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.