Abstract
Targeted electrical stimulation to specific thalamic regions offers a therapeutic approach for patients with refractory focal and generalized epilepsy who are not candidates for resective surgery. However, clinical outcome varies significantly, in particular for focal epilepsy, influenced by several factors, notably the precise anatomical and functional alignment between cortical regions generating epileptic discharges and the targeted thalamic stimulation sites. Here we hypothesized that targeting thalamic nuclei with precise anatomical and functional connections to epileptic cortical areas (an approach that we refer to as hodological matching) could enhance neuromodulatory effects on focal epileptic discharges. To investigate this, we examined three thalamic subnuclei (pulvinar nucleus, anterior nucleus, and ventral intermediate nucleus/ventral oral posterior nuclei) in a retrospective study involving 32 focal epilepsy patients. Specifically, we first identified hodologically organized thalamocortical fibers connecting these nuclei to individual seizure onset zones (SOZs), combining neuroimaging and electrophysiological techniques. Further, analysis of 216 spontaneous seizures revealed the critical role of matched thalamic nuclei in seizure development and termination. Importantly, electrical stimulation of hodologically-matched thalamic nuclei immediately suppressed intracortical interictal epileptiform discharges, contrasting with ineffective outcomes from stimulation of unmatched targets. Finally, we retrospectively evaluated 7 patients with a chronic hodologically-matched neurostimulation system, which led to a clinically relevant reduction in seizure frequency (median reduction 86.5%), that outstands the current clinical practice of unmatched targets (39%). Our results underscore the potential of hodological thalamic targeting to modulate epileptiform activity in specific cortical regions, highlighting the promise of precision medicine in thalamic neuromodulation for focal refractory epilepsy.