Montage Matters: The Influence of Transcranial Alternating Current Stimulation on Human Physiological Tremor

Background Classically, studies adopting non-invasive transcranial electrical stimulation have placed greater importance on the position of the primary “stimulating” electrode than the secondary “reference” electrode. However, recent current density modeling suggests that ascribing a neutral role to the reference electrode may prove an inappropriate oversimplification. Hypothesis We set out to test the hypothesis that the behavioral effects of transcranial electrical stimulation are critically dependent on the position of the return (“reference”) electrode. Methods We examined the effect of transcranial alternating current stimulation (sinusoidal waveform with no direct current offset at a peak-to-peak amplitude of 2000 μA and a frequency matched to each participant's peak tremor frequency) on physiological tremor in a group of healthy volunteers (N = 12). We implemented a sham-controlled experimental protocol where the position of the stimulating electrode remained fixed, overlying primary motor cortex, whilst the position of the return electrode varied between two cephalic (fronto-orbital and contralateral primary motor cortex) and two extracephalic (ipsilateral and contralateral shoulder) locations. We additionally controlled for the role of phosphenes in influencing motor output by assessing the response of tremor to photic stimulation, through self-reported phosphene ratings. Results Altering only the position of the return electrode had a profound behavioral effect: only the montage with extracephalic return contralateral to the primary stimulating electrode significantly entrained physiological tremor (15.9% ± 6.1% increase in phase stability, 1 S.E.M.). Photic stimulation also entrained tremor (11.7% ± 5.1% increase in phase stability). Furthermore, the effects of electrical stimulation are distinct from those produced from direct phosphene induction, in that the latter were only seen with the fronto-orbital montage that did not affect the tremor. Conclusion The behavioral effects of transcranial alternating current stimulation appear to be critically dependent on the position of the reference electrode, highlighting the importance of electrode montage when designing experimental and therapeutic protocols.