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Background: Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact., Methods: We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations., Results: BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI., Conclusions: We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Aims: Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under-researched in psychiatry., Methods: We obtained body mass index (BMI) and magnetic resonance imaging-derived regional cortical thickness, surface area from 836 bipolar disorders (BD) and 1600 control individuals from 14 sites within the ENIGMA-BD Working Group. We identified regionally specific profiles of cortical thickness using K-means clustering and studied clinical characteristics associated with individual cortical profiles., Results: We detected two clusters based on similarities among participants in cortical thickness. The lower thickness cluster (46.8% of the sample) showed thinner cortex, especially in the frontal and temporal lobes and was associated with diagnosis of BD, higher BMI, and older age. BD individuals in the low thickness cluster were more likely to have the diagnosis of bipolar disorder I and less likely to be treated with lithium. In contrast, clustering based on similarities in the cortical surface area was unrelated to BD or BMI and only tracked age and sex., Conclusions: We provide evidence that both BD and obesity are associated with similar alterations in cortical thickness, but not surface area. The fact that obesity increased the chance of having low cortical thickness could explain differences in cortical measures among people with BD. The thinner cortex in individuals with higher BMI, which was additive and similar to the BD-associated alterations, may suggest that treating obesity could lower the extent of cortical thinning in BD., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Lithium treatment of bipolar disorder (BD) has been associated with less cognitive impairment and fewer changes in structural brain anatomy compared to other treatments. However, the studies are heterogeneous and few assess whether these effects are related. The objective of this study was to evaluate and relate cognitive performance and structural neuroanatomy in patients treated with and without lithium., Methods: Cross-sectional study that included 48 subjects with BD-I, of which 22 were treated with lithium and 26 without lithium. Performance was assessed on Wechsler III (WAIS III), TMT A and B (Trial Making Test) neuropsychological tests, California verbal learning test (CVLT), Rey complex figure test and Wisconsin card sorting test. Brain structures obtained by magnetic resonance imaging (MRI) were evaluated. The standardised mean difference (SMD) between both groups was calculated, adjusted for confounding variables using a propensity score, and the Spearman correlation coefficient (ρ) was used to assess the relationship between cognitive performance and neuroanatomical regions., Results: Compared to the group without lithium, the group with lithium had fewer perseverative errors in the Wisconsin test (SMD = -0.69) and greater left and right cortical areas (SMD = 0.85; SMD = 0.92); greater surface area in the left anterior cingulate (SMD = 1.32), right medial orbitofrontal cortex (SMD = 1.17), right superior frontal gyrus (SMD = 0.82), and right and left precentral gyrus (SMD = 1.33; SMD = 0.98); greater volume of the right amygdala (SMD = 0.57), right hippocampus (SMD = 0.66), right putamen (SMD = 0.87) and right thalamus (SMD = .67). In the lithium group, a correlation was found with these errors and the thickness of the left precentral gyrus (ρ = -0.78), the volume of the right thalamus (ρ = -0.44), and the right amygdala (ρ = 0.6)., Conclusions: The lithium group had better cognitive flexibility and greater dimension in some frontal and subcortical cortical regions. Furthermore, there was a moderate to high correlation between performance in this executive function and the thickness of the right precentral gyrus, and the volumes of the thalamus and the right amygdala. These findings could suggest a neuroprotective effect of lithium., (Copyright © 2020 Asociación Colombiana de Psiquiatría. Published by Elsevier España, S.L.U. All rights reserved.)

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles  and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression., (© 2021. The Author(s).)

Background: Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear., Aims: We studied how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed., Method: This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model., Results: A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = -0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure., Conclusions: Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.

Introduction: Lithium treatment of bipolar disorder (BD) has been associated with less cognitive impairment and fewer changes in structural brain anatomy compared to other treatments. However, the studies are heterogeneous and few assess whether these effects are related. The objective of this study was to evaluate and relate cognitive performance and structural neuroanatomy in patients treated with and without lithium., Methods: Cross-sectional study that included 48 subjects with BD-I, of which 22 were treated with lithium and 26 without lithium. Performance was assessed on Wechsler III (WAIS III), TMT A and B (Trial Making Test) neuropsychological tests, California verbal learning test (CVLT), Rey complex figure test and Wisconsin card sorting test. Brain structures obtained by magnetic resonance imaging (MRI) were evaluated. The standardised mean difference (SMD) between both groups was calculated, adjusted for confounding variables using a propensity score, and the Spearman correlation coefficient (ρ) was used to assess the relationship between cognitive performance and neuroanatomical regions., Results: Compared to the group without lithium, the group with lithium had fewer perseverative errors in the Wisconsin test (SMD = -0.69) and greater left and right cortical areas (SMD = 0.85; SMD = 0.92); greater surface area in the left anterior cingulate (SMD = 1.32), right medial orbitofrontal cortex (SMD = 1.17), right superior frontal gyrus (SMD = 0.82), and right and left precentral gyrus (SMD = 1.33; SMD = 0.98); greater volume of the right amygdala (SMD = 0.57), right hippocampus (SMD = 0.66), right putamen (SMD = 0.87) and right thalamus (SMD=.67). In the lithium group, a correlation was found with these errors and the thickness of the left precentral gyrus (ρ = -0.78), the volume of the right thalamus (ρ =-0.44), and the right amygdala (ρ = 0.6)., Conclusions: The lithium group had better cognitive flexibility and greater dimension in some frontal and subcortical cortical regions. Furthermore, there was a moderate to high correlation between performance in this executive function and the thickness of the right precentral gyrus, and the volumes of the thalamus and the right amygdala. These findings could suggest a neuroprotective effect of lithium., (Copyright © 2020 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47-67.00, ROC-AUC = 71.49%, 95% CI = 69.39-73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70-60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen's Kappa = 0.83, 95% CI = 0.829-0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.

Background: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample., Method: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls., Results: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression., Conclusion: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Social and environmental factors are known risk factors and modulators of mental health disorders. We here conducted a nonsystematic review of the neuroimaging literature studying the effects of poverty, urbanicity, and community violence, highlighting the opportunities of studying non-Western developing societies such as those in Latin America. Social and environmental factors in these communities are widespread and have a large magnitude, as well as an unequal distribution, providing a good opportunity for their characterization. Studying the effect of poverty in these settings could help to explore the brain effect of economic improvements, disentangle the effect of absolute and relative poverty, and characterize the modulating impact of poverty on the underlying biology of mental health disorders. Exploring urbanicity effects in highly unequal cities could help identify the specific factors that modulate this effect as well as examine a possible dose-response effect by studying megacities. Studying brain changes in those living among violence, which is particularly high in places such as Latin America, could help to characterize the interplay between brain predisposition and exposure to violence. Furthermore, exploring the brain in an adverse environment should shed light on the mechanisms underlying resilience. We finally provide examples of two methodological approaches that could contribute to this field, namely a big cohort study in the developing world and a consortium-based meta-analytic approach, and argue about the potential translational value of this research on the development of effective social policies and successful personalized medicine in disadvantaged societies., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The 4D Flow MRI technique provides a three-dimensional representation of blood flow over time, making it possible to evaluate the hemodynamics of the cardiovascular system both qualitatively and quantitatively. In this article, we describe the application of the 4D Flow technique in a 3T scanner; in addition to the technical parameters, we discuss the advantages and limitations of the technique and its possible clinical applications. We used 4D Flow MRI to study different body areas (chest, abdomen, neck, and head) in 10 volunteers. We obtained 3D representations of the patterns of flow and quantitative hemodynamic measurements. The technique makes it possible to evaluate the pattern of blood flow in large and midsize vessels without the need for exogenous contrast agents., (Copyright © 2013 SERAM. Published by Elsevier Espana. All rights reserved.)