Regional Brain Age Deviations Reveal Divergent Developmental Pathways in Youth

Normative modeling of brain development has gained traction for quantifying individual deviations in maturation. The brain age gap (BAG), the difference between predicted age from magnetic resonance imaging features and chronological age, offers a potential individualized normative metric of neurodevelopment. However, consistent patterns across psychiatric disorders remain elusive, and no studies have examined whether BAG can predict developmental trajectories within an inclusive continuous model of youth's cognition and behavior.

Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (ages 9-15, n = 9074), we built 8 region-specific brain age models using volumes, thicknesses, and surface areas of parcels from the Brainnetome adolescent atlas. We derived psychiatric diagnoses from a parental questionnaire. Multivariate linear regression analysis was used to assess case-control differences and cross-sectional continuous cognitive/behavioral profiles. We modeled cognitive/behavioral trajectories using a multivariate joint latent class mixed model and assessed the relationship with BAG values using multinomial logistic regression.

Children with attention-deficit/hyperactivity disorder showed negative BAGs across multiple regions (Cohen's d = -0.12 to -0.08), while subcortical BAG emerged as a transdiagnostic indicator of younger-appearing brains (d = -0.07, false discovery rate-corrected p = .024). Older-appearing brains were associated with a high-cognition, low-symptom profile, whereas younger-appearing brains were associated with a low-cognition profile. Three developmental trajectories were identified: stable, toward externalizing behaviors, and toward internalizing behaviors. Widespread positive BAG predicted evolution toward internalizing behaviors but reduced the likelihood of the externalizing trajectory.

Integrating BAG with continuous cognitive and behavioral profiles yielded a plausible framework for early identification of atypical trajectories, potentially contributing to personalized medicine in psychiatry.