From network hub to therapeutic target: the role of mediodorsal thalamic nucleus in epilepsy

Mediodorsal thalamic nucleus (MD) is a pivotal hub for cortical functions, characterized by significant heterogeneity in its anatomical connectivity, cytoarchitecture, and function, constituting a complex nucleus composed of multiple functionally specialized subregions. We elaborates on the heterogeneous anatomical connectivity of MD and its crucial role in supporting higher cognitive functions such as working memory, cognitive control, and emotional integration. It then focuses on the multifaceted role of MD within epileptic pathological networks. Substantial evidence indicates that MD in patients with epilepsy exhibits structural atrophy and abnormalities in functional connectivity, with its activity being recruited early during seizures and likely involved in seizure propagation and generalization. However, the therapeutic efficacy of neuromodulation targeting MD, such as deep brain stimulation (DBS), remains contentious, highlighting the current insufficient understanding of its distinct functional subregions and specific pathway mechanisms. Finally, the review discusses the challenges and future directions in translating MD into an effective therapeutic target. It emphasizes that future research must endeavor to elucidate its causal mechanisms within epileptic networks at the subregional level, account for the heterogeneity of seizure onset frequencies, and develop precise intervention strategies targeting specific epileptogenic pathways, thereby advancing novel therapies focused on thalamocortical circuits toward clinical application.