Elsevier

Clinical Neurophysiology

Volume 128, Issue 9, September 2017, Pages 1774-1809
Clinical Neurophysiology

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

https://doi.org/10.1016/j.clinph.2017.06.001Get rights and content

Highlights

  • The application of low intensity TES in humans appears to be safe.

  • The profile of AEs in terms of frequency, magnitude and type is comparable in different populations.

  • Structured checklists and interviews as recommended procedures are provided in this paper.

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.

Introduction

The aim of this review is to update the safety of low-intensity electric stimulation based on available published research and clinical data in animal models and in human studies until the end of 2016. The essentials of the present manuscript were agreed upon at a two-day safety conference held in Göttingen, Germany on 6–7th September, 2016. Participants included research and clinical experts from neurophysiology, neurology, cognitive neuroscience and psychiatry. Representatives of transcranial electrical stimulation (TES) equipment manufacturers contributed to regulatory issues.

For the purposes of this review, data from published articles that encompassed more than 18,000 stimulation sessions in ∼8000 subjects, according to a recent review (Bikson et al., 2016), using low intensity stimulation (<4 mA; see definitions below) up to 60 min duration/day were included. Literature searches investigated by experts on the related fields covered studies using transcranial direct current stimulation (tDCS), alternating current stimulation (tACS) and random noise stimulation (tRNS), with key words Adverse Events (AE) or Reactions (AR) and/or safety (see definitions below), in order to assess stimulation-related risks and to better understand of the risk-benefit ratio of these procedures. We relied on summarizing and interpreting data on (1) available animal studies, (2) computational modeling and (3) testing in human trials, including reports on healthy subjects, patients and on theoretically vulnerable populations, such as children, elderly and pregnant women. With regard to animal data the main effort was devoted to understanding the translation of findings to human applications (e.g., the relationship of dose of the stimulation and safety). Concerning patients, only the most frequently investigated clinical groups were included (major depression, chronic pain and stroke), because of lack of data in other populations. Special stimulation conditions that are increasingly used during the last years, e.g., combination of TES with other methods, such as stimulating patients with intracranial implants, combination of TES with transcranial magnetic stimulation (TMS) or functional magnetic resonance imaging (fMRI), as well as “do it yourself” use of TES for neuro-enhancement purposes, were also considered, because of the theoretical increased risk in these conditions. Furthermore, other stimulation settings than ‘transcranial’, in which recent safety data are available, were also integrated (e.g., using transcutaneous spinal direct current stimulation (tsDCS) and applying optic nerve stimulation (ONS)).

In general, human studies that evaluate parameters of neuronal damage, such as neuron specific enolase (NSE), magnetic resonance imaging (MRI) (Nitsche et al., 2004), electroencephalography (EEG), and neuropsychological tests (Iyer et al., 2005, Tadini et al., 2011) support the safety of tDCS. However, it is also important to underscore the fact that the safety of low intensity TES is mostly derived from an analysis of secondary outcomes in TES clinical trials assessing efficacy as the primary outcome.

In this paper, we first provide an overview of the technical parameters and basic principles of low intensity TES used alone or combined with other methods, safety aspects of the stimulation with a summary of the published AEs in healthy subjects and different patient populations. The presumed mechanisms of TES and the efficacy of TES in eliciting desired outcomes are not relevant for the scope of this review except for instances, in which they inform about safety. Other stimulation methods that are applying specific (brand) waveforms or conditions, such as cranial electrical stimulation (CES) are also not incorporated here, but have been comprehensively reviewed by other authors (Mindes et al., 2015). We also present recent regulatory issues and recommend rules for reporting in research and clinical practice, and finally we summarize existing data and provide recommendations for future safety monitoring. Consensus with regard to the definitions, recommendations, etc. were reached by using a modified Delphi method, in this case a structured interactive communication technique (Kleymeyer, 1976). The experts first summarized safety data related to their fields and answered questions in more rounds. The key results were presented and discussed in Göttingen at the meeting. After that the experts were encouraged to support or revise their earlier answers in light of the replies of other members of the panel and in response to reviewers’ critiques.

We adopt suggested definitions as already published (e.g., Bikson et al., 2016, Woods et al., 2016) except that we chose the term “burden” instead of “tolerability” in accordance with the Declaration of Helsinki (1964) (Last revision 2013). The following terms are used in this paper:

Low intensity TES: This is defined as intensities <4 mA, a total stimulation duration of up to 60 min per day, and using electrode sizes between 1 cm2 and 100 cm2 (delivering ≤7.2 coulombs of charge) (Bikson et al., 2016) to apply frequencies between 0 and 10,000 Hz. The intensity of tDCS is always defined as peak-to-baseline, while with tACS peak-to-baseline or peak-to-peak intensities can be used. The type of current is direct current or bipolar alternating current (Guleyupoglu et al., 2013).

Safety can probably only be considered in relative terms. According to the definition of the European Medical Device Directive, ‘safe’ is a condition where all risks are accepted risks (Annex I; § I. General Requirements). However, all stimulation protocols carry a certain degree of risk and could cause problems in specific circumstances. Many problems cannot be detected until extensive research or clinical experience is gained. The current approach in this field is to estimate the potential of a protocol becoming a hazard that could result in safety problems (e.g., using too high intensities or too long durations of stimulation). Hazard is a potential for an AE. Risk is a measure of the combination of the hazard, the likelihood of occurrence of the AE and the severity (Altenstetter, 2003, McAllister and Jeswiet, 2003) (See also: http://www.who.int/medical_devices/publications/en/MD_Regulations.pdf). The conclusion that a procedure is safe is based on a comprehensive and unbiased documentation of all AEs in relation to the frequency of application of the procedure. Risk must be differentiated from burden, a procedure may be burdensome (e.g., produce much discomfort) but nevertheless safe (e.g., not having any relevant risk for permanent damage).

Generally and according to the Common Terminology Criteria for Adverse Events (AEs) (https://evs.nci.nih.gov/ftp1/CTCAE/Archive/CTCAE_4.02_2009-09-15_QuickReference_5x7_Locked.pdf), AEs are undesirable, uncomfortable or harmful effects that are observed after a medical intervention that may or may not be causally related to it. Here, we prefer the term AE to the term Side Effect (SE), which is frequently employed synonymously to describe AEs. A SE should be a consequence different than the intended effect, and might be good or bad (beneficial or adverse). An example of a good SE might be an improvement of memory by an intervention for depression. An AE is by definition always bad. In the context of the present paper the term SE will not be used in accordance with recommendations in the ICH guidelines (Baber, 1994, Food and Drug Administration, 2011). According to this classification, a mild AE (MAEs – grade 1) is defined as involving mild symptoms for which no medical treatment is necessary (i.e. skin redness or tingling during tDCS), while a moderate AE (grade 2) indicates the need of local or noninvasive treatment (e.g., in the case of TES, the local application of a cream after a skin burn). Serious AEs (grade 3) (SAE) are severe or medically significant but not immediately life-threatening events, include the requirement for inpatient hospitalization or prolongation of hospitalization. Life threatening SAEs include any event that may be life threatening (grade 4) or death from the AE (grade 5).

Suspected Adverse Reaction (AR) means any AE for which there is a reasonable possibility (causality is probable, likely or certain) that the intervention caused the AE (Baber, 1994, Food and Drug Administration, 2011). The distinction between AE and AR is not always clear, first because causality often cannot be proven unambiguously, and second because some effects (e.g., sedation) may be in some instances good but in other instances bad for the patient. Another point to be considered is unexpectedness. An AE or suspected AE is generally considered unexpected if it is not listed in the information brochure or is not listed at the specificity or severity level that has been observed or it is not consistent with the risk information described in the investigational plan (FDA regulations, 21CFR312.32, safety reporting). Unexpected ARs require particular attention because their correlation with the procedure may be neglected. If for example, someone is treated using tDCS and is hit by a car an hour later, this is usually not considered as AR. However, if it is due to sedation and cognitive impairment it may indeed be an AR. Corresponding to the definitions above, mild, moderate and severe ARs may be defined. The risk-benefit ratio is the overall ratio of all potential benefits of a procedure divided by all the ARs of a procedure. Usually, a procedure is only acceptable if the beneficial effects outweigh the risks.

Section snippets

Assumptions regarding dose-response relationship, animal studies

TES dose is defined by all of the parameters of the stimulation device that affect the generated electric field (EF) in the body with units of V/m (or, equivalently, mV/mm) (Peterchev et al., 2012). This includes the parameters of the electrode montage (skin contact area), the waveform applied to the electrodes and at the case of tACS, the stimulation frequency.

The parameters delivered by the stimulation equipment are well defined and reproducible, while other influencing factors are not (e.g.,

Interaction of EF with tissue, electroporation, galvanotaxis

A variety of montages ranging from two large, pad electrodes to arrays of smaller electrodes are used for tDCS (Alam et al., 2016) with a typical current of 1–2 mA (0.03–2 mA/cm2 current to electrode area ratios depending on the electrode size); this results in cortical EF strengths of up to 0.4–0.8 V/m (Ruffini et al., 2013b) with typical durations of 10–30 min. Both the applied current and the resulting brain EFs are ∼1000-fold lower than those for pulsed stimulation used for electroconvulsive

Modeling (heating, induced voltages)

Computational models of current flow relate tDCS surface dose with subject-specific brain current density (Peterchev et al., 2012, Ruffini et al., 2014, Truong et al., 2013). The precision of the prediction depends on the accuracy of the model (not simply the complexity; (Bikson and Datta, 2012). For a given electrode montage, increasing the current results in a proportional increase in the EF throughout the head – such that, for any given montage, 2 mA will produce an EF in each brain region

Electrode design for TES

A bipolar electrode configuration is the minimal requirement and customarily used for tDCS, with one target electrode placed over the site of the desired cortical stimulation and one remote “return” electrode (but see: Bikson et al., 2010). The return electrode may be placed on the scalp (the most frequently used site), concentrically around the target electrode (Laplacian montage) (Bortoletto et al., 2016, Datta et al., 2009a), extracephalically (e.g., Moliadze et al., 2010, Schambra et al.,

Historical background of electrical stimulation

The history of electric stimulation starts with the application of electricity generated by electric fish, which are able to generate 2 ms long pulses, up to 600 V and up to 1 A. Because the purpose of this feature is to stun prey, electric fish are unsafe by design. Immediately after the invention of the voltaic pile around 1800, several books were published on the use of the pile in a variety of mostly neurological diseases (Althaus, 1860, Augustin, 1801, Grappengiesser, 1801, Hellwag and

Ethics

Previous studies using transcranial stimulation suggest that ethical awareness was and is always linked to the social definitions and moral issues, both in health and disease (Harris and Almerigi, 2009, Moan and Heath, 1972). Nowadays a very careful assessment of the Institutional Review Boards (IRB) and Ethical Committees of a given institute is required before a study is initiated. Nevertheless, the main responsibility with regard to the appropriate conduct and maintenance of a rigorous

How to assure safety in the future?

AEs have been rare and minor in the course of thousands of hours of TES in controlled settings. CE certified stimulation devices are current-controlled; they limit the maximum current delivered per electrode (<2–4 mA), the maximum stimulation voltage with an auto-abort option if the pre-set current cannot be delivered beyond a defined voltage level and the maximum total current delivered through all electrodes at any moment. They force users to set the program duration, and check impedance

Summary

Given the growing interest in the non-invasive TES technologies, in this paper a range of researchers, clinicians, ethicists and developers of devices/new technologies summarized safety and ethical issues surrounding the use of TES for the treatment of nervous system disorders as well as for non-therapeutic uses, including cognitive and functional enhancement. Low intensity TES so far appears to be a safe technique. Typical AEs are itching, burning sensations under the electrode or transient,

Acknowledgment

We would like to thank Prof. Dr. Michael Siniatchkin for his helpful comments in the chapter summarizing the AEs of tDCS in pediatric populations and to Dr. Oluwole Awosika for his contribution in the chapter Published AEs in the post-stroke treatment. We thank Christine Crozier and Dr. Thomas Crozier for language editing of the manuscript. Felipe Fregni is supported by NIH research grants and also a grant from Labuschagne Foundation. Dr. Hallett is supported by the NINDS Intramural Program.

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