Progression of adverse effects over consecutive sessions of transcranial direct current stimulation

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Accepted Manuscript
Letter to the Editor Progression of adverse effects over consecutive sessions of transcranial direct current stimulation Aaron Kortteenniemi, Amir-Homayoun Javadi, Jan Wikgren, Soili M. Lehto PII: S1388-2457 (17) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. We read the paper by Antal et al. (2017) with great interest, and felt that it provided an excellent overview of the safety aspects of transcranial electrical stimulation (tES). However, we noticed that while multi-day stimulation studies were discussed, potential changes in adverse effects (AEs) over consecutive sessions were not, and the lack of knowledge on the matter was pointed out by the authors. We recently completed an experiment in which we investigated this issue. the onset of the study, the participants were instructed to abstain from alcohol use for 12 hours and consume no more than two doses during the preceding 24 hours, to abstain from caffeine for 3 hours, and to abstain from smoking and heavy physical exercise for one hour before each session.

Abbreviations
Before the first stimulation session, the participants completed the 10-item version of the Cohen's Perceived Stress Scale (PSS) questionnaire (Cohen et al. 1982). Each participant received 20 minutes of 2 mA stimulation using a neuroConn DC stimulator (neuroConn GmbH, Ilmenau, Germany).
The sham group received 15 seconds of ramping up and ramping down at the beginning, after which stimulation was discontinued. The duration of the session was constant, regardless of the stimulation type. The electrodes (5×5 cm) were conductive rubber placed inside sponge pads soaked with 12 ml of saline. The anode was placed at site F3 and the cathode at site F4 according to the international 10-20 electroencephalography electrode placement system. After the stimulation, both the participant and the experimenter filled in a form in which they were asked to estimate possible skin redness (using a mirror), tiredness, mood changes, headache and sensations under the electrodes on a scale of 0-100.
The data contained excess zeros and were non-normally distributed. We compared the variables of interest (i.e., skin redness, tiredness, mood changes, headache and sensations under the electrodes) between the groups using the Mann-Whitney U-test. For more detailed analysis, a fixed-effects In Mann-Whitney U-test analyses, the intensity of skin redness under the electrodes was significantly (p<0.05) higher in the active group on all days when reported by the participant, and on days 2, 3 and 5 when reported by the experimenter. The active group reported less headache than the sham group on days 4 and 5.
Belonging to the active group predicted a higher likelihood of skin redness in fixed-effects ZIP.
Higher age predicted a stronger erythema reaction in participant-reported mixed-effects ZIP, while in the experimenter-reported model, age, belonging to the active group and higher baseline scores for perceived stress were significant predictors. There was a significant interaction, suggesting that higher age was a stronger predictor of skin redness in the active group than in the sham group in the model utilizing experimenter-reported scores, and borderline significant (p=0.0547) in the model utilizing participant-reported scores. There was a significant interaction between PSS scores and belonging to the active group in both models, but in opposite directions. The number of stimulation sessions was not a predictor (Table 1).
In While confirming that receiving active tDCS predicted skin redness (Ezquerro et al. 2017;Antal et al. 2017), we observed that increased age predicted an increased intensity of redness, particularly in the active group. Sensations under the electrodes, tiredness and mood did not differ between the groups, perhaps reflecting the successful sham protocol, particularly in the case of the sensations induced. However, our power calculations suggest that higher-than-expected numbers of participants may be needed to detect most of the above side effects.
We saw no changes in AEs over the stimulation period of five days, which suggests that repetitive sessions do not modify tDCS AEs. However, these observations need to be confirmed with different stimulation protocols and populations. In general, both the participants and the experimenter reported the same AEs.
As Antal and co-workers pointed out, while the tDCS AEs are mild and thus manageable, there are still several aspects to them that the community of researchers and clinicians are not familiar with, including the effect of repeated sessions and factors predicting different AEs. However, there is an abundance of existing data that could be used to gain more detailed insights into the predictors of tES AEs. Therefore, investigating such predictors could help in identifying protocols suitable for different groups of individuals, and in achieving an ideal risk-benefit ratio for tES treatments.