superior parietal lobule (false discovery rate <0.05). There were no significant group differences in cortical surface area., Conclusion: A lifetime history of auditory hallucinations in BD was associated with cortical thickness alterations in both the left HG and the superior parietal lobule. Contrary to our hypothesis, BD+ showed thicker, rather than thinner cortex compared to BD-. Replications in independent samples are needed., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Objective: Anxiety symptoms are common in older adults with depression, but whether severe anxiety is associated with poorer outcomes of depression is unknown. The objective of the present study was to examine the association between severity of anxiety and severity of depression and physical illness, suicidality, and physical and cognitive functioning in older adults with depression., Methods: We included 218 older adults with diagnoses of a depressive disorder according to the ICD-10 criteria; their mean age (SD) was 75.6 (7.2), and 67.0% were women. The Geriatric Anxiety Inventory (GAI) was used to measure the severity of anxiety symptoms. The Montgomery-Aasberg Depression Rating Scale (MADRS) was used to assess the severity of depression. We obtained information on the level of functioning with the Physical Self-Maintenance Scale (PSMS) by Lawton and Brody and on cognition with the Mini-Mental State Examination (MMSE) and the Clock-Drawing Test (CDT). Physical health was determined based on information regarding falls and weight loss and an assessment of each patient's general medical condition. The treating physician evaluated current suicidality in a comprehensive and standardized way., Results: Higher GAI scores were significantly associated with scores on the MADRS (β = 0.233, p = 0.002) and suicidality (β = 0.206, p = 0.006). Levels of physical or cognitive functioning were not associated with the GAI score., Conclusion: The severity of anxiety symptoms was associated with the severity of depression and suicidality in older adults with depressive disorders. The results could indicate a need to focus greater attention on the treatment of anxiety and suicidality in older patients with depression., (© 2018 S. Karger AG, Basel.)

Background: Excessive 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., Method: 1.5 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., Results: Increasing 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., Conclusion: The 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.

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., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Neuroimaging studies have demonstrated associations between smaller auditory cortex volume and auditory hallucinations (AH) in schizophrenia. Reduced cortical volume can result from a reduction of either cortical thickness or cortical surface area, which may reflect different neuropathology. We investigate for the first time how thickness and surface area of the auditory cortex relate to AH in a large sample of schizophrenia spectrum patients., Methods: Schizophrenia spectrum (n = 194) patients underwent magnetic resonance imaging. Mean cortical thickness and surface area in auditory cortex regions (Heschl's gyrus [HG], planum temporale [PT], and superior temporal gyrus [STG]) were compared between patients with (AH+, n = 145) and without (AH-, n = 49) a lifetime history of AH and 279 healthy controls., Results: AH+ patients showed significantly thinner cortex in the left HG compared to AH- patients (d = 0.43, P = .0096). There were no significant differences between AH+ and AH- patients in cortical thickness in the PT or STG, or in auditory cortex surface area in any of the regions investigated. Group differences in cortical thickness in the left HG was not affected by duration of illness or current antipsychotic medication., Conclusions: AH in schizophrenia patients were related to thinner cortex, but not smaller surface area of the left HG, a region which includes the primary auditory cortex. The results support that structural abnormalities of the auditory cortex underlie AH in schizophrenia., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: The primary aim of this study was to examine anxiety symptoms as measured by the Geriatric Anxiety Inventory (GAI) in older patients with depression, dementia, or psychotic disorders. The secondary aim was to conduct a principal component analysis (PCA) of the GAI and to examine whether its subscales differ between the 3 disorders., Methods: We included data from 428 patients who were admitted to a department of geriatric psychiatry and examined according to a standardized protocol. The GAI was used to measure current anxiety symptoms., Results: The GAI symptoms occurred more frequently in the group with depression than in the other 2 groups. The PCA of the GAI with oblimin rotation resulted in a 2-component solution, labelled as "worries" (explained variance 46.3%, Cronbach's α 0.92) and "physical symptoms" (explained variance 7.1%, Cronbach's α 0.85)., Conclusion: The results indicate that in old age, anxiety is especially prevalent in depression. The 2-component solution indicates that the GAI measures 2 different aspects of anxiety with different symptomatology., (© 2016 S. Karger AG, Basel.)

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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Both brain structural abnormalities and neurocognitive impairments are core features of schizophrenia. We have previously reported enlargements in subcortical brain structure volumes and impairment of neurocognitive functioning as measured by the MATRICS Cognitive Consensus Battery (MCCB) in early onset schizophrenia spectrum disorders (EOS). To our knowledge, no previous study has investigated whether neurocognitive performance and volumetric abnormalities in subcortical brain structures are related in EOS., Methods: Twenty-four patients with EOS and 33 healthy controls (HC) were included in the study. Relationships between the caudate nucleus, the lateral and fourth ventricles volumes and neurocognitive performance were investigated with multivariate linear regression analyses. Intracranial volume, age, antipsychotic medication and IQ were included as independent predictor-variables., Results: The caudate volume was negatively correlated with verbal learning performance uniquely in the EOS group (r=-.454, p=.034). There were comparable positive correlations between the lateral ventricular volume and the processing speed, attention and reasoning and problem solving domains for both the EOS patients and the healthy controls. Antipsychotic medication was related to ventricular enlargements, but did not affect the brain structure-function relationship., Conclusion: Enlargement of the caudate volume was related to poorer verbal learning performance in patients with EOS. Despite a 32% enlargement of the lateral ventricles in the EOS group, associations to processing speed, attention and reasoning and problem solving were similar for both the EOS and the HC groups.

The current study aims to fill a gap in the knowledge base by investigating the structural brain characteristics of individuals with schizophrenia and superior intellectual abilities. Subcortical volumes, cortical thickness and cortical surface area were examined in intellectually normal and intellectually superior participants with schizophrenia and their IQ-matched healthy controls, as well as in intellectually low schizophrenia participants. We replicated significant diagnostic group effects on hippocampal and ventricular size after correction for multiple comparisons. There were no statistically significant effects of intellectual level or of the interaction between diagnostic group and intellectual level. Effect sizes indicated that differences between schizophrenia and healthy control participants were of similar magnitude at both intellectual levels for all three types of morphological data. A secondary analysis within the schizophrenia group, including participants with low intellectual abilities, yielded numerical, but no statistically significant differences on any structural brain measure. The present findings indicate that the brain structure abnormalities in schizophrenia are present at all intellectual levels, and individuals with schizophrenia and superior intellectual abilities have brain structure abnormalities of the same magnitude as individuals with schizophrenia and normal intellectual abilities., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

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.

The cerebral cortex is highly convoluted, and principal folding patterns are determined early in life. Degree of cortical folding in adult life may index aberrations in brain development. Results from previous studies of cortical folding in schizophrenia are inconsistent. Here we investigated cortical folding patterns in the hitherto largest sample of patients with schizophrenia drawn from two independent cohorts. Magnetic resonance imaging scans were acquired from 207 patients and 206 healthy subjects recruited to two separate research projects in Sweden and Norway. Local gyrification index (lGI) was estimated continuously across the cortex using automated methods. Group differences in lGI were analyzed using general linear models. Patients had lower lGI in three large clusters of the cortex with peak differences found in the left precentral gyrus, right middle temporal gyrus, and right precuneus. Similar, although not completely overlapping results were found when the two cohorts were analyzed separately. There were no significant interaction effects between age and diagnosis and gender and diagnosis. The finding of reduced degree of folding in large regions of the cerebral cortex across two independent samples indicates that reduced gyrification is an inherent feature of the brain pathology in schizophrenia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

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., (© 2014.)

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., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Disrupted-in-Schizophrenia-1 (DISC1) has been suggested as a susceptibility locus for a broad spectrum of psychiatric disorders. Risk variants have been associated with brain structural changes, which overlap alterations reported in schizophrenia and bipolar disorder patients. We used genome-wide genotyping data for a Norwegian sample of healthy controls (n = 171) and patients with a history of psychosis (n = 184), to investigate 61 SNPs in the DISC1 region for putative association with structural magnetic resonance imaging (sMRI) measures (hippocampal volume; mean cortical thickness; and total surface area, as well as cortical thickness and area divided into four lobar measures). SNP rs821589 was associated with mean temporal and total brain cortical thickness in controls (P(adjusted) = 0.009 and 0.02, respectively), but not in patients. SNPs rs11122319 and rs1417584 were associated with mean temporal cortical thickness in patients (P(adjusted) = 0.04 and 0.03, respectively), but not in controls, and both SNPs have previously been highly associated with DISC1 gene expression. There were significant genotype ×  case-control interactions. There was no significant association between SNPs and cortical area or hippocampal volume in controls, or with any of the structural measures in cases, after correction for multiple comparisons. In conclusion, DISC1 SNPs might impact brain structural variation, possibly differently in psychosis patients versus controls, but independent replication will be needed to confirm our findings., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The 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., Method: In 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., Results: In both schizophrenia patients and healthy controls, an increasing number of OCs was significantly related to lower lGI in the left pars triangularis (p<0.0005) in Broca's area. For five other anatomical cortical parcellations in the left hemisphere, a similar trend was demonstrated. No significant relationships between OCs and lGI were found in the right hemisphere and there were no significant case-control differences in lGI., Conclusions: The 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.

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., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

Background: Because of evidence from genetic linkage and genome-wide association studies, as well as suggested involvement of infection, the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1 has been implicated in the development of schizophrenia., Methods: Here, we investigated how gene variants across the MHC region are associated with brain structure in a large ethnically homogenous sample (n = 420), including patients with schizophrenia spectrum disorders and other severe mental illness and healthy control subjects., Results: We demonstrate highly significant associations between common gene markers in the MHC region and cerebral ventricular volume specifically in schizophrenia spectrum patients (uncorrected p values between 1.16 × 10⁻⁴ and 2.00 × 10⁻⁷). One single nucleotide polymorphism, rs2596532, survives Bonferroni correction for multiple testing across all single nucleotide polymorphisms and brain structure measures (adjusted p value 5.59 × 10⁻⁴)., Conclusions: The results indicate that MHC variants are implicated in characteristic brain abnormalities of schizophrenia., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Relationships between prefrontal and temporal lobe grey matter volumes as assessed by magnetic resonance imaging and neurocognitive test results have been reported in schizophrenia. This investigation aimed to localize brain regions where cortical thickness and neurocognitive performance were related, and investigate if such relationships might differ in schizophrenia patients and healthy controls. Sixty-seven patients with schizophrenia and 69 healthy controls were characterized by neurocognitive testing and by brain cortical thickness maps. Putative cortical thickness/cognitive score relationships were investigated with contrast analyses of general linear models for the combined sample. Regions in which relationships were present were further investigated for diagnostic interaction. In the combined sample, significant positive relationships were found between frontal, temporal and occipital regions and tests for verbal IQ, verbal learning and executive functions. Diagnostic interaction was found for the relationships between verbal IQ and the right temporo-occipital junction and the left middle occipital gyrus. In conclusion, the significant relationships between cortical thickness and neurocognitive performances were localized in brain areas known to be involved in cognition. The relationships were similar in patients and controls, except for the right temporo-occipital and left occipital cortical areas, indicating a disrupted structure-function relationship in patients with schizophrenia compared to healthy control subjects., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have thinner brain cortices compared with healthy control subjects. Neurodevelopment is vulnerable to obstetric complications (OCs) such as hypoxia and birth trauma, factors that are also related to increased risk of developing schizophrenia. With the hypothesis that OCs might explain the thinner cortices found in schizophrenia, we studied patients with schizophrenia and healthy controls subjects for association between number and severity of OCs and variation in cortical thickness., Methods: MRI scans of 54 adults with schizophrenia or schizoaffective disorder and 54 healthy controls were acquired at Karolinska Institutet, Stockholm, Sweden. Measures of brain cortical thickness were obtained using automated computer processing (FreeSurfer). OCs were assessed from obstetric records and scored blindly according to the McNeil-Sjöström scale. At numerous cortical locations, putative effects of OCs on cortical thickness variation were tested for each trimester, for labour, for composite OC scores, severe OC scores, and hypoxia scores among patients and controls separately., Results: Number and severity of OCs varied among both patient and control subjects but were not associated with cortical thickness in either of the groups. Patients demonstrated thinner brain cortices but there were no significant differences in number and severity of OC scores across groups., Conclusion: In the present study, number and severity of obstetric complications were not associated with brain cortical thickness, in patients with schizophrenia or in healthy control subjects. The thinner brain cortices found in patients with schizophrenia were not explained by a history of OCs.