Computational modeling of frequency-dependent neocortical response to thalamic neurostimulation in epilepsy

The therapeutic application of centromedian nucleus stimulation (CMS) has been limited by uncertainties regarding its mechanism of action. In this study, we used stereoelectro-encephalography (SEEG) signals recorded from a patient with refractory epilepsy, caused by focal cortical dysplasia, which is a malformation of cortical development. SEEG recordings revealed that neocortical interictal discharges could be suppressed by CMS. These effects were found to be frequency-dependent: while 50 Hz CMS induced no change in neocortical epileptiform activity, CMS at 70 Hz, 100 Hz and 150 Hz led to periods of suppression of neocortical epileptiform activity. These periods were shown to have different durations depending on the stimulation protocol. We developed a neurophysiologically-plausible thalamocortical model to explain these observations. This model included glutamatergic subpopulations and GABAergic subpopulations in the neocortical and the thalamic compartments. Synaptic inhibition and short-term plasticity mechanisms were integrated into the latter compartment. We hypothesized that the enhanced activation of thalamic inhibitory subpopulations during high frequency CMS (>70Hz) would result in GABA spillover which activated synaptic GABAergic receptors on the thalamocortical relay cells. This decreased the thalamic driving-input to the neocortex, hence suppressing interictal discharges in the dysplastic neocortical tissue. While inhibition of thalamocortical relay cells was maximal for CMS at 70 Hz and 100 Hz, this was not the case for 150 Hz CMS, suggesting that presynaptic GABAergic receptors were activated and that the rate of GABA reuptake was increased. Thus, our model suggests that the transient suppression of the neocortical epileptic activity with CMS may be primarily due to extra-synaptic tonic inhibition in the thalamocortical relay cells. These findings contribute to a deeper understanding of high-frequency CMS in epilepsy and pave the way for further research and optimization of this therapeutic approach.