Hemispheric asymmetry in cortical thinning reflects intrinsic organization of the neurotransmitter systems and homotopic functional connectivity.

Hemispheric lateralization and its origins have been of great interest in neuroscience for over a century. The left-right asymmetry in cortical thickness may stem from differential maturation of the cerebral cortex in the two hemispheres. Here, we investigated the spatial pattern of hemispheric differences in cortical thinning during adolescence, and its relationship with the density of neurotransmitter receptors and homotopic functional connectivity. Using longitudinal data from IMAGEN study (N = 532), we found that many cortical regions in the frontal and temporal lobes thinned more in the right hemisphere than in the left. Conversely, several regions in the occipital and parietal lobes thinned less in the right (vs. left) hemisphere. We then revealed that regions thinning more in the right (vs. left) hemispheres had higher density of neurotransmitter receptors and transporters in the right (vs. left) side. Moreover, the hemispheric differences in cortical thinning were predicted by homotopic functional connectivity. Specifically, regions with stronger homotopic functional connectivity showed a more symmetrical rate of cortical thinning between the left and right hemispheres, compared with regions with weaker homotopic functional connectivity. Based on these findings, we suggest that the typical patterns of hemispheric differences in cortical thinning may reflect the intrinsic organization of the neurotransmitter systems and related patterns of homotopic functional connectivity.

Coupled changes between ruminating thoughts and resting-state brain networks during the transition into adulthood.

Perseverative negative thoughts, known as rumination, might arise from emotional challenges and preclude mental health when transitioning into adulthood. Due to its multifaceted nature, rumination can take several ruminative response styles, that diverge in manifestations, severity, and mental health outcomes. Still, prospective ruminative phenotypes remain elusive insofar. Longitudinal study designs are ideal for stratifying ruminative response styles, especially with resting-state functional MRI whose setup naturally elicits people's ruminative traits. Here, we considered self-rated questionnaires on rumination and psychopathology, along with resting-state functional MRI data in 595 individuals assessed at age 18 and 22 from the IMAGEN cohort. We conducted independent component analysis to characterize eight single static resting-state functional networks in each subject and session and furthermore conducted a dynamic analysis, tackling the time variations of functional networks during the entire scanning time. We then investigated their longitudinal mediation role between changes in three ruminative response styles (reflective pondering, brooding, and depressive rumination) and changes in internalizing and co-morbid externalizing symptoms. Four static and two dynamic networks longitudinally differentiated these ruminative styles and showed complemental sensitivity to internalizing and co-morbid externalizing symptoms. Among these networks, the right frontoparietal network covaried with all ruminative styles but did not play any mediation role towards psychopathology. The default mode, the salience, and the limbic networks prospectively stratified these ruminative styles, suggesting that maladaptive ruminative styles are associated with altered corticolimbic function. For static measures, only the salience network played a longitudinal causal role between brooding rumination and internalizing symptoms. Dynamic measures highlighted the default-mode mediation role between the other ruminative styles and co-morbid externalizing symptoms. In conclusion, we identified the ruminative styles' psychometric and neural outcome specificities, supporting their translation into applied research on young adult mental healthcare.

Adolescent to young adult longitudinal development of subcortical volumes in two European sites with four waves.

Adolescent subcortical structural brain development might underlie psychopathological symptoms, which often emerge in adolescence. At the same time, sex differences exist in psychopathology, which might be mirrored in underlying sex differences in structural development. However, previous studies showed inconsistencies in subcortical trajectories and potential sex differences. Therefore, we aimed to investigate the subcortical structural trajectories and their sex differences across adolescence using for the first time a single cohort design, the same quality control procedure, software, and a general additive mixed modeling approach. We investigated two large European sites from ages 14 to 24 with 503 participants and 1408 total scans from France and Germany as part of the IMAGEN project including four waves of data acquisition. We found significantly larger volumes in males versus females in both sites and across all seven subcortical regions. Sex differences in age-related trajectories were observed across all regions in both sites. Our findings provide further evidence of sex differences in longitudinal adolescent brain development of subcortical regions and thus might eventually support the relationship of underlying brain development and different adolescent psychopathology in boys and girls.

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

BACKGROUND: Alzheimer'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 increasing brain atrophy, respectively. METHODS: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. RESULTS: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. CONCLUSIONS: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play.

Trans-ancestry meta-analysis of genome wide association studies of inhibitory control.

Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries (N = 14,877) using cognitive traits derived from the stop-signal task, namely - go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger sample sizes are necessary to robustly identify associations. In Europeans, the polygenic risk for ADHD was significantly associated with GoRT SD and the polygenic risk for schizophrenia was associated with GoRT, while in East Asians polygenic risk for schizophrenia was associated with SSRT. These results support the potential of executive function measures as endophenotypes of neuropsychiatric disorders. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.

Anxiety onset in adolescents: a machine-learning prediction.

Recent longitudinal studies in youth have reported MRI correlates of prospective anxiety symptoms during adolescence, a vulnerable period for the onset of anxiety disorders. However, their predictive value has not been established. Individual prediction through machine-learning algorithms might help bridge the gap to clinical relevance. A voting classifier with Random Forest, Support Vector Machine and Logistic Regression algorithms was used to evaluate the predictive pertinence of gray matter volumes of interest and psychometric scores in the detection of prospective clinical anxiety. Participants with clinical anxiety at age 18-23 (N = 156) were investigated at age 14 along with healthy controls (N = 424). Shapley values were extracted for in-depth interpretation of feature importance. Prospective prediction of pooled anxiety disorders relied mostly on psychometric features and achieved moderate performance (area under the receiver operating curve = 0.68), while generalized anxiety disorder (GAD) prediction achieved similar performance. MRI regional volumes did not improve the prediction performance of prospective pooled anxiety disorders with respect to psychometric features alone, but they improved the prediction performance of GAD, with the caudate and pallidum volumes being among the most contributing features. To conclude, in non-anxious 14 year old adolescents, future clinical anxiety onset 4-8 years later could be individually predicted. Psychometric features such as neuroticism, hopelessness and emotional symptoms were the main contributors to pooled anxiety disorders prediction. Neuroanatomical data, such as caudate and pallidum volume, proved valuable for GAD and should be included in prospective clinical anxiety prediction in adolescents.

Arc controls alcohol cue relapse by a central amygdala mechanism.

Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of the AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (Arc)/ARG3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol cue exposure may thus be a selective new mechanism for relapse prevention.

Differential associations of adolescent versus young adult cannabis initiation with longitudinal brain change and behavior.

Leveraging ~10 years of prospective longitudinal data on 704 participants, we examined the effects of adolescent versus young adult cannabis initiation on MRI-assessed cortical thickness development and behavior. Data were obtained from the IMAGEN study conducted across eight European sites. We identified IMAGEN participants who reported being cannabis-naïve at baseline and had data available at baseline, 5-year, and 9-year follow-up visits. Cannabis use was assessed with the European School Survey Project on Alcohol and Drugs. T1-weighted MR images were processed through the CIVET pipeline. Cannabis initiation occurring during adolescence (14-19 years) and young adulthood (19-22 years) was associated with differing patterns of longitudinal cortical thickness change. Associations between adolescent cannabis initiation and cortical thickness change were observed primarily in dorso- and ventrolateral portions of the prefrontal cortex. In contrast, cannabis initiation occurring between 19 and 22 years of age was associated with thickness change in temporal and cortical midline areas. Follow-up analysis revealed that longitudinal brain change related to adolescent initiation persisted into young adulthood and partially mediated the association between adolescent cannabis use and past-month cocaine, ecstasy, and cannabis use at age 22. Extent of cannabis initiation during young adulthood (from 19 to 22 years) had an indirect effect on psychotic symptoms at age 22 through thickness change in temporal areas. Results suggest that developmental timing of cannabis exposure may have a marked effect on neuroanatomical correlates of cannabis use as well as associated behavioral sequelae. Critically, this work provides a foundation for neurodevelopmentally informed models of cannabis exposure in humans.

Cortical profiles of numerous psychiatric disorders and normal development share a common pattern.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Covariation of preadult environmental exposures, adult brain imaging phenotypes, and adult personality traits.

Exposure to preadult environmental exposures may have long-lasting effects on mental health by affecting the maturation of the brain and personality, two traits that interact throughout the developmental process. However, environment-brain-personality covariation patterns and their mediation relationships remain unclear. In 4297 healthy participants (aged 18-30 years), we combined sparse multiple canonical correlation analysis with independent component analysis to identify the three-way covariation patterns of 59 preadult environmental exposures, 760 adult brain imaging phenotypes, and five personality traits, and found two robust environment-brain-personality covariation models with sex specificity. One model linked greater stress and less support to weaker functional connectivity and activity in the default mode network, stronger activity in subcortical nuclei, greater thickness and volume in the occipital, parietal and temporal cortices, and lower agreeableness, consciousness and extraversion as well as higher neuroticism. The other model linked higher urbanicity and better socioeconomic status to stronger functional connectivity and activity in the sensorimotor network, smaller volume and surface area and weaker functional connectivity and activity in the medial prefrontal cortex, lower white matter integrity, and higher openness to experience. We also conducted mediation analyses to explore the potential bidirectional mediation relationships between adult brain imaging phenotypes and personality traits with the influence of preadult environmental exposures and found both environment-brain-personality and environment-personality-brain pathways. We finally performed moderated mediation analyses to test the potential interactions between macro- and microenvironmental exposures and found that one category of exposure moderated the mediation pathways of another category of exposure. These results improve our understanding of the effects of preadult environmental exposures on the adult brain and personality traits and may facilitate the design of targeted interventions to improve mental health by reducing the impact of adverse environmental exposures.

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation.

BACKGROUND: It has not yet been determined if the commonly reported cannabis-psychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders. METHODS: We examined whether the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 1740 of the individuals of the European IMAGEN cohort. Secondary analysis examined the relationships between lifetime cannabis use, PRS-Sz and the various sub-scales of the CAPE-42. Sensitivity analyses including covariates, including a PRS for cannabis use, were conducted and results were replicated using data from 1223 individuals in the Dutch Utrecht cannabis cohort. RESULTS: PRS-Sz significantly predicted cannabis use (p = 0.027) and PLE (p = 0.004) in the IMAGEN cohort. In the full model, considering PRS-Sz and covariates, cannabis use was also significantly associated with PLE in IMAGEN (p = 0.007). Results remained consistent in the Utrecht cohort and through sensitivity analyses. Nevertheless, there was no evidence of a mediation or moderation effects. CONCLUSIONS: These results suggest that cannabis use remains a risk factor for PLEs, over and above genetic vulnerability for schizophrenia. This research does not support the notion that the cannabis-psychosis link is limited to individuals who are genetically predisposed to psychosis and suggests a need for research focusing on cannabis-related processes in psychosis that cannot be explained by genetic vulnerability.

A causal association of ANKRD37 with human hippocampal volume.

Human hippocampal volume has been separately associated with single nucleotide polymorphisms (SNPs), DNA methylation and gene expression, but their causal relationships remain largely unknown. Here, we aimed at identifying the causal relationships of SNPs, DNA methylation, and gene expression that are associated with hippocampal volume by integrating cross-omics analyses with genome editing, overexpression and causality inference. Based on structural neuroimaging data and blood-derived genome, transcriptome and methylome data, we prioritized a possibly causal association across multiple molecular phenotypes: rs1053218 mutation leads to cg26741686 hypermethylation, thus leads to overactivation of the associated ANKRD37 gene expression in blood, a gene involving hypoxia, which may result in the reduction of human hippocampal volume. The possibly causal relationships from rs1053218 to cg26741686 methylation to ANKRD37 expression obtained from peripheral blood were replicated in human hippocampal tissue. To confirm causality, we performed CRISPR-based genome and epigenome-editing of rs1053218 homologous alleles and cg26741686 methylation in mouse neural stem cell differentiation models, and overexpressed ANKRD37 in mouse hippocampus. These in-vitro and in-vivo experiments confirmed that rs1053218 mutation caused cg26741686 hypermethylation and ANKRD37 overexpression, and cg26741686 hypermethylation favored ANKRD37 overexpression, and ANKRD37 overexpression reduced hippocampal volume. The pairwise relationships of rs1053218 with hippocampal volume, rs1053218 with cg26741686 methylation, cg26741686 methylation with ANKRD37 expression, and ANKRD37 expression with hippocampal volume could be replicated in an independent healthy young (n = 443) dataset and observed in elderly people (n = 194), and were more significant in patients with late-onset Alzheimer's disease (n = 76). This study revealed a novel causal molecular association mechanism of ANKRD37 with human hippocampal volume, which may facilitate the design of prevention and treatment strategies for hippocampal impairment.

Trajectories of cortical structures associated with stress across adolescence: a bivariate latent change score approach.

BACKGROUND: Stress exposure in childhood and adolescence has been linked to reductions in cortical structures and cognitive functioning. However, to date, most of these studies have been cross-sectional, limiting the ability to make long-term inferences, given that most cortical structures continue to develop through adolescence. METHODS: Here, we used a subset of the IMAGEN population cohort sample (N = 502; assessment ages: 14, 19, and 22 years; mean age: 21.945 years; SD = 0.610) to understand longitudinally the long-term interrelations between stress, cortical development, and cognitive functioning. To these ends, we first used a latent change score model to examine four bivariate relations - assessing individual differences in change in the relations between adolescent stress exposure and volume, surface area, and cortical thickness of cortical structures, as well as cognitive outcomes. Second, we probed for indirect neurocognitive effects linking stress to cortical brain structures and cognitive functions using rich longitudinal mediation modeling. RESULTS: Latent change score modeling showed that greater baseline adolescence stress at age 14 predicted a small reduction in the right anterior cingulate volume (Std. ß = -.327, p = .042, 95% CI [-0.643, -0.012]) and right anterior cingulate surface area (Std. ß = -.274, p = .038, 95% CI [-0.533, -0.015]) across ages 14-22. These effects were very modest in nature and became nonsignificant after correcting for multiple comparisons. Our longitudinal analyses found no evidence of indirect effects in the two neurocognitive pathways linking adolescent stress to brain and cognitive outcomes. CONCLUSION: Findings shed light on the impact of stress on brain reductions, particularly in the prefrontal cortex that have consistently been implicated in the previous cross-sectional studies. However, the magnitude of effects observed in our study is smaller than that has been reported in past cross-sectional work. This suggests that the potential impact of stress during adolescence on brain structures may likely be more modest than previously noted.

Cognitive and brain development is independently influenced by socioeconomic status and polygenic scores for educational attainment.

Genetic factors and socioeconomic status (SES) inequalities play a large role in educational attainment, and both have been associated with variations in brain structure and cognition. However, genetics and SES are correlated, and no prior study has assessed their neural associations independently. Here we used a polygenic score for educational attainment (EduYears-PGS), as well as SES, in a longitudinal study of 551 adolescents to tease apart genetic and environmental associations with brain development and cognition. Subjects received a structural MRI scan at ages 14 and 19. At both time points, they performed three working memory (WM) tasks. SES and EduYears-PGS were correlated (r = 0.27) and had both common and independent associations with brain structure and cognition. Specifically, lower SES was related to less total cortical surface area and lower WM. EduYears-PGS was also related to total cortical surface area, but in addition had a regional association with surface area in the right parietal lobe, a region related to nonverbal cognitive functions, including mathematics, spatial cognition, and WM. SES, but not EduYears-PGS, was related to a change in total cortical surface area from age 14 to 19. This study demonstrates a regional association of EduYears-PGS and the independent prediction of SES with cognitive function and brain development. It suggests that the SES inequalities, in particular parental education, are related to global aspects of cortical development, and exert a persistent influence on brain development during adolescence.

Autistic traits and alcohol use in adolescents within the general population.

It has been suggested that autistic traits are associated with less frequent alcohol use in adolescence. Our study seeks to examine the relationship between autistic traits and alcohol use in a large adolescent population. Leveraging data from the IMAGEN cohort, including 2045 14-year-old adolescents that were followed-up to age 18, we selected items on social preference/skills and rigidity from different questionnaires. We used linear regression models to (1) test the effect of the sum scores on the prevalence of alcohol use (AUDIT-C) over time, (2) explore the relationship between autistic traits and alcohol use patterns, and (3) explore the specific effect of each autistic trait on alcohol use. Higher scores on the selected items were associated with trajectories of less alcohol use from the ages between 14 and 18 (b = - 0.030; CI 95% = - 0.042, - 0.017; p < 0.001). Among adolescents who used alcohol, those who reported more autistic traits were also drinking less per occasion than their peers and were less likely to engage in binge drinking. We found significant associations between alcohol use and social preference (p < 0.001), nervousness for new situations (p = 0.001), and detail orientation (p < 0.001). Autistic traits (social impairment, detail orientation, and anxiety) may buffer against alcohol use in adolescence.

Orbitofrontal cortex volume links polygenic risk for smoking with tobacco use in healthy adolescents.

BACKGROUND: Tobacco smoking remains one of the leading causes of preventable illness and death and is heritable with complex underpinnings. Converging evidence suggests a contribution of the polygenic risk for smoking to the use of tobacco and other substances. Yet, the underlying brain mechanisms between the genetic risk and tobacco smoking remain poorly understood. METHODS: Genomic, neuroimaging, and self-report data were acquired from a large cohort of adolescents from the IMAGEN study (a European multicenter study). Polygenic risk scores (PGRS) for smoking were calculated based on a genome-wide association study meta-analysis conducted by the Tobacco and Genetics Consortium. We examined the interrelationships among the genetic risk for smoking initiation, brain structure, and the number of occasions of tobacco use. RESULTS: A higher smoking PGRS was significantly associated with both an increased number of occasions of tobacco use and smaller cortical volume of the right orbitofrontal cortex (OFC). Furthermore, reduced cortical volume within this cluster correlated with greater tobacco use. A subsequent path analysis suggested that the cortical volume within this cluster partially mediated the association between the genetic risk for smoking and the number of occasions of tobacco use. CONCLUSIONS: Our data provide the first evidence for the involvement of the OFC in the relationship between smoking PGRS and tobacco use. Future studies of the molecular mechanisms underlying tobacco smoking should consider the mediation effect of the related neural structure.

Sex differences in neural correlates of common psychopathological symptoms in early adolescence.

BACKGROUND: Sex-related differences in psychopathology are known phenomena, with externalizing and internalizing symptoms typically more common in boys and girls, respectively. However, the neural correlates of these sex-by-psychopathology interactions are underinvestigated, particularly in adolescence. METHODS: Participants were 14 years of age and part of the IMAGEN study, a large (N = 1526) community-based sample. To test for sex-by-psychopathology interactions in structural grey matter volume (GMV), we used whole-brain, voxel-wise neuroimaging analyses based on robust non-parametric methods. Psychopathological symptom data were derived from the Strengths and Difficulties Questionnaire (SDQ). RESULTS: We found a sex-by-hyperactivity/inattention interaction in four brain clusters: right temporoparietal-opercular region (p < 0.01, Cohen's d = -0.24), bilateral anterior and mid-cingulum (p < 0.05, Cohen's d = -0.18), right cerebellum and fusiform (p < 0.05, Cohen's d = -0.20) and left frontal superior and middle gyri (p < 0.05, Cohen's d = -0.26). Higher symptoms of hyperactivity/inattention were associated with lower GMV in all four brain clusters in boys, and with higher GMV in the temporoparietal-opercular and cerebellar-fusiform clusters in girls. CONCLUSIONS: Using a large, sex-balanced and community-based sample, our study lends support to the idea that externalizing symptoms of hyperactivity/inattention may be associated with different neural structures in male and female adolescents. The brain regions we report have been associated with a myriad of important cognitive functions, in particular, attention, cognitive and motor control, and timing, that are potentially relevant to understand the behavioural manifestations of hyperactive and inattentive symptoms. This study highlights the importance of considering sex in our efforts to uncover mechanisms underlying psychopathology during adolescence.

Linked patterns of biological and environmental covariation with brain structure in adolescence: a population-based longitudinal study.

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n = 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA r range: 0.30-0.65, all PFDR < 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|ρ| = 0.31-0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|ρ| = 0.24-0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|ρ| = 0.10-0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives.

Do ADHD-impulsivity and BMI have shared polygenic and neural correlates?

There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this overlap. The neural and polygenic correlates of this association have not been thoroughly examined. In participants of the IMAGEN study, we found that impulsivity symptoms and body mass index (BMI) were associated (r = 0.10, n = 874, p = 0.014 FWE corrected), as were their respective polygenic risk scores (PRS) (r = 0.17, n = 874, p = 6.5 × 10-6 FWE corrected). We then examined whether the phenotypes of impulsivity and BMI, and the PRS scores of ADHD and BMI, shared common associations with whole-brain grey matter and the Monetary Incentive Delay fMRI task, which associates with reward-related impulsivity. A sparse partial least squared analysis (sPLS) revealed a shared neural substrate that associated with both the phenotypes and PRS scores. In a last step, we conducted a bias corrected bootstrapped mediation analysis with the neural substrate score from the sPLS as the mediator. The ADHD PRS associated with impulsivity symptoms (b = 0.006, 90% CIs = 0.001, 0.019) and BMI (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. The BMI PRS associated with BMI (b = 0.014, 95% CIs = 0.003, 0.033) and impulsivity symptoms (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. A common neural substrate may (in part) underpin shared genetic liability for ADHD and BMI and the manifestation of their (observable) phenotypic association.

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.