Parametrizing alternating current stimulation for neuromodulation

The clinical use of alternating current stimulation (ACS) has been confounded by heterogeneity in patient responses. Optimization of this treatment requires understanding the dependence of neuronal responses on ACS parameters. We sought to characterize neuronal responses across varying ACS frequencies and amplitudes and assess the extent to which changes in neuronal activity persist beyond the cessation of the stimulation, thereby informing ACS optimization pathways and evaluating the potential for sustained neuromodulation. We delivered subcutaneous ACS while recording intracortical electrophysiological activity in adult rats. We applied ACS for 1 or 20 minutes and analyzed ensuing spiking activity, power spectra, and low-frequency to high-frequency phase-amplitude coupling (LF-HF PAC). Both durations of ACS elicited a modulation of firing patterns (either in rate or entrainment) in most neurons, in a stimulation frequency- and amplitude-dependent manner. Changes in firing rate were more frequent, albeit modest, whereas changes in entrainment were rarer, but pronounced. Increasing ACS amplitude or frequency increased the degree of entrainment. Further, entrainment changes persisted beyond the 20-minute ACS, at half their online level. Neuronal power and LF-HF PAC increased proximal to excited, but decreased near suppressed neurons. Neuronal entrainment was observed alongside decreased power and LF-HF PAC. The prominent entrainment response to prolonged high-frequency ACS observed here supports the potential of ACS for facilitating signal integration and promoting functional reorganization via spike timing-dependent plasticity. In turn, we found broader temporal windows of excitation under low ACS frequencies engendered greater variability in spike timing, which may be utilized to reduce hypersynchronous or task-irrelevant activity.