Functional Connectivity Subtypes in Major Depressive Disorder: Insights Into Connection Patterns and Neurobiological Mechanisms

Motivation: Major depressive disorder (MDD) is heterogeneous with underlying mechanisms insufficiently studied. Subtyping can help address this heterogeneity. Goal(s): To identify specific MDD subtypes and their representative brain regions (epicenters) based on brain functional connectivity (FC) alterations, and investigate their biological mechanisms. Approach: Consensus clustering was applied for subtyping MDD patients. A regression model and correlation analyses with genetic/neurotransmitter profiles were used to quantify FC alterations and explore underlying biological mechanisms, respectively. Results: Two stable subtypes emerged, exhibiting divergent overall FC patterns with shared and unique epicenters in crucial brain networks, along with shared and varied genetic and neurotransmitter associations. Impact: The present study suggested the presence of two distinct FC-based subtypes in MDD characterized by shared and different epicenters and biological basis, and enhanced the understanding of MDD heterogeneity.