Transcranial electric stimulation modulates firing rate at clinically relevant intensities

Background Notwithstanding advances with low-intensity transcranial electrical stimulation (tES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. Objective To measure electric fields magnitude and their effects on neuronal firing rate of hippocampal neurons in freely moving rats, and to establish calibrated computational models of current flow. Methods Current flow models were calibrated on electric field measures in the motor cortex (n=2 anesthetized rats) and hippocampus. A Neuropixels 2.0 probe with 384 channels was used in an in-vivo rat model of tES (n = 4 freely moving and 2 urethane anesthetized rats) to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 μA of applied skull currents). Results Electric fields of as low as 0.35 V/m (0.25 - 0.47) acutely modulated average firing rate in the hippocampus. At these intensities, firing rate effects increased monotonically with electric field intensity at a rate of 11.5 % per V/m (7.2 - 18.3). For the majority of excitatory neurons, firing increased for soma-depolarizing stimulation and diminished for soma-hyperpolarizing stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. Conclusion In awake animals, electric fields modulate spiking rate above levels previously observed in vitro. Firing rate effects are likely mediated by somatic polarization of pyramidal neurons. We recommend that all future rodent experiments directly measure electric fields to insure rigor and reproducibility.