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

Fennan Jia; Xiao Chen; Xingran Wang; Chuansheng Quan; Jing Ruan; Yuexiang Huang; Xiaoqian Fu; Yan Wang; Hongyan Sun; Lili Liu; Yuan Zhou; Chaogan Yan; Yansong Liu; Xiangdong Du

doi:10.1093/psyrad/kkaf014

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

Psychoradiology. 2025 May 28:5:kkaf014. doi: 10.1093/psyrad/kkaf014. eCollection 2025.

Authors

Fennan Jia^{1

2}, Xiao Chen³, Xingran Wang^{1

2}, Chuansheng Quan⁴, Jing Ruan¹, Yuexiang Huang², Xiaoqian Fu^{1

2}, Yan Wang², Hongyan Sun², Lili Liu², Yuan Zhou³, Chaogan Yan³, Yansong Liu², Xiangdong Du^{1

2}

Affiliations

¹ School of Medicine, Soochow University, Suzhou 215137, China.
² Department of Mood Disorders, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, China.
³ Department of Cognitive and Developmental Psychology, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China.
⁴ Department of Psychology, Zhangjiagang Fourth People's Hospital, Zhangjiagang, Jiangsu 215699, China.

Abstract

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.

Keywords: GDNF; fALFF; fMRI; major depressive disorder; rumination.