Centromedian Nucleus Connectivity with Brainstem Nuclei Unveils a Common Mechanism for Seizure Control

Background Epilepsy affects approximately 50 million individuals worldwide, with nearly one-third developing drug-resistant epilepsy (DRE). The centromedian nucleus of the thalamus (CM) and the brainstem are integral components of seizure-modulating networks and represent promising targets for neuromodulation. This study aimed to map structural connectivity between CM and specific brainstem nuclei using probabilistic tractography and to evaluate whether connectivity patterns correlate with seizure reduction following CM-stimulation Methods Diffusion MRI data from 100 healthy subjects from the Human Brain Connectome database were analyzed to characterize CM–brainstem connectivity. Additionally, 11 patients with generalized DRE who underwent deep brain stimulation (DBS) or responsive neurostimulation (RNS) targeting CM were retrospectively studied. Volumes of tissue activated (VTAs) were used as tractography seeds, and connectivity strength was quantified as probability of connectivity (ProbC), corrected for distance. Two subanalyses were performed by dividing patients into two or three groups based on the threshold for seizure frequency reduction (SFR). Results In the two-group analysis, responders (>50% SFR) exhibited significantly higher connectivity between VTAs and the nucleus of the solitary tract (NTS) compared with non-responders (<50% SFR), and NTS connectivity was the only parameter significantly correlated with seizure reduction (r=0.762, p<0.001). The three-group analysis confirmed that high responders (>50% SFR) had stronger NTS connectivity than both partial (SFR = 50%) and low responders (<50% SFR), who showed greater connectivity with raphe nuclei. Conclusions CM–NTS structural connectivity may underlie therapeutic response to CM-neuromodulation, suggesting a potential shared mechanism with vagus nerve stimulation.