Original ArticleVariability in Response to Transcranial Direct Current Stimulation of the Motor Cortex
Introduction
Transcranial direct current stimulation (TDCS) is a widely-used tool in which a small constant direct current (usually 1–2 mA) (0.029–0.057 mA/cm2) is applied through large pad electrodes placed on the scalp (see overview in Ref. [1]). It is thought that this changes the excitability of neurons in the brain by hyperpolarizing or depolarizing their membrane potential [2], [3]. Experiments in the 1960's on cat and rat cortex showed that direct polarization for periods of several minutes produced long lasting changes in neural firing rates for several hours afterwards [4], [5], [6]. These were thought to involve synaptic plasticity since the effects were abolished by inhibitors of protein synthesis.
Similar lasting effects of TDCS in humans have been described in the motor cortex: Nitsche and Paulus found that anodal TDCS (i.e. with the anode over motor areas) increased excitability of corticospinal output, as tested using single pulse transcranial magnetic stimulation (TMS), whereas cathodal stimulation had the opposite effect [7]. Subsequent studies suggested that the effects depended on synaptic plasticity since they were abolished by pretreatment with drugs that interfered with NMDA receptor function [2], [3]. However, despite the ever increasing number of studies using TDCS in fields from cognitive neuroscience to rehabilitation, there are few studies of the variability of the effects that are produced [8]. The latter is particularly important if TDCS is to be used therapeutically since any successful treatment should have repeatable effects on a high proportion of treated individuals.
Given the existence of interindividual differences in response to other plasticity protocols such as paired associative stimulation (PAS) and theta-burst stimulation (TBS) in which 30–50% participants fail to respond in the “canonical” way [9], [10], [11], [12], [13], [14], [15], [16], [17], we decided to perform a pragmatic exploratory study of variation in response to TDCS. We chose one variety of TDCS protocol (2 mA with electrode size 35 cm2; 0.057 mA/cm2) [18] for 10 min over motor cortex) [19] and tested the after-effects on corticospinal excitability in the standard way in relaxed healthy individuals. The selection of 2 mA (0.057 mA/cm2) was determined by the fact that it is now becoming standard in an increasing number of behavioral, cognitive, and clinical studies due to an implicit assumption that higher intensities will enhance efficacy of stimulation [18], [20]. There are no detailed studies comparing different durations of TDCS at 2 mA (0.057 mA/cm2), although 10 min has previously been shown to have robust after-effects [19]. Participants were similar to those used in some previous papers (student volunteers) and were selected according to usual criteria. In essence we tried to create a fairly “typical” dataset to maximize the likelihood that the results would be applicable to other experimental situations.
We are aware that the results of this particular study may not apply to all varieties of TDCS, or to studies with more stringent participant inclusion criteria. However, the large variance in the response we observed suggests that it may be important to test whether other TDCS protocols are similarly affected. In the face of such variation we were also interested in whether it might be possible to predict how well a person might respond to TDCS. A number of determinants have been identified [17], and previously we had found that the response to TBS protocols was well predicted by the latency difference between MEPs evoked by single TMS pulses of different orientations [10]. It is likely that these latency differences are surrogate measures of interneuron network recruitment within the primary motor cortex [10], [21]. Evidence also suggests that TDCS distinctively modulates different interneuron networks in a polarity specific manner [22], [23]. We therefore examined whether latency difference measured by TMS with different orientations correlates with the responses to TDCS.
Section snippets
Subjects
Fifty-three right-handed subjects (33 females, 20 males; 18–52 years old, mean age ± SD: 26.83 ± 8.97) participated in the study. None of the participants displayed any contraindications to TMS or TDCS, took any medication on a regular basis or had a positive history of psychiatric or neurologic diseases [24]. All participants gave written consent. The study was approved by the Ethics Committee of the University College London.
Recordings
During the experiment subjects were seated on a comfortable chair.
Results
All subjects reported light tingling over the electrode positions which completely vanished within several seconds up to 5 min. Two subjects developed tension headache after TDCS which persisted throughout the day of the experiment after both sessions (anodal and cathodal).
Baseline physiological measurements are shown in Table 1 and were not significantly different between stimulation conditions. Figure 1A and B plot the raw MEP data from all subjects for anodal and cathodal stimulation. There
Discussion
As far as we know this is the first large scale prospective study of the variation in after-effects of a TDCS protocol in healthy young volunteers. It was an exploratory study and for pragmatic reasons we chose to examine only one particular variety of TDCS with fairly typical choices of intensity (2 mA), duration (10 min), electrode montage (large bipolar cephalic) and target site (primary motor cortex). We used an intensity of 2 mA, which is higher than that used in most early TDCS studies [1]
Conclusion
The effects of TDCS are highly variable, as in other plasticity-inducing protocols, with around 50% of individuals having poor or absent responses. We do not know if these results can be extrapolated to measures other than corticospinal excitability, such as the effects of TDCS on motor learning. However, it would be important to test this in future studies, particularly those in which TDCS is being used to treat neurological conditions. If half of the recruited participants are unlikely to
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This study was mainly supported by EU FP7 Collaborative Project (223524: Plasticise). Sarah Wiethoff is supported by a PhD-studentship of the Brain Research Trust.
Masashi Hamada is supported by the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad.
Conflict of interest: M.H. serves as a medical advisor for Pfizer Japan Inc. Other authors declare no potential conflicts of interest relating to the subject of this report.
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These authors contributed equally.