Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines

A Antal; I Alekseichuk; M Bikson; J Brockmöller; A R Brunoni; R Chen; L G Cohen; G Dowthwaite; J Ellrich; A Flöel; F Fregni; M S George; R Hamilton; J Haueisen; C S Herrmann; F C Hummel; J P Lefaucheur; D Liebetanz; C K Loo; C D McCaig; C Miniussi; P C Miranda; V Moliadze; M A Nitsche; R Nowak; F Padberg; A Pascual-Leone; W Poppendieck; A Priori; S Rossi; P M Rossini; J Rothwell; M A Rueger; G Ruffini; K Schellhorn; H R Siebner; Y Ugawa; A Wexler; U Ziemann; M Hallett; W Paulus

doi:10.1016/j.clinph.2017.06.001

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines

Clin Neurophysiol. 2017 Sep;128(9):1774-1809. doi: 10.1016/j.clinph.2017.06.001. Epub 2017 Jun 19.

Authors

A Antal¹, I Alekseichuk², M Bikson³, J Brockmöller⁴, A R Brunoni⁵, R Chen⁶, L G Cohen⁷, G Dowthwaite⁸, J Ellrich⁹, A Flöel¹⁰, F Fregni¹¹, M S George¹², R Hamilton¹³, J Haueisen¹⁴, C S Herrmann¹⁵, F C Hummel¹⁶, J P Lefaucheur¹⁷, D Liebetanz², C K Loo¹⁸, C D McCaig¹⁹, C Miniussi²⁰, P C Miranda²¹, V Moliadze²², M A Nitsche²³, R Nowak²⁴, F Padberg²⁵, A Pascual-Leone²⁶, W Poppendieck²⁷, A Priori²⁸, S Rossi²⁹, P M Rossini³⁰, J Rothwell³¹, M A Rueger³², G Ruffini²⁴, K Schellhorn³³, H R Siebner³⁴, Y Ugawa³⁵, A Wexler³⁶, U Ziemann³⁷, M Hallett³⁸, W Paulus²

Affiliations

¹ Department of Clinical Neurophysiology, University Medical Center Göttingen, Georg August University, Göttingen, Germany. Electronic address: [email protected].
² Department of Clinical Neurophysiology, University Medical Center Göttingen, Georg August University, Göttingen, Germany.
³ Department of Biomedical Engineering, The City College of New York, New York, USA.
⁴ Department of Clinical Pharmacology, University Medical Center Goettingen, Germany.
⁵ Service of Interdisciplinary Neuromodulation, Department and Institute of Psychiatry, Laboratory of Neurosciences (LIM-27) and Interdisciplinary Center for Applied Neuromodulation University Hospital, University of São Paulo, São Paulo, Brazil.
⁶ Division of Neurology, Department of Medicine, University of Toronto and Krembil Research Institute, Toronto, Ontario, Canada.
⁷ Human Cortical Physiology and Neurorehabilitation Section, National Institute of Neurological Disorders and Stroke NIH, Bethesda, USA.
⁸ The Magstim Company, Whitland, UK.
⁹ Department of Health Science and Technology, Aalborg University, Aalborg, Denmark; Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Erlangen, Germany; EBS Technologies GmbH, Europarc Dreilinden, Germany.
¹⁰ Universitätsmedizin Greifswald, Klinik und Poliklinik für Neurologie, Greifswald, Germany.
¹¹ Spaulding Neuromodulation Center, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA.
¹² Brain Stimulation Division, Medical University of South Carolina, and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.
¹³ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Institute of Biomedical Engineering and Informatics, Technische Universität Ilmenau, Germany.
¹⁵ Experimental Psychology Lab, Department of Psychology, European Medical School, Carl von Ossietzky Universität, Oldenburg, Germany.
¹⁶ Defitech Chair of Clinical Neuroengineering, Centre of Neuroprosthetics (CNP) and Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), Geneva, Switzerland; Defitech Chair of Clinical Neuroengineering, Clinique Romande de Réadaptation, Swiss Federal Institute of Technology (EPFL Valais), Sion, Switzerland.
¹⁷ Department of Physiology, Henri Mondor Hospital, Assistance Publique - Hôpitaux de Paris, and EA 4391, Nerve Excitability and Therapeutic Team (ENT), Faculty of Medicine, Paris Est Créteil University, Créteil, France.
¹⁸ School of Psychiatry & Black Dog Institute, University of New South Wales, Sydney, Australia.
¹⁹ Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK.
²⁰ Center for Mind/Brain Sciences CIMeC, University of Trento, Rovereto, Italy; Cognitive Neuroscience Section, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
²¹ Institute of Biophysics and Biomedical Engineering, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
²² Institute of Medical Psychology and Medical Sociology, University Hospital of Schleswig-Holstein (UKSH), Campus Kiel, Christian-Albrechts-University, Kiel, Germany.
²³ Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany; Department of Neurology, University Hospital Bergmannsheil, Bochum, Germany.
²⁴ Neuroelectrics, Barcelona, Spain.
²⁵ Department of Psychiatry and Psychotherapy, Munich Center for Brain Stimulation, Ludwig-Maximilian University Munich, Germany.
²⁶ Division of Cognitive Neurology, Harvard Medical Center and Berenson-Allen Center for Noninvasive Brain Stimulation at Beth Israel Deaconess Medical Center, Boston, USA.
²⁷ Department of Information Technology, Mannheim University of Applied Sciences, Mannheim, Germany.
²⁸ Center for Neurotechnology and Experimental Brain Therapeutich, Department of Health Sciences, University of Milan Italy; Deparment of Clinical Neurology, University Hospital Asst Santi Paolo E Carlo, Milan, Italy.
²⁹ Department of Medicine, Surgery and Neuroscience, Human Physiology Section and Neurology and Clinical Neurophysiology Section, Brain Investigation & Neuromodulation Lab, University of Siena, Italy.
³⁰ Area of Neuroscience, Institute of Neurology, University Clinic A. Gemelli, Catholic University, Rome, Italy.
³¹ UCL Institute of Neurology, London, UK.
³² Department of Neurology, University Hospital of Cologne, Germany.
³³ neuroCare Group GmbH, Munich, Germany.
³⁴ Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.
³⁵ Department of Neurology, Fukushima Medical University, Fukushima, Japan; Fukushima Global Medical Science Center, Advanced Clinical Research Center, Fukushima Medical University, Japan.
³⁶ Department of Science, Technology & Society, Massachusetts Institute of Technology, Cambridge, MA, USA.
³⁷ Department of Neurology & Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
³⁸ Human Motor Control Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.

Abstract

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m² that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

Keywords: Adverse events; Safety; TES; tACS; tDCS.

Publication types

Review
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / physiology*
Burns, Electric / etiology
Burns, Electric / prevention & control
Humans
Practice Guidelines as Topic / standards*
Transcranial Direct Current Stimulation / adverse effects
Transcranial Direct Current Stimulation / ethics*
Transcranial Direct Current Stimulation / standards*

Abstract

Publication types

MeSH terms

Grants and funding