Population clustering of structural brain aging and its association with brain development.

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.

Genetic-Dependent Brain Signatures of Resilience: Interactions among Childhood Abuse, Genetic Risks and Brain Function.

Resilience to emotional disorders is critical for adolescent mental health, especially following childhood abuse. Yet, brain signatures of resilience remain undetermined due to the differential susceptibility of the brain's emotion processing system to environmental stresses. Analyzing brain's responses to angry faces in a longitudinally large-scale adolescent cohort (IMAGEN), we identified two functional networks related to the orbitofrontal and occipital regions as candidate brain signatures of resilience. In girls, but not boys, higher activation in the orbitofrontal-related network was associated with fewer emotional symptoms following childhood abuse, but only when the polygenic burden for depression was high. This finding defined a genetic-dependent brain (GDB) signature of resilience. Notably, this GDB signature predicted subsequent emotional disorders in late adolescence, extending into early adulthood and generalizable to another independent prospective cohort (ABCD). Our findings underscore the genetic modulation of resilience-brain connections, laying the foundation for enhancing adolescent mental health through resilience promotion.

Variation in moment-to-moment brain state engagement changes across development and contributes to individual differences in executive function.

Neural variability, or variation in brain signals, facilitates dynamic brain responses to ongoing demands. This flexibility is important during development from childhood to young adulthood, a period characterized by rapid changes in experience. However, little is known about how variability in the engagement of recurring brain states changes during development. Such investigations would require the continuous assessment of multiple brain states concurrently. Here, we leverage a new computational framework to study state engagement variability (SEV) during development. A consistent pattern of SEV changing with age was identified across cross-sectional and longitudinal datasets (N>3000). SEV developmental trajectories stabilize around mid-adolescence, with timing varying by sex and brain state. SEV successfully predicts executive function (EF) in youths from an independent dataset. Worse EF is further linked to alterations in SEV development. These converging findings suggest SEV changes over development, allowing individuals to flexibly recruit various brain states to meet evolving needs.

Regional patterns of human cortex development correlate with underlying neurobiology.

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 cortical thickness development and aging trajectories unfold 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 the variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.

Personality, Social Factors, Brain Functioning, Familial Risk, and Trajectories of Alcohol Misuse in Adolescence.

Importance: The development of an alcohol use disorder in adolescence is associated with increased risk of future alcohol dependence. The differential associations of risk factors with alcohol use over the course of 8 years are important for preventive measures. Objective: To determine the differential associations of risk-taking aspects of personality, social factors, brain functioning, and familial risk with hazardous alcohol use in adolescents over the course of 8 years. Design, Setting, and Participants: The IMAGEN multicenter longitudinal cohort study included adolescents recruited from European schools in Germany, the UK, France, and Ireland from January 2008 to January 2019. Eligible participants included those with available neuropsychological, self-report, imaging, and genetic data at baseline. Adolescents who were ineligible for magnetic resonance imaging or had serious medical conditions were excluded. Data analysis was conducted from July 2021 to September 2022. Exposure: Personality testing, psychosocial factors, brain functioning, and familial risk of alcohol misuse. Main Outcome and Measures: Hazardous alcohol use as measured with the Alcohol Use Disorders Identification Test scores, a main planned outcome of the IMAGEN study. Alcohol misuse trajectories at ages 14, 16, 19, and 22 years were modeled using latent growth curve models. Results: A total of 2240 adolescents (1110 female [49.6%] and 1130 male [50.4%]) were included in the study. There was a significant negative association of psychosocial resources (ß = -0.29; SE = 0.03; P < .001) with the general risk of alcohol misuse as well as a significant positive association of the risk-taking aspects of personality with the intercept (ß = 0.19; SE = 0.04; P < .001). Furthermore, there were significant positive associations of the social domain (ß = 0.13; SE = 0.02; P < .001) and the personality domain (ß = 0.07; SE = 0.02; P < .001) with trajectories of alcohol misuse development over time (slope). Family history of substance misuse was negatively associated with general risk of alcohol misuse (ß = -0.04; SE = 0.02; P = .045) and its development over time (ß = -0.03; SE = 0.01; P = .01). Brain functioning showed no significant association with intercept or slope of alcohol misuse in the model. Conclusions and Relevance: The findings of this cohort study suggest known risk factors of adolescent drinking may contribute differentially to future alcohol misuse. This approach may inform more individualized preventive interventions.

Adolescent maturation of cortical excitation-inhibition balance based on individualized biophysical network modeling.

The balance of excitation and inhibition is a key functional property of cortical microcircuits which changes through the lifespan. Adolescence is considered a crucial period for the maturation of excitation-inhibition balance. This has been primarily observed in animal studies, yet human in vivo evidence on adolescent maturation of the excitation-inhibition balance at the individual level is limited. Here, we developed an individualized in vivo marker of regional excitation-inhibition balance in human adolescents, estimated using large-scale simulations of biophysical network models fitted to resting-state functional magnetic resonance imaging data from two independent cross-sectional (N = 752) and longitudinal (N = 149) cohorts. We found a widespread relative increase of inhibition in association cortices paralleled by a relative age-related increase of excitation, or lack of change, in sensorimotor areas across both datasets. This developmental pattern co-aligned with multiscale markers of sensorimotor-association differentiation. The spatial pattern of excitation-inhibition development in adolescence was robust to inter-individual variability of structural connectomes and modeling configurations. Notably, we found that alternative simulation-based markers of excitation-inhibition balance show a variable sensitivity to maturational change. Taken together, our study highlights an increase of inhibition during adolescence in association areas using cross sectional and longitudinal data, and provides a robust computational framework to estimate microcircuit maturation in vivo at the individual level.

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.

Investigating grey matter volumetric trajectories through the lifespan at the individual level.

Adolescents exhibit remarkable heterogeneity in the structural architecture of brain development. However, due to limited large-scale longitudinal neuroimaging studies, existing research has largely focused on population averages, and the neurobiological basis underlying individual heterogeneity remains poorly understood. Here we identify, using the IMAGEN adolescent cohort followed up over 9 years (14-23 y), three groups of adolescents characterized by distinct developmental patterns of whole-brain gray matter volume (GMV). Group 1 show continuously decreasing GMV associated with higher neurocognitive performances than the other two groups during adolescence. Group 2 exhibit a slower rate of GMV decrease and lower neurocognitive performances compared with Group 1, which was associated with epigenetic differences and greater environmental burden. Group 3 show increasing GMV and lower baseline neurocognitive performances due to a genetic variation. Using the UK Biobank, we show these differences may be attenuated in mid-to-late adulthood. Our study reveals clusters of adolescent neurodevelopment based on GMV and the potential long-term impact.

[Ethical Considerations of Including Minors in Clinical Trials Using the Example of the Indicated Prevention of Psychotic Disorders]. / Minderjährige in klinischen Prüfungen: Ethische Abwägungen ihres Einbezugs am Beispiel der indizierten Prävention psychotischer Erkrankungen.

Ethical Considerations of Including Minors in Clinical Trials Using the Example of the Indicated Prevention of Psychotic Disorders Abstract: As a vulnerable group, minors require special protection in studies. For this reason, researchers are often reluctant to initiate studies, and ethics committees are reluctant to authorize such studies. This often excludes minors from participating in clinical studies. This exclusion can lead to researchers and clinicians receiving only incomplete data or having to rely on adult-based findings in the treatment of minors. Using the example of the study "Computer-Assisted Risk Evaluation in the Early Detection of Psychotic Disorders" (CARE), which was conducted as an 'other clinical investigation' according to the Medical Device Regulation, we present a line of argumentation for the inclusion of minors which weighs the ethical principles of nonmaleficence (especially regarding possible stigmatization), beneficence, autonomy, and fairness. We show the necessity of including minors based on the development-specific differences in diagnostics and early intervention. Further, we present specific protective measures. This argumentation can also be transferred to other disorders with the onset in childhood and adolescence and thus help to avoid excluding minors from appropriate evidence-based care because of insufficient studies.

Distinct personality profiles associated with disease risk and diagnostic status in eating disorders.

BACKGROUND: Personality traits have been associated with eating disorders (EDs) and comorbidities. However, it is unclear which personality profiles are premorbid risk rather than diagnostic markers. METHODS: We explored associations between personality and ED-related mental health symptoms using canonical correlation analyses. We investigated personality risk profiles in a longitudinal sample, associating personality at age 14 with onset of mental health symptoms at ages 16 or 19. Diagnostic markers were identified in a sample of young adults with anorexia nervosa (AN, n = 58) or bulimia nervosa (BN, n = 63) and healthy controls (n = 47). RESULTS: Two significant premorbid risk profiles were identified, successively explaining 7.93 % and 5.60 % of shared variance (Rc2). The first combined neuroticism (canonical loading, rs = 0.68), openness (rs = 0.32), impulsivity (rs = 0.29), and conscientiousness (rs = 0.27), with future onset of anxiety symptoms (rs = 0.87) and dieting (rs = 0.58). The other, combined lower agreeableness (rs = -0.60) and lower anxiety sensitivity (rs = -0.47), with future deliberate self-harm (rs = 0.76) and purging (rs = 0.55). Personality profiles associated with "core psychopathology" in both AN (Rc2 = 80.56 %) and BN diagnoses (Rc2 = 64.38 %) comprised hopelessness (rs = 0.95, 0.87) and neuroticism (rs = 0.93, 0.94). For BN, this profile also included impulsivity (rs = 0.60). Additionally, extraversion (rs = 0.41) was associated with lower depressive risk in BN. LIMITATIONS: The samples were not ethnically diverse. The clinical cohort included only females. There was non-random attrition in the longitudinal sample. CONCLUSIONS: The results suggest neuroticism and impulsivity as risk and diagnostic markers for EDs, with neuroticism and hopelessness as shared diagnostic markers. They may inform the design of more personalised prevention and intervention strategies.

Interplay of early negative life events, development of orbitofrontal cortical thickness and depression in young adulthood.

Background: Early negative life events (NLE) have long-lasting influences on neurodevelopment and psychopathology. Reduced orbitofrontal cortex (OFC) thickness was frequently associated with NLE and depressive symptoms. OFC thinning might mediate the effect of NLE on depressive symptoms, although few longitudinal studies exist. Using a complete longitudinal design with four time points, we examined whether NLE during childhood and early adolescence predict depressive symptoms in young adulthood through accelerated OFC thinning across adolescence. Methods: We acquired structural MRI from 321 participants at two sites across four time points from ages 14 to 22. We measured NLE with the Life Events Questionnaire at the first time point and depressive symptoms with the Center for Epidemiologic Studies Depression Scale at the fourth time point. Modeling latent growth curves, we tested whether OFC thinning mediates the effect of NLE on depressive symptoms. Results: A higher burden of NLE, a thicker OFC at the age of 14, and an accelerated OFC thinning across adolescence predicted young adults' depressive symptoms. We did not identify an effect of NLE on OFC thickness nor OFC thickness mediating effects of NLE on depressive symptoms. Conclusions: Using a complete longitudinal design with four waves, we show that NLE in childhood and early adolescence predict depressive symptoms in the long term. Results indicate that an accelerated OFC thinning may precede depressive symptoms. Assessment of early additionally to acute NLEs and neurodevelopment may be warranted in clinical settings to identify risk factors for depression.

Light Cannabis Use and the Adolescent Brain: An 8-years Longitudinal Assessment of Mental Health, Cognition, and Reward Processing.

RATIONALE: For decades, cannabis has been the most widely used illicit substance in the world, particularly among youth. Research suggests that mental health problems associated with cannabis use may result from its effect on reward brain circuit, emotional processes, and cognition. However, findings are mostly derived from correlational studies and inconsistent, particularly in adolescents. OBJECTIVES AND METHODS: Using data from the IMAGEN study, participants (non-users, persistent users, abstinent users) were classified according to their cannabis use at 19 and 22 years-old. All participants were cannabis-naïve at baseline (14 years-old). Psychopathological symptoms, cognitive performance, and brain activity while performing a Monetary Incentive Delay task were used as predictors of substance use and to analyze group differences over time. RESULTS: Higher scores on conduct problems and lower on peer problems at 14 years-old (n = 318) predicted a greater likelihood of transitioning to cannabis use within 5 years. At 19 years of age, individuals who consistently engaged in low-frequency (i.e., light) cannabis use (n = 57) exhibited greater conduct problems and hyperactivity/inattention symptoms compared to non-users (n = 52) but did not differ in emotional symptoms, cognitive functioning, or brain activity during the MID task. At 22 years, those who used cannabis at both 19 and 22 years-old n = 17), but not individuals that had been abstinent for ≥ 1 month (n = 19), reported higher conduct problems than non-users (n = 17). CONCLUSIONS: Impairments in reward-related brain activity and cognitive functioning do not appear to precede or succeed cannabis use (i.e., weekly, or monthly use). Cannabis-naïve adolescents with conduct problems and more socially engaged with their peers may be at a greater risk for lighter yet persistent cannabis use in the future.

How social is social media for transgender and gender-diverse youth? Association of online social experiences with internalizing mental health problems.

Adolescents spend a critical amount of their free time on the Internet and social media. Transgender and gender-diverse (TGD) adolescents, who report elevated rates of mental health issues, especially internalizing problems, have both positive and negative online social experiences (e.g., support and cyberbullying). This can have both beneficial and/or harmful effects on their mental health. Given the lack of research, the present study examined TGD adolescents' online (social) experiences and the association of positive and negative online social experiences with internalizing problems. The sample consisted of n = 165 TGD adolescents (11-18 years) diagnosed with gender dysphoria who attended a Gender Identity Service for children and adolescents (Hamburg GIS) in Germany between January 2020 and December 2022 during the COVID-19 pandemic. Positive (use of online support networks) and negative online social experiences (cyberbullying or other adverse online interactions) were assessed using study-specific items and internalizing problems using the Youth Self-Report. Frequencies of various online (social) experiences were analyzed, and a multiple linear regression analysis was performed to test their association with internalizing problems. In total, 42% of participants reported positive online social experiences (use of online support networks) and 51% of participants reported negative online social experiences (cyberbullying or other adverse online interactions). There was no significant association between negative online social experiences and internalizing problems but between positive online social experiences and more internalizing problems (adjusted R2 = .01). TGD adolescents may seek online support, especially when struggling with mental health problems. Therefore, it is crucial to support youth navigating these online spaces more safely and positively and to empower them to buffer against potentially harmful experiences. Furthermore, strengthening offline relations with peers and family members is pivotal, given their importance for TGD adolescents' mental health.

Intensive Longitudinal Social Sensing in Patients With Psychosis Spectrum Disorders: An Exploratory Pilot Study.

BACKGROUND: Psychosis spectrum disorders are characterized by significant alterations in social functioning, which is a major factor for patient recovery. Despite its importance, objectively quantifying the complex day-to-day social behavior in real-life settings has rarely been attempted. Here, we conducted a pilot study with wearable sensors that passively and continuously register interactions with other participants. We hypothesized that the amount and pattern of social interaction was associated with the severity of psychotic symptoms. STUDY DESIGN: We recruited 7 patients with psychosis spectrum disorders and 18 team members from a Soteria-style ward. Each participant wore a radio frequency identification badge, sending and receiving signals from nearby badges, allowing passive quantification of social interactions. In addition, symptom severity was assessed weekly by the Positive and Negative Syndrome Scale (PANSS). STUDY RESULTS: During an 11-week period, we identified 17 970 interactions among patients and staff. On average, patients spent 2.6 h per day interacting, capturing relevant aspects of daily social life. Relative daily interaction time, average interaction duration, and clustering coefficient, a measure of local network integration, were significantly associated with lower PANSS scores. Self-reported interaction time did not correlate with measured interaction time or with PANSS, indicating the importance of objective markers. CONCLUSIONS: This pilot study demonstrates the feasibility of passively recording social interaction of patients and staff at high resolution and for a long observation period in a real-life setting in a psychiatric department. We show links between quantified social interaction and psychopathology that may facilitate development and personalization of targeted treatments.

Social media use and experiences among transgender and gender diverse adolescents.

Objectives: For transgender and gender diverse (TGD) adolescents, the internet and social media have several risks and benefits. The present study aims at assessing how and for which purposes TGD adolescents use the internet and social media and how often they experience support compared to cyberbullying online. Methods: The sample comprised 114 TGD adolescents diagnosed with gender dysphoria who attended a Gender Identity Service for children and adolescents (Hamburg GIS). Internet and social media use and experiences were assessed using modified items from a German representative study and self-constructed items relating to TGD-specific online experiences. Frequencies of internet/social media use and various online experiences were analyzed and compared to data from the German general population. Results: Compared to peers from the general population, TGD adolescents reported similar offline and online activities and spent similarly long time online (internet: M = 4.16 h, social media: M = 2.84 h). All TGD adolescents sought TGD-specific information online. TGD adolescents used the internet to experiment with their gender identity (60%), and for the purpose of their coming out (31%) and their social transition (88%). About half of the sample each reported either online support (45%) and/or cyberbullying (48%). Conclusions: While TGD adolescents used the internet and social media for similar purposes as peers from the general population, they also used the internet and social media to gain TGD-specific information and for gender identity expression and exploration. They reported both positive and negative experiences online, calling for future studies investigating how online experiences affect TGD adolescents' mental health and gender identity development.

Randomized controlled trial of individualized arousal-biofeedback for children and adolescents with disruptive behavior disorders (DBD).

Disruptive behavior disorders [including conduct disorder (CD) and oppositional defiant disorder (ODD)] are common childhood and adolescent psychiatric conditions often linked to altered arousal. The recommended first-line treatment is multi-modal therapy and includes psychosocial and behavioral interventions. Their modest effect sizes along with clinically and biologically heterogeneous phenotypes emphasize the need for innovative personalized treatment targeting impaired functions such as arousal dysregulation. A total of 37 children aged 8-14 years diagnosed with ODD/CD were randomized to 20 sessions of individualized arousal biofeedback using skin conductance levels (SCL-BF) or active treatment as usual (TAU) including psychoeducation and cognitive-behavioral elements. The primary outcome was the change in parents´ ratings of aggressive behavior measured by the Modified Overt Aggression Scale. Secondary outcome measures were subscales from the Child Behavior Checklist, the Inventory of Callous-Unemotional traits, and the Reactive-Proactive Aggression Questionnaire. The SCL-BF treatment was neither superior nor inferior to the active TAU. Both groups showed reduced aggression after treatment with small effects for the primary outcome and large effects for some secondary outcomes. Importantly, successful learning of SCL self-regulation was related to reduced aggression at post-assessment. Individualized SCL-BF was not inferior to active TAU for any treatment outcome with improvements in aggression. Further, participants were on average able to self-regulate their SCL, and those who best learned self-regulation showed the highest clinical improvement, pointing to specificity of SCL-BF regulation for improving aggression. Further studies with larger samples and improved methods, for example by developing BF for mobile use in ecologically more valid settings are warranted.

Machine learning models for diagnosis and risk prediction in eating disorders, depression, and alcohol use disorder.

This study uses machine learning models to uncover diagnostic and risk prediction markers for eating disorders (EDs), major depressive disorder (MDD), and alcohol use disorder (AUD). Utilizing case-control samples (ages 18-25 years) and a longitudinal population-based sample (n=1,851), the models, incorporating diverse data domains, achieved high accuracy in classifying EDs, MDD, and AUD from healthy controls. The area under the receiver operating characteristic curves (AUC-ROC [95% CI]) reached 0.92 [0.86-0.97] for AN and 0.91 [0.85-0.96] for BN, without relying on body mass index as a predictor. The classification accuracies for MDD (0.91 [0.88-0.94]) and AUD (0.80 [0.74-0.85]) were also high. Each data domain emerged as accurate classifiers individually, with personality distinguishing AN, BN, and their controls with AUC-ROCs ranging from 0.77 to 0.89. The models demonstrated high transdiagnostic potential, as those trained for EDs were also accurate in classifying AUD and MDD from healthy controls, and vice versa (AUC-ROCs, 0.75-0.93). Shared predictors, such as neuroticism, hopelessness, and symptoms of attention-deficit/hyperactivity disorder, were identified as reliable classifiers. For risk prediction in the longitudinal population sample, the models exhibited moderate performance (AUC-ROCs, 0.64-0.71), highlighting the potential of combining multi-domain data for precise diagnostic and risk prediction applications in psychiatry.

Adolescents' pain-related ontogeny shares a neural basis with adults' chronic pain in basothalamo-cortical organization.

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.

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.

Population clustering of structural brain aging and its association with brain development.

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.