Whole brain modeling reveals subtype specific regulation for adolescent major depressive disorder

Adolescent major depressive disorder exhibits substantial intrinsic subtype heterogeneity, necessitating the development of subtype-specific therapeutic strategies. Using the Boston Adolescent Neuroimaging of Depression and Anxiety dataset, we identified two subtypes with distinct clinical features. For each subtype, we constructed a whole-brain model and performed virtual stimulation to assess regulatory effects at global (whole-brain) and regional (classical depression-related targets) levels. Here we show that the two subtypes require different but stable stimulation modalities, excitatory or inhibitory, to normalize brain activity. Optimal stimulation intensities for restoring static and dynamic features vary across targets and subtypes, whereas the stimulation modality remains consistent within each subtype. Notably, localized stimulation of subtype-specific targets within classical depression-related regions produces more effective and stable outcomes than whole-brain stimulation. These findings provide a computational framework for identifying subtype-specific regulatory strategies in adolescent major depressive disorder, bridging whole-brain modeling with potential clinical translation.