Mimicking and mitigating the cutaneous response to transcranial electrical stimulation using interferential and combinatorial techniques

Abstract

Transcranial electrical stimulation (tES) is a promising adjunct treatment for neurological impairment and mental health disorders. The modulatory effects of tES are small to moderate, and accrue over days to weeks with repeated administration, but these effects are also inconsistent across individuals, which poses a challenge for its clinical administration. Some of the variability in tES may stem from uncontrolled behavioral factors, and inadequate dosing of current across individuals, so new strategies are needed to address these issues. We evaluated the biophysics of emerging techniques for tES and provided new testable hypotheses for the tolerability of interferentail and combinatorial waveforms. Millisecond pulsatile currents may serve as suitable alternatives to alternating currents in modulating neural spike timing from tES. Pulsatile currents limit spike generation in nerves and may be tolerated above the standard limit of 2 mA when combined with a direct current to block nerve activation. Additionally, we posit that combinations of kilohertz interferential currents can mimic the nerve response of different tES waveforms but with minimal modulation of cortical neurons, providing a new strategy for active placebo stimulation. These results will help guide design of interferential tES strategies for better blinding and provide a testable model for evaluating the tolerability of new combinatorial strategies.