The authors have declared that no competing interests exist.
Conceived and designed the experiments: SK. Performed the experiments: SK. Analyzed the data: SK. Contributed reagents/materials/analysis tools: SK AGW. Wrote the manuscript: SK. Reviewed and approved the manuscript: AGW.
Transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) has beneficial effects on motor performance and motor learning in healthy subjects and is emerging as a promising tool for motor neurorehabilitation. Applying tDCS concurrently with a motor task has recently been found to be more effective than applying stimulation before the motor task. This study extends this finding to examine whether such task-concurrent stimulation further enhances motor learning on a dual M1 montage.
Twenty healthy, right-handed subjects received anodal tDCS to the right M1, dual tDCS (anodal current over right M1 and cathodal over left M1) and sham tDCS in a repeated-measures design. Stimulation was applied for 10 mins at 1.5 mA during an explicit motor learning task. Response times (RT) and accuracy were measured at baseline, during, directly after and 15 mins after stimulation. Motor cortical excitability was recorded from both hemispheres before and after stimulation using single-pulse transcranial magnetic stimulation.
Task-concurrent stimulation with a dual M1 montage significantly reduced RTs by 23% as early as with the onset of stimulation (p<0.01) with this effect increasing to 30% at the final measurement. Polarity-specific changes in cortical excitability were observed with MEPs significantly reduced by 12% in the left M1 and increased by 69% in the right M1.
Performance improvement occurred earliest in the dual M1 condition with a stable and lasting effect. Unilateral anodal stimulation resulted only in trendwise improvement when compared to sham. Therefore, task-concurrent dual M1 stimulation is most suited for obtaining the desired neuromodulatory effects of tDCS in explicit motor learning.
Transcranial direct current stimulation (tDCS) is a non-invasive stimulation technique that induces robust excitability changes in the human motor cortex [
TDCS of the primary motor cortex (M1) is an important target for motor learning and rehabilitation [
However, recent research demonstrated that bilaterally stimulating both motor cortices simultaneously was more effective at improving performance at a finger-sequencing task than the conventional unilateral montage [
However, despite the clinical effectiveness of dual M1 stimulation, there are neuronal compensation mechanisms in the lesioned brain as well as post-injury differences across the patient population [
Since tDCS modulates and does not induce neuronal firing, performing a behavioural task concurrently would enhance the stimulation-induced differences in cortical excitability. In line with this, Stagg et al. [
Therefore, the present study aimed to establish how the dual M1 electrode montage benefits from task-concurrent stimulation. Anodal tDCS to the right M1, dual M1 stimulation and sham stimulation were applied during an explicit motor learning task and performance was compared between the conditions before, during, immediately after and 15 mins after the end of stimulation. We tested the hypothesis that dual M1 stimulation would improve finger-sequencing coordination more than unilateral anodal stimulation and compared both against the sham stimulation condition. Motor cortical excitability was measured before and after the intervention to elucidate possible differences between the conditions and we examined whether it is possible to achieve bidirectional simultaneous modulation of cortical excitability in the dual stimulation condition.
Subjects provided written informed consent and the experimental protocol was performed in accordance with the Declaration of Helsinki and approved by the Faculty of Health Sciences Research Ethics Committee, Trinity College Dublin, Ireland.
Twenty healthy young adults (12 females; mean age 25.6 years ± 4.5 SD) participated in this study. They showed no signs of any medical or neurological disease or intake of any CNS-active medication as evaluated by a medical questionnaire that was examined by a health practitioner. All were right handed, as determined by the Edinburgh Handedness Inventory [
TDCS was delivered through two saline-soaked, sponge electrodes using a battery-driven, constant-current stimulator (Magstim Company Limited, Whitland, Wales, UK). The electrodes were held in place with use of a MindCap (NewRonika, Italy).
In all conditions, the anode (25 cm2) was fixed over the right M1, corresponding to position C4 of the 10-20 EEG system, centred over the ‘hot-spot’ of the resting first dorsal interosseus (FDI) hand muscle as determined by single-pulse TMS. In the dual condition, the cathode (25 cm2) was placed over the FDI hand area of the left M1, corresponding to position C3, also determined by single-pulse TMS. In the anodal condition, the cathode (35 cm2) was fixed as a reference electrode contralaterally at the fronto-orbital region or F3 of the 10-20 EEG system. This position for the return electrode has been shown to be functionally ineffective in experimental designs [
Current intensity was 1.5 mA (current density of 0.06 mA/cm2) and applied for 10 mins. For sham stimulation, current flow increased gradually over a 5s interval reaching the designated 1.5 mA to mimic the initial sensation of real tDCS and the stimulation was then ramped down after 10s and decreased gradually over a 5s interval, so that a conditioning effect on cortical excitability was not induced.
To detect changes of corticospinal excitability, motor-evoked potentials (MEPs) of the resting FDI were recorded after stimulation of their motor-cortical representational fields by single-pulse TMS. Electromyography (EMG) signals were amplified, band-pass filtered (10 to 50 Hz) and sampled at 1,000 Hz, using conductive adhesive Ag/AgCl electrodes (Tyco Healthcare, Mansfield, UK) in a belly tendon montage. EMGs were recorded through an Octal BioAmp (AD Instruments, Oxford, UK). The peak-to-peak amplitudes of the MEPs were detected by an AD-Instrument custom-written script (LabChart v.7, AD Instruments, Oxford, UK).
TMS was applied using a Magstim Rapid stimulator (Magstim Company Limited, Whitland, Wales, UK) connected to a figure of eight coil (70mm). The coil was positioned tangentially on the scalp with the handle pointing backward at an angle of 45° to the midline. It was placed over the contralateral motor cortex at the optimal site for stimulating the FDI. This optimum coil position (‘hot-spot’) was defined as the position where TMS consistently resulted in the largest mean MEP amplitude. A tight-fitting Lycra cap was placed on the subjects’ head to mark the optimal coil position for TMS. Once placed, the cap and head were marked such as to be able to fit it in the same place when re-fitting the cap after tDCS.
The resting motor threshold (RMT) was defined as the minimum TMS intensity, which achieved peak-to-peak MEP amplitude of 50-100µV in the resting FDI muscle in 3 out of 6 stimulations. Twenty MEPs (in intervals of 3.5 s) at an intensity that was 120% RMT were acquired from each hemisphere at the three time points PRE, POST1 and POST2 (see section 2.2). The hemisphere that was tested first was randomised and counterbalanced for every measurement.
The experiment was run in Psychopy, an open-source experimental-control software package [
Instructions for a single trial were to memorise the six-sequence numerical pattern made up of the numbers 6-9 and repeat the movements of this key sequence six times as quickly and as accurately as possible with the corresponding buttons on the keyboard with their left hand (6 = little finger, 7= ring finger, 8 = middle finger, 9 = index finger). During memorising, the four consecutive boxes labelled ‘6’, ‘7’, ‘8’, ‘9’ were always displayed at the centre of the screen and these were highlighted with an asterisk one at a time for 500 ms. Subjects were shown the pattern twice before a ‘Go’ command signalled them to start the finger response. Reaction time (RT) was recorded from the appearance of the ‘go’ signal and RT was recorded for every individual button press. After the sixth repetition of the pattern, the instructions “Hit ‘S’ for next sequence” appear on the screen and the subject would initiate the next trial. There were 12 trials in total and the total duration of the task was 6 min on average.
All responses were recorded during a trial and so it was any 36 button presses of either 6, 7, 8 or 9 that would be counted before initiating the next trial, as opposed to 36 ‘correct’ button presses. In order to maintain fluency of the finger movements, subjects were instructed to keep going with the pattern, even if a number was ‘missed’ rather than start from the beginning of the sequence.
At the start of every experimental session, subjects carried out two trials (corresponding to two sequences) as practice trials, but these were the only practice trials in the entire session such as to not miss potential immediate effects following tDCS intervention.
The sequences were chosen to be of varying difficulty, in terms of use of the less dextrous little and ring finger (e.g. 679769 vs. 879698) and in terms of ease of memorising the sequence (e.g. 879698 vs. 986987). Sequences never included consecutives of the same numbers and an effort was made to equalise the ratio of digit presses across sequences. The motor task always used the same 12 sequences, however, there were 3 versions of the task, in which the order of the sequences was randomised. Subjects would use one version of the task per experimental session, so that each subject used each version once, this was pseudo-randomised and counterbalanced.
A sham-controlled, repeated-measures design was carried out. Each subject participated in three testing sessions, during which they received anodal, dual or sham tDCS. The order of condition was randomised and best care was taken to counterbalance carefully, but the condition order combinations DAS and SAD (where D = “dual”, A = ”anodal” and S = ”sham”) were applied four times whereas all other combinations (i.e. ADS, ASD, DSA and SDA) were applied three times. The order of condition was into account in statistical analyses. All stimulation sessions were separated by at least 1 week.
Motor cortical excitability and performance on the explicit motor learning task were measured at several time points (
The measurements of reaction times the motor task (RT) and the measurements of motor cortical excitability (MEP) were acquired following the same systematic order as shown in this diagram. There were a total of four measurements of motor performance and three measurements of motor cortical excitability.
At the end of every experimental session, the subjects completed a visual analogue scale to rate (from 1-7) their current level of fatigue, concentration and perceived pain during the tDCS stimulation.
Motor performance on the explicit motor learning task was quantified by the average reaction times (RTs) of every button press and by the per cent accuracy. The standard deviation of RTs for every block was calculated as an index of variability of RTs. For statistical analyses, the mean RTs and the mean accuracy were analysed for every block and compared against each other. Normality was tested using the Shapiro-Wilk test of normality. Where motor parameters were not normally distributed, they were found to be normally distributed in log-space and were transformed logarithmically before statistical analyses. The MEP data were transformed using square root transformation to obtain normal distribution before statistical analyses. The data shown in the tables and figures are untransformed values. Where the assumption of sphericity was not met, the Greenhouse-Geisser correction was applied. All data are reported as mean ± standard deviation (SD).
Statistical analyses were performed separately for each via a two-way repeated-measures (condition: anodal, dual, sham; condition x time points: PRE, DURING, POST1, POST2) analysis of variance (ANOVA). Due to the considerable practice effects of the motor task, the order of conditions from every subject will be entered as a covariate in an additional analysis of covariance (ANCOVA) for the mean RTs.
For the changes in motor cortical excitability, the MEP amplitudes for each subject were averaged for every block and a two-way repeated-measures ANOVA (condition: anodal, dual, sham; condition x time points: PRE, POST1, POST2) was conducted for each hemisphere separately (left, right). All statistical analyses were performed using SPSS v.20 (SPSS Inc., Chicago, IL, USA).
All 20 subjects completed the 3 experimental sessions. The motor performance data is depicted in
* = p<0.05 and ** = p<0.01 from the ANOVA; # = p<0.05 and ## = p<0.01 from the ANCOVA; Error bars are 95% confidence intervals (CI) calculated on the transformed data and transformed back to the original scale.
Error bars are 95% confidence intervals (CI) calculated on the transformed data and transformed back to the original scale.
anodal | RT ( |
0.392 (0.134) | 0.330 (0.086) | 0.315 (0.079) | 0.313 (0.076) |
Acc. ( |
80.52 (16.99) | 80.78 (12.76) | 82.84 (11.37) | 84.68 (9.57) | |
dual | RT ( |
0.404 (0.111) | 0.314 (0.074) | 0.303 (0.071) | 0.285 (0.063) |
Acc. ( |
82.60 (11.67) | 82.34 (16.20) | 83.35 (9.72) | 84.20 (10.58) | |
sham | RT ( |
0.384 (0.076) | 0.347 (0.071) | 0.336 (0.069) | 0.343 (0.069) |
Acc. ( |
82.28 (18.02) | 82.27 (17.59) | 81.39 (21.25) | 81.41 (18.13) | |
The four time points are measurements at baseline (PRE), during tDCS (DURING), immediately after tDCS (POST1) and approximately 15 mins after the end of tDCS (POST2) Reaction times (RT) are expressed in seconds and accuracy (Acc.) in per cent. |
Wrong answers were not excluded in this task, because a missed or a wrong button press still gives insight into the fluidity of finger coordination in repeating the numerical sequence. There was very little fluctuation of accuracy across stimulation condition and thus incorrect answers are evenly distributed across blocks: there was no main effect of time (
There was a significant overall decrease of RTs over time (ANOVA main effect of time
The changes in motor task performance in the anodal condition were significantly different to sham condition at POST2 when compared to baseline (F1,19=6.38, p<0.05;
In order to control for the practice effects associated with the motor task, the order of conditions every subject underwent was entered as a covariate into the additional ANCOVA. There was no significant interaction between the condition order and the main effect of time (
Overall, all subjects improved their finger-coordination in this task over time. The anodal and the dual stimulation conditions improved motor performance further, but this occured earlier and lasted longer in the dual tDCS stimulation condition relative to sham. Performance improvements in the anodal condition were, to some extent, driven by the order that the conditions were administered. There was very little fluctuation of accuracy across the blocks, which means that subjects improved at the task without a noticeable speed/accuracy trade-off.
There was no significant difference in the self-rated visual analogue scale for fatigue, concentration and perceived pain (all p>0.05; all
anodal | avg. | 0.387 | 0.415 | 0.440 | 0.341 | 0.486 | 0.497 |
dual | avg. | 0.410 | 0.308 | 0.363 | 0.375 | 0.563 | 0.634 |
sham | avg. | 0.367 | 0.372 | 0.378 | 0.410 | 0.434 | 0.425 |
The four time points are measurements at baseline (PRE), approximately 8 mins after the end of tDCS (POST1) and approximately 20 mins after the end of tDCS (POST2)
There was a significant reduction in MEPs in the dual condition in the left hemisphere.
**=p<0.01, *=p<0.05; Error bars are 95% confidence intervals (CI) calculated on the transformed data and transformed back to the original scale.
Both active stimulation conditions were associated with an excitability-enhancing effect at both time points in the right hemisphere, but this was significantly larger in the dual condition.
**=p<0.01, *=p<0.05; Error bars are 95% confidence intervals (CI) calculated on the transformed data and transformed back to the original scale.
For the left hemisphere, these revealed no main effect of stimulation condition (
For the right hemisphere, there was no significant main effect of stimulation condition (
While only the dual condition was found to be statistically different to the sham and anodal conditions for the left hemisphere in the form of reduced MEP amplitudes (see
We investigated the effects of administering dual tDCS during an explicit motor learning task. The impact tDCS has on motor learning and how this effect is enhanced through task-concurrent stimulation has so far only been demonstrated for the conventional unilateral electrode montage. Our results suggest that simultaneously stimulating both motor cortices further enhances the benefits of task-concurrent stimulation.
Both active tDCS conditions showed an improvement in task performance over time, but only the dual condition was found to be significantly different from the sham condition after controlling for the order of conditions. As early as at the time of stimulation onset, reaction times (RTs) were significantly reduced by 23% in the dual condition compared with a 9% reduction in the sham condition (p<0.01). This RT reduction increased to 30% at the final measurement, compared with an 11% reduction in the sham condition at the same time point. There was a clear trend for an effect in the anodal condition (RTs were 20% lower at the last measurement), but this did not reach significance compared to sham (see
Our results confirm that administering tDCS during an explicit motor learning task is beneficial to performance in healthy subjects. The literature suggests this is above that provided by stimulation prior to task execution [
During motor learning, synaptic efficacy in the motor cortex is enhanced, driven by Hebbian synaptic modifications and mediated by long-term potentiation (LTP) and NMDA-specific glutamate receptor function. There is increasing evidence suggesting that the lasting effects of tDCS also involve LTP-like synaptic mechanisms [
A more mechanistic explanation for the timing-dependent interaction has previously been attributed to metaplasticity, which is essentially a regulatory mechanism that prevents destabilisation of the existing cortical network from dynamic cortical changes such as LTP. As outlined by Kuo et al. [
In the present study, the dual M1 electrode montage was associated with early and lasting performance improvement. Notably, the blocks with the most decreased reaction times were also associated with the lowest standard deviations, suggesting a stable effect and low inter-subject variability for this condition (see
It has been speculated that the measurable improvement in motor performance associated with dual M1 stimulation is mediated by inhibitory interhemispheric projections. Here, the direct excitability- and performance-enhancing effect of the anodal current is amplified by the reduced inhibitory projections coming from the homologous left M1 due to the positioning of the cathodal return electrode. In other words, the motor cortex of the motor-performing hand is additionally released from the normal amount of inhibition originating from its counterpart in the other hemisphere. Studies reporting an increase in motor skill acquisition in the ipsilateral hand following unilateral cathodal stimulation mechanistically support the role of interhemispheric projections in corticomotor functioning [
Two separate studies, both using resting-state fMRI to investigate the changes in functional connectivity between the primary motor cortices induced by dual tDCS, report a decrease in interhemispheric projections in the unilateral-anodal and the dual condition, but only the dual condition was associated with increases in intracortical projections [
Consistent with previous research, we observed a simultaneous modulation of cortical excitability in different directions in the dual stimulation condition. That is, the average MEP amplitudes were found to be statistically lower than sham in the left hemisphere and statistically higher than sham in the right hemisphere. This is in keeping with findings reported by Williams et al. [
According to the gating principle of plasticity, the increased neuronal firing rates induced by the motor task are further amplified by the excitability-enhancing transcranial stimulation, resulting in increased postsynaptic strength [
Looking at
In conclusion, this study demonstrates that active tDCS applied concurrently to a finger-sequencing coordination task is effective at improving the rate of learning compared with sham stimulation. The bilateral stimulation of both motor cortices is more appropriate than the conventional unilateral anodal stimulation, as motor learning was significantly greater in this condition compared with sham stimulation. In the dual M1 condition, it was also possible to obtain simultaneous modulation of cortical excitability in different directions in the two motor cortices and, further, excitability in the area under the anode was significantly enhanced in the dual compared to the unilateral anodal stimulation condition. Thus, task-concurrent dual M1 stimulation is very effective at determining the desired neuromodulatory effects of tDCS. Optimising these stimulation parameters has important implications for the rehabilitative approaches that are being developed.
The authors would like to thank Tom Broughton from AD Instruments for writing the script used in the analysis of the electromyography data. We also thank Tonya Moloney for giving useful comments in the initial stage of this project and Dave Fletcher for his continuous technical assistance.