Mapping ADHD Heterogeneity and Biotypes through Topological Deviations in Morphometric Similarity Networks

Attention-deficit/hyperactivity disorder (ADHD) is characterized by considerable clinical heterogeneity. This study investigates whether normative modelling of topological properties derived from brain morphometry similarity networks can provide robust stratification markers for ADHD children. Leveraging multisite neurodevelopmental datasets (discovery: 446 ADHD, 708 controls; validation: 554 ADHD, 123 controls), we constructed morphometric similarity networks and developed normative models for three topological metrics: degree centrality, nodal efficiency, and participation coefficient. Through semi-supervised clustering, we delineated putative biotypes and examined their clinical profiles. We further contextualized brain profiles of these biotypes in terms of their neurochemical and functional correlates using large-scale databases, and assessed model generalizability in an independent cohort. ADHD exhibited atypical hub organization across all three topological metrics, with significant case-control differences primarily localized to a covarying multi-metric component in the orbitofrontal cortex. Three biotypes emerged: one characterized by severe overall symptoms and longitudinally persistent emotional dysregulation, accompanied by pronounced topological alterations in the medial prefrontal cortex and pallidum; a second by predominant hyperactivity/impulsivity accompanied by changes in the anterior cingulate cortex and pallidum; and a third by marked inattention with alterations in the superior frontal gyrus. These neural profiles of each biotype showed distinct neurochemical and functional correlates. Critically, the core findings were replicated in an independent validation cohort. Our comprehensive approach reveals three distinct ADHD biotypes with unique clinical-neural patterns, advancing our understanding of ADHD’s neurobiological heterogeneity and laying the groundwork for personalized treatment.