White Matter Functional Connectome Topology and Its Clinical Correlations in Adolescent Major Depressive Disorder

Abstract Background Adolescence is a critical period for brain network remodeling and the onset of Major Depressive Disorder (MDD); however, white matter (WM) functional topology in adolescent MDD remains underexplored. Given that WM functional signals reflect meaningful neural activity and are disrupted in psychiatric disorders, this study aimed to characterize WM functional connectome alterations in adolescents with MDD and examine their clinical associations. Methods Resting-state fMRI data were obtained from a cohort of adolescents with MDD (n = 320) and healthy controls (HCs, n = 144), as well as from an independent replication cohort. Following the construction of thresholded WM functional networks, graph-theoretical analyses were used to calculate global topological properties. Canonical correlation analysis (CCA) was used to examine associations between topology and clinical symptoms, while exploratory classification assessed their discriminative information and generalizability. Furthermore, subgroup analyses evaluated the effects of suicide attempt history, non-suicidal self-injury, childhood trauma, and sex. Results Compared with HCs, adolescent MDD exhibited significant reductions in the clustering coefficient, characteristic path length, and local efficiency. CCA identified distinct covariation patterns: reduced global integration was linked to severe suicidal ideation and depressed mood, while impaired local segregation was associated with vegetative symptoms such as weight loss and insomnia. Subgroup analyses revealed significant sexual dimorphism, with male patients demonstrating more severe topological impairments than females. A similar pattern was observed in the independent replication cohort. The classification analysis achieved above-chance accuracy (69.6% and 60% in the two cohorts). Conclusions Our results reveal a topologically shifted WM functional connectome structure in adolescent MDD, providing new clues to aid understanding the pathophysiology of its pathophysiology.