Joseph Tomy Linda Iris, Köksal-Ersöz Elif, Nica Anca, Yochum Maxime, Benquet Pascal, Wendling Fabrice
University of Rennes, Inserm-U1099, LTSI, Rennes, France.
Inria Lyon Research Center, Villeurbanne, France.
PLoS Comput Biol. 2025 Apr 28;21(4):e1012943. doi: 10.1371/journal.pcbi.1012943. eCollection 2025 Apr.
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.
中央中核刺激（CMS）的治疗应用因作用机制不明而受到限制。在本研究中，我们使用了立体脑电图（SEEG）信号，该信号来自一名由局灶性皮质发育异常（一种皮质发育畸形）引起的难治性癫痫患者。SEEG记录显示，CMS可抑制新皮质发作间期放电。这些效应具有频率依赖性：50Hz的CMS对新皮质癫痫样活动无影响，而70Hz、100Hz和150Hz的CMS可导致新皮质癫痫样活动的抑制期。这些抑制期的持续时间因刺激方案而异。我们建立了一个神经生理学上合理的丘脑皮质模型来解释这些观察结果。该模型包括新皮质和丘脑区域的谷氨酸能亚群和γ-氨基丁酸能亚群。突触抑制和短期可塑性机制被整合到丘脑区域。我们假设，高频CMS（>70Hz）期间丘脑抑制性亚群的增强激活会导致γ-氨基丁酸（GABA）溢出，从而激活丘脑皮质中继细胞上的突触GABA能受体。这减少了丘脑向新皮质的驱动输入，从而抑制了发育异常的新皮质组织中的发作间期放电。虽然70Hz和100Hz的CMS对丘脑皮质中继细胞的抑制作用最大，但150Hz的CMS并非如此，这表明突触前GABA能受体被激活，GABA再摄取速率增加。因此，我们的模型表明，CMS对新皮质癫痫活动的短暂抑制可能主要是由于丘脑皮质中继细胞的突触外强直抑制。这些发现有助于更深入地理解癫痫中的高频CMS，并为进一步研究和优化这种治疗方法铺平道路。
