Brain stimulation by network resonance with weak electric fields probed by optogenetics in vitro

Transcranial Alternating Current Stimulation (tACS) is a novel brain stimulation paradigm that is investigated as a non-invasive modality for treating neuropsychiatric disorders and augmenting cognition. tACS likely enhances endogenous oscillations in cortex. Yet, no consensus has been reached about which stimulation parameters, in particular stimulation amplitude and frequency, are the most effective. We hypothesized that resonance at the network level mediates enhancement of cortical oscillations by tACS. In this study, we used a novel experimental framework to study the mechanism by which tACS modulates cortical network activity. We combined optogenetic patterning of spontaneous activity with application of weak electric fields (EF) in live slices of mouse cortex in vitro. We entrained the networks at 1 Hz using optogenetic stimulation of layer V pyramidal cells that expressed channelrhodopsin 2. We then applied EF at the endogenous frequency, the first harmonic and two nearby frequencies (1, 2, 0.8 and 1.2 Hz, respectively). In agreement with our hypothesis, we observed that stimulation at the endogenous frequency caused the most pronounced enhancement of the ongoing network activity. Such novel mechanistic insight may pave the way towards more refined and therefore more effective tACS neurotherapeutics.