Caron Davide, Canal-Alonso Ángel, Panuccio Gabriella
Enhanced Regenerative Medicine, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
BISITE Research Group, University of Salamanca, 37008 Salamanca, Spain.
Biology (Basel). 2022 Feb 26;11(3):371. doi: 10.3390/biology11030371.
Mesial temporal lobe epilepsy (MTLE) is the most common partial complex epilepsy in adults and the most unresponsive to medications. Electrical deep brain stimulation (DBS) of the hippocampus has proved effective in controlling seizures in epileptic rodents and in drug-refractory MTLE patients. However, current DBS paradigms implement arbitrary fixed-frequency or patterned stimuli, disregarding the temporal profile of brain electrical activity. The latter, herein included hippocampal spontaneous firing, has been shown to follow lognormal temporal dynamics. Here, we present a novel paradigm to devise DBS protocols based on stimulation patterns fashioned as a surrogate brain signal. We focus on the interictal activity originating in the hippocampal subfield CA3, which has been shown to be anti-ictogenic. Using 4-aminopyridine-treated hippocampus-cortex slices coupled to microelectrode array, we pursue three specific aims: (1) address whether lognormal temporal dynamics can describe the CA3-driven interictal pattern, (2) explore the possibility of restoring the non-seizing state by mimicking the temporal dynamics of this anti-ictogenic pattern with electrical stimulation, and (3) compare the performance of the CA3-surrogate against periodic stimulation. We show that the CA3-driven interictal activity follows lognormal temporal dynamics. Further, electrical stimulation fashioned as a surrogate interictal pattern exhibits similar efficacy but uses less pulses than periodic stimulation. Our results support the possibility of mimicking the temporal dynamics of relevant brain signals as a straightforward DBS strategy to ameliorate drug-refractory epilepsy. Further, they herald a paradigm shift in neuromodulation, wherein a compromised brain signal can be recreated by the appropriate stimuli distribution to bypass trial-and-error studies and attain physiologically meaningful DBS operating modes.
内侧颞叶癫痫（MTLE）是成人中最常见的部分性复杂性癫痫，也是对药物最无反应的癫痫类型。海马体的深部脑电刺激（DBS）已被证明在控制癫痫啮齿动物和药物难治性MTLE患者的癫痫发作方面有效。然而，目前的DBS模式采用任意固定频率或模式化刺激，而忽略了脑电活动的时间特征。后者，包括海马体的自发放电，已被证明遵循对数正态时间动态。在这里，我们提出了一种新的模式，以基于作为替代脑信号的刺激模式来设计DBS方案。我们专注于起源于海马体CA3亚区的发作间期活动，该活动已被证明具有抗癫痫发作作用。使用与微电极阵列耦合的4-氨基吡啶处理的海马体-皮质切片，我们追求三个特定目标：（1）确定对数正态时间动态是否可以描述CA3驱动的发作间期模式，（2）探索通过电刺激模仿这种抗癫痫发作模式的时间动态来恢复非癫痫发作状态的可能性，以及（3）比较CA3替代物与周期性刺激的性能。我们表明，CA3驱动的发作间期活动遵循对数正态时间动态。此外，作为替代发作间期模式形成的电刺激表现出相似的疗效，但使用的脉冲比周期性刺激少。我们的结果支持将相关脑信号的时间动态作为一种直接的DBS策略来改善药物难治性癫痫的可能性。此外，它们预示着神经调节领域的范式转变，其中受损的脑信号可以通过适当的刺激分布来重建，以绕过反复试验研究并实现具有生理意义的DBS操作模式。
