Integrative neuroimaging-transcriptomic analysis of neurodevelopment in adolescent-onset mental health problems

Abstract Mental health problems often emerge in childhood and adolescence, yet the neurodevelopmental and molecular processes underlying their onset remain poorly understood. Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study, we examined structural and functional brain cortical changes in youth who developed ADHD, conduct, anxiety, depressive, oppositional defiant, or somatic problems over a two year follow up period compared to healthy controls in five neuroimaging modalities (including structural MRI, resting-state fMRI, and task-based fMRI). We applied partial least squares (PLS) regression to link spatial patterns of neurodevelopmental changes to cortical gene expression profiles derived from the Allen Human Brain Atlas (AHBA). Pathway enrichment was assessed using spin-permutation-derived gene rankings. Significant neurodevelopmental alterations were observed in the ADHD and conduct groups only. PLS analysis further revealed significant spatial associations between their neurodevelopmental changes and gene expression distributions (Spearman rₛ >0.64). In ADHD, pathway enrichment highlighted mitochondrial respiration, oxidative phosphorylation, aerobic electron transport, ATP synthesis, and mitochondrial organization, with additional negative-end enrichment for synaptic protein interaction pathways. In conduct problems, all significant pathways were enriched among genes whose cortical expression patterns were inversely aligned with the conduct-problem imaging phenotype and involved translational machinery, ribosomal function, mitochondrial respiration, mitochondrial translation, protein targeting to mitochondria, and broader RNA/protein regulatory processes. These findings reveal distinct cortical transcriptomic patterns associated with adolescent-onset ADHD and conduct problems, with mitochondrial energy metabolism emerging as a prominent molecular correlate of ADHD-related cortical development and a distinct inverse transcriptional pattern characterizing conduct-related development. Together, our findings suggest that these externalizing problems are associated with neurodevelopmental alterations embedded within distinct cortical molecular contexts.