Electrical stimulation of the central nervous system is a promising alternative for the treatment of pharmacoresistant epilepsy. Successful clinical and experimental stimulation is most usually carried out as continuous trains of current or voltage pulses fired at rates of 100 Hz or above, since lower frequencies yield controversial results. On the other hand, stimulation frequency should be as low as possible, in order to maximize implant safety and battery efficiency. Moreover, the development of stimulation approaches has been largely empirical in general, while they should be engineered with the neurobiology of epilepsy in mind if a more robust, efficient, efficacious, and safe application is intended. In an attempt to reconcile evidence of therapeutic effect with the understanding of the underpinnings of epilepsy, our group has developed a nonstandard form of low-frequency stimulation with randomized interpulse intervals termed nonperiodic stimulation (NPS). The rationale was that an irregular temporal pattern would impair neural hypersynchronization, which is a hallmark of epilepsy. In this review, we start by briefly revisiting the literature on the molecular, cellular, and network level mechanisms of epileptic phenomena in order to highlight this often-overlooked emergent property of cardinal importance in the pathophysiology of the disease. We then review our own studies on the efficacy of NPS against acute and chronic experimental seizures and also on the anatomical and physiological mechanism of the method, paying special attention to the hypothesis that the lack of temporal regularity induces desynchronization. We also put forward a novel insight regarding the temporal structure of NPS that may better encompass the set of findings published by the group: the fact that intervals between stimulation pulses have a distribution that follows a power law and thus may induce natural-like activity that would compete with epileptiform discharge for the recruitment of networks. We end our discussion by mentioning ongoing research and future projects of our lab.

中文翻译：

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非周期性刺激治疗难治性癫痫：应用、机制和新见解

中枢神经系统的电刺激是治疗药物耐药性癫痫的有希望的替代方法。成功的临床和实验刺激通常是作为以 100 Hz 或更高频率发射的连续电流或电压脉冲序列进行的，因为较低的频率会产生有争议的结果。另一方面，刺激频率应尽可能低，以最大限度地提高植入安全性和电池效率。此外，刺激方法的开发总体上在很大程度上是经验性的，而如果想要更强大、更高效、更有效和更安全的应用，它们应该在设计时考虑到癫痫的神经生物学。为了将治疗效果的证据与对癫痫基础的理解相协调，我们小组开发了一种非标准形式的低频刺激，具有随机的脉冲间隔，称为非周期性刺激 (NPS)。其基本原理是不规则的时间模式会损害神经超同步，这是癫痫的一个标志。在这篇综述中，我们首先简要回顾了关于癫痫现象的分子、细胞和网络水平机制的文献，以强调这一在疾病病理生理学中具有重要意义的经常被忽视的新兴特性。然后，我们回顾了我们自己关于 NPS 对急性和慢性实验性癫痫发作的疗效以及该方法的解剖和生理机制的研究，特别注意缺乏时间规律性导致不同步的假设。我们还提出了一个关于 NPS 时间结构的新见解，它可能更好地包含该小组发表的一系列发现：刺激脉冲之间的间隔具有遵循幂律的分布，因此可能会诱发类似自然的活动，将与癫痫样放电竞争网络的招募。我们通过提及我们实验室正在进行的研究和未来的项目来结束我们的讨论。