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.

Adolescent binge drinking has been associated with higher risks for the development of many health problems throughout the lifespan. Adolescents undergo multiple changes that involve the co-development processes of brain, personality and behavior; therefore, certain behavior, such as alcohol consumption, can have disruptive effects on both brain development and personality maturation. However, these effects remain unclear due to the scarcity of longitudinal studies. In the current study, we used multivariate approaches to explore discriminative features in brain functional architecture, personality traits, and genetic variants in 19-year-old individuals (n = 212). Taking advantage of a longitudinal design, we selected features that were more drastically altered in drinkers with an earlier onset of binge drinking. With the selected features, we trained a hierarchical model of support vector machines using a training sample (n = 139). Using an independent sample (n = 73), we tested the model and achieved a classification accuracy of 71.2%. We demonstrated longitudinally that after the onset of binge drinking the developmental trajectory of improvement in impulsivity slowed down. This study identified the disrupting effects of adolescent binge drinking on the developmental trajectories of both brain and personality.

Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14-18 years old) followed in the IMAGEN study (n = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) (n = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as post-hoc analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 (p < 0.05; OR<1). Two SNPs remain significant after correction by false discovery rate (FDR): rs9343525 in CNR1 (pcorrected =0.042, OR = 0.73) and rs507961 in MGLL (pcorrected = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 (CNR1) and rs507961 (MGLL) remained significantly associated with positive AUDIT screens (p < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction (p = 0.006) involving rs484061 (MGLL), rs4963307 (DAGLA), and rs7766029 (CNR1) predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, p = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.

Sleep is an important contributor for neural maturation and emotion regulation during adolescence, with long-term effects on a range of white matter tracts implicated in affective processing in at-risk populations. We investigated the effects of adolescent sleep patterns on longitudinal changes in white matter development and whether this is related to the emergence of emotional (internalizing) problems. Sleep patterns and internalizing problems were assessed using self-report questionnaires in adolescents recruited in the general population followed up from age 14-19 years (N = 111 White matter structure was measured using diffusion tensor imaging (DTI) and estimated using fractional anisotropy (FA). We found that longitudinal increases in time in bed (TIB) on weekends and increases in TIB-variability between weekdays to weekend, were associated with an increase in FA in various interhemispheric and cortico-striatal tracts. Extracted FA values from left superior longitudinal fasciculus mediated the relationship between increases in TIB on weekends and a decrease in internalizing problems. These results imply that while insufficient sleep might have potentially harmful effects on long-term white matter development and internalizing problems, longer sleep duration on weekends (catch-up sleep) might be a natural counteractive and protective strategy.

Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cerebral cortex development unfolds along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of variance associated with regional cortical thickness trajectories. Adult cortical change patterns are best explained by cholinergic and glutamatergic neurotransmission. These relationships are supported by developmental gene expression trajectories and translate to longitudinal data from over 8,000 adolescents, explaining up to 59% of developmental change at population- and 18% at single-subject level. Integrating multilevel brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand typical and atypical brain development in living humans.

Structural brain aging has demonstrated strong inter-individual heterogeneity and mirroring patterns with brain development. However, due to the lack of large-scale longitudinal neuroimaging studies, most of the existing research focused on the cross-sectional changes of brain aging. In this investigation, we present a data-driven approach that incorporate both cross-sectional changes and longitudinal trajectories of structural brain aging and identified two brain aging patterns among 37,013 healthy participants from UK Biobank. Participants with accelerated brain aging also demonstrated accelerated biological aging, cognitive decline and increased genetic susceptibilities to major neuropsychiatric disorders. Further, by integrating longitudinal neuroimaging studies from a multi-center adolescent cohort, we validated the "last in, first out" mirroring hypothesis and identified brain regions with manifested mirroring patterns between brain aging and brain development. Genomic analyses revealed risk loci and genes contributing to accelerated brain aging and delayed brain development, providing molecular basis for elucidating the biological mechanisms underlying brain aging and related disorders.

Eating disorders are common in adolescence and are devastating and strongly comorbid with other psychiatric disorders. Yet little is known about their etiology, knowing which would aid in developing effective preventive measures.

Mental disorders represent an increasing personal and financial burden and yet treatment development has stagnated in recent decades. Current disease classifications do not reflect psychobiological mechanisms of psychopathology, nor the complex interplay of genetic and environmental factors, likely contributing to this stagnation. Ten years ago, the longitudinal IMAGEN study was designed to comprehensively incorporate neuroimaging, genetics, and environmental factors to investigate the neural basis of reinforcement-related behavior in normal adolescent development and psychopathology. In this article, we describe how insights into the psychobiological mechanisms of clinically relevant symptoms obtained by innovative integrative methodologies applied in IMAGEN have informed our current and future research aims. These aims include the identification of symptom groups that are based on shared psychobiological mechanisms and the development of markers that predict disease course and treatment response in clinical groups. These improvements in precision medicine will be achieved, in part, by employing novel methodological tools that refine the biological systems we target. We will also implement our approach in low- and medium-income countries to understand how distinct environmental, socioeconomic, and cultural conditions influence the development of psychopathology. Together, IMAGEN and related initiatives strive to reduce the burden of mental disorders by developing precision medicine approaches globally.

Animal studies have shown that the adolescent brain is sensitive to disruptions in endocannabinoid signaling, resulting in altered neurodevelopment and lasting behavioral effects. However, few studies have investigated ties between cannabis use and adolescent brain development in humans.

Deviation from normal adolescent brain development precedes manifestations of many major psychiatric symptoms. Such altered developmental trajectories in adolescents may be linked to genetic risk for psychopathology.

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.

Little is understood about the dynamic interplay between brain morphology and cognitive ability across the life course. Additionally, most existing research has focused on global morphology measures such as estimated total intracranial volume, mean thickness, and total surface area.

The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (N = 14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (p = 5.0 × 10-4) and higher plasma cotinine levels (p = 7.0 × 10-5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (n = 1,263) and with higher DRD2 gene expression in the striatum (p = 0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking.

During late adolescence, the brain undergoes ontogenic organization altering subcortical-cortical circuitry. This includes regions implicated in pain chronicity, and thus alterations in the adolescent ontogenic organization could predispose to pain chronicity in adulthood - however, evidence is lacking. Using resting-state functional magnetic resonance imaging from a large European longitudinal adolescent cohort and an adult cohort with and without chronic pain, we examined links between painful symptoms and brain connectivity. During late adolescence, thalamo-, caudate-, and red nucleus-cortical connectivity were positively and subthalamo-cortical connectivity negatively associated with painful symptoms. Thalamo-cortical connectivity, but also subthalamo-cortical connectivity, was increased in adults with chronic pain compared to healthy controls. Our results indicate a shared basis in basothalamo-cortical circuitries between adolescent painful symptomatology and adult pain chronicity, with the subthalamic pathway being differentially involved, potentially due to a hyperconnected thalamo-cortical pathway in chronic pain and ontogeny-driven organization. This can inform neuromodulation-based prevention and early intervention.

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.

Imaging genetics offers the possibility of detecting associations between genotype and brain structure as well as function, with effect sizes potentially exceeding correlations between genotype and behavior. However, study results are often limited due to small sample sizes and methodological differences, thus reducing the reliability of findings. The IMAGEN cohort with 2000 young adolescents assessed from the age of 14 onwards tries to eliminate some of these limitations by offering a longitudinal approach and sufficient sample size for analyzing gene-environment interactions on brain structure and function. Here, we give a systematic review of IMAGEN publications since the start of the consortium. We then focus on the specific phenotype 'drug use' to illustrate the potential of the IMAGEN approach. We describe findings with respect to frontocortical, limbic and striatal brain volume, functional activation elicited by reward anticipation, behavioral inhibition, and affective faces, and their respective associations with drug intake. In addition to describing its strengths, we also discuss limitations of the IMAGEN study. Because of the longitudinal design and related attrition, analyses are underpowered for (epi-) genome-wide approaches due to the limited sample size. Estimating the generalizability of results requires replications in independent samples. However, such densely phenotyped longitudinal studies are still rare and alternative internal cross-validation methods (e.g., leave-one out, split-half) are also warranted. In conclusion, the IMAGEN cohort is a unique, very well characterized longitudinal sample, which helped to elucidate neurobiological mechanisms involved in complex behavior and offers the possibility to further disentangle genotype × phenotype interactions.

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.

Extensive research has demonstrated that rs1360780, a common single nucleotide polymorphism within the FKBP5 gene, interacts with early-life stress in predicting psychopathology. Previous results suggest that carriers of the TT genotype of rs1360780 who were exposed to child abuse show differences in structure and functional activation of emotion-processing brain areas belonging to the salience network. Extending these findings on intermediate phenotypes of psychopathology, we examined if the interaction between rs1360780 and child abuse predicts resting-state functional connectivity (rsFC) between the amygdala and other areas of the salience network. We analyzed data of young European adults from the general population (N = 774; mean age = 18.76 years) who took part in the IMAGEN study. In the absence of main effects of genotype and abuse, a significant interaction effect was observed for rsFC between the right centromedial amygdala and right posterior insula (p < .025, FWE-corrected), which was driven by stronger rsFC in TT allele carriers with a history of abuse. Our results suggest that the TT genotype of rs1360780 may render individuals with a history of abuse more vulnerable to functional changes in communication between brain areas processing emotions and bodily sensations, which could underlie or increase the risk for psychopathology.

Psychological androgyny has long been associated with greater cognitive flexibility, adaptive behavior, and better mental health, but whether a similar concept can be defined using neural features remains unknown. Using the neuroimaging data from 9620 participants, we found that global functional connectivity was stronger in the male brain before middle age but became weaker after that, when compared with the female brain, after systematic testing of potentially confounding effects. We defined a brain gender continuum by estimating the likelihood of an observed functional connectivity matrix to represent a male brain. We found that participants mapped at the center of this continuum had fewer internalizing symptoms compared with those at the 2 extreme ends. These findings suggest a novel hypothesis proposing that there exists a neuroimaging concept of androgyny using the brain gender continuum, which may be associated with better mental health in a similar way to psychological androgyny.

Environmental adversities constitute potent risk factors for psychiatric disorders. Evidence suggests the brain adapts to adversity, possibly in an adversity-type and region-specific manner. However, the long-term effects of adversity on brain structure and the association of individual neurobiological heterogeneity with behavior have yet to be elucidated. Here we estimated normative models of structural brain development based on a lifespan adversity profile in a longitudinal at-risk cohort aged 25 years (n = 169). This revealed widespread morphometric changes in the brain, with partially adversity-specific features. This pattern was replicated at the age of 33 years (n = 114) and in an independent sample at 22 years (n = 115). At the individual level, greater volume contractions relative to the model were predictive of future anxiety. We show a stable neurobiological signature of adversity that persists into adulthood and emphasize the importance of considering individual-level rather than group-level predictions to explain emerging psychopathology.