Nonperiodic stimulation for the treatment of refractory epilepsy: Applications, mechanisms, and novel insights

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.