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

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. McCaigC. 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

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

315 Citationer (Scopus)

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 6.3–13 A/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 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.

Originalsprog	Engelsk
Tidsskrift	Clinical Neurophysiology
Vol/bind	128
Udgave nummer	9
Sider (fra-til)	1774-1809
ISSN	1388-2457
DOI	https://doi.org/10.1016/j.clinph.2017.06.001
Status	Udgivet - 2017

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10.1016/j.clinph.2017.06.001

http://europepmc.org/articles/pmc5985830?pdf=render

Citationsformater

Antal, A., Alekseichuk, I., Bikson, M., Brockmöller, J., Brunoni, A. R., Chen, R., Cohen, L. G., Dowthwaite, G., Ellrich, J., Flöel, A., Fregni, F., George, M. S., Hamilton, R., Haueisen, J., Herrmann, C. S., Hummel, F. C., Lefaucheur, J. P., Liebetanz, D., Loo, C. K., ... Paulus, W. (2017). Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Clinical Neurophysiology, 128(9), 1774-1809. https://doi.org/10.1016/j.clinph.2017.06.001

Antal, A, Alekseichuk, I, Bikson, M, Brockmöller, J, Brunoni, AR, Chen, R, Cohen, LG, Dowthwaite, G, Ellrich, J, Flöel, A, Fregni, F, George, MS, Hamilton, R, Haueisen, J, Herrmann, CS, Hummel, FC, Lefaucheur, JP, Liebetanz, D, Loo, CK, McCaig, CD, Miniussi, C, Miranda, PC, Moliadze, V, Nitsche, MA, Nowak, R, Padberg, F, Pascual-Leone, A, Poppendieck, W, Priori, A, Rossi, S, Rossini, PM, Rothwell, J, Rueger, MA, Ruffini, G, Schellhorn, K, Siebner, HR, Ugawa, Y, Wexler, A, Ziemann, U, Hallett, M & Paulus, W 2017, 'Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines', Clinical Neurophysiology, bind 128, nr. 9, s. 1774-1809. https://doi.org/10.1016/j.clinph.2017.06.001

@article{132932726e2e4d8498144078d5033510,

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

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 {\textquoteleft}conventional{\textquoteright} 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 6.3–13 A/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 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 G{\"o}ttingen, Germany, on September 6–7, 2016 and were refined thereafter by email correspondence.",

keywords = "Adverse events, Safety, tACS, tDCS, TES",

author = "A. Antal and I. Alekseichuk and M. Bikson and J. Brockm{\"o}ller and Brunoni, {A. R.} and R. Chen and Cohen, {L. G.} and G. Dowthwaite and J. Ellrich and A. Fl{\"o}el and F. Fregni and George, {M. S.} and R. Hamilton and J. Haueisen and Herrmann, {C. S.} and Hummel, {F. C.} and Lefaucheur, {J. P.} and D. Liebetanz and Loo, {C. K.} and McCaig, {C. D.} and C. Miniussi and Miranda, {P. C.} and V. Moliadze and Nitsche, {M. A.} and R. Nowak and F. Padberg and A. Pascual-Leone and W. Poppendieck and A. Priori and S. Rossi and Rossini, {P. M.} and J. Rothwell and Rueger, {M. A.} and G. Ruffini and K. Schellhorn and Siebner, {H. R.} and Y. Ugawa and A. Wexler and U. Ziemann and M. Hallett and W. Paulus",

year = "2017",

doi = "10.1016/j.clinph.2017.06.001",

language = "English",

volume = "128",

pages = "1774--1809",

journal = "Clinical Neurophysiology",

issn = "1388-2457",

publisher = "Elsevier Ireland Ltd",

number = "9",

}

TY - JOUR

T1 - Low intensity transcranial electric stimulation

T2 - Safety, ethical, legal regulatory and application guidelines

AU - Antal, A.

AU - Alekseichuk, I.

AU - Bikson, M.

AU - Brockmöller, J.

AU - Brunoni, A. R.

AU - Chen, R.

AU - Cohen, L. G.

AU - Dowthwaite, G.

AU - Ellrich, J.

AU - Flöel, A.

AU - Fregni, F.

AU - George, M. S.

AU - Hamilton, R.

AU - Haueisen, J.

AU - Herrmann, C. S.

AU - Hummel, F. C.

AU - Lefaucheur, J. P.

AU - Liebetanz, D.

AU - Loo, C. K.

AU - McCaig, C. D.

AU - Miniussi, C.

AU - Miranda, P. C.

AU - Moliadze, V.

AU - Nitsche, M. A.

AU - Nowak, R.

AU - Padberg, F.

AU - Pascual-Leone, A.

AU - Poppendieck, W.

AU - Priori, A.

AU - Rossi, S.

AU - Rossini, P. M.

AU - Rothwell, J.

AU - Rueger, M. A.

AU - Ruffini, G.

AU - Schellhorn, K.

AU - Siebner, H. R.

AU - Ugawa, Y.

AU - Wexler, A.

AU - Ziemann, U.

AU - Hallett, M.

AU - Paulus, W.

PY - 2017

Y1 - 2017

N2 - 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 6.3–13 A/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 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.

AB - 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 6.3–13 A/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 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.

KW - Adverse events

KW - Safety

KW - tACS

KW - tDCS

KW - TES

U2 - 10.1016/j.clinph.2017.06.001

DO - 10.1016/j.clinph.2017.06.001

M3 - Review

C2 - 28709880

AN - SCOPUS:85022025439

SN - 1388-2457

VL - 128

SP - 1774

EP - 1809

JO - Clinical Neurophysiology

JF - Clinical Neurophysiology

IS - 9

ER -

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

Abstract

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