Substantia nigra iron-related alterations, white matter disruption, and functional network dysconnectivity in temporal lobe epilepsy: a multimodal neuroimaging study

Abstract Background Although the substantia nigra (SN) has been implicated in temporal lobe epilepsy (TLE) pathophysiology, clinical studies remain scarce. This study aimed to characterize alterations in SN susceptibility, white matter (WM) microstructure, and functional connectivity (FC), as well as their associations with cognitive functions in TLE patients. Methods This study included 20 right-TLE (RTLE), 21 left-TLE (LTLE), and 23 healthy controls (HCs). Multimodal neuroimaging was used to assess the susceptibility, diffusion tensor imaging metrics, and FC of SN subregions. Group differences were examined by analysis of covariance. Exploratory correlation analyses were performed to evaluate associations between imaging metrics and cognitive performance. Results RTLE patients showed higher susceptibility (post-hoc P = 0.015 vs. HCs; P = 0.002 vs. LTLE) and radial diffusivity (RD) (post-hoc P = 0.014 vs. HCs; P = 0.001 vs. LTLE) in the contralateral substantia nigra pars reticulata (SNr), alongside lower fractional anisotropy (FA) (post-hoc P = 0.009 vs. HCs; P = 0.006 vs. LTLE) in the contralateral substantia nigra pars compacta (SNc). LTLE patients exhibited decreased FA in the ipsilateral SNr (post-hoc P < 0.001 vs. HCs; P = 0.001 vs. RTLE) and reduced connectivity between the left SNc and the right superior parietal lobule ( P = 0.026, cluster-level FDR corrected). Susceptibility and RD positively correlated in the contralateral SNr of RTLE cohorts ( r = 0.564, uncorrected P = 0.010). Exploratory analyses suggested associations between SNr susceptibility, FA, and cognitive performance in TLE patients (all uncorrected P < 0.05). Conclusions Our multimodal findings suggest subregion- and laterality-specific alterations in the SN of patients with TLE, with patterns differing between RTLE and LTLE.