Abstract
BACKGROUND: Transcranial direct current stimulation (tDCS) is investigated to modulate neuronal function by applying a fixed low-intensity direct current to scalp. OBJECTIVES: We critically discuss evidence for a monotonic response in effect size with increasing current intensity, with a specific focus on a question if increasing applied current enhance the efficacy of tDCS. METHODS: We analyzed tDCS intensity does-response from different perspectives including biophysical modeling, animal modeling, human neurophysiology, neuroimaging and behavioral/clinical measures. Further, we discuss approaches to design dose-response trials. RESULTS: Physical models predict electric field in the brain increases with applied tDCS intensity. Data from animal studies are lacking since a range of relevant low-intensities is rarely tested. Results from imaging studies are ambiguous while human neurophysiology, including using transcranial magnetic stimulation (TMS) as a probe, suggests a complex state-dependent non-monotonic dose response. The diffusivity of brain current flow produced by conventional tDCS montages complicates this analysis, with relatively few studies on focal High Definition (HD)-tDCS. In behavioral and clinical trials, only a limited range of intensities (1-2 mA), and typically just one intensity, are conventionally tested; moreover, outcomes are subject brain-state dependent. Measurements and models of current flow show that for the same applied current, substantial differences in brain current occur across individuals. Trials are thus subject to inter-individual differences that complicate consideration of population-level dose response. CONCLUSION: The presence or absence of simple dose response does not impact how efficacious a given tDCS dose is for a given indication. Understanding dose-response in human applications of tDCS is needed for protocol optimization including individualized dose to reduce outcome variability, which requires intelligent design of dose-response studies.