Cellular and Neural Network Mechanism of Transcranial Electric Stimulation

揭示神经刺激技术的机制是大脑倡议(RFA-NS-20-006)的一个重要目标。经颅电刺激(TES)是一种非侵入性的神经调节技术，通过在大脑中产生微弱的电场，对癫痫的控制、行为和认知提供广泛的影响。这些弱电场如何与神经活动有效地相互作用仍是一个悬而未决的问题，TES的作用机制仍不清楚。我们的实验室最近发现，触觉耦合(非突触神经电场耦合)在神经元招募中发挥着重要作用，并可能解释TES诱导的效应。我们建议检验触觉耦合是TES的作用机制的假说。结合体外电压成像技术、转基因小鼠的光遗传刺激和体内电生理实验，我们将在以下三个独立的特定目标上研究触觉耦合与TES诱导的三种效应之间的联系：1)研究触觉耦合在TES诱导的发作间期棘波传播速度调节中的作用。2)确定触觉耦合在TES致痫抑制中的作用。3)研究触觉耦合在TES诱发的神经振荡效应中的作用。这一提议如果成功，将为TES诱导的效应提供新的见解，揭示TES的作用机制，并为这种非突触治疗方式开发效率更高的改进TES方案打开大门。

Unveiling mechanisms of neural stimulation technologies is an important goal of the Brain Initiative (RFA-NS-20-006). Transcranial electric stimulation (TES) is a non-invasive neuromodulation technique to provide wide-range effects on seizure control, behaviors, and cognition by generating weak electric fields in the brain. It is still an open question of how these weak electric fields can interact effectively with neural activity, and the mechanism of action of TES is still unknown. Our laboratory has recently found that ephaptic coupling (non-synaptic neural coupling by electric fields) plays a significant role in neural recruitment and could possibly explain the TES-induced effects. We propose to test the hypothesis that ephaptic coupling is the mechanism of action of TES. With the combination of in-vitro novel voltage imaging techniques and optogenetic stimulation in the transgenic mice and in-vivo electrophysiological experiments, we will study the links between the ephaptic coupling and three known TES-induced effects in the following independent specific aims: 1) Investigate the role of ephaptic coupling in TES-induced propagation speed modulation of interictal spikes. 2) Determine the role of ephaptic coupling in TES-induced seizure suppression. 3) Study the role of ephaptic coupling in TES-induced effects on neural oscillations. This proposal, if successful, will provide a novel insight into TES-induced effects, reveal the mechanism of action of TES, and open the door to the development of improved TES protocols with improved efficiency for this non-synaptic therapeutic modality.