The Amplified Burden of Depression in Drug-Resistant Epilepsy: Role of Limbic Network Dynamic Reconfiguration

Objectives: To explore potential associations between drug resistance and limbic network (LN) dynamic functional interactions in temporal lobe epilepsy (TLE), whether these LN alterations are associated with and potentially mediate comorbid depression severity, and their potential neurochemical and transcriptomic underpinnings. Methods: This cross-sectional study included 49 patients in the Responsive group, 33 patients in the Resistant group, and 50 healthy controls (HCs). Using resting-state fMRI, we derived LN dynamic integration coefficients and used non-negative matrix factorization (NMF) to identify coactivation patterns. Depressive symptoms (Self-Rating Depression Scale, SDS), LN integration, and NMF pattern expression were compared across groups (ANOVA) and correlated. Mediation analysis tested if LN integration mediated the relationship between drug resistance status and SDS scores. LN integration differences were spatially correlated with neurotransmitter receptor density and Allen Human Brain Atlas transcriptomic data. Results: Patients in the Resistant group reported significantly higher SDS scores than patients in the Responsive group (p = 0.008). LN integration with the dorsal attention network (DAN) and fronto-parietal network (FPN) was significantly lower in the Resistant group compared to the Responsive group (p = 0.001; p < 0.001). NMF analysis identified key LN-DAN (p = 0.013) and LN-FPN (p < 0.001) coactivation patterns. In TLE patients, DAN-LN integration was negatively correlated with depressive symptoms (r = -0.28, p = 0.01), and lower integration levels significantly mediated the relationship between group status (Resistant vs. Responsive) and increased symptom severity (p < 0.001). These LN integration coefficient differences (Responsive group vs. Resistant group) were associated with 5-hydroxytryptamine 1B (5-HT1B; r = 0.29, p = 0.036) and dopamine D2 (D2; r = -0.29, p = 0.034) receptor densities, and linked to gene expression pathways including telomerase activity regulation (p < 0.001). Interpretation: This study identifies dynamic LN dysregulation, supported by distinct neurochemical and transcriptomic profiles, as a core bridging mechanism potentially contributing to comorbid depression linked to drug response status in TLE patients.