Introduction

Transcranial direct current stimulation (tDCS) is a non-invasive method of electrical stimulation of the cortex and has been shown to modulate brain activity specific to the site and parameters of stimulation [1]. tDCS research has ranged from the investigation of its physiological effects on brain activity and function [1], to a range of clinical applications, most notably chronic pain [2]–[5], depression [6] and stroke [7].

Clinical evaluation of tDCS is considered superior to that of other non-invasive brain stimulation methods because the stimulation condition can be concealed through the use of a sham condition [8]. Sham tDCS involves an identical process to active stimulation but, without the participant’s knowledge, the stimulator is switched off after around 30 seconds. Gandiga, et al. [9] reviewed the results of two crossover studies involving participants undergoing tDCS at 1 mA intensity or sham and found that the stimulation condition could not be distinguished by participants or blinded investigators. Ambrus et al. [10] highlighted the benefit of naivety by showing that, although even experienced participants could be effectively blinded using 1 mA or sham, when the participant was an experienced tDCS investigator, blinding was less effective. That is, even with low intensity tDCS, naivety is important for effective blinding from sham.

Many clinical trials involving tDCS use 2 mA stimulation and presume effective blinding [for example 2,3]. Largely on the basis of these trials, tDCS is considered a very promising therapeutic tool. tDCS at 2 mA is associated with more sensory effects than tDCS at 1 mA [11], which clearly casts doubt over assumption of effective blinding. Almost all trials of tDCS for chronic pain identified in a recent Cochrane review [12] used stimulation intensities of 2 mA. Only one parallel study [5] reported difficulties with participant blinding and even then did not elaborate on those difficulties. Conversely two parallel trials of tDCS for depression reported that effective treatment masking was maintained [13], [14]. Our group recently undertook a clinical crossover study [15] of tDCS at 2 mA for chronic back pain and found that participants may have been able to distinguish between the active stimulation and sham condition and a crossover study of tDCS for food cravings has similarly reported inadequate blinding [16].The use of a crossover design might be particularly problematic because exposure of participants to both active stimulation and sham increases the likelihood that they will distinguish one as more credible than the other. In addition to concerns over participant blinding, blinded assessors may also be able to distinguish between conditions because of skin redness that is observable at the electrode sites, primarily under the reference electrode, after active but not sham stimulation [11]. Given the growing endorsement of 2 mA tDCS as a therapeutic tool, it is remarkable that the assumption that such studies are effectively blinded has not been formally tested. The need for such testing was recently highlighted in a review of challenges for tDCS research [11]. We aimed to determine how well 2 mA tDCS can be blinded against a sham stimulation condition. Our primary research questions were “At stimulation intensities of 2 mA, do people correctly judge the true stimulation condition more than would be expected by chance and is this judgement influenced by previous exposure to sham or real stimulation?” and “At stimulation intensities of 2 mA, is skin redness at the visible electrode site more visible to the blinded assessor following active stimulation than it is following sham?”.

Methods

This study had full approval from the School of Health Sciences and Social Care Research Ethics Committee, Brunel University and conformed to the Helsinki declaration. All participants gave written informed consent. This study used a double-blind randomised crossover design.

Results

We recruited 100 participants (75 female). The mean (SD) age was 24 (8.3), range 18–62. Fifty-four participants were randomly allocated to receive active stimulation followed by sham. Ninety-nine participants completed the first stimulation session in full. One female participant withdrew from the study in the first session because they could not tolerate the stimulation. Three participants (2 female) did not attend for a second session: two stated that they were too busy to participate further and one did not respond to correspondence. We obtained complete data from 96 participants.

Participant Blinding

Table 1 presents the data for participants’ judgements of the stimulation condition.

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Table 1. Participant’s judgements of the stimulation condition, for each stimulation condition and session.

https://doi.org/10.1371/journal.pone.0047514.t001

Session one.

72% of participants who received active stimulation, and 56% of participants who received the sham, correctly judged the stimulation condition. Overall, 65% of participants correctly judged the stimulation condition they received which represents a “fair” level of agreement (κ = 0.28, 95% confidence interval (CI) 0.09 to 0.47 p = 0.005).

Session two.

89% of participants who received active stimulation and 88% of participants who received sham judged correctly, which represents a “good” level of agreement (κ = 0.77, 95%CI 0.64 to 0.90), p<0.001).

Assessor Blinding

Table 2 presents the frequency that the assessor noticed skin redness at the visible electrode site(s) under both stimulation conditions. The assessor noticed skin redness at the electrode site(s) following stimulation significantly more often following active stimulation than following sham stimulation in both the first session, with a “moderate” level of agreement (κ = 0.512, 95%CI 0.363 to 0.66, p<0.001), and in the second session (κ = 0.677, 95%CI 0.534 to 0.82, p<0.001). Skin redness was noted after 60% of active stimulation sessions and after 1% of sham stimulation sessions.

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Table 2. Assessors judgements of skin redness at the electrode site, for each stimulation condition.

https://doi.org/10.1371/journal.pone.0047514.t002

Discussion

Our results demonstrate that tDCS at 2 mA is not associated with effective blinding when compared with the commonly used sham using this electrode montage and stimulation procedure. For a proportion of tDCS naïve participants, blinding is maintained, but the probability of a participant correctly identifying the stimulation condition is greater than would be expected by chance. Given the high agreement in the second session, the threat to participant blinding appears substantially worse for crossover trials. Participants were more confident in their judgement where they judged that they were receiving active stimulation after the first session though this difference diminished by the second stimulation session.

It is highly likely that the sensory effects of active stimulation were responsible for compromising participant blinding. Familiarity with the experience of stimulation and the ability to compare between sessions amplified this issue after the second stimulation session. Reports of persistent itch or tingling during stimulation in response to the adverse events question are suggestive of this. Most participants probably would not consider these sensations to be adverse effects and so only a minority reported them. Assessor blinding was also compromised in a substantial proportion (60%) of active stimulation in both sessions and this represents an important potential source of bias, regardless of study design, in studies where outcomes are assessed in the immediate post stimulation period.

The current finding has substantial implications for much of the existing literature relating to tDCS. For example, 2 mA intensity and similar electrode montages have been used in almost all trials of tDCS for chronic pain [11], the majority of sham controlled tDCS trials for depression, [6], [13], [14] and all trials of tDCS for reducing cravings [16], [18]–[20]. All of these studies have reported superior efficacy of active stimulation over sham and while some [13], [14] report adequate participant blinding, the issue of assessor blinding was not assessed. While we cannot predict the degree of influence that inadequate blinding may have had in these studies, non-specific effects of interventions are known to be important in such clinical conditions [21], [22]. Further, there is evidence that incomplete blinding leads to exaggerated effects in clinical studies with subjective outcomes [23], and that placebo effects are larger with physical placebo interventions [22]. Thus, we contend that clinical studies that have used 2 mA tDCS should be interpreted with renewed caution. This point is emphasised by the recognised phenomenon that trials of new clinical interventions are often associated with small study effects and a publication bias that influence the evidence base, with a propensity for negative studies to not reach full publication [24], [25].

How might blinding of tDCS at this intensity be improved? Assessor blinding might be ensured by having the participant wear headgear that conceals the area under the electrodes. It is possible that longer ramping times may improve participant blinding but this may not be sufficient where participants are aware of sensations throughout the stimulation period. McFadden et al. [26] demonstrated that the pre-application of topical anaesthetics to electrode sites substantially reduced (but did not abolish) the sensations associated with stimulation, although the same process would be difficult at more posterior locations in participants with hair. Any modified sham protocol will require rigorous testing to ensure adequate blinding.

An alternative approach may be to reduce stimulation intensity. Indeed, it is not clear that higher stimulation intensities are necessary in clinical studies [11]. Effects on cortical excitability have been clearly demonstrated at intensities of 1 mA [1] and there is evidence to suggest that successful participant blinding is achievable under these conditions [9], [10]. Using intensities of 1 mA in future research may represent a more methodologically sound option, although it is plausible that reducing the intensity may reduce potential efficacy. Future studies of tDCS may benefit from other methods to optimise blinding, for example de facto masking [27], in which the treatment is not blinded but both treatments are presented as the active one. De facto masking might be more problematic if a non-stimulation sham is used that carries less credibility with participants but would seem very possible if the “sham” condition is active tDCS over a distinct brain area that is not hypothesized to elicit specific treatment effects.

That we found inadequate blinding using a therapy widely held as blindable [8] raises the possibility that clinical trials of other therapies are vulnerable to similar problems. One obvious example is in trials of TENS, in which the sham condition often involves a deactivated TENS unit and as such there will be distinct differences in the experience of stimulation. It is important to also acknowledge that inadequate blinding is not the only threat to the validity of clinical trials and continued attention should be paid in the design of trials to ensuring rigour in the selection and allocation process of future trials [28].

Our study has some limitations. We did not investigate the perceptual correlates of stimulation in any detail. We took this decision so as to minimise the risk that participants would over-scrutinize the experience of tDCS, which we felt would not accurately reflect the conditions of the average clinical trial. As such we cannot tell with confidence which factors most impacted on blinding. The VAS scale that we used to measure participants’ confidence in their judgements has not been specifically validated for that task and may have lacked sensitivity and validity, although this would not confound our results so much as reduce our power to detect non-blinding. The predominance of female participants might plausibly have affected our results. There is some evidence that differences exist between males and females, in pain threshold and pain evoked by a standard noxious stimulus, but the nature of the difference depends upon the type of stimulus and the context in which it is tested (see [29]for a review). There is also some debate as to whether pain thresholds vary in females according to stage of their menstrual cycle [30]–[32]. However, randomisation of the order of stimulation should mitigate any potential impact of these issues on our data. Finally the persistence of noticeable skin redness that persists beyond the immediate post-stimulation period represents a further risk to participant blinding and suggests that our results may underestimate the scale of the problem.

In conclusion, contrary to the assumption of blinding, which underpins the growing support of tDCS for clinical conditions, our data show that both participant and assessor blinding is compromised at 2 mA intensity when using this electrode montage and stimulation procedure. The findings have important implications for the interpretation of studies which have utilised this approach and for the design of future tDCS studies.