Elucidating Development Trajectories of Brain Functional Abnormalities in Major Depressive Disorder Utilizing a Data-Driven Disease Progression Model

Concerns have arisen regarding the heterogeneity of patients with major depressive disorder (MDD), particularly when the varying disease progression trajectories among individuals are overlooked. Recognizing these distinct trajectories is crucial for personalized assessments and accurate disease progression predictions in MDD, posing a significant challenge in clinical practice. We utilized a data-driven subtype and stage inference (SuStaIn) model to infer trajectories based on cross-sectional amplitude of low-frequency fluctuations (ALFF) derived from resting-state functional magnetic resonance imaging data of 833 patients with MDD and 834 healthy controls. Based on distinct trajectories, two subtypes of MDD were identified: Subtype 1 showed declining ALFF from paracentral lobule (PCL) to thalamus to medial orbitofrontal cortex (OFCmed), with higher core depression scores and gray matter atrophy, whereas Subtype 2 had an opposing trajectory, with initial OFCmed ALFF decrease gradually extending to PCL. Our findings contribute to a better understanding of MDD heterogeneity and facilitate precise disease progression predictions.