Cellular and Neural Network Mechanism of Transcranial Electric Stimulation

揭示神经刺激技术的机制是Brain Initiative （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，通过在大脑中产生弱电场，对癫痫发作控制、行为和认知提供大范围的影响。这些弱电场如何有效地与神经活动相互作用仍然是一个悬而未决的问题，TES的作用机制仍然是未知的。我们的实验室最近发现，触电偶联（电场引起的非突触神经偶联）在神经招募中起着重要作用，并可能解释tes诱导的效应。我们提出验证触觉耦合是TES作用机制的假设。我们将结合体外新型电压成像技术、转基因小鼠光遗传刺激和体内电生理实验，研究ephaptic偶联与三种已知的es诱导效应之间的联系，其独立的具体目的如下：1)研究ephaptic偶联在es诱导的间期峰传播速度调制中的作用。2)确定脑电偶联在tes诱导癫痫发作抑制中的作用。3)研究触觉偶联在tes诱导的神经振荡效应中的作用。这一建议如果成功，将提供对TES诱导效应的新见解，揭示TES的作用机制，并为开发改进的TES方案打开大门，提高这种非突触治疗方式的效率。

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.