Subtypes of adolescent major depressive disorder characterized by divergent information dynamics in sensory-association cortices

Abstract

Adolescent major depressive disorder (MDD) involves complex and heterogeneous alterations in brain functional organization. A possible explanation is the disruption of individualized brain maturation during adolescence, which typically transitions from lower-order sensory to higher-order association regions. To test this hypothesis, we analyzed resting-state functional MRI data using advanced matrix decomposition techniques to extract organizational gradients, temporal dynamics, and information flow. Clustering sensory–association gradient features in our main sample (NMDD = 302 and NControls = 207; ages 11-17) revealed two subtypes. Subtype 1 showed bottom‑up (sensory‑to‑association) flow, reduced synergy but heightened redundancy in sensory cortices, and a highly modular yet globally inefficient network—patterns consistent with aberrant sensory processing and impaired integration. Subtype 2 instead displayed a top‑down (association‑to‑sensory) flow, reduced synergy in association areas, elevated redundancy in sensory regions, and network efficiency between subtype 1 and healthy controls, suggesting compensatory higher‑order engagement. Subtypes also differed in age-related changes, clinical profiles, and neurobiological processing. These patterns were largely replicated in an independent sample (NMDD = 73 and NControls = 28). Overall, the sensory-association axis distinguishes MDD subtypes, integrating functional heterogeneity, cortical dynamics, developmental trajectories, and genetic influences, offering new insights for pathophysiology and precision psychiatry.