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Background: Magnetic Resonance Imaging (MRI)-based imaging techniques are useful for assessing white matter (WM) structural and microstructural integrity in the context of infection and inflammation. The purpose of this scoping review was to assess the range of work on the use of WM neuroimaging approaches to understand the impact of congenital and perinatal viral infections or exposures on the developing brain., Methods: This scoping review was conducted according to the Arksey and O' Malley framework. A literature search was performed in Web of Science, Scopus and PubMed for primary research articles published from database conception up to January 2022. Studies evaluating the use of MRI-based WM imaging techniques in congenital and perinatal viral infections or exposures were included. Results were grouped by age and infection., Results: A total of 826 articles were identified for screening and 28 final articles were included. Congenital and perinatal infections represented in the included studies were cytomegalovirus (CMV) infection (n = 12), human immunodeficiency virus (HIV) infection (n = 11) or exposure (n = 2) or combined (n = 2), and herpes simplex virus (HSV) infection (n = 1). The represented MRI-based WM imaging methods included structural MRI and diffusion-weighted and diffusion tensor MRI (DWI/ DTI). Regions with the most frequently reported diffusion metric group differences included the cerebellar region, corticospinal tract and association fibre WM tracts in both children with HIV infection and children who are HIV-exposed uninfected. In qualitative imaging studies, WM hyperintensities were the most frequently reported brain abnormality in children with CMV infection and children with HSV infection., Conclusion: There was evidence that WM imaging techniques can play a role as diagnostic and evaluation tools assessing the impact of congenital infections and perinatal viral exposures on the developing brain. The high sensitivity for identifying WM hyperintensities suggests structural brain MRI is a useful neurodiagnostic modality in assessing children with congenital CMV infection, while the DTI changes associated with HIV suggest metrics such as fractional anisotropy have the potential to be specific markers of subtle impairment or WM damage in neuroHIV., (© 2024. The Author(s).)

Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges by harmonizing data collection to identify consistent brain signatures of OCD that are reproducible and generalizable. Single-shell diffusion measures (e.g., fractional anisotropy), multi-shell Neurite Orientation Dispersion and Density Imaging (NODDI) and fixel-based measures, were extracted from skeletonized white matter tracts in 260 medication-free adults with OCD and 252 healthy controls. We additionally performed structural connectome analysis. We compared cases with controls and cases with early (<18) versus late (18+) OCD onset using mixed-model and Bayesian multilevel analysis. Compared with healthy controls, adult OCD individuals showed higher fiber density in the sagittal stratum (B[SE] = 0.10[0.05], P = 0.04) and credible evidence for higher fiber density in several other tracts. When comparing early (n = 145) and late-onset (n = 114) cases, converging evidence showed lower integrity of the posterior thalamic radiation -particularly radial diffusivity (B[SE] = 0.28[0.12], P = 0.03)-and lower global efficiency of the structural connectome (B[SE] = 15.3[6.6], P = 0.03) in late-onset cases. Post-hoc analyses indicated divergent direction of effects of the two OCD groups compared to healthy controls. Age of OCD onset differentially affects the integrity of thalamo-parietal/occipital tracts and the efficiency of the structural brain network. These results lend further support for the role of the thalamus and its afferent fibers and visual attentional processes in the pathophysiology of OCD., (© 2024. The Author(s).)

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

Imaging genetics provides an opportunity to discern associations between genetic variants and brain imaging phenotypes. Historically, the field has focused on adults and adolescents; very few imaging genetics studies have focused on brain development in infancy and early childhood (from birth to age 6 years). This is an important knowledge gap because developmental changes in the brain during the prenatal and early postnatal period are regulated by dynamic gene expression patterns that likely play an important role in establishing an individual's risk for later psychiatric illness and neurodevelopmental disabilities. In this review, we summarize findings from imaging genetics studies spanning from early infancy to early childhood, with a focus on studies examining genetic risk for neuropsychiatric disorders. We also introduce the Organization for Imaging Genomics in Infancy (ORIGINs), a working group of the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium, which was established to facilitate large-scale imaging genetics studies in infancy and early childhood., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Importance: Anemia affects millions of pregnant women and their children worldwide, particularly in low- and middle-income countries. Although anemia in pregnancy is a well-described risk factor for cognitive development, the association with child brain structure is poorly understood., Objective: To explore the association of anemia during pregnancy and postnatal child anemia with brain structure in early life., Design, Setting, and Participants: This neuroimaging nested cohort study was embedded within the Drakenstein Child Health Study (DCHS), a population-based birth cohort in South Africa. Pregnant individuals were enrolled into the DCHS between 2012 and 2015 from 2 clinics in a periurban setting. Mother-child pairs were assessed prospectively; follow-up is ongoing. A subgroup of children had brain magnetic resonance imaging (MRI) at age 2 to 3 years from 2015 to 2018. This study focused on the 147 pairs with structural neuroimaging and available hemoglobin data. Data analyses were conducted in 2021 and 2022., Exposures: Mothers had hemoglobin measurements during pregnancy, and a subgroup of children had hemoglobin measurements during early life. Anemia was classified as hemoglobin levels less than 11 g/dL based on World Health Organization guidelines; children younger than 6 months were classified using local guidelines., Main Outcomes and Measures: Child brain volumes of global, subcortical, and corpus callosum structures were quantified using T1-weighted MRI. Linear regression models were used to analyze the associations between maternal and child anemia with child brain volumes, accounting for potential confounders., Results: Of 147 children (mean [SD] age at MRI, 34 [2] months; 83 [56.5%] male) with high-resolution MRI scans, prevalence of maternal anemia in pregnancy was 31.3% (46 of 147; median [IQR] gestation of measurement: 13 [9-20] weeks). Maternal anemia during pregnancy was significantly associated with smaller volumes of the child caudate bilaterally (adjusted percentage difference, -5.30% [95% CI, -7.01 to -3.59]), putamen (left hemisphere: -4.33% [95% CI, -5.74 to -2.92]), and corpus callosum (-7.75% [95% CI, -11.24 to -4.26]). Furthermore, antenatal maternal hemoglobin levels were also associated with brain volumes in the caudate (left hemisphere: standardized β = 0.15 [95% CI, 0.02 to 0.28]; right hemisphere: β = 0.15 [95% CI, 0.02 to 0.27]), putamen left hemisphere (β = 0.21 [95% CI, 0.07 to 0.35]), and corpus callosum (β = 0.24 [95% CI, 0.09 to 0.39]). Prevalence of child anemia was 52.5% (42 of 80; median [IQR] age of measurement: 8.0 [2.7 to 14.8] months). Child anemia was not associated with brain volumes, nor did it mediate the association of maternal anemia during pregnancy with brain volumes., Conclusions and Relevance: In this cohort study, anemia in pregnancy was associated with altered child brain structural development. Given the high prevalence of antenatal maternal anemia worldwide, these findings suggest that optimizing interventions during pregnancy may improve child brain outcomes.

Oxytocin plays a vital role in social behavior and homeostatic processes, with animal models indicating that oxytocin receptor (OXTR) expression patterns in the brain influence behavior and physiology. However, the developmental trajectory of OXTR gene expression is unclear. By analyzing gene expression data in human post-mortem brain samples, from the prenatal period to late adulthood, we demonstrate distinct patterns of OXTR gene expression in the developing brain, with increasing OXTR expression along the course of the prenatal period culminating in a peak during early childhood. This early life OXTR expression peak pattern appears slightly earlier in a comparative macaque sample, which is consistent with the relative immaturity of the human brain during early life compared to macaques. We also show that a network of genes with strong spatiotemporal couplings with OXTR is enriched in several psychiatric illness and body composition phenotypes. Taken together, these results demonstrate that oxytocin signaling plays an important role in a diverse set of psychological and somatic processes across the lifespan., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with brain alterations particularly involving fronto-cerebellar and meso-cortico-limbic circuitry. However, such abnormalities have additionally been reported in other psychiatric conditions, and until recently there has been few large-scale investigations to compare such findings. The current study uses the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium method of standardising structural brain measures to quantify case-control differences and to compare brain-correlates of substance use disorders with those published in relation to other psychiatric disorders. Using the ENIGMA protocols, we report effect sizes derived from a meta-analysis of alcohol (seven studies, N = 798, 54% are cases) and cannabis (seven studies, N = 447, 45% are cases) dependent cases and age- and sex-matched controls. We conduct linear analyses using harmonised methods to process and parcellate brain data identical to those reported in the literature for ENIGMA case-control studies of major depression disorder (MDD), schizophrenia (SCZ) and bipolar disorder so that effect sizes are optimally comparable across disorders. R elationships between substance use disorder diagnosis and subcortical grey matter volumes and cortical thickness were assessed with intracranial volume, age and sex as co-variates . After correcting for multiple comparisons, AUD case-control meta-analysis of subcortical regions indicated significant differences in the thalamus, hippocampus, amygdala and accumbens, with effect sizes (0.23) generally equivalent to, or larger than |0.23| those previously reported for other psychiatric disorders (except for the pallidum and putamen). On measures of cortical thickness, AUD was associated with significant differences bilaterally in the fusiform gyrus, inferior temporal gyrus, temporal pole, superior frontal gyrus, and rostral and caudal anterior cingulate gyri. Meta-analysis of CUD case-control studies indicated reliable reductions in amygdala, accumbens and hippocampus volumes, with the former effect size comparable to, and the latter effect size around half of that reported for alcohol and SCZ. CUD was associated with lower cortical thickness in the frontal regions, particularly the medial orbitofrontal region, but this effect was not significant after correcting for multiple testing. This study allowed for an unbiased cross-disorder comparison of brain correlates of substance use disorders and showed alcohol-related brain anomalies equivalent in effect size to that found in SCZ in several subcortical and cortical regions and significantly greater alterations than those found in MDD in several subcortical and cortical regions. Although modest, CUD results overlapped with findings reported for AUD and other psychiatric conditions, but appear to be most robustly related to reduce thickness of the medial orbitofrontal cortex., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine., (© 2021 European Sleep Research Society.)

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date., Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide., Design, Setting, and Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019., Main Outcomes and Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status., Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004)., Conclusions and Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.

The relationship between cognitive performance, macro and microstructural brain anatomy and accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock in healthy adolescents has not been studied. Healthy adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort Study were studied cross sectionally. The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 44 adolescents aged 9 to 12 years old. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration residual (AAR) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent neurocognitive testing, T1 structural magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI). Correlation tests were run between the two epigenetic aging measures and 10 cognitive functioning domains, to assess for differences in cognitive performance as epigenetic aging increases. In order to investigate the associations of epigenetic age acceleration on brain structure, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, and cortical surface area, as well as DTI measures of white matter microstructural integrity. In addition to negatively affecting two cognitive domains, visual memory (p = .026) and visual spatial acuity (p = .02), epigenetic age acceleration was associated with alterations of brain volumes, cortical thickness, cortical surface areas and abnormalities in neuronal microstructure in a range of regions. Stress was a significant predictor (p = .029) of AAR. Understanding the drivers of epigenetic age acceleration in adolescents could lead to valuable insights into the development of neurocognitive impairment in adolescents.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures., (© 2019 Society for the Study of Addiction.)

Magnetic resonance imaging (MRI) is an indispensable tool for investigating brain development in young children and the neurobiological mechanisms underlying developmental risk and resilience. Sub-Saharan Africa has the highest proportion of children at risk of developmental delay worldwide, yet in this region there is very limited neuroimaging research focusing on the neurobiology of such impairment. Furthermore, paediatric MRI imaging is challenging in any setting due to motion sensitivity. Although sedation and anesthesia are routinely used in clinical practice to minimise movement in young children, this may not be ethical in the context of research. Our study aimed to investigate the feasibility of paediatric multimodal MRI at age 2-3 years without sedation, and to explore the relationship between cortical structure and neurocognitive development at this understudied age in a sub-Saharan African setting. A total of 239 children from the Drakenstein Child Health Study, a large observational South African birth cohort, were recruited for neuroimaging at 2-3 years of age. Scans were conducted during natural sleep utilising locally developed techniques. T1-MEMPRAGE and T2-weighted structural imaging, resting state functional MRI, diffusion tensor imaging and magnetic resonance spectroscopy sequences were included. Child neurodevelopment was assessed using the Bayley-III Scales of Infant and Toddler Development. Following 23 pilot scans, 216 children underwent scanning and T1-weighted images were obtained from 167/216 (77%) of children (median age 34.8 months). Furthermore, we found cortical surface area and thickness within frontal regions were associated with cognitive development, and in temporal and frontal regions with language development (beta coefficient ≥0.20). Overall, we demonstrate the feasibility of carrying out a neuroimaging study of young children during natural sleep in sub-Saharan Africa. Our findings indicate that dynamic morphological changes in heteromodal association regions are associated with cognitive and language development at this young age. These proof-of-concept analyses suggest similar links between the brain and cognition as prior literature from high income countries, enhancing understanding of the interplay between cortical structure and function during brain maturation., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain imaging studies in children with prenatal methamphetamine exposure (PME) suggest structural and functional alterations of striatal, frontal, parietal, and limbic regions. However, no longitudinal studies have investigated changes in structural connectivity during the first 2 years of formal schooling. The aim of this study was to explore the effects of PME on structural connectivity of brain networks in children over the critical first 2 years of formal schooling when foundational learning takes place. Networks are expected to gradually increase in global connectedness while segregating into defined systems. Graph theoretical analysis was used to investigate changes in structural connectivity at age 6 and 8 years in children with and without PME. While healthy control children showed increased connectivity in frontal and limbic hubs over time, children with PME showed increased connectivity in the superior parietal cortex and striatum in their global network. Furthermore, compared to control children, those with PME were characterized by less change in segregation of structural networks over time. These findings are consistent with previous work on regions implicated in children with PME, but they additionally demonstrate alterations in structural connectivity between regions that underlie primary cognitive, behavioral, and emotional development. Understanding patterns of network development during critical periods in at-risk children may inform strategies for supporting this group of children in these developmental tasks important for lifelong brain health and development., (© 2020 Wiley Periodicals, Inc.)

Objective: To investigate the association between neurocognitive impairment, neuroimaging, and systemic inflammation in perinatally infected adolescents living with HIV (PHIV) on antiretroviral therapy (ART). Systemic inflammation may be one mechanism driving neurocognitive impairment despite ART, but this has not been investigated in adolescence when the brain is undergoing rapid development., Setting: Cape Town, South Africa., Methods: Baseline data were drawn from the Cape Town Adolescent Antiretroviral Cohort. PHIV on ART >6 months completed a comprehensive neurocognitive test battery. Diffusion tensor imaging and structural brain magnetic resonance imaging was done to determine whole brain fractional anisotropy, mean diffusion (MD), grey and white matter volumes, and cortical thickness. We examined how neurocognitive and neurostructural measures were associated with a concurrently measured marker of systemic inflammation, high-sensitive C-reactive protein (hs-CRP)., Results: One hundred sixty-eight PHIV ages 9-12 years (mean CD4 980 cells/µL; 85.3% viral load <50 copies/mL) and 43 controls were included in the analysis. PHIV had similar hs-CRP (P = 0.17) to controls, after participants with hs-CRP >10 were excluded from the analysis. Forty-eight percent of the PHIV in this analysis have a neurocognitive disorder. Whole brain grey (P = 0.049) and white matter volumes (P = 0.044) were lowest in PHIV with a major neurocognitive disorder. Higher MD, was found in PHIV with a major neurocognitive disorder (P = 0.002). Among PHIV with a neurocognitive disorder, hs-CRP negatively correlated with general intelligence, visual spatial acuity, and executive function (all P = < 0.05). Whole brain MD correlated with higher hs-CRP values (P = < 0.01) in PHIV., Conclusions: A marker of systemic inflammation was associated with both neurocognitive impairment and MD increases in PHIV.

Background: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results., Methods: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations., Discussion: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

There is evidence of HIV affecting cognitive functioning across age groups, with adult studies showing related deficits in frontostriatal and hippocampal regional activity. Additionally, delayed initiation of antiretroviral treatment (ART) has been associated with poorer cognitive outcomes in HIV-infected youth. Little is known, however, of the neural correlates underlying such cognitive deficits in youth populations. We investigated maintenance working memory-related brain activity in South African HIV-infected youth and controls, and the effect of ART initiation age on underlying structures. Sixty-four perinatally infected youth (ages 9-12) and 20 controls (ages 9-13) underwent functional magnetic resonance imaging (fMRI) while completing 1-back and 0-back blocks of the N-back task. At an uncorrected p value threshold of 0.001, the HIV-infected group showed decreased activation in the left superior temporal gyrus, pre- and postcentral gyri, insula, and putamen as well as bilateral hippocampus, and mid cingulum. The HIV patients with delayed ART initiation showed less activation during processing conditions in the mid cingulum; left inferior parietal gyrus; and right inferior frontal, bilateral thalamic, and superior temporal regions. When these regions were tested for structural differences, the mid cingulum and right inferior frontal gyrus, insula, and thalamus were found to have less cortical thickness, surface area, or volume in the group with delayed ART initiation. Regional differences between HIV-infected youth and controls noted in the N-back task are consistent with impairments in structures involved in maintenance working memory. These data support earlier ART initiation in perinatally infected individuals.

Neurotoxicity associated with the antiretroviral efavirenz (EFV) has been documented in HIV-infected adults, but there are no data on the impact of EFV on brain function in adolescents. We investigated potential alterations in fronto-striatal function associated with EFV use in adolescents. A total of 86 adolescents underwent a Stop Signal Anticipation Task (SSAT) during functional MRI (fMRI), 39 HIV+ adolescents receiving EFV, 27 HIV+ adolescents on antiretroviral therapy without EFV (matched on age, gender, education, CD4 cell count and HIV viral load) and 20 HIV- matched controls (matched on age and gender). The task required participants to give timed GO responses with occasional STOP signals at fixed probabilities. Reactive inhibition was modelled as a correct STOP response and proactive inhibition was modelled after response slowing as the STOP probability increases. A priori mask-based regions associated with reactive and proactive inhibition were entered into two respective multivariate ANOVAs. The EFV treatment group showed significantly blunted proactive inhibitory behavioural responses compared to HIV+ adolescents not receiving EFV. There was no difference in reactive inhibition between treatment groups. We also demonstrated a significant effect of EFV treatment on BOLD signal in proactive inhibition regions. There was no difference in regions involved in reactive inhibition. We found no differences between adolescents not receiving EFV and HIV- controls, showing that functional and behavioural differences were unique to the EFV group. Here, we demonstrate for the first time a potential adverse impact of EFV on higher cortical function in young HIV+ adolescents.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R 2  = 0.041, P corr  < 0.001) and cingulum (right: R 2  = 0.041, left: R 2  = 0.040, P corr  < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. 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.

Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects., Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T 1 -weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen's d=0.1., Results: The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset., Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection 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.

Large-scale consortium efforts such as Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) and other collaborative efforts show that combining statistical data from multiple independent studies can boost statistical power and achieve more accurate estimates of effect sizes, contributing to more reliable and reproducible research. A meta- analysis would pool effects from studies conducted in a similar manner, yet to date, no such harmonized protocol exists for resting state fMRI (rsfMRI) data. Here, we propose an initial pipeline for multi-site rsfMRI analysis to allow research groups around the world to analyze scans in a harmonized way, and to perform coordinated statistical tests. The challenge lies in the fact that resting state fMRI measurements collected by researchers over the last decade vary widely, with variable quality and differing spatial or temporal signal-to-noise ratio (tSNR). An effective harmonization must provide optimal measures for all quality data. Here we used rsfMRI data from twenty-two independent studies with approximately fifty corresponding T1-weighted and rsfMRI datasets each, to (A) review and aggregate the state of existing rsfMRI data, (B) demonstrate utility of principal component analysis (PCA)-based denoising and (C) develop a deformable ENIGMA EPI template based on the representative anatomy that incorporates spatial distortion patterns from various protocols and populations.

There is extensive evidence of an association between early adversity and enduring neural changes that impact socioemotional processing throughout life. Yet little is known about the effects of on-going social discrimination on socioemotional functioning. Here we examined how cumulative experiences of social discrimination impact brain response during empathic responding-a crucial issue in South Africa, given its historical apartheid context and continuing legacies. White and Black South Africans completed measures of social adversity (early adversity and social discrimination), and underwent fMRI while viewing video clips depicting victims and perpetrators of apartheid crimes. Increased neural response was detected in brain regions associated with cognitive rather than affective empathy, and greater social adversity was associated with reduced reported compassion across participants. Notably, social discrimination (due to income level, weight, gender) in White participants was associated with increased amygdala reactivity, whereas social discrimination (due to race) in Black participants mediated the negative associations of temporoparietal junction and inferior frontal gyrus activation with compassion during emotionally provocative conditions. These findings suggest that (i) social discrimination has comparable associations at the neural level as other psychosocial stressors, and that (ii) the mechanisms underlying empathic responding vary as a function of the type of social discrimination experienced.

The prevailing paradigm for psychopharmacology focuses on understanding brain mechanisms as the key to finding new medications and improving clinical outcomes, but frustration with slow progress has inspired many pleas for new approaches. Evolutionary psychiatry brings in an additional basic science that poses new questions about why natural selection left us vulnerable to so many mental disorders, and new insights about how drugs work. The integration of neuroscience with evolutionary psychiatry is synergistic, going beyond reductionism to provide a model like the one used by the rest of medicine. It recognizes negative emotions as symptoms, that are, like pain and cough, useful defenses whose presence should initiate a search for causes. An integrative evolutionary approach explains why agents that block useful aversive responses are usually safe, and how to anticipate when they may cause harm. More generally, an evolutionary framework suggests novel practical strategies for finding and testing new drugs.
., (© 2019, AICH – Servier GroupCopyright © 2019 AICH – Servier Group. All rights reserved.)

In psychiatric research, nuclear imaging complements MRI. A recent neuroimaging review of social anxiety disorder focused predominantly on MRI, omitting the contribution of nuclear imaging methods. Nuclear imaging investigations of neural activity are sparse but have generally yielded results consistent with studies performed using MRI. Evidence for disturbances in neurotransmitter systems in social anxiety disorder is limited but suggestive of both serotonergic and dopaminergic dysfunction. Research focusing on additional molecular targets using existing and novel tracers, combined with recent technologic innovations and trends in collaborative methodology, may shape future nuclear imaging endeavors in this field., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: To describe the structural brain changes, neurocognitive and mental health associations in adolescents perinatally infected with HIV-1 infection., Design: Cross-sectional., Methods: Two hundred and four adolescents with perinatally acquired HIV and 44 uninfected frequency-matched controls aged 9-11 years were enrolled within the Cape Town Adolescent Antiretroviral Cohort. Diffusion tensor imaging and structural brain MRI was done to determine fractional anisotropy, mean diffusivity, grey and white matter volumes, cortical thickness and cortical surfractional anisotropy area. Correlation coefficients were calculated between total grey and white matter volume, cortical surface area, cortical thickness, whole brain fractional anisotropy and whole brain mean diffusivity and clinical and laboratory parameters including general intellectual functioning, Becks Youth Inventory, Child Motivation Scale and Child Behaviour Checklist., Results: HIV-infected adolescents performed worse than controls on the Wechsler Abbreviated Scale of Intelligence (WASI; P < 0.01). HIV-infected adolescents had significant fractional anisotropy decreases, mean diffusivity increases and decreases in cerebral grey matter volumes, cortical surface area and decreased gyrification. Whole-brain mean fractional anisotropy was significantly reduced in the HIV-infected group (P = 0.031). There were significant correlation coefficients between greater total grey (P = 0.008) and white matter volume (P = 0.004) with the WASI and the Becks self-concept subscale (P = 0.038). Lower whole brain fractional anisotropy was associated with higher scores on the Becks anger (P = 0.018) and disruptive behaviour subscales (P = 0.031). Higher whole brain mean diffusivity was associated with apathy (P = 0.046)., Conclusion: The pattern of increased risk of white matter microstructure alterations, smaller grey matter volumes, reduced cortical surface area and decreased gyrification, suggests abnormal neurodevelopment in perinatally infected younger adolescents.

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.)

Childhood maltreatment, including abuse and neglect, may have sustained effects on the integrity and functioning of the brain, alter neurophysiological responsivity later in life, and predispose individuals toward psychiatric conditions involving socioaffective disturbances. This meta-analysis aims to quantify associations between self-reported childhood maltreatment and brain function in response to socioaffective cues in adults. Seventeen functional magnetic resonance imaging studies reporting on data from 848 individuals examined with the Childhood Trauma Questionnaire were included in a meta-analysis of whole-brain findings, or a review of region of interest findings. The spatial consistency of peak activations associated with maltreatment exposure was tested using activation likelihood estimation, using a threshold of p < .05 corrected for multiple comparisons. Adults exposed to childhood maltreatment showed significantly increased activation in the left superior frontal gyrus and left middle temporal gyrus, and decreased activation in the left superior parietal lobule and the left hippocampus. Although hyperresponsivity to socioaffective cues in the amygdala and ventral anterior cingulate cortex in correlation with maltreatment severity is a replicated finding in region of interest studies, null results are reported as well. The findings suggest that childhood maltreatment has sustained effects on brain function into adulthood, and highlight potential mechanisms for conveying vulnerability to development of psychopathology.

Background: Abuse of methamphetamine (MA) is a global health concern. Previous 1 H-MRS studies have found that, with methamphetamine abstinence (MAA), there are changes in n-acetyl-aspartate (NAA/Cr), myo-inositol (mI/Cr), choline (Cho/Cr and Cho/NAA), and glutamate with glutamine (Glx) metabolites. Limited studies have investigated the effect of acute MAA, and acute-to-short-term MAA on brain metabolites., Methods: Adults with chronic MA dependence (n = 31) and healthy controls (n = 22) were recruited. Two-dimensional chemical shift 1 H-MRS imaging (TR2000 ms, TE30 ms) slice was performed and included voxels in bilateral anterior-cingulate (ACC), frontal-white-matter (FWM), and dorsolateral-prefrontal-cortices (DLPFC). Control participants were scanned once. The MA group was scanned twice, with acute (1.5 ± 0.6 weeks, n = 31) and short-term MAA (5.1 ± 0.8 weeks, n = 22). The change in 1 H-MRS metabolites over time (n = 19) was also investigated. Standard 1 H-MRS metabolites are reported relative to Cr + PCr., Results: Acute MAA showed lower n-acetyl-aspartate (NAA) and n-acetyl-aspartate with n-acetyl-aspartyl-glutamate (NAA + NAAG) in left DLPFC, and glycerophosphocholine with phosphocholine (GPC + PCh) in left FWM. Short-term MAA showed lower NAA + NAAG and higher myo-inositol (mI) in right ACC, lower NAA and NAA + NAAG in the left DLPFC, and lower GPC + PCh in left FWM. Over time, MAA showed decreased NAA and NAA + NAAG and increased mI in right ACC, decreased NAA and NAA + NAAG in right FWM, and decreased in mI in left FWM., Conclusion: In acute MAA, there was damage to the integrity of neuronal tissue, which was enhanced with short-term MAA. From acute to short-term MAA, activation of neuroinflammatory processes are suggested. This is the first 1 H-MRS study to report the development of neuroinflammation with loss of neuronal integrity in MAA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Muscle fatigue is a disturbed homeostatic state characterized by a temporary inability to maintain force output and has lasting effects on the brain in the period immediately after exercise, such as decreased interhemispheric functional connectivity (FC). Stimulants that increase dopamine and norepinephrine neurotransmission can enhance performance during muscle fatiguing exercise (i.e. are ergogenic). We recently demonstrated that methylphenidate (MPH) increased force output and increased FC between the insular (IC) and hand motor cortex during a fatiguing handgrip task. However, whether resting FC is altered in the recovery period after enhanced force is unknown. The objective of these follow-up analyses was to examine the effects of performing a fatiguing handgrip task with MPH on subsequent resting state FC. In a double-blind counter-balanced design, participants ingested placebo or MPH and in a magnetic resonance imaging scanner performed: a six-minute pre-task resting scan, a fatiguing handgrip task during scanning, and then a six-minute post-task resting scan. We investigated task-related force and resting state FC pre- and post-task between: (1) interhemispheric motor cortices (M1) and (2) the right IC and left hand motor area. We found 1) a post-task reduction in M1 interhemispheric FC and that the extent of reduciton was negatively correlated with enhanced mean trial force in MPH conditions. 2) MPH but not placebo increased post-task FC between the right IC and left hand motor area. This study demonstrates that using MPH during a muscle fatiguing task has lasting effects on the brain that are markedly different from drug naïve conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Methamphetamine dependence can lead to psychotic symptoms which may be mediated by frontal, striatal, limbic, and thalamic regions. There are few neuroimaging data that allow comparison of individuals with methamphetamine dependence who do, and do not, have psychosis. Two complementary imaging techniques were employed to investigate neurocircuitry associated with methamphetamine dependence with and without psychotic symptoms., Methods: Three groups of participants were recruited: methamphetamine dependent (MAA) (N = 11), methamphetamine dependent with psychotic symptoms (MAP) (N = 14), and controls (N = 14). Resting brain glucose metabolism was measured using [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and cerebral perfusion was assessed using arterial spin labelling (ASL) magnetic resonance imaging., Results: Methamphetamine abusers (MAA and MAP groups) had decreased glucose metabolism compared to healthy controls in the left insula, left precentral gyrus, and the anterior cingulate cortex. Compared to MAA participants, MAP participants had 1) decreased glucose metabolism in the left precentral gyrus and the left inferior frontal gyrus and 2) increased glucose metabolism in the putamen and pallidum. MAP participants also had increased cerebral perfusion in the right putamen and right pallidum compared to MAA., Conclusion: Findings support the involvement of frontal, striatal, and limbic regions in methamphetamine dependence. Furthermore, they indicate that glucose metabolism and cerebral perfusion in these regions are disrupted in methamphetamine dependent individuals with psychotic symptoms., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic methamphetamine use is associated with executive functioning deficits that suggest dysfunctional cognitive control networks (CCNs) in the brain. Likewise, abnormal connectivity between intrinsic CCNs and default mode networks (DMNs) has also been associated with poor cognitive function in clinical populations. Accordingly, we tested the extent to which methamphetamine use predicts abnormal connectivity between these networks, and whether, as predicted, these abnormalities are compounded in patients with a history of methamphetamine-associated psychosis (MAP). Resting-state fMRI data were acquired from 46 methamphetamine-dependent patients [19 with MAP, 27 without (MD)], as well as 26 healthy controls (CTRL). Multivariate network modelling and whole-brain voxel-wise connectivity analyses were conducted to identify group differences in intrinsic connectivity across four cognitive control and three DMN networks identified using an independent components analysis approach (meta-ICA). The relationship of network connectivity and psychotic symptom severity, as well as antipsychotic treatment and methamphetamine use variables, was also investigated. Robust evidence of hyper-connectivity was observed between the right frontoparietal and anterior DMN networks in MAP patients, and 'normalized' with increased duration of treatment with antipsychotics. Attenuation of anticorrelated anterior DMN-dorsal attention network activity was also restricted to this group. Elevated coupling detected in MD participants between anterior and posterior DMN networks became less apparent with increasing duration of abstinence from methamphetamine. In summary, we observed both alterations of RSN connectivity between DMN networks with chronic methamphetamine exposure, as well as DMN-CCN coupling abnormalities consistent with possible MAP-specific frontoparietal deficits in the biasing of task-appropriate network activity., (© 2016 Society for the Study of Addiction.)

Evidence suggests that women who suffer from intimate partner violence (IPV) and posttraumatic stress disorder (PTSD) have structural and functional alterations in specific brain regions. Yet, little is known about how brain connectivity may be altered in individuals with IPV, but without PTSD. Women exposed to IPV (n = 18) and healthy controls (n = 18) underwent structural brain imaging using a Siemens 3T MRI. Global and regional brain network connectivity measures were determined, using graph theory analyses. Structural covariance networks were created using volumetric and cortical thickness data after controlling for intracranial volume, age and alcohol use. Nonparametric permutation tests were used to investigate group differences. Findings revealed altered connectivity on a global and regional level in the IPV group of regions involved in cognitive-emotional control, with principal involvement of the caudal anterior cingulate, the middle temporal gyrus, left amygdala and ventral diencephalon that includes the thalamus. To our knowledge, this is the first evidence showing different brain network connectivity in global and regional networks in women exposed to IPV, and without PTSD. Altered cognitive-emotional control in IPV may underlie adaptive neural mechanisms in environments characterized by potentially dangerous cues.

Neuroimaging abnormalities are common in chronically infected HIV-positive individuals. The majority of studies have focused on structural or functional brain outcomes in samples infected with clade B HIV. While preliminary work reveals a similar structural imaging phenotype in patients infected with clade C HIV, no study has examined functional connectivity (FC) using resting-state functional magnetic resonance imaging (rs-fMRI) in clade C HIV. In particular, we were interested to explore HIV-only effects on neurocognitive function using associations with rs-fMRI. In the present study, 56 treatment-naïve, clade C HIV-infected participants (age 32.27 ± 5.53 years, education 10.02 ± 1.72 years, 46 female) underwent rs-fMRI and cognitive testing. Individual resting-state networks were correlated with global deficit scores (GDS) in order to explore associations between them within an HIV-positive sample. Results revealed ten regions in six resting-state networks where FC inversely correlated with GDS scores (worse performance). The networks affected included three independent attention networks: the default mode network (DMN), sensorimotor network, and basal ganglia. Connectivity in these regions did not correlate with plasma viral load or CD4 cell count. The design of this study is unique and has not been previously reported in clade B. The abnormalities related to neurocognitive performance reported in this study of clade C may reflect late disease stage and/or unique host/viral dynamics. Longitudinal studies will help to clarify the clinical significance of resting-state alterations in clade C HIV.

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Many psychiatric disorders are characterized by altered social cognition. The importance of social cognition has previously been recognized by the National Institute of Mental Health Research Domain Criteria project, in which it features as a core domain. Social task-based functional magnetic resonance imaging (fMRI) currently offers the most direct insight into how the brain processes social information; however, resting-state fMRI may be just as important in understanding the biology and network nature of social processing. Resting-state fMRI allows researchers to investigate the functional relationships between brain regions in a neutral state: so-called resting functional connectivity (RFC). There is evidence that RFC is predictive of how the brain processes information during social tasks. This is important because it shifts the focus from possibly context-dependent aberrations to context-independent aberrations in functional network architecture. Rather than being analysed in isolation, the study of resting-state brain networks shows promise in linking results of task-based fMRI results, structural connectivity, molecular imaging findings, and performance measures of social cognition-which may prove crucial in furthering our understanding of the social brain., (Copyright © 2017 John Wiley & Sons, Ltd.)

Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric co-morbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in gray matter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multi-site imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples. An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients ( n  = 174) and healthy control (HC)-participants ( n  = 213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium.

Childhood adversity plays an important role for development of major depressive disorder (MDD). There are differences in subcortical brain structures between patients with MDD and healthy controls, but the specific impact of childhood adversity on such structures in MDD remains unclear. Thus, aim of the present study was to investigate whether childhood adversity is associated with subcortical volumes and how it interacts with a diagnosis of MDD and sex. Within the ENIGMA-MDD network, nine university partner sites, which assessed childhood adversity and magnetic resonance imaging in patients with MDD and controls, took part in the current joint mega-analysis. In this largest effort world-wide to identify subcortical brain structure differences related to childhood adversity, 3036 participants were analyzed for subcortical brain volumes using FreeSurfer. A significant interaction was evident between childhood adversity, MDD diagnosis, sex, and region. Increased exposure to childhood adversity was associated with smaller caudate volumes in females independent of MDD. All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis). There was no interaction effect between childhood adversity and MDD diagnosis on subcortical brain volumes. Childhood adversity is one of the contributors to brain structural abnormalities. It is associated with subcortical brain abnormalities that are relevant to psychiatric disorders such as depression., (Copyright © 2016. Published by Elsevier Ltd.)

Infection with human immunodeficiency virus (HIV) is associated with neuroimaging alterations. However, little is known about the topological organization of whole-brain networks and the corresponding association with cognition. As such, we examined structural whole-brain white matter connectivity patterns and cognitive performance in 29 HIV+ young adults (mean age = 25.9) with limited or no HIV treatment history. HIV+ participants and demographically similar HIV- controls (n = 16) residing in South Africa underwent magnetic resonance imaging (MRI) and neuropsychological testing. Structural network models were constructed using diffusion MRI-based multifiber tractography and T 1 -weighted MRI-based regional gray matter segmentation. Global network measures included whole-brain structural integration, connection strength, and structural segregation. Cognition was measured using a neuropsychological global deficit score (GDS) as well as individual cognitive domains. Results revealed that HIV+ participants exhibited significant disruptions to whole-brain networks, characterized by weaker structural integration (characteristic path length and efficiency), connection strength, and structural segregation (clustering coefficient) than HIV- controls (p < 0.05). GDSs and performance on learning/recall tasks were negatively correlated with the clustering coefficient (p < 0.05) in HIV+ participants. Results from this study indicate disruption to brain network integrity in treatment-limited HIV+ young adults with corresponding abnormalities in cognitive performance.

Background: Methamphetamine (MA) use may lead to white matter injury and to a range of behavioral problems and psychiatric disorders, including psychosis. The present study sought to assess white matter microstructural impairment as well as impulsive behavior in MA dependence and MA-associated psychosis (MAP)., Methods: Thirty patients with a history of MAP, 39 participants with MA dependence and 40 healthy controls underwent diffusion tensor imaging (DTI). Participants also completed the UPPS-P impulsive behavior questionnaire. We applied tract-based spatial statistics (TBSS) to investigate group differences in mean diffusivity (MD), fractional anisotropy (FA), axial (λ‖ ) and radial diffusivity (λ⊥ ), and their association with impulsivity scores and psychotic symptoms., Results: The MAP group displayed widespread higher MD, λ‖ and λ⊥ levels compared to both controls and the MA group, and lower FA in extensive white matter areas relative to controls. MD levels correlated positively with negative psychotic symptoms in MAP. No significant DTI group differences were found between the MA group and controls. Both clinical groups showed high levels of impulsivity, and this dysfunction was associated with DTI measures in frontal white matter tracts., Conclusions: MAP patients show distinct patterns of impaired white matter integrity of global nature relative to controls and the MA group. Future work to investigate the precise nature and timing of alterations in MAP is needed. The results are further suggestive of frontal white matter pathology playing a role in impulsivity in MA dependence and MAP. Hum Brain Mapp 37:2055-2067, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Neuroimaging research has reported differences in resting-state functional connectivity (RFC) between social anxiety disorder (SAD) patients and healthy controls (HCs). Limited research has examined the effect of treatment on RFC in SAD. We performed a study to identify differences in RFC between SAD and HC groups, and to investigate the effect of pharmacotherapy on RFC in SAD. Seed-based RFC analysis was performed on technetium-99m hexamethylpropylene amine oxime (Tc-99m HMPAO) SPECT scans using a cross-subject approach in SPM-12. Seeds were chosen to represent regions in a recently published network model of SAD. A second-level regression analysis was performed to further characterize the underlying relationships identified in the group contrasts. Twenty-three SAD participants were included, of which 18 underwent follow-up measures after an 8-week course of citalopram or moclobemide. Fifteen healthy control (HC) scans were included. SAD participants at baseline demonstrated several significant connectivity disturbances consistent with the existing network model as well as one previously unreported finding (increased connectivity between cerebellum and posterior cingulate cortex). After therapy, the SAD group demonstrated significant increases in connectivity with dorsal anterior cingulate cortex which may explain therapy-induced modifications in how SAD sufferers interpret emotions in others and improvements in self-related and emotional processing., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Social and affective research in humans is increasingly using functional and structural neuroimaging techniques to aid the understanding of how hormones, such as testosterone, modulate a wide range of psychological processes. We conducted a meta-analysis of functional magnetic resonance imaging (fMRI) studies of testosterone administration, and of fMRI studies that measured endogenous levels of the hormone, in relation to social and affective stimuli. Furthermore, we conducted a review of structural MRI i.e. voxel based morphometry (VBM) studies which considered brain volume in relation to testosterone levels in adults and in children. In the included testosterone administration fMRI studies, which consisted of female samples only, bilateral amygdala/parahippocampal regions as well as the right caudate were significantly activated by social-affective stimuli in the testosterone condition. In the studies considering endogenous levels of testosterone, stimuli-invoked activations relating to testosterone levels were noted in the bilateral amygdala/parahippocampal regions and the brainstem. When the endogenous testosterone studies were split by sex, the significant activation of the brain stem was seen in the female samples only. Significant stimuli-invoked deactivations relating to endogenous testosterone levels were also seen in the right and left amygdala/parahippocampal regions studies. The findings of the VBM studies were less consistent. In adults larger volumes in the limbic and temporal regions were associated with higher endogenous testosterone. In children, boys showed a positive correlation between testosterone and brain volume in many regions, including the amygdala, as well as global grey matter volume, while girls showed a neutral or negative association between testosterone levels and many brain volumes. In conclusion, amygdalar and parahippocampal regions appear to be key target regions for the acute actions of testosterone in response to social and affective stimuli, while neurodevelopmentally the volumes of a broader network of brain structures are associated with testosterone levels in a sexually dimorphic manner.

Background: Early-life adversity is a risk for obsessive-compulsive disorder (OCD), but the impact at the neural level is less clear., Aims: To investigate the association between brain volumes and early-life adversity in individuals with a diagnosis of OCD only., Method: The Childhood Trauma Questionnaire (CTQ-28) was used to assess early-life adversity in 21 participants with OCD and 25 matched healthy controls. The relationship between global and regional brain volume and early-life adversity was measured using voxel-based morphometry (VBM). All data were corrected for multiple comparisons using family-wise error (FWE) at P<0.05., Results: In the OCD group, correlations with total CTQ scores were positively associated with a larger right orbitofrontal cortex volume. Physical neglect was higher in the OCD group than in controls and was positively associated with larger right cerebellum volume in the OCD group only., Conclusions: Larger brain volumes may reflect underlying developmental neuropathology in adults with OCD who also have experience of childhood trauma., (© The Royal College of Psychiatrists 2016.)

Background: Children exposed to alcohol in utero demonstrate reduced white matter microstructural integrity. While early evidence suggests altered functional brain connectivity in the lateralization of motor networks in school-age children with prenatal alcohol exposure (PAE), the specific effects of alcohol exposure on the establishment of intrinsic connectivity in early infancy have not been explored., Methods: Sixty subjects received functional imaging at 2 to 4 weeks of age for 6 to 8 minutes during quiet natural sleep. Thirteen alcohol-exposed (PAE) and 14 age-matched control (CTRL) participants with usable data were included in a multivariate model of connectivity between sensorimotor intrinsic functional connectivity networks. Seed-based analyses of group differences in interhemispheric connectivity of intrinsic motor networks were also conducted. The Dubowitz neurological assessment was performed at the imaging visit., Results: Alcohol exposure was associated with significant increases in connectivity between somatosensory, motor networks, brainstem/thalamic, and striatal intrinsic networks. Reductions in interhemispheric connectivity of motor and somatosensory networks did not reach significance., Conclusions: Although results are preliminary, findings suggest PAE may disrupt the temporal coherence in blood oxygenation utilization in intrinsic networks underlying motor performance in newborn infants. Studies that employ longitudinal designs to investigate the effects of in utero alcohol exposure on the evolving resting-state networks will be key in establishing the distribution and timing of connectivity disturbances already described in older children., (Copyright © 2016 by the Research Society on Alcoholism.)

Since the sample size of a typical neuroimaging study lacks sufficient statistical power to explore unknown genomic associations with brain phenotypes, several international genetic imaging consortia have been organized in recent years to pool data across sites. The challenges and achievements of these consortia are considered here with the goal of leveraging these resources to study addiction. The authors of this review have joined together to form an Addiction working group within the framework of the ENIGMA project, a meta-analytic approach to multisite genetic imaging data. Collectively, the Addiction working group possesses neuroimaging and genomic data obtained from over 10,000 subjects. The deadline for contributing data to the first round of analyses occurred at the beginning of May 2015. The studies performed on this data should significantly impact our understanding of the genetic and neurobiological basis of addiction., (© 2016 Elsevier B.V. All rights reserved.)

The aim of the present study was to investigate the effect of HIV infection on cortical and subcortical regions of the frontal-striatal system involved in the inhibition of voluntary movement. Functional MRI (fMRI) studies suggest that human immunodeficiency virus (HIV) infection is associated with frontostriatal dysfunction. While frontostriatal systems play a key role in behavioral inhibition, there are to our knowledge no fMRI studies investigating the potential impact of HIV on systems involved during the inhibition of voluntary movement. A total of 17 combined antiretroviral therapy (cART) naïve HIV+ participants as well as 18 age, gender, ethnic, education matched healthy controls performed a modified version of the stop-signal paradigm. This paradigm assessed behavior as well as functional brain activity associated with motor execution, reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing before stopping). HIV+ participants showed significantly slower responses during motor execution compared to healthy controls, whereas they had normal proactive response slowing. Putamen hypoactivation was evident in the HIV+ participants based on successful stopping, indicating subcortical dysfunction during reactive inhibition. HIV+ participants showed normal cortical functioning during proactive inhibition. Our data provide evidence that HIV infection is associated with subcortical dysfunction during reactive inhibition, accompanied by relatively normal higher cortical functioning during proactive inhibition. This suggests that HIV infection may primarily involve basic striatal-mediated control processes in cART naïve participants.

Brain imaging studies over two decades have delineated the neural circuitry of anxiety and related disorders, particularly regions involved in fear processing and in obsessive-compulsive symptoms. The neural circuitry of fear processing involves the amygdala, anterior cingulate, and insular cortex, while cortico-striatal-thalamic circuitry plays a key role in obsessive-compulsive disorder. More recently, neuroimaging studies have examined how psychotherapy for anxiety and related disorders impacts on these neural circuits. Here we conduct a systematic review of the findings of such work, which yielded 19 functional magnetic resonance imaging studies examining the neural bases of cognitive-behavioral therapy (CBT) in 509 patients with anxiety and related disorders. We conclude that, although each of these related disorders is mediated by somewhat different neural circuitry, CBT may act in a similar way to increase prefrontal control of subcortical structures. These findings are consistent with an emphasis in cognitive-affective neuroscience on the potential therapeutic value of enhancing emotional regulation in various psychiatric conditions.