Disrupted thalamic functional hierarchy on resting-state fMRI in idiopathic generalized epilepsy

Abstract Objective Abnormal thalamo-cerebral and thalamo-cerebellar interactions are implicated in idiopathic generalized epilepsy (IGE), but their influence on thalamic functional hierarchy remains unclear. This study aimed to characterize thalamic functional hierarchy across varying connectivity strengths in IGE. Materials and methods Resting-state functional magnetic resonance imaging (fMRI) data were collected for 144 IGE patients and 222 healthy controls. The voxel-wise thalamo-cerebral and thalamo-cerebellar functional connectivity (FC) was first computed. Connectome gradient mapping was applied separately to anticorrelated and correlated connectivity strengths for both thalamo-cerebral and thalamo-cerebellar pathways. Furthermore, the first three thalamic gradient features were investigated using eccentricity. Results In both healthy controls and patients with IGE, the thalamus predominantly coupled with low-order unimodal networks under anticorrelated conditions, and with high-order cognitive networks under correlated conditions. Moreover, connectome-dependent alterations were further observed in the limbic network, attentional network, and cerebellar systems in IGE. Additionally, thalamic gradients in IGE showed marked distributional abnormalities across a broad range of connectivity strengths. Notably, both thalamo-cerebral and thalamo-cerebellar eccentricity revealed shared increases and decreases within motor and cognitive thalamic nuclei, together with additional pathway-specific abnormalities unique to the thalamo-cerebellar system. These dispersion abnormalities were associated with poorer working memory performance in IGE, with three significant thalamic clusters identified (all p ≤ 0.008). Conclusion These fMRI findings demonstrate disruption of the thalamic functional hierarchy, manifested as nucleus-specific alterations in integration and segregation in IGE. Collectively, this study provides novel insights into thalamic functional abnormalities in epilepsy. Key Points Question The hierarchical disruption of thalamo-cerebral and thalamo-cerebellar pathways in idiopathic generalized epilepsy and its clinical significance remains unclear. Findings Both pathways show altered functional hierarchy, with eccentricity changes in specific thalamic nuclei linked to slower working memory performance in idiopathic generalized epilepsy. Relevance statement This study revealed nucleus-specific integration-segregation disruptions in IGE that correlated with poorer working memory performance, providing an important window into thalamic dysfunction mechanisms.