Corticothalamic loops and cellular networks: Implications for thalamic neuromodulation in epilepsy

Thalamic neuromodulation has emerged as a promising therapy to reduce seizures in patients with drug-resistant epilepsy who are not candidates for resective or ablative surgical treatments. This advance creates therapeutic opportunities for patients with seizure foci that are generalized, poorly localized, multifocal, or in eloquent cortex. However, optimal treatment requires improved understanding of the thalamocortical circuits and cellular mechanisms that support seizure initiation, propagation, and termination. With its dense, nucleus-specific reciprocal connectivity with cortical and limbic regions and intrinsic oscillatory properties, the thalamus is well-constructed and well-positioned to influence epileptic activity. Importantly, distinct thalamic nuclei exhibit differing engagement depending on seizure type and propagation patterns. Here, we review current knowledge of thalamocortical anatomy and function, cellular mechanisms of ictal propagation, and the role of the thalamus in generalized and focal seizures, with emphasis on human studies. We further examine how these anatomical and mechanistic insights inform neuromodulatory interventions aimed at improving seizure control.