Activity of the default mode network mediates the effect of peripheral plasma glial cell line-derived neurotrophic factor levels on rumination in major depressive disorder patients.

Background: Rumination is a pivotal psychopathological process in major depressive disorder (MDD). The neurotrophic hypothesis suggests that glial cell line-derived neurotrophic factor (GDNF) might play a role in brain dysfunction and clinical symptoms of MDD. However, the relationship remains unclear.

Methods: Thirty-three individuals with MDD and 33 healthy controls (HCs) underwent functional magnetic resonance imaging (fMRI) while performing a rumination state task designed to induce sustained, active rumination. The Ruminative Response Scale (RRS) was administered to assess individual rumination tendency. Brain activity within the default mode network (DMN) subsystems during rumination was characterized using both fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity (FC) analyses. Serum levels of GDNF and inflammatory markers [interleukin (IL)-6, IL-8, and C-reactive protein] were quantified in all participants. We then examined the relationships between regional brain activity (fALFF values), GDNF levels, and rumination severity (RRS scores) in the MDD group.

Results: Compared to HCs, MDD patients exhibited significantly reduced serum levels of both GDNF (t = -3.204, P = 0.002) and IL-8 (t = -3.239, P = 0.002). Significant interaction effects were observed in fALFF within both the dorsal medial prefrontal cortex (DMPFC; F = 25.075, P < 0.001) and medial temporal lobe (MTL; F = 28.753, P < 0.001) subsystems of the DMN. Mediation analysis revealed that the relationship between GDNF levels and brooding rumination in MDD patients was mediated by neural activity within the DMPFC subsystem.

Conclusions: In MDD patients, GDNF levels were associated with neural activity within the DMPFC subsystem of the DMN, which statistically mediated the link to rumination severity.