Medication and Developmental Stage Shape the Brain-Age Gap in ADHD

Identifying robust biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) remains challenging. The brain-age gap (BAG), which is the difference between predicted biological brain age and chronological age, has been proposed as a marker of atypical neurodevelopment, yet findings have been inconsistent across studies, limiting its clinical translation. We hypothesized that two major sources of heterogeneity, medication status and developmental stage, contribute to these discrepancies. To test this, we analyzed structural MRI data from a large multi-site cohort (N = 947; ages 7-26 years). Individuals with ADHD were stratified by medication history (medicated vs. unmedicated) and developmental stage (childhood vs. adolescence) and compared with matched typically developing controls. We estimated global- and network-level BAG using publicly available pretrained models. Our results revealed that BAG differences were contingent on medication status, with abnormalities predominantly observed in unmedicated individuals. Developmental stage further moderated the presence of this effect: BAG abnormalities were present significantly in children with ADHD but not in adolescents. Network-level analyses demonstrated spatial specificity, with significant effects in visual, ventral attention, and dorsal attention networks. Together, these findings provide compelling evidence that BAG in ADHD is both medication- and development-dependent, highlighting the need to account for treatment exposure and developmental stage when evaluating BAG as a biomarker and further underscoring the importance of early intervention during childhood.