Response of neocortical dysplasia to thalamic high-frequency stimulation

The therapeutic application of centromedian nucleus stimulation (CMS) has been limited by the lack of knowledge of its mechanism of action. In this study, we used stereoelectroencephalography (SEEG) signals recorded from a patient with epilepsy, caused by focal cortical dysplasia. The recordings revealed frequency-dependent suppression of neocortical interictal discharges linked to the application of CMS. There was no change in neocortical interictal discharges with 50Hz CMS, but with CMS at 70Hz, 100Hz and 150Hz, varying periods of suppression were observed during and/or after stimulation. We developed a physiologically-plausible thalamocortical model to explain this observation. This model included glutamatergic subpopulations and GABAergic subpopulations (VIP, PV, SST, NGFC) in the neocortical compartment. Extrasynaptic inhibition and short-term plasticity mechanisms were integrated into a rudimentary thalamic compartment. We hypothesised that with CMS the inhibitory subpopulations in the thalamus would be strongly activated. The subsequent GABA spillover could then activate extrasynaptic GABAergic receptors of the thalamic cells. During CMS at 70Hz and 100Hz, the decrease of thalamic drive to the neocortex effectively suppresses interictal discharges in the dysplastic tissue. Whereas during 150Hz CMS, we hypothesised that the activation of presynaptic GABA-B receptors and an increased rate of GABA reuptake shortens the suppression period. Thus, our model suggests that transitory suppression of the neocortical epileptic activity with CMS may primarily be due to the extrasynaptic tonic inhibition in the thalamus. These findings contribute to a deeper understanding of high-frequency CMS in epilepsy and paves the way for further research and optimization of this therapeutic approach.