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 (+29 others)
2017 Clinical Neurophysiology  
Coil for Magnetic Stimulation and methods for using the same (H-coil); in relation to the latter, he has received license fee payments from the NIH (from Brainsway) for licensing of this patent. He has received honoraria from publishing from Cambridge University Press, Oxford University Press, and Elsevier. Dr. Hallett has research grants from UniQure for a clinical trial of AAV2-GDNF for Parkinson Disease, Merz for treatment studies of focal hand dystonia, and Allergan for studies of methods
more » ... inject botulinum toxins. Michael A. Nitsche serves on a scientific advisory board for Neuroelectrics. Pedro C. Miranda serves on the scientific advisory board for Neuroelectrics, Barcelona, Spain, receives license fee payments for US Patent #7,407,478, and receives research funds from Novocure, Israel. Christoph Herrmann has received honoraria as editor from Elsevier Publishers, Amsterdam, The Netherlands, and has filed a patent application on brain stimulation. Klaus Schellhorn works as a full-time employee (Chief Technical Officer) of neuroCare Group. . Alberto Priori founded Newronika srl Company (Italy), he has patents on brain stimulation and is stakeholder of the company. Giulio Ruffini holds patents on multichannel brain stimulation and the combination of EEG and brain stimulation, and is a Neuroelectrics shareholder. Rafal Nowak works as a fulltime employee for Neuroelectrics. Colleen Loo has received equipment support from Soterix Medical for investigator-initiated research. Jens Ellrich has received honoraria from 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 1-2 mA and during tACS at higher peak-to-peak intensities above 2 mA. 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 <4 mA, up to 60 min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3 to 13 A/m 2 that are over an order of magnitude above those produced by tDCS in humans. Using AC 10 stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10 mA, 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.
doi:10.1016/j.clinph.2017.06.001 pmid:28709880 pmcid:PMC5985830 fatcat:6guy6fen2nbxxmhrka5kdsbhyy