Abstract
BACKGROUND: Major depressive disorder (MDD) is a heterogeneous condition characterized by significant intersubject variability in clinical presentations. Recent neuroimaging studies have indicated that MDD involves altered brain connectivity across widespread regions. However, the variability in abnormal connectivity among MDD patients remains understudied. METHODS: Utilizing a large, multi-site dataset comprising 1,276 patients with MDD and 1,104 matched healthy controls, this study aimed to investigate the intersubject variability of structural covariance (IVSC) and functional connectivity (IVFC) in MDD. RESULTS: Patients with MDD demonstrated higher IVSC in the precuneus and lingual gyrus, but lower IVSC in the medial frontal gyrus, calcarine, cuneus, and cerebellum anterior lobe. Conversely, they exhibited an overall increase in IVFC across almost the entire brain, including the middle frontal gyrus, anterior cingulate cortex, hippocampus, insula, striatum, and precuneus. Correlation and mediation analyses revealed that abnormal IVSC was positively correlated with gray matter atrophy and mediated the relationship between abnormal IVFC and gray matter atrophy. As the disease progressed, IVFC increased in the left striatum, insula, right lingual gyrus, posterior cingulate, and left calcarine. Pharmacotherapy significantly reduced IVFC in the right insula, superior temporal gyrus, and inferior parietal lobule. Furthermore, we found significant but distinct correlations between abnormal IVSC and IVFC and the distribution of neurotransmitter receptors, suggesting potential molecular underpinnings. Further analysis confirmed that abnormal patterns of IVSC and IVFC were reproducible and MDD specificity. CONCLUSIONS: These results elucidate the heterogeneity of abnormal connectivity in MDD, underscoring the importance of addressing this heterogeneity in future research.