Subcortical Structures and Epilepsy

Epilepsy is a network disorder characterized by dynamic interactions between cortical and subcortical circuits that collectively facilitate seizure initiation, propagation, maintenance, and termination. While cortical structures have traditionally dominated epilepsy research, diagnostic evaluation, and therapeutic targets, recent years have witnessed growth in exploring the role of subcortical structures beyond the well-studied limbic system for several decades. Structures such as the thalamus have emerged as critical nodes in epileptic networks, with growing evidence from neuromodulation studies underscoring its critical role in seizure dynamics. This shift reflects a paradigm change from localized cortical focus models to a more comprehensive understanding of distributed cortical-subcortical networks in epilepsy pathophysiology.

In this review, we explore different subcortical structures and their involvement in both generalized and focal epilepsies, suggesting that there must be continued research into cortical-subcortical network dynamics. The thalamus (anterior, centromedian, and pulvinar nuclei) is highlighted as a critical hub for seizure dynamics and a validated target for neuromodulation. The cerebellum is recast as an active participant in seizure modulation and a site of pathology, rather than a passive structure. The basal ganglia are detailed as modulators of seizure propagation, while the corpus callosum is identified as a primary pathway for bilateral ictal spread. Hypothalamic hamartomas are presented as a unique model of intrinsic subcortical epileptogenesis. The brainstem's potential role in facilitating seizure propagation and its implication in SUDEP is also discussed. The manuscript further explores the fundamental concept of failed lateral inhibition within cortical-subcortical networks as a key mechanism in epileptogenesis.

Subcortical structures are integral components of epileptic networks, with roles ranging from seizure initiation and propagation to modulation and termination. A nuanced understanding of specific subcortical nuclei (e.g., thalamic subnuclei) is essential for advancing targeted neuromodulation therapies like deep brain stimulation. Future research and therapeutic strategies must adopt an integrated cortical-subcortical network perspective to improve surgical outcomes, develop novel treatments, and reduce morbidity in epilepsy.