Connectome-wide dysconnectivity signature tracks clinical status in major depressive disorder

Major depressive disorder (MDD) is increasingly conceptualized as a dysconnection syndrome involving widespread brain network disruptions. However, most neuroimaging studies rely on within-sample case–control comparisons, leaving unclear whether identified connectivity patterns generalize across populations or explain clinical variation within patients. In this cross-sectional observational study, we test whether a depression-related connectivity pattern from a Japanese cohort (824 controls, 229 MDD) generalizes to a German cohort (923 controls, 694 MDD) using polyconnectomic scores (PCS), a metric for quantifying whole-brain connectivity disturbances. PCS MDD significantly distinguished patients from controls ( z = 5.1, P < 0.001), with the highest scores in acutely depressed patients. Its diagnostic signal was distributed across the connectome, with performance declining under stricter edge-level thresholds. PCS MDD captured a spatially specific dysconnectivity pattern that explained variance beyond mean within- and between-network connectivity summaries. No associations were found between PCS MDD and past disease course in MDD patients. By contrast, patients with higher PCS MDD exhibited greater current symptom severity ( r = 0.09, P = 0.022), particularly loss of pleasure ( r = 0.12, P FDR = 0.041). These findings demonstrate that a depression-related connectivity pattern generalizes across populations and relates selectively to current symptom severity.