Enhancing NeuroImaging Genetics Through Meta-Analysis Research Articles

Large-scale analysis of structural brain asymmetries during neurodevelopment: Associations with age and sex in 4265 children and adolescents.

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.

Genetics impact risk of Alzheimer’s disease through mechanisms modulating structural brain morphology in late life

BackgroundAlzheimer’s disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or...

From teeth to brain: dental caries causally affects the cortical thickness of the banks of the superior temporal sulcus

ObjectivesDental caries is one of the most prevalent oral diseases and causes of tooth loss. Cross-sectional studies observed epidemiological associations between dental caries and brain degeneration disorders, while it is unknown whether dental caries causally affect the cerebral structures. This study tested whether genetically proxied DMFS (the sum of Decayed, Missing, and Filled tooth Surfaces) causally impacts the brain cortical structure using Mendelian randomization (MR).MethodsThe summary-level GWAS meta-analysis data from the GLIDE consortium were used for DMFS, including 26,792 participants. ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) consortium GWAS summary data of 51,665 patients were used for brain structure. This study estimated the causal effects of DMFS on the surface area (SA) and thickness (TH) of the global cortex and functional cortical regions accessed by magnetic resonance imaging (MRI). Inverse-variance weighted (IVW) was used as the primary estimate, the MR pleiotropy residual sum and outlier (MR-PRESSO), the MR-Egger intercept test, and leave-one-out analyses were used to examine the potential horizontal pleiotropy.ResultsGenetically proxied DMFS decreases the TH of the banks of the superior temporal sulcus (BANSSTS) with or without global weighted (weighted, β = − 0.0277 mm, 95% CI: − 0.0470 mm to − 0.0085 mm, P = 0.0047; unweighted, β = − 0.0311 mm, 95% CI: − 0.0609 mm to − 0.0012 mm, P = 0.0412). The causal associations were robust in various sensitivity analyses.ConclusionsDental caries causally decrease the cerebral cortical thickness of the BANKSSTS, a cerebral cortical region crucial for language-related functions, and is the most affected brain region in Alzheimer’s disease. This investigation provides the first evidence that dental caries causally affects brain structure, proving the existence of teeth-brain axes. This study also suggested that clinicians should highlight the causal effects of dental caries on brain disorders during the diagnosis and treatments, the cortical thickness of BANKSSTS is a promising diagnostic measurement for dental caries-related brain degeneration.

Gray matter covariations in autism: out-of-sample replication using the ENIGMA autism cohort

BackgroundAutism spectrum disorder (henceforth autism) is a complex neurodevelopmental condition associated with differences in gray matter (GM) volume covariations, as reported in our previous study of the Longitudinal European Autism Project (LEAP) data. To make progress on the identification of potential neural markers and to validate the robustness of our previous findings, we aimed to replicate our results using data from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) autism working group.MethodsWe studied 781 autistic and 927 non-autistic individuals (6–30 years, IQ ≥ 50), across 37 sites. Voxel-based morphometry was used to quantify GM volume as before. Subsequently, we used spatial maps of the two autism-related independent components (ICs) previously identified in the LEAP sample as templates for regression analyses to separately estimate the ENIGMA-participant loadings to each of these two ICs. Between-group differences in participants’ loadings on each component were examined, and we additionally investigated the relation between participant loadings and autistic behaviors within the autism group.ResultsThe two components of interest, previously identified in the LEAP dataset, showed significant between-group differences upon regressions into the ENIGMA cohort. The associated brain patterns were consistent with those found in the initial identification study. The first IC was primarily associated with increased volumes of bilateral insula, inferior frontal gyrus, orbitofrontal cortex, and caudate in the autism group relative to the control group (β = 0.129, p = 0.013). The second IC was related to increased volumes of the bilateral amygdala, hippocampus, and parahippocampal gyrus in the autism group relative to non-autistic individuals (β = 0.116, p = 0.024). However, when accounting for the site-by-group interaction effect, no significant main effect of the group can be identified (p > 0.590). We did not find significant univariate association between the brain measures and behavior in autism (p > 0.085).LimitationsThe distributions of age, IQ, and sex between LEAP and ENIGMA are statistically different from each other. Owing to limited access to the behavioral data of the autism group, we were unable to further our understanding of the neural basis of behavioral dimensions of the sample.ConclusionsThe current study is unable to fully replicate the autism-related brain patterns from LEAP in the ENIGMA cohort. The diverse group effects across ENIGMA sites demonstrate the challenges of generalizing the average findings of the GM covariation patterns to a large-scale cohort integrated retrospectively from multiple studies. Further analyses need to be conducted to gain additional insights into the generalizability of these two GM covariation patterns.

Data-driven biomarkers better associate with stroke motor outcomes than theory-based biomarkers.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have associated motor outcomes with the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to model chronic motor outcomes after stroke and compares the accuracy of these associations to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients from the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Stroke Recovery Working Group. Using the explained variance metric to measure the strength of the association between chronic motor outcomes and imaging biomarkers, we compared theory-based biomarkers, like lesion load to known motor tracts, to three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had stronger associations with chronic motor outcomes accuracy than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R 2 = 0.210, P < 0.001), performing significantly better than the theory-based biomarkers of lesion load of the corticospinal tract (R 2 = 0.132, P < 0.001) and of multiple descending motor tracts (R 2 = 0.180, P < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R 2 = 0.200, P < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R 2 = 0.167, P < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved the strength of associations for theory-based and data-driven biomarkers. Combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R 2 = 0.241, P < 0.001. Overall, these results demonstrate that out-of-sample associations between chronic motor outcomes and data-driven imaging features, particularly when lesion data is represented in terms of structural disconnection, are stronger than associations between chronic motor outcomes and theory-based biomarkers. However, combining both theory-based and data-driven models provides the most robust associations.

Causal association of COVID-19 with brain structure changes: Findings from a non-overlapping 2-sample Mendelian randomization study

Recent cohort studies suggested that SARS-CoV-2 infection is associated with changes in brain structure. However, the potential causal relationship remains unclear. We performed a two-sample Mendelian randomization analysis to determine whether genetic susceptibility of COVID-19 is causally associated with changes in cortical and subcortical areas of the brain. This 2-sample MR (Mendelian Randomization) study is an instrumental variable analysis of data from the COVID-19 Host Genetics Initiative (HGI) meta-analyses round 5 excluding UK Biobank participants (COVID-19 infection, N = 1,348,701; COVID-19 severity, N = 1,557,411), the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Global and regional cortical measures, N = 33,709; combined hemispheric subcortical volumes, N = 38,851), and UK Biobank (left/right subcortical volumes, N = 19,629). A replication analysis was performed on summary statistics from different COVID-19 GWAS study (COVID-19 infection, N = 80,932; COVID-19 severity, N = 72,733). We found that the genetic susceptibility of COVID-19 was not significantly associated with changes in brain structures, including cortical and subcortical brain structure. Similar results were observed for different (1) MR estimates, (2) COVID-19 GWAS summary statistics, and (3) definitions of COVID-19 infection and severity. This study suggests that the genetic susceptibility of COVID-19 is not causally associated with changes in cortical and subcortical brain structure.

Childhood trauma moderates schizotypy-related brain morphology: analyses of 1182 healthy individuals from the ENIGMA schizotypy working group.

Schizotypy represents an index of psychosis-proneness in the general population, often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy. We addressed this question using data from a total of 1182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical gray matter volume and cortical thickness were determined. A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of morphological changes directly associated with increasing levels of schizotypy or increasing levels of childhood trauma exposure. These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Unravelling the liver-brain connection: A two-sample Mendelian randomization study investigating the causal relationship between NAFLD and cortical structure

BackgroundNon-alcoholic fatty liver disease (NAFLD) has been linked to cognitive decline and neuropsychiatric conditions, implying a potential connection between NAFLD and brain health. However, the causal association between NAFLD and cortical changes remains uncertain. This study aimed to examine the causal impact of NAFLD on cortical structures using a two-sample Mendelian randomization (MR) approach. MethodsSummary data from genome-wide association studies (GWAS) for NAFLD were gathered from large-scale cohorts. Surface area (SA) and cortical thickness (TH) measurements were derived from Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium magnetic resonance imaging (MRI) data of 33,992 participants. Inverse-variance weighted (IVW) served as the primary method. Additional sensitivity analyses, including MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, and weighted median procedures, were conducted to detect heterogeneity and pleiotropy. ResultsOur MR analysis revealed that NAFLD led to notable alterations in cortical structures, particularly in the pars orbitalis gyrus. Specifically, genetically predicted NAFLD was linked to a decrease in TH (β = -0.008 mm, 95 % CI: −0.013 mm to −0.004 mm, P = 3.00 × 10−4) within this region. No significant heterogeneity and pleiotropy were identified. ConclusionThe two-sample MR study supports the existence of a liver-brain axis by demonstrating a causal association between NAFLD and changes in cortical structures. These findings emphasize the potential association between NAFLD and brain health, which could have implications for preventing and treating cognitive deficits and neuropsychiatric conditions in patients with NAFLD.

Intrusive Traumatic Re-Experiencing Domain: Functional Connectivity Feature Classification by the ENIGMA PTSD Consortium

BackgroundIntrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. MethodsData were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium (n= 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)–only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. A random forest classification model was built on a training set using cross-validation, and the averaged cross-validation model performance for classification was evaluated using the area under the curve. The model was tested using a fully independent portion of the data (test dataset), and the test area under the curve was evaluated. ResultsrsFC signatures differentiated TE-only participants from PTSD and ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and ITRED-only participants mainly involved default mode network–related pathways. Some unique features, such as connectivity within the frontoparietal network, differentiated TE-only participants from one group (PTSD or ITRED-only) but to a lesser extent from the other group. ConclusionsNeural network connectivity supports ITRED as a novel neurobiologically based approach to classifying posttrauma psychopathology.

Genetic Insights into Obesity and Brain: Combine Mendelian Randomization Study and Gene Expression Analysis.

As a major public-health concern, obesity is imposing an increasing social burden around the world. The link between obesity and brain-health problems has been reported, but controversy remains. To investigate the relationship among obesity, brain-structure changes and diseases, a two-stage analysis was performed. At first, we used the Mendelian-randomization (MR) approach to identify the causal relationship between obesity and cerebral structure. Obesity-related data were retrieved from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and the UK Biobank, whereas the cortical morphological data were from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. Further, we extracted region-specific expressed genes according to the Allen Human Brian Atlas (AHBA) and carried out a series of bioinformatics analyses to find the potential mechanism of obesity and diseases. In the univariable MR, a higher body mass index (BMI) or larger visceral adipose tissue (VAT) was associated with a smaller global cortical thickness (pBMI = 0.006, pVAT = 1.34 × 10-4). Regional associations were found between obesity and specific gyrus regions, mainly in the fusiform gyrus and inferior parietal gyrus. Multivariable MR results showed that a greater body fat percentage was linked to a smaller fusiform-gyrus thickness (p = 0.029) and precuneus surface area (p = 0.035). As for the gene analysis, region-related genes were enriched to several neurobiological processes, such as compound transport, neuropeptide-signaling pathway, and neuroactive ligand-receptor interaction. These genes contained a strong relationship with some neuropsychiatric diseases, such as Alzheimer's disease, epilepsy, and other disorders. Our results reveal a causal relationship between obesity and brain abnormalities and suggest a pathway from obesity to brain-structure abnormalities to neuropsychiatric diseases.

Lack of structural brain alterations associated with insomnia: findings from the ENIGMA-Sleep Working Group.

Existing neuroimaging studies have reported divergent structural alterations in insomnia disorder (ID). In the present study, we performed a large-scale coordinated meta-analysis by pooling structural brain measures from 1085 subjects (mean [SD] age 50.5[13.9]years, 50.2% female, 17.4% with insomnia) across three international Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA)-Sleep cohorts. Two sites recruited patients with ID/controls: Freiburg (University of Freiburg Medical Center, Freiburg, Germany) 42/43 and KUMS (Kermanshah University of Medical Sciences, Kermanshah, Iran) 42/49, while the Study of Health in Pomerania (SHIP-Trend,University MedicineGreifswald,Greifswald,Germany) recruited population-based individuals with/without insomnia symptoms 75/662. The influence of insomnia on magnetic resonance imaging-based brain morphometry using an insomnia brain score was then assessed. Within each cohort, we used an ordinary least-squares linear regression to investigate the link between the individual regional cortical and subcortical volumes and the presence of insomnia symptoms. Then, we performed a fixed-effects meta-analysis across cohorts based on the first-level results. For the insomnia brain score, weighted logistic ridge regression was performed on one sample (Freiburg), which separated patients with ID from controls to train a model based on the segmentation measurements. Afterward, the insomnia brain scores were validated using the other two samples. The model was used to predict the log-odds of the subjects with insomnia given individual insomnia-related brain atrophy. After adjusting for multiple comparisons, we did not detect any significant associations between insomnia symptoms and cortical or subcortical volumes, nor could we identify a global insomnia-related brain atrophy pattern. Thus, we observed inconsistent brain morphology differences between individuals with and without insomnia across three independent cohorts. Further large-scale cross-sectional/longitudinal studies using both structural and functional neuroimaging are warranted to decipher the neurobiology of insomnia.

Concurrent validity and reliability of suicide risk assessment instruments: A meta-analysis of 20 instruments across 27 international cohorts.

A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior. We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments. Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Network Centrality and Modularity of Structural Covariance Networks in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study.

Introduction: Cortical thickness (CT) and surface area (SA) are established biomarkers of brain pathology in posttraumatic stress disorder (PTSD). Structural covariance networks (SCNs) are represented as graphs with brain regions as nodes and correlations between nodes as edges. Methods: We built SCNs for PTSD and control groups using 148 CT and SA measures that were harmonized for site in n = 3439 subjects from Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA)-Psychiatric Genomics Consortium (PGC) PTSD. We compared centrality between PTSD and controls as well as interactions of diagnostic group with age, sex, and comorbid major depressive disorder (MDD) status. We investigated associations between network modularity and diagnostic grouping. Results: Nodes with higher CT-based centrality in PTSD compared with controls included the left inferior frontal sulcus, left fusiform gyrus, left superior temporal gyrus, and right inferior temporal gyrus. Children (<10 years) and adolescents (10-21) with PTSD showed greater centrality in frontotemporal areas compared with young (22-39) and middle-aged adults (40-59) with PTSD, who showed higher centrality in occipital areas. The PTSD diagnostic group interactions with sex and comorbid MDD showed altered centrality in occipital regions, along with greater visual network (VN) modularity in PTSD subjects compared with controls. Conclusion: Structural covariance in PTSD is associated with centrality differences in occipital areas and VN modularity differences in a large well-powered sample. In the context of extensive structural covariance remodeling taking place before and during adolescence, the present findings suggest a process of cortical remodeling that commences with trauma and/or the onset of PTSD but may also predate these events. Impact statement Centrality is a graph theory measure that offers insights into a node's relationship with all other nodes in the brain. Centrality pinpoints the drivers of brain communication within networks and nodes and may be a promising target for treatments such as neuromodulation. Modularity can pinpoint modules that exist within larger networks and quantify the connections between these modules. Centrality and modularity complement functional and structural connectivity measurements within specific brain networks.

Large-Scale Analysis of Brain Morphometry in Anorexia Nervosa

In the current issue of Biological Psychiatry, Walton et al. (1) report outcomes of a large-scale investigation into the brain morphometry of anorexia nervosa (AN). The study is a result of a collaboration across 22 global sites that have been brought together under the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium (2). ENIGMA began in 2009 and now comprises more than 50 groups working to pool data in neuroscience, psychiatry, neurology, and genetics to address questions concerning brain structure and function in health and disease.

Schizophrenia Polygenic Risk During Typical Development Reflects Multiscale Cortical Organization

BackgroundSchizophrenia is widely recognized as a neurodevelopmental disorder. Abnormal cortical development in otherwise typically developing children and adolescents may be revealed using polygenic risk scores for schizophrenia (PRS-SCZ). MethodsWe assessed PRS-SCZ and cortical morphometry in typically developing children and adolescents (3–21 years, 46.8% female) using whole-genome genotyping and T1-weighted magnetic resonance imaging (n = 390) from the PING (Pediatric Imaging, Neurocognition, and Genetics) cohort. We contextualized the findings using 1) age-matched transcriptomics, 2) histologically defined cytoarchitectural types and functionally defined networks, and 3) case-control differences of schizophrenia and other major psychiatric disorders derived from meta-analytic data of 6 ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) working groups, including a total of 12,876 patients and 15,670 control participants. ResultsHigher PRS-SCZ was associated with greater cortical thickness, which was most prominent in areas with heightened gene expression of dendrites and synapses. PRS-SCZ–related increases in vertexwise cortical thickness were mainly distributed in association cortical areas, particularly the ventral attention network, while relatively sparing koniocortical type cortex (i.e., primary sensory areas). The large-scale pattern of cortical thickness increases related to PRS-SCZ mirrored the pattern of cortical thinning in schizophrenia and mood-related psychiatric disorders derived from the ENIGMA consortium. Age group models illustrate a possible trajectory from PRS-SCZ–associated cortical thickness increases in early childhood toward thinning in late adolescence, with the latter resembling the adult brain phenotype of schizophrenia. ConclusionsCollectively, combining imaging genetics with multiscale mapping, our work provides novel insight into how genetic risk for schizophrenia affects the cortex early in life.

Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa: A Coordinated Analysis by the ENIGMA Eating Disorders Working Group

BackgroundThe pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. MethodsWe analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). ResultsIn AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen’s d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. ConclusionsThe effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.

Feasibility of FreeSurfer Processing for T1-Weighted Brain Images of 5-Year-Olds: Semiautomated Protocol of FinnBrain Neuroimaging Lab.

Pediatric neuroimaging is a quickly developing field that still faces important methodological challenges. Pediatric images usually have more motion artifact than adult images. The artifact can cause visible errors in brain segmentation, and one way to address it is to manually edit the segmented images. Variability in editing and quality control protocols may complicate comparisons between studies. In this article, we describe in detail the semiautomated segmentation and quality control protocol of structural brain images that was used in FinnBrain Birth Cohort Study and relies on the well-established FreeSurfer v6.0 and ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium tools. The participants were typically developing 5-year-olds [n = 134, 5.34 (SD 0.06) years, 62 girls]. Following a dichotomous quality rating scale for inclusion and exclusion of images, we explored the quality on a region of interest level to exclude all regions with major segmentation errors. The effects of manual edits on cortical thickness values were relatively minor: less than 2% in all regions. Supplementary Material cover registration and additional edit options in FreeSurfer and comparison to the computational anatomy toolbox (CAT12). Overall, we conclude that despite minor imperfections FreeSurfer can be reliably used to segment cortical metrics from T1-weighted images of 5-year-old children with appropriate quality assessment in place. However, custom templates may be needed to optimize the results for the subcortical areas. Through visual assessment on a level of individual regions of interest, our semiautomated segmentation protocol is hopefully helpful for investigators working with similar data sets, and for ensuring high quality pediatric neuroimaging data.

Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age‐related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non‐negative matrix factorization (NMF) is a data‐driven approach that detects covarying patterns (components) within high‐dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self‐reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta‐Analysis) Military Brain Injury working group. Regressions were used to examine TBI‐ and mTBI‐related associations in NMF‐derived components while adjusting for age, sex, post‐traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age‐dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age‐dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.

Brain structural covariance network differences in adults with alcohol dependence and heavy-drinking adolescents.

Graph theoretic analysis of structural covariance networks (SCN) provides an assessment of brain organization that has not yet been applied to alcohol dependence (AD). We estimated whether SCN differences are present in adults with AD and heavy-drinking adolescents at age 19 and age 14, prior to substantial exposure to alcohol. Cross-sectional sample of adults and a cohort of adolescents. Correlation matrices for cortical thicknesses across 68 regions were summarized with graph theoretic metrics. A total of 745 adults with AD and 979 non-dependent controls from 24 sites curated by the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA)-Addiction consortium, and 297 hazardous drinking adolescents and 594 controls at ages 19 and 14 from the IMAGEN study, all from Europe. Metrics of network segregation (modularity, clustering coefficient and local efficiency) and integration (average shortest path length and global efficiency). The younger AD adults had lower network segregation and higher integration relative to non-dependent controls. Compared with controls, the hazardous drinkers at age 19 showed lower modularity [area-under-the-curve (AUC) difference = -0.0142, 95% confidence interval (CI) = -0.1333, 0.0092; P-value = 0.017], clustering coefficient (AUC difference = -0.0164, 95% CI = -0.1456, 0.0043; P-value = 0.008) and local efficiency (AUC difference = -0.0141, 95% CI = -0.0097, 0.0034; P-value = 0.010), as well as lower average shortest path length (AUC difference = -0.0405, 95% CI = -0.0392, 0.0096; P-value = 0.021) and higher global efficiency (AUC difference = 0.0044, 95% CI = -0.0011, 0.0043; P-value = 0.023). The same pattern was present at age 14 with lower clustering coefficient (AUC difference = -0.0131, 95% CI = -0.1304, 0.0033; P-value = 0.024), lower average shortest path length (AUC difference = -0.0362, 95% CI = -0.0334, 0.0118; P-value = 0.019) and higher global efficiency (AUC difference = 0.0035, 95% CI = -0.0011, 0.0038; P-value = 0.048). Cross-sectional analyses indicate that a specific structural covariance network profile is an early marker of alcohol dependence in adults. Similar effects in a cohort of heavy-drinking adolescents, observed at age 19 and prior to substantial alcohol exposure at age 14, suggest that this pattern may be a pre-existing risk factor for problematic drinking.