Abstracts

Rationale: Epilepsy, characterized by recurrent seizures caused by excessive synchronized electrical discharges, affects over 50 million people globally, and approximately 30% of these, experience intractable and disabling seizures. For medically refractory epilepsy (MRE), the current standard of care is the resection of the epileptogenic zone (EZ). However, if the cortical area is unsuitable for safe removal, neuromodulation techniques such as thalamic Deep Brain Stimulation (DBS) are alternative treatments. The involvement of the thalamus in epilepsy dates to the late 1950’, with the "centrencephalic" concept for generalized seizures, involving thalamic nuclei in spike-wave discharges. The anterior nucleus of the thalamus (ANT) is currently the only FDA-approved DBS target for epilepsy, though outcomes vary depending on the patient's specific epileptogenic network. Here, we argue the effectiveness of DBS could be improved by targeting thalamic subnuclei that have preferential connectivity to the epileptogenic zone (EZ), an approach that we refer to as hodological matching.


Methods: To explore this hypothesis, we tested a unique cohort of 26 patients undergoing stereoelectroencephalography (SEEG) exploration. We focused on three thalamic subnuclei: the ANT, the ventral intermediate/ventral oral posterior (VIM/VOP) nucleus, and the pulvinar nucleus (PUL). During hospitalization, we first performed neuroimaging and thalamocortical evoked potential to define the anatomical organization of the thalamic nuclei. We then investigated mechanisms of thalamocortical interactions in 216 spontaneous seizures with simultaneous recordings of the thalamus and the EZ. We computed h2 correlation and Granger Causality coefficient. Finally, we applied high-frequency stimulation of the thalamus and analyzed the effect on interictal epileptiform discharges (IEDs).


Results: In our first analysis, we validated the hodological organization of thalamocortical fibers via electrophysiology and neuroimaging techniques, confirming distinct connectivity patterns between these thalamic nuclei and various cortical areas. Our connectivity analysis performed during ictal events highlighted significant role of thalamic involvement in seizure dynamics, particularly in seizure termination. This was observed through specific firing patterns and altered connectivity during ictal events. Such interactions were particularly prominent when the cortical EZ was matching the thalamic nuclei of interest. Further, electrical stimulation of hodologically-matched nuclei immediately suppressed IEDs, and chronic stimulation in two patients resulted in a reduction in seizure frequency.


Conclusions: Overall, targeting DBS to match the hodology of thalamocortical connections appears to be a promising approach to enhance treatment efficacy for refractory epilepsy. This study's results indicate that hodologically-matched thalamic DBS can suppress pathological discharges and reduce seizure frequency, offering a potential strategy to improve clinical outcomes for patients with intractable epilepsy.


Funding: funding from NIH to Gonzalez-Martinez