Trajectories of brain organisation transition from predicting externalising to internalising symptoms across adolescence

Abstract

Understanding the dynamics of brain-behaviour relationships during adolescence is critical for elucidating the neurodevelopmental basis of mental health. Leveraging two large-scale longitudinal cohorts--the Adolescent Brain Cognitive Development (ABCD) and IMAGEN studies, comprising over 10,000 participants aged 10 to 22 years with six waves of multimodal neuroimaging and behavioural data, we applied multi-view sparse canonical correlation analysis to investigate evolving associations between structural MRI, resting-state functional connectivity, and multi-domain behavioural measures. Our findings reveal four fundamental patterns of developmental reorganisation in brain-psychopathology relationships. First, symptom profiles evolved from predominantly externalising features (aggression, attention problems) at ages 10-12 toward global psychopathology by age 14, then transitioned toward internalising features (e.g., anxiety, depression) by ages 19-22, reflecting fundamental shifts in vulnerability from behavioural dysregulation to affective disturbance. Second, cortical thickness exhibited negative associations with externalising symptom profiles throughout development. During early adolescence (ages 10-14) this was driven by broadly distributed decreases across sensorimotor, temporal, visual, and cingulate regions alongside overall mean cortical thickness. After 14, this diffuse pattern shifted towards late maturing association cortices, notably the dorsolateral prefrontal and lateral temporal cortices. Third, this was accompanied by subcortical effects that exhibited greater age-specificity: whilst cerebellar volume contributions were evident at most timepoints, basal ganglia volume influence was principally evident in early development (ages 10-12), with thalamic structures and global subcortical grey matter volume becoming dominant at age 14, marking a transition in which subcortical structures mediate psychopathology associations. Fourth, functional connectivity showed a more dynamic developmental trajectory. During early adolescence, symptom associations were driven by positive connectivity between cognitive control and sensorimotor networks, whereas late adolescence exhibited predominantly positive connectivity patterns, transitioning from dense sensorimotor-frontoparietal configurations to more specific patterns involving the central executive and default-mode networks. These findings fundamentally challenge static biomarker models, demonstrating that adolescent psychopathology reflects developmentally contingent brain-behaviour relationships rather than static neural markers. Age 14 emerges as a critical inflection point marked by convergent thalamic reconfiguration, global subcortical grey matter dominance, and symptom profile transitions. This work provides an empirical foundation for precision mental health strategies tailored to specific developmental windows, with implications for reducing psychiatric burden in youth.