Elsevier

Brain Stimulation

Volume 7, Issue 3, May–June 2014, Pages 468-475
Brain Stimulation

Original Article
Variability in Response to Transcranial Direct Current Stimulation of the Motor Cortex

https://doi.org/10.1016/j.brs.2014.02.003Get rights and content

Abstract

Background

Responses to a number of different plasticity-inducing brain stimulation protocols are highly variable. However there is little data available on the variability of response to transcranial direct current stimulation (TDCS).

Objective

We tested the effects of TDCS over the motor cortex on corticospinal excitability. We also examined whether an individual's response could be predicted from measurements of onset latency of motor evoked potential (MEP) following stimulation with different orientations of monophasic transcranial magnetic stimulation (TMS).

Methods

Fifty-three healthy subjects participated in a crossover-design. Baseline latency measurements with different coil orientations and MEPs were recorded from the first dorsal interosseous muscle prior to the application of 10 min of 2 mA TDCS (0.057 mA/cm2). Thirty MEPs were measured every 5 min for up to half an hour after the intervention to assess after-effects on corticospinal excitability.

Results

Anodal TDCS at 2 mA facilitated MEPs whereas there was no significant effect of 2 mA cathodal TDCS. A two-step cluster analysis suggested that approximately 50% individuals had only a minor, or no response to TDCS whereas the remainder had a facilitatory effect to both forms of stimulation. There was a significant correlation between the latency difference of MEPs (anterior–posterior stimulation minus latero-medial stimulation) and the response to anodal, but not cathodal TDCS.

Conclusions

The large variability in response to these TDCS protocols is in line with similar studies using other forms of non-invasive brain stimulation. The effects highlight the need to develop more robust protocols, and understand the individual factors that determine responsiveness.

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

References (42)

  • H. Voytovych et al.

    Lithium: a switch from LTD- to LTP-like plasticity in human cortex

    Neuropharmacology

    (2012)
  • V. Conde et al.

    Cortical thickness in primary sensorimotor cortex influences the effectiveness of paired associative stimulation

    Neuroimage

    (2012)
  • F. Maeda et al.

    Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation

    Clin Neurophysiol

    (2000)
  • N. Zafar et al.

    Comparative assessment of best conventional with best theta burst repetitive transcranial magnetic stimulation protocols on human motor cortex excitability

    Clin Neurophysiol

    (2008)
  • B. Fritsch et al.

    Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning

    Neuron

    (2010)
  • M.A. Nitsche et al.

    Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans

    J Physiol

    (2003)
  • D. Liebetanz et al.

    Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability

    Brain

    (2002)
  • D.P. Purpura et al.

    Intracellular activities and evoked potential changes during polarization of motor cortex

    J Neurophysiol

    (1965)
  • W.M. Landau et al.

    Analysis of the form and distribution of evoked cortical potentials under the influence of polarizing currents

    J Neurophysiol

    (1964)
  • L.J. Bindman et al.

    The Action of brief polarizing currents on the cerebral cortex of the rat (1) during current flow and (2) in the production of long-lasting after-effects

    J Physiol

    (1964)
  • M.A. Nitsche et al.

    Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans

    Neurology

    (2001)
  • Cited by (595)

    View all citing articles on Scopus

    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.

    1

    These authors contributed equally.

    View full text