Zeinab Esmaeilpour1, Paola Marangolo2, Benjamin M Hampstead3, Sven Bestmann4, Elisabeth Galletta5, Helena Knotkova6, Marom Bikson7. 1. Department of Biomedical Engineering, The City College of New York of CUNY, New York, NY 10031, USA; Biomedical Engineering Department, Amirkabir University of Technology, Tehran, Iran. Electronic address: zesmaeilpour@ccny.cuny.edu. 2. Dipartimento di Studi Umanistici, University Federico II, Naples and IRCCS Fondazione Santa Lucia, Rome Italy. 3. VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA; Department of Psychiatry, University of Michigan, Ann Arbor, MI 48105, USA. 4. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, UK. 5. Rusk Rehabilitation Medicine, New York University Langone Medical Center, USA. 6. MJHS Institute for Innovation in Palliative Care, New York, NY, USA; Department of Family and Social Medicine, Albert Einstein College of Medicine, The Bronx, NY, USA. 7. Department of Biomedical Engineering, The City College of New York of CUNY, New York, NY 10031, USA.
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.
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.
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