Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

Deviations from a typical development of the cerebellum in youth are associated with psychopathology, executive functions and educational outcomes.

BACKGROUND: Understanding deviations from typical brain development is a promising approach to comprehend pathophysiology in childhood and adolescence. We investigated if cerebellar volumes different than expected for age and sex could predict psychopathology, executive functions and academic achievement. METHODS: Children and adolescents aged 6-17 years from the Brazilian High-Risk Cohort Study for Mental Conditions had their cerebellar volume estimated using Multiple Automatically Generated Templates from T1-weighted images at baseline (n = 677) and at 3-year follow-up (n = 447). Outcomes were assessed using the Child Behavior Checklist and standardized measures of executive functions and school achievement. Models of typically developing cerebellum were based on a subsample not exposed to risk factors and without mental-health conditions (n = 216). Deviations from this model were constructed for the remaining individuals (n = 461) and standardized variation from age and sex trajectory model was used to predict outcomes in cross-sectional, longitudinal and mediation analyses. RESULTS: Cerebellar volumes higher than expected for age and sex were associated with lower externalizing specific factor and higher executive functions. In a longitudinal analysis, deviations from typical development at baseline predicted inhibitory control at follow-up, and cerebellar deviation changes from baseline to follow-up predicted changes in reading and writing abilities. The association between deviations in cerebellar volume and academic achievement was mediated by inhibitory control. CONCLUSIONS: Deviations in the cerebellar typical development are associated with outcomes in youth that have long-lasting consequences. This study highlights both the potential of typical developing models and the important role of the cerebellum in mental health, cognition and education.

Disentangling the influences of parental genetics on offspring's cognition, education, and psychopathology via genetic and phenotypic pathways.

BACKGROUND: Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth. METHODS: Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers. RESULTS: Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms. CONCLUSIONS: Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Are serum brain-derived neurotrophic factor concentrations related to brain structure and psychopathology in late childhood and early adolescence?

OBJECTIVE: Mental disorders can have a major impact on brain development. Peripheral blood concentrations of brain-derived neurotrophic factor (BDNF) are lower in adult psychiatric disorders. Serum BDNF concentrations and BDNF genotype have been associated with cortical maturation in children and adolescents. In 2 large independent samples, this study tests associations between serum BDNF concentrations, brain structure, and psychopathology, and the effects of BDNF genotype on BDNF serum concentrations in late childhood and early adolescence. METHODS: Children and adolescents (7-14 years old) from 2 cities (n = 267 in Porto Alegre; n = 273 in São Paulo) were evaluated as part of the Brazilian high-risk cohort (HRC) study. Serum BDNF concentrations were quantified by sandwich ELISA. Genotyping was conducted from blood or saliva samples using the SNParray Infinium HumanCore Array BeadChip. Subcortical volumes and cortical thickness were quantified using FreeSurfer. The Development and Well-Being Behavior Assessment was used to identify the presence of a psychiatric disorder. RESULTS: Serum BDNF concentrations were not associated with subcortical volumes or with cortical thickness. Serum BDNF concentration did not differ between participants with and without mental disorders, or between Val homozygotes and Met carriers. CONCLUSIONS: No evidence was found to support serum BDNF concentrations as a useful marker of developmental differences in brain and behavior in early life. Negative findings were replicated in 2 of the largest independent samples investigated to date.

Peripheral levels of superoxide dismutase and glutathione peroxidase in youths in ultra-high risk for psychosis: a pilot study.

IntroductionOxidative stress has been documented in chronic schizophrenia and in the first episode of psychosis, but there are very little data on oxidative stress prior to the disease onset. OBJECTIVE: This work aimed to compare serum levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in young individuals at ultra-high risk (UHR) of developing psychosis with a comparison healthy control group (HC). METHODS: Thirteen UHR subjects and 29 age- and sex-matched healthy controls (HC) were enrolled in this study. Clinical assessment included the Comprehensive Assessment of At-Risk Mental States (CAARMS), the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I) or the Kiddie-SADS-Present and Lifetime Version (K-SADS-PL), and the Global Assessment of Functioning (GAF) scale. Activities of SOD and GPx were measured in serum by the spectrophotometric method using enzyme-linked immunosorbent assay kits. RESULTS: After adjusting for age and years of education, there was a significant lower activity of SOD and lower GPX activity in the UHR group compared to the healthy control group (rate ratio [RR]=0.330, 95% CI 0.187; 0.584, p<0.001 and RR=0.509, 95% CI 0.323; 0.803, p=0.004, respectively). There were also positive correlations between GAF functioning scores and GPx and SOD activities. CONCLUSION: Our results suggest that oxidative imbalances could be present prior to the onset of full-blown psychosis, including in at-risk stages. Future studies should replicate and expand these results.

Association between irritability and bias in attention orienting to threat in children and adolescents.

BACKGROUND: Irritability, a frequent complaint in children with psychiatric disorders, reflects increased predisposition to anger. Preliminary work in pediatric clinical samples links irritability to attention bias to threat, and the current study examines this association in a large population-based sample. METHODS: We studied 1,872 children (ages 6-14) using the Development and Well-Being Assessment (DAWBA), Childhood Behavior Checklist (CBCL), and dot-probe tasks. Irritability was defined using CBCL items that assessed temper tantrums and hot temper. The dot-probe task assessed attention biases for threat-related (angry face) stimuli. Multiple regression analysis was used to assess specificity of associations to irritability when adjusting for demographic variables and co-occurring psychiatric traits. Propensity score matching analysis was used to increase causal inference when matching for demographic variables and co-occurring psychiatric traits. RESULTS: Irritability was associated with increased attention bias toward threat-related cues. Multiple regression analysis suggests associations between irritability and threat bias are independent from demographic variables, anxiety, and externalizing traits (attention-deficit/hyperactivity, conduct, and headstrong/hurtful), but not from broad internalizing symptoms. Propensity score matching analysis indicated that this association was found for irritable versus nonirritable groups matched on demographic and co-occurring traits including internalizing symptoms. CONCLUSIONS: Irritability in children is associated with biased attention toward threatening information. This finding, if replicated, warrants further investigation to examine the extent to which it contributes to chronic irritability and to explore possible treatment implications.

Psychopathology and friendship in children and adolescents: disentangling the role of co-occurring symptom domains with serial mediation models.

The consolidation of social friendship groups is a vital part of human development. The objective of this study is to understand the direct and indirect influences of three major symptomatic domains-emotional, hyperkinetic, and conduct-on friendship. Specifically, we aim to study if the associations of one domain with friendship may be mediated by co-occurring symptoms from another domain. A total of 2512 subjects aged 6-14 years participated in this study. Friendship was evaluated by the Development and Well-Being Assessment's friendship section. We evaluated two main constructs as outcomes: (1) social isolation and (2) friendship latent construct. Emotional, hyperkinetic, and conduct symptomatic domains were evaluated with the Strengths and Difficulties Questionnaire (SDQ). All SDQ domains were positively associated with social isolation and negatively associated with friendship latent construct in univariate analysis. However, serial mediation models showed that the association between conduct domains with social isolation was mediated by emotion and hyperkinetic domains. Moreover, the associations between emotional and hyperkinetic domains with friendship latent construct in non-isolated children were mediated by the conduct domain. Emotion and hyperkinetic domains were directly and indirectly associated with social isolation, whereas conduct was directly and indirectly associated with overall friendship in non-isolated children. Results suggest that interventions aimed to improve social life in childhood and adolescence may have stronger effects if directed towards the treatment of emotion and hyperkinetic symptoms in socially isolated children and directed towards the treatment of conduct symptoms in children with fragile social connections.

Perinatal complications, lipid peroxidation, and mental health problems in a large community pediatric sample.

Replicated evidence indicates that perinatal complications are associated with increased markers of oxidative stress and with mental health problems in children. However, there are fewer reports on the impact of perinatal complications in later phases of development. We aimed to investigate the estimated effects of perinatal complications on levels of lipid peroxidation and on psychopathology in children and adolescents. The study is part of the High Risk Cohort Study for Psychiatric Disorders; the population was composed by 554 students, 6-14 years of age. Serum levels of malondialdehyde, a product of lipid peroxidation, were measured by the TBARS method. A household interview with parents and caregivers was conducted and included inquiries about perinatal history, the Child Behavior Checklist (CBCL), and parent's evaluation, using the Mini International Psychiatric Interview (MINI). We created a cumulative risk index, conceptualized as each individual's cumulative exposure to perinatal complications. Results indicate that perinatal complications were associated with higher levels of TBARS. After adjusting for age, gender, socio-economic status, CBCL total problems score, parental psychopathology, and childhood maltreatment, children exposed to 3 or more perinatal complications had an 26.9% (95% CI 9.9%, 46.6%) increase in TBARS levels, relative to the unexposed group. Exploratory mediation analysis indicated that TBARS levels partially mediated the association between perinatal complications and externalizing problems. In conclusion, an adverse intrauterine and/or early life environment, as proxied by the cumulative exposure to perinatal complications, was independently associated with higher levels of lipid peroxidation in children and adolescents.

Serum copeptin in children exposed to maltreatment.

AIM: Childhood maltreatment (CM) has been related to a persistent reprograming of stress-response. Copeptin is a marker of hypothalamic-pituitary-adrenal axis activation; however, few studies have examined copeptin levels in children exposed to CM. The aim of this study was to compare serum copeptin levels in children reporting child abuse and/or neglect and children with no history of CM. METHODS: This study included 65 children with a positive history of moderate to severe CM, as reported by themselves and their parent(s) during a clinical interview, and 71 children with no history of CM as a comparison group. CM was considered moderate to severe based on the child-reported frequency of being exposed to events related to sexual abuse, physical abuse, emotional abuse, emotional neglect, and/or physical neglect. Child psychopathology symptoms were assessed using the Child Behavior Checklist (CBCL). We measured serum copeptin concentration using enzyme-linked immunosorbent assay. RESULTS: Children exposed to CM exhibited higher levels of serum copeptin compared to children without CM when controlling for sex, age, and psychiatric morbidity. The CBCL total score, including internalizing and externalizing symptoms, was higher in children with CM. We found no correlation between copeptin and CBCL scores for internalizing symptoms and externalizing symptoms. CONCLUSION: CM is associated with copeptin serum levels independently of age, sex, and symptom severity. Copeptin is a promising new biomarker for children with a history of abuse and/or neglect.

Is waiting for rewards good for you? No association between impulsive choice, psychopathology, and functional outcomes in a large cohort sample.

Background: A stronger preference for immediate rewards has been reported in individuals with ADHD and other disorders. However, the consistency of the associations between this preference and psychiatric conditions as well as functional outcomes have been questioned. Research on its association with longitudinal outcomes is scarce. Methods: The current study used data on a choice delay task (CDT) from a school-based cohort of Brazilian children with those at higher risk for psychiatric disorders over-sampled (n = 1917). The sample included typically developing children (n = 1379), those with ADHD (n = 213), and other disorders. The frequency of the trials where children chose a larger later reward versus a smaller sooner reward was compared for those with ADHD and typically developing children. Cross-sectionally and longitudinally, the study also evaluated whether children's preference for larger delayed rewards at baseline predicted the presence of psychiatric disorders and functional life outcomes (academic performance, alcohol use, early pregnancy, criminal conviction, BMI). Results: Children with ADHD and their typically developing peers performed similarly on the CDT. Their baseline task performance was not related to psychiatric conditions or life outcomes. Conclusions: The current results raise questions regarding the use of the CDT with diverse populations and whether a preference for larger delayed rewards is predictive of positive long-term outcomes as widely assumed.

Mental health conditions in Lesbian, Gay, Bisexual, Transgender, Queer and Asexual youth in Brazil: A call for action.

BACKGROUND: Lesbian, Gay, Bisexual, Transgender, Queer, and Asexual (LGBTQA+) youth have a greater chance of experiencing stressful life events when compared to cisgender heterosexual peers, which can lead to mental health problems. We aimed to estimate the prevalence of mental disorders among LGBTQA+ youths from two large cities in Brazil. METHODS: Participants were 13-22 years old youths from the 3rd wave of the Brazilian High-Risk Cohort for Psychiatric Disorders (n = 1475). Mental disorders were assessed using the Development and Well-Being Behavior Assessment. Sexual orientation and gender identity were assessed using a self-report confidential questionnaire. Data were analyzed through logistic regressions (adjusting for sociodemographic) using sampling weights to account for attrition and our oversampling high-risk design. RESULTS: 15.18% of the sample described themselves as LGBTQA+. The LGBTQA+ group presented higher rates of anxiety disorders (30.14% vs. 13.37%; OR = 3.37; 95%CI:2.51-4.50), depressive disorders (27.75% vs. 15.34%; OR = 2.17; 95%CI:1.60-2.93) and post-traumatic stress disorder (4.98% vs. 2.25%; OR = 4.20; 95%CI:2.24-7.82), if compared with the cisgender heterosexual group. No difference was found for conduct disorders (2.97% vs. 5.21%; OR = 0.82; 95%CI:0.35-1.65) or attention deficit hyperactivity disorder (5.92% vs. 3.28%; OR = 1.56; 95%CI:0.83-2.79). LIMITATIONS: Although recruitment was performed at 57 schools in the two cities, sampling was non-probabilistic and included only urban areas, which might bias prevalence estimates and group comparisons. CONCLUSIONS: Our results elucidate the mental health disparities between LGBTQA+ people and cisgender heterosexuals in Brazil. It highlights the need to promote the inclusion of this population in policy formulation and support actions to mitigate the suffering related to sexual orientation and gender identity.

Mental health interventions following COVID-19 and other coronavirus infections: a systematic review of current recommendations and meta-analysis of randomized controlled trials.

OBJECTIVE: To review the most common mental health strategies aimed at alleviating and/or preventing mental health problems in individuals during the coronavirus disease 2019 (COVID-19) and other coronavirus pandemics. METHODS: We conducted a systematic review of the literature assessing three databases (PubMed, SCOPUS, and PsycINFO). A meta-analysis was performed with data from randomized controlled trials (RCTs). For non-RCT studies, a critical description of recommendations was performed. RESULTS: From a total of 2,825 articles, 125 were included. Of those, three RCTs were included in the meta-analysis. The meta-analysis revealed that the interventions promoted better overall mental health outcomes as compared to control groups (standardized mean difference [SMD] = 0.87 [95%CI 0.33-1.41], p < 0.001, I2 = 69.2%), but did not specifically improve anxiety (SMD = 0.98 [95%CI -0.17 to 2.13], p > 0.05; I2 = 36.8%). Concerning the systematic review, we found a large body of scientific literature proposing recommendations involving psychological/psychiatric interventions, self-care, education, governmental programs, and the use of technology and media. CONCLUSIONS: We found a large body of expert recommendations that may help health practitioners, institutional and governmental leaders, and the general population cope with mental health issues during a pandemic or a crisis period. However, most articles had a low level of evidence, stressing the need for more studies with better design (especially RCTs) investigating potential mental health interventions during COVID-19. PROSPERO REGISTRATION: CRD42020190212.

Neuroimaging Studies of Nonsuicidal Self-Injury in Youth: A Systematic Review.

Nonsuicidal self-injury (NSSI) is prevalent and affects mainly the youth population. It is prospectively associated with suicide attempts, making it a target for suicide prevention. Recently, several studies have investigated neural pathways of NSSI using neuroimaging. However, there is a lack of systematized appraisal of these findings. This systematic review aims to identify and summarize the main neuroimaging findings of NSSI in youth. We followed PRISMA statement guidelines and searched MEDLINE, APA PsycInfo, and Google Scholar databases for neuroimaging studies, irrespective of imaging modality, specifically investigating NSSI in samples with a mean age of up to 25 years old. Quality assessment was made using the Newcastle-Ottawa and Joanna Briggs Institute scales. The initial search retrieved 3030 articles; 21 met inclusion criteria, with a total of 938 subjects. Eighteen studies employed functional neuroimaging techniques such as resting-state and task-based fMRI (emotional, interpersonal exposure/social exclusion, pain, reward, and cognitive processing paradigms). Three studies reported on structural MRI. An association of NSSI behavior and altered emotional processing in cortico-limbic neurocircuitry was commonly reported. Additionally, alterations in potential circuits involving pain, reward, interpersonal, self-processing, and executive function control processes were identified. NSSI has complex and diverse neural underpinnings. Future longitudinal studies are needed to understand its developmental aspects better.

Predictors of gaming disorder in children and adolescents: a school-based study.

OBJECTIVE: To determine whether psychiatric and gaming pattern variables are associated with gaming disorder in a school-based sample. METHODS: We analyzed data from the Brazilian High-Risk Cohort for Psychiatric Disorders, a community sample aged 10 to 18, using questionnaires on gaming use patterns. We applied the Gaming Addiction Scale to diagnose gaming disorder and the Development and Well-Being Behavior Assessment for other diagnoses. RESULTS: Out of 407 subjects, 83 (20.4%) fulfilled the criteria for gaming disorder. More role-playing game players were diagnosed with gaming disorder that any other genre. Gaming disorder rates increased proportionally to the number of genres played. Playing online, being diagnosed with a mental disorder, and more hours of non-stop gaming were associated with higher rates of gaming disorder. When all variables (including age and gender) were considered in a logistic regression model, the number of genres played, the number of non-stop hours, the proportion of online games, and having a diagnosed mental disorder emerged as significant predictors of gaming disorder. CONCLUSION: Each variable seems to add further risk of gaming disorder among children and adolescents. Monitoring the length of gaming sessions, the number and type of genres played, time spent gaming online, and behavior changes may help parents or guardians identify unhealthy patterns of gaming behavior.

Polyenvironmental and polygenic risk scores and the emergence of psychotic experiences in adolescents.

Psychotic experiences (PE) are forms of hallucinations and delusions neither reaching the intensity and functional impairment required to be regarded as full psychotic symptoms nor a psychotic disorder. Here we investigated the ability to predict PE using multiple models (regressions, mediation and moderation) using polygenic risk score for psychotic experiences (PE-PRS), polygenic risk score for schizophrenia (SCZ-PRS), and polyenvironmental risk score (PERS) in youth from a Brazilian sample. The scores were not able to predict outcome, either when both scores were combined (PERS + PE-PRS and PERS + SCZ-PRS) or separately. Our results show that there is no association between PE and PRS or PERS among adolescents in our Brazilian sample. The lack of association may be a result of the absence of better representativeness regarding genetic and environmental factors of our population.

Obsessive-Compulsive Symptoms, Polygenic Risk Score, and Thalamic Development in Children From the Brazilian High-Risk Cohort for Mental Conditions (BHRCS).

Background: Thalamic volume measures have been linked to obsessive-compulsive disorder (OCD) in children and adolescents. However, it is unclear if alterations in thalamic volumes occur before or after symptom onset and if there is a relation to the presence of sub-clinical obsessive-compulsive symptoms (OCS). Here, we explore the relationship between OCS and the rate of thalamic volume change in a cohort of children and youth at high risk to develop a mental disorder. A secondary aim was to determine if there is a relationship between OCS and the individual's OCD polygenic risk score (OCD-PRS) and between the rate of thalamic volume change and the OCD-PRS. Methods: The sample included 378 children enrolled in the longitudinal Brazilian High-Risk Cohort for Mental Conditions. Participants were assessed for OCS and the symmetrized percent change (SPC) of thalamic volume across two time-points separated by 3 years, along with the OCD-PRS. Zero-altered negative binomial models were used to analyze the relationship between OCS and thalamic SPC. Multiple linear regressions were used to examine the relationship between thalamic SPC and OCD-PRS. Results: A significant relationship between OCS and the right thalamus SPC (p = 0.042) was found. There was no significant relationship between changes in thalamic volume SPC and OCD-PRS. Conclusions: The findings suggest that changes in the right thalamic volume over the course of 3 years in children may be associated to OCS. Future studies are needed to confirm these results and further characterize the specific nature of OCS symptoms associated with thalamic volumes.

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

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.

Assessment of Neurobiological Mechanisms of Cortical Thinning During Childhood and Adolescence and Their Implications for Psychiatric Disorders.

Importance: Many psychiatric disorders can be conceptualized as disorders of brain maturation during childhood and adolescence. Discovering the neurobiological underpinnings of brain maturation may elucidate molecular pathways of vulnerability and resilience to such disorders. Objective: To investigate the underlying neurobiological mechanisms of age-associated cortical thinning during maturation and their implications for psychiatric disorders. Design, Setting, and Participants: This multicohort analysis used data from 3 community-based studies. The Saguenay Youth Study provided data from 1024 adolescents who were recruited at a single site in Quebec, Canada. The IMAGEN cohort provided data from 1823 participants who were recruited in 8 European cities. The Brazil High Risk Cohort Study for the Development of Childhood Psychiatric Disorders provided data from 815 participants who were recruited in 2 Brazilian cities. Cortical thickness was estimated from the results of magnetic resonance imaging (MRI) scans, and age-associated cortical thinning was estimated in 34 cortical regions. Gene expression from the Allen Human Brain Atlas was aligned with the same regions. Similarities in the interregional profiles of gene expression and the profiles of age-associated cortical thinning were measured. The involvement of dendrites, dendritic spines, and myelin was tested using 3 gene panels. Enrichment for genes associated with psychiatric disorders was tested among the genes associated with thinning and their coexpression networks. Data analysis was conducted between March and October 2019. Main Outcomes and Measures: MRI-derived estimates of age-associated cortical thinning and gene expression in 34 cortical regions. Results: A total of 3596 individuals aged 9 to 21 years were included in this study. Of those, 1803 participants (50.1%) were female, and the mean (SD) age was 15.2 (2.6) years. Interregional profiles of age-associated cortical thinning were associated with interregional gradients in the expression of genes associated with dendrites, dendritic spines, and myelin; the variance in thinning explained by the gene panels across different points ranged from 0.45% to 10.55% for the dendrite panel, 0.00% to 9.98% for the spine panel, and 0.19% to 26.39% for the myelin panel. These genes and their coexpression networks were enriched for genes associated with several psychiatric disorders. Conclusions and Relevance: In this study, genetic similarity between interregional variation in cortical thinning during maturation and multiple psychiatric disorders suggests overlapping molecular underpinnings. This finding adds to the understanding of the neurodevelopmental mechanisms of psychiatric disorders.