In the case of brain stimulation, it is clear that most of the participants are also interested in its safety, which was unknown only 100 years ago and the subject of many studies. At that time, we did not yet know about its effects on our lives, so we had to find out for ourselves where this technology could lead. So let’s rely on all the historical studies on a thousand or more subjects to show why stimulation is so important to the life of many of us and why it can turn their life around 180 degrees,
This brief review updates and reviews the evidence for the safety of tDCS. Safety is objectively defined here and so far without any data on serious adverse effects, the criteria of which are strictly defined. Special attention is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants and home users. Evidence from relevant animal models suggests that direct current stimulation (tDCS) brain damage occurs at predicted cerebral current densities (6.3–13 A/m2) that are ORDER OF HIGHER than those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human studies (≤ 40 min, ≤ 4 mA, ≤ 7.2 Coulombs) has produced no reports of serious adverse effect or irreversible damage over 33 200 sessions and 1000 subjects with repeated sessions. This includes a wide range of subjects, including people from potentially vulnerable population groups.
This report aims to update the latest knowledge on the safety of tDCS. Excluding subjects with pre-existing conditions from participating in clinical trials (eg, excluding depressed subjects from stroke studies and excluding subjects with stroke from depression studies) reduces the number of complicated cases tested with tDCS. This is how we always discuss exact numbers and show the direct safety of this technology.
Definitions and considerations of dose metrics for tDCS safety
tDCS is non-invasive and requires a suitable electrolyte buffer (conductive gel, paste or saline) between the electrode and the skin., tDCS , as used in current human trials, involves only a solid continuous direct current. The lowercase “t” in tDCS is therefore important to emphasize the proper name, which indicates a specific stimulation approach. Similarly, neither oscillating transcranial direct current stimulation (monophasic square wave) nor rectified or monophasic sine wave is included in tDCS as defined here.
Any electrode from which current enters the body is an anode and any electrode from which current exits the body is a cathode. tDCS must have at least one anode electrode and one cathode electrode. With electrodes of either polarity, the direction of measured excitability changes can vary depending on brain state and dose parameters such as stimulation intensity and duration.
The duration of tDCS/DCS (in seconds or minutes) indicates how long the current is at a steady-state level and does not include the rise and fall periods, which typically last 10–30 seconds in studies using minutes of stimulation. tDCS/DCS is current-controlled, meaning that the voltage is varied to maintain a constant current, usually below 20 V, although much of this voltage (especially any time-dependent component) may reflect electrode and skin impedance. We examined data from human tDCS studies by dose. Meta-analyses of tDCS inevitably collapse across different testing conditions; (eg 1 mA intensity in adults with epilepsy using 25 cm2 electrodes vs. 1 mA intensity in healthy children using 35 cm2 electrodes).
Number of sessions by duration and a number of subjects in repeated sessions by duration Preliminary analysis of total sessions and dose in the tDCS literature of published studies meeting our inclusion criteria. We searched the Pubmed database for the keywords “transcranial direct current stimulation” limited to articles published in English. We included only studies that met the following inclusion criteria: used tDCS, tested on human subjects, reported original research, used electrolyte-soaked absorbent material, clearly stated dosage information, and published before July 2013. 488 out of 1072 papers were considered. tDCS dosage and number of sessions were extracted from them. tDCS dosing includes current intensity, electrode size, duration, and position (not shown here). The number of sessions refer to the number of completed tDCS procedures (eg, number of subjects times sessions per subject). If one subject completed more than 4 sessions in one week, it was further classified as a repeat session.
For the purposes of this safety review, we limit the inclusion of human trials with tDCS to those with “conventional” protocols (eg, intensities and durations of waveforms). Conventional currents range from 0.1 mA (occasionally used as a simulation) to 4.0 mA, with most studies using 1.0 mA and 2 .0 mA. Conventional durations range from 4 seconds (used only for transient changes; to 40 minutes (more than 10 minutes of stimulation is commonly used to produce permanent changes).
Standard tDCS electrodes (pads) are typically 5 × 5 cm or 5 × 7 cm square, although both smaller and larger electrode assemblies as well as circular pads have been explored. Standard tDCS electrode assemblies use either metal or conductive rubber electrodes. Electrolytes are most often isotonic saline (saturated in a sponge that surrounds the electrode), but conductive gels and/or creams have also been used. Pad electrodes are usually limited to a maximum of 3–4 due to size and materials. High-definition (HD) electrodes are circular <1 cm in diameter with a sintered Ag/AgCl electrode and conductive gel or paste. It is possible to use a higher number and density of HD electrodes. When one or more HD electrodes are used, tDCS is called High-Definition tDCS (HD-tDCS), regardless of the number of electrodes or whether the stimulation is optimized.
Definition and considerations of serious adverse effects for tDCS safety.
In this review, the safety of tDCS indicates the absence of serious adverse effect including brain tissue damage related to tDCS application. It is necessary to precisely define this margin of safety for clinical trials and especially for experiments on translational animal models. For clinical trials based on international and US guidelines on serious adverse events from medical devices (including the Office of Research and Human Protection (OHRP) of the US Department of Health and Human Services (HSS); FDA regulations at 21 CFR 312.32; 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice; ISO/DIS 14155.
Computational models predict skin current density to brain current density, and thus their ratio. The exploratory analysis compared a range of montages at extremes of head anatomy (e.g. infantile to obese, healthy and stroke). Additional models were solved to increase the depth of the study (computational forward modeling methods are detailed in Figure 3). Models contained some or all of the following tissue masks: skin (0.465 S/m), fat (0.025 S/m), bone (0.01 S/m), CSF (1.65 S/m), gray matter (0.276 S/m ), white matter (0.126 S/m), intervertebral discs (0.16133 S/m), ligament (0.250922 S/m), spinal cord (0.171267 S/m), air (1×10 −15 S/m), electrode (5.99 x 107 S/m), sponge (1.4 S/m) and gel (4.0 S/m).
The study included nineteen combinations of six different head types (pediatric, small adult, medium adult, medium adult stroke, large adult, and obese adult) and ten different electrode assembly (two using HD electrodes and eight using sponge electrodes 5 × 7 cm). . (Top) Because the electrodes are placed on the scalp during tDCS, and due to the conductivity and anatomy of the underlying tissue, most of the current does not reach the brain, and the portion that does reach the brain is scattered. Therefore, the current density in the skin is always higher than in the brain. (Bottom) The maximum current density in skin and brain (and their ratio) depends on several factors, including electrode mounting. For a single head, the ratio is predicted for various conventional and HD mounts. The ratio of skin to brain ranges from more than 10:1 to 400:1. The maximum brain current density was 0.23 A/m2 for a small adult head and 0.32 A/m2 for a child’s head.
To adapt these results to humans, we developed a high-resolution rat model and predicted the brain current flow generated for each montage used (Figure 3). By comparing the resulting peak current density (or electric field) per mA applied in the rat brain to the maximum electric field produced per mA in the human brain, we are able to design a scaling factor. The scaling factor determined was 288 for Fritsch and colleagues, 240 for Liebetanz and colleagues, and 134 for the Jankord and colleagues studies. Combining the reported current thresholds for damage in animal models with the appropriate scaling factors between rats and humans results in predicted human damage thresholds of 173 mA based on Fritsch, 120 mA based on Liebetanz, and 67 mA based on Jankord. These scaled values are an order of magnitude higher than the peak current levels used during tDCS.
Animal data suggest possible damage at electric field thresholds orders of magnitude above those generated by conventional tDCS protocols. Rat brain lesion threshold as reported by three different groups using slightly different methods. The estimated minimum induced current density for brain lesions ranged from 12, 17, 6.3 A/m2 (corresponding to electric fields of 42, 61, to 23 V/m).
A Meta-analysis of the total number of tDCS sessions (Figure 2) failed to identify a single record of a tDCS-related serious adverse effect across 33,200 sessions. Among these, over 1,000 subjects received tDCS repeatedly (multiple sessions over days) without serious adverse effects. There are also data on individual patients who received more than 100 tDCS treatment sessions without any indication of adverse effects resulting from cumulative exposure . These include patients with schizophrenia who received maintenance tDCS once to twice daily on a home basis over a 3-year period (ie > 1000 sessions); and depressed patients who completed multiple cycles of tDCS (total >100 sessions) safely, assessed using structured side effect questionnaires and formal neuropsychological testing.
Furthermore, thirty-three healthy volunteers received up to 30 sessions (6 weeks) of tDCS (2 mA, 20 minutes, high-power adhesive electrodes) without serious adverse event. Special attention to tDCS for safety in children As is typical of most investigational techniques, experience with tDCS in children has been limited compared to adults, and applications in the developing brain require further consideration. Less than 5% of published studies of tDCS involve the pediatric population. In children, a possible dosage adjustment should be considered for both safety and efficacy. Specific systems and techniques are needed to record side effects, potential adverse events, and effects and tolerability measures.
In studies involving children, at least 2800 sessions were applied to almost 500 subjects. No serious side effects were reported. tDCS has been studied in children with a variety of diagnoses, including cerebral palsy, stroke, encephalitis, epilepsy, schizophrenia, and attention deficit hyperactivity disorder. According to Clinicaltrials.gov, current studies in pediatric applications of tDCS include perinatal stroke, cerebral palsy, dystonia, childhood-onset schizophrenia, attention deficit hyperactivity disorder, and autism. The relatively limited nature of this experience with tDCS in the pediatric population> compared to adults is illustrated in Figure 7. Specifically for children with.
Current intensities ranged from 0.7 to 2.0 mA, with 9–20 minute sessions varying between single or serial sessions (maximum of 10 consecutive daily sessions) . The most commonly reported minor adverse events included tingling or discomfort under the electrode sites, reported in both active and simulated conditions. Pediatric studies are also investigating the synergistic application of tDCS during rehabilitation sessions to enhance motor plasticity (clinicaltrials.gov #NCT02170285). One study in children with congenital hemiparesis combined restraint-induced movement therapy and tDCS. This serial study applies tDCS in the M1-SO cathodal contralesion montage at an intensity of 0.7 mA for the first 20 minutes during a 2-hour rehabilitation session involving the more affected arm. A randomized, controlled clinical trial of 24 children aged 6–18 years with perinatal stroke and hemiparesis combined intensive motor learning therapy with tDCS. Subjects received contralesional M1 cathodal 1 mA tDCS (or sham) during the first 20 min of a two-hour therapy session on 10 consecutive weekdays.
Examination of safety outcomes in 12 and 24 subjects, including both paretic and unaffected upper extremity function, revealed no serious adverse effects. Other case reports without serious adverse effects include a 16-year-old with stroke and hemiparesis who received 1 mA contralateral cathodal stimulation for 10 days with treatment and a 15-year-old with schizophrenia and refractory auditory hallucinations who received 2 weeks of better-timed cathodal stimulation for 20 minutes per day with no adverse effects (Kirton, unpublished). A study of tDCS motor learning improvement in 24 typically developing children aged 6–18 found no serious adverse effects (Kirton, in review). Children performed the motor learning task repeatedly over 3 days, randomized to sham, 1 mA contralateral M1 anodal, 1 or 2 mA ipsilateral cathodal M1 stimulation during the first 20 min of each training session. Specific safety outcomes included any decline in the trained or untrained arm, as well as a decline in multiple untrained motor tasks before and after the intervention.
All functional outcomes improved with tDCS. Slight tingling or itching of the scalp was reported in 55% of subjects but never precluded participation. If effective, tDCS could be particularly beneficial in treating cognitive, motor, and psychiatric symptoms of neurodegenerative diseases as well as decline associated with normal aging (see reviews. We identified 15 studies that evaluated the effects of tDCS in patients with Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, corticobasal degeneration, and frontotemporal dementia.A total of more than 275 patients (some assigned to sham conditions) received 7 to 30 minutes of stimulation in each of 1 to 10 sessions at an intensity between 1 and 2.8 mA. 10 studies comment on safety. Four studies noted typical side effects (ie, itching, tingling, burning), as well as temporary headaches and dizziness. It is also worth noting that a review of eight tDCS studies in the geriatric depression literature found no significant side effects of stimulation.
Overall, there were no unexpected or serious adverse events in more than 40 studies involving more than 600 older adults, regardless of cognitive or disease status. Thus, there is currently no evidence of an increased risk of serious adverse effects in aging subjects. Special Considerations of tDCS for Stroke Safety In studies of tDCS in people with stroke, adults and children, published since 2014, there are 2 studies reporting minor adverse events, including mild headache, drowsiness, and mixed feelings. In addition, there are several reports of early withdrawal from the study, with up to 14 people from 6 studies out of a total of 507 participants in 33 studies. Reporting criteria and reasons for discontinuation vary and include personal reasons (eg, unrelated health problems, refusal to participate, etc.) that were not serious adverse effects as defined here.
To date, to our knowledge, no persistent decrements in behavioral performance or mood following tDCS have been documented in stroke populations. However, particular care is required regarding the methods used to determine whether a possible adverse change in behavior or mood was caused or exacerbated by tDCS (see discussion above). Most stroke survivors commonly exhibit one or more behavioral deficits (eg, motor, sensory, perceptual, cognitive, speech-language, swallowing, etc.). Furthermore, approximately 30% of stroke survivors report depression compared to 4-7.3% of the general adult population (Centers for Disease Control; CDC) and the presence and severity of depression can change over time. Special attention to tDCS for safety in mood disorders Therapeutically emergent (hypo)mania (TEM) is a potentially serious adverse effect that can occur in depressed patients during pharmacological treatment with antidepressants, for example up to > 2.3% of patients with unipolar depression.
The probability of developing TEM is influenced by a number of factors, including the effectiveness of the agent used and the individual characteristics of the patient. In the literature, there are four separate case reports and some reports in randomized clinical trials (1 case in and 6 cases in, of which 5 patients received tDCS combined with sertraline after tDCS treatment) induction of mania or hypomania. It is important to note that some of these patients were not known to have bipolar disorder. Most of these episodes spontaneously resolved when tDCS was stopped for a few days or with small dose adjustments or the introduction of new pharmacotherapy. However, one case was characterized by a violent episode of mania with psychotic features. In the other 5 patients who received sertraline in combination with tDCS, it is not possible to determine with certainty which intervention (or both) was responsible for the symptoms and thus were not serious adverse events as defined in this review.
Stimulation montage may be a factor, with one patient becoming hypomanic with a montage involving greater stimulation of deep central brain regions but not with the usual frontal montage used to treat depression. It is difficult to estimate the exact frequency of this adverse event (ie induction of manic/hypomanic episodes) or establish causality with tDCS. Therefore, it is unclear whether a diagnosis of bipolar disorder puts a patient at a theoretically higher risk of a manic switch with tDCS than has been suggested with other brain stimulation therapies. Conservatively, the same recommendations can be made for tDCS in depressed patients as for antidepressant treatment. However, in keeping with the scope of this review, we highlight the lack of convincing evidence that tDCS increases the risk of manic transition. In depression studies, over 4160 sessions have been administered to over 430 subjects (Figure 7) with no documented serious adverse effects.
Special Considerations of tDCS for Home Use Safety With progress toward clinical use of tDCS for a wide variety of applications, home use (as opposed to clinic administration) is likely to become more common. There is evidence that beneficial effects can be achieved with cumulative sessions, including when paired with a behavioral program to improve outcomes (eg, cognitive or physical exercises to restore function). Therefore, repeated administration of tDCS over time is likely to be necessary for the effectiveness of many treatments. In this sense, home use may also be useful to continue or maintain an initial therapeutic benefit that may last for months (eg 100 sessions or more). Alternatively, for other applications, tDCS can be used “on-demand” for situational use (eg, to increase or maintain attentional vigilance). These potential scenarios raise interest in remote clinical trials. Repeat and/or spontaneous clinic visits are often unlikely due to time constraints as well as logistical and scheduling issues.
While all of these concerns also apply to administration in the clinic, the long-term and variable naturalistic situation of home use, as well as issues related to self-administered stimulation, require special attention. There have been relatively few clinical trials involving the home use of tDCS. One study used home-based tDCS to treat trigeminal neuralgia using a crossover design. Participants (n = 17) were instructed to self-apply tDCS at home during two 2-week periods separated by one month in which they applied active stimulation (1 mA) and sham (in random order) to the primary motor cortex. Participants were provided with battery-powered equipment used in conventional clinical trials, and study staff were available by telephone. Active stimulation has been found to be effective in reducing pain with no reported adverse effects and is generally well tolerated. The study had a relatively high dropout rate, with only 10 subjects meeting both study conditions. The first use of these guidelines was used to develop a protocol for use in participants with multiple sclerosis (MS). The protocol centers around a specially designed pre-programmed device that contains code to “unlock” the application of only one stimulation (or sham) session at a time.
The code is issued remotely by a technician via HIPAA-compliant video conference and is provided only after all security checks have been completed. With this protocol, targeting 10 sessions over two weeks, 24 participants completed 232 sessions without any adverse event or discontinuation of any session. High tolerance and compliance were achieved. A controlled and sequential study design to expand use outside the clinic and without the presence of an investigator/clinician will provide the safest and best route for home use. This review examined the evidence for the safety of tDCS. Evidence of DCS brain damage in animal models occurs at intensities orders of magnitude higher than those used in conventional tDCS. To date, based on a total of over 33,000 sessions and over 1,000 subjects who have received repeated tDCS sessions, there is no evidence of irreversible injury caused by conventional tDCS protocols within a wide range of stimulation parameters (≤ 40 min, ≤ 4 mA, ≤ 7.2 C).
This analysis consolidates and adds to the existing evidence on the safety of tDCS and facilitates further research on tDCS in human subjects. These conclusions are consistent with previous analyzes and a review focusing on single-center experience. Link to published research at PubMed
