Background Default mode network (DMN) disruption and systemic inflammation are hallmarks of major depressive disorder (MDD), but their relationship with behavioral impairments is unclear. This study aimed to characterize DMN spatiotemporal dynamics in MDD and link them to inflammation and behavioral deficits. Method Resting-state functional magnetic resonance imaging data were obtained from 87 MDD and 104 healthy controls (HC). Periodic spatiotemporal patterns (PSTPs) were defined by the switching of anti-correlation between the DMN and task-positive network. Functional couplings between DMN and cerebral networks within these patterns were then calculated. Subsequently, associations between DMN subsystem couplings and behaviors were assessed, and lasso regression was used to evaluate their predictive effects on behavior. Moderation analyses and cytokine-based subgroup comparisons were further conducted to examine the effect of inflammation on brain–behavior relationships. Results In MDD, couplings within the DMN increased, whereas couplings between DMN and attention and salience networks decreased. Additionally, the association was observed between DMN B coupling and Trail Making Test Part B (TMT-B) performance in MDD. These alterations also predicted the digital span test (DST). Moderation analyses showed that interleukin (IL)-17 A strengthened DMN–behavior associations, whereas IL-8 attenuated them. Consistently, higher IL-17 A levels were associated with more pronounced DMN coupling abnormalities, while lower IL-8 levels were linked to DST and TMT-B deficits. Conclusions This study demonstrates internal enhancement and external decoupling of the DMN in MDD, along with the differential modulation of inflammation on brain–behavior relationships. These findings provide new insights into the pathophysiology of MDD. Trial registration Not applicable.
Chen et al. (2026) studied this question.