Secondary Logo

Journal Logo

Anodal transcranial direct current stimulation modulates GABAB-related intracortical inhibition in the M1 of healthy individuals

Tremblay, Saraa,b; Beaulé, Vincenta,b; Lepage, Jean-Françoisa,b; Théoret, Hugoa,b

doi: 10.1097/WNR.0b013e32835c36b8
MOTOR SYSTEMS
Free

It is known that transcranial direct current stimulation (tDCS) can induce polarity-specific shifts in brain excitability of the primary motor cortex (M1) with anodal tDCS enhancing and cathodal tDCS reducing cortical excitability. However, less is known about its impact on specific intracortical inhibitory mechanisms, such as γ-aminobutyric acid B (GABAB)-mediated inhibition. Consequently, the aim of the present study was to assess the impact of anodal and cathodal tDCS on M1 intracortical inhibition in healthy individuals. Long-interval intracortical inhibition (LICI) and cortical silent period (CSP) duration, both presumably mediated by GABAB receptors, were assessed using transcranial magnetic stimulation immediately before and after a 20 min session of tDCS over the left M1. Anodal tDCS significantly enhanced motor evoked potential size and reduced CSP duration, whereas it had no effect on LICI. Cathodal stimulation did not significantly modulate motor evoked potential size, CSP duration or LICI. This study provides evidence that anodal tDCS, presumably by synaptic plasticity mechanisms, has a direct effect on GABAB-meditated inhibition assessed by the CSP, but not by LICI. Our results further suggest that CSP and LICI probe distinct intracortical inhibitory mechanisms as they are differentially modulated by anodal tDCS. Finally, these data may have clinical value in patients in whom a pathological increase in CSP duration is present, such as schizophrenia.

aPsychology department, University of Montreal

bResearch Center, Sainte-Justine Hospital, Montreal, Quebec, Canada

Correspondence to Hugo Théoret, PhD, Département de Psychologie, Centre de recherche en neuropsychologie et cognition, Université de Montréal, CP 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7 Tel: +1 51 434 363 62; fax: +1 51 434 357 87; e-mail: hugo.theoret@umontreal.ca

Received October 3, 2012

Accepted November 2, 2012

Back to Top | Article Outline

Introduction

Transcranial direct current stimulation (tDCS) allows the modulation of cortical excitability by polarity-specific weak electric current stimulation. Anodal stimulation enhances cortical excitability, whereas cathodal stimulation reduces it. These modulations in cortical excitability are reflected by changes in transcranial magnetic stimulation (TMS) induced motor evoked potential (MEP) size, which are enhanced following anodal tDCS and reduced following cathodal tDCS 1. Pharmacological studies suggest that these inhibitory and facilitatory effects are influenced by drugs modifying both membrane excitability and synaptic plasticity 1,2 and mediated by N-methyl-D-aspartate receptors 3. This is in agreement with recent animal studies confirming the involvement of activity-dependent synaptic plasticity mechanisms in tDCS polarity-specific excitability shifts 4. Therefore, it is thought that anodal stimulation results in long-term potentiation (LTP; 4) a long lasting enhancement in signal transmission implicated in learning and memory.

To investigate the impact of tDCS on brain excitability, most studies use variations in MEP size to quantify changes in cortical excitability 5. Only a handful of TMS studies have examined the effect of anodal 6–8 or cathodal stimulation 5,7,9 on intracortical inhibitory mechanisms. Results from these studies suggest that anodal stimulation decreases short-interval intracortical inhibition 6,8, presumably mediated by γ-aminobutyric acid A (GABAA) receptors 10, but does not affect long-interval intracortical inhibition (LICI; 6), presumably mediated by GABAB receptors 11. However, the little evidence available on the effects of tDCS on the cortical silent period (CSP), presumably also mediated by GABAB receptors 12, is contradictory; one study reported an increase of CSP duration in controls after cathodal stimulation 9, whereas others reported no effect of anodal 6,7 or cathodal tDCS 7 on CSP.

Recently, Stagg et al. 13 showed that excitatory anodal tDCS reduces GABA levels as revealed by magnetic resonance spectroscopy, suggesting that the facilitatory effects of tDCS could be partly explained by a decrease in GABAergic inhibition. However, this study does not permit to pinpoint the effect of tDCS on specific GABAB processes. The present study aimed to investigate the effect of cathodal and anodal tDCS on intracortical inhibitory mechanisms mediated by GABAB receptors.

Back to Top | Article Outline

Materials and methods

Participants

A total of 10 participants (five men and five women), aged between 19 and 28 years (mean=23.3), were recruited through advertisements. The following exclusion criteria were used: psychiatric or neurological history, traumatic brain injury, presence of a pacemaker, piece of metal implanted in the skull or history of fainting, seizures or substance abuse. Participants were all right-handed. The study was approved by the local ethics committee and all participants provided written informed consent before testing. Participants received a financial compensation of $60 CAN for their participation.

Back to Top | Article Outline

Procedure

The study consisted of two 90-min sessions separated by at least 48 h. One session consisted of anodal tDCS and the other of cathodal tDCS. Session order was pseudorandomly determined across participants. TMS stimulation of the left primary motor cortex (M1) was performed before and after tDCS.

Back to Top | Article Outline

Transcranial magnetic stimulation

TMS was delivered through an 8 cm figure-of-eight coil connected to a MagPro stimulator (Medtronic, Minneapolis, Minnesota, USA). The coil was positioned flat on the head of the participants with an angle of 45° from the midline and with the handle pointing backwards. The induced current was biphasic with an anterior–posterior direction. The optimal site of stimulation was defined as the coil position from which TMS produced MEPs of maximum amplitude in the target muscle of the controlateral hand. Two self-adhesive electrodes were placed on the first dorsal interosseus (FDI) muscle to measure motor contraction. A ground electrode was positioned over the wrist. The electromyographic (EMG) signal was amplified with a bandwidth of 20–1000 Hz using a Powerlab 4/30 system (ADInstruments, Colorado Springs, Colorado, USA). MEPs were recorded using Scope v4.0 software (ADInstruments) and stored offline for analysis. A Brainsight frameless stereotaxic system (Rogue Research Inc., Montréal, Quebec, Canada) was used to ensure stable coil positioning over the stimulation site and to properly position tDCS electrodes over M1.

Two identical TMS sessions were conducted before and after tDCS. At first, the intensity of stimulation was adjusted to elicit MEPs of averaged amplitude of 1 mV peak-to-peak. To induce CSP, single-pulse TMS with an intensity of 1 mV peak-to-peak was delivered while participants maintained a voluntary isometric muscle contraction of the right FDI at ∼20% of maximal strength 14. A LICI protocol was then carried out by applying two pulses at an intensity adjusted to produce test stimulus (TS) amplitudes between 0.20 and 1.50 mV at an interstimulus interval of 100 ms. The intensity of the conditioning stimulus and the TS were identical. Ten MEPs were collected for CSP and LICI. Twenty single-pulse MEPs were also collected at 1 mV peak-to-peak intensity. All TMS pulses were applied at a time interval of 7–10 s. For LICI and CSP measurements, TMS intensity was adjusted again after tDCS to produce peak-to-peak amplitudes of 1 mV to ensure that modulations of LICI and CSP were not linked to modifications in threshold but rather to changes in intracortical inhibition.

Back to Top | Article Outline

Transcranial direct current stimulation

Electrical current was delivered using a Magstim DC Stimulator (Magstim Ltd, Wales, UK) through a pair of conductive rubber electrodes inserted into saline-soaked sponges. A small squared electrode (25 cm2) was positioned over the left FDI hotspot previously determined using TMS as the site-inducing maximal FDI muscle contractions. A second rectangular electrode (35 cm2) was positioned above the right supraorbital area. The electrodes were oriented parallel to the central sulcus and eyebrows. It has been shown that this site provides optimal modulation of corticospinal excitability in M1 1. The polarity of the electrical stimulation (anodal or cathodal) was dependent on the polarity of the electrode positioned over M1. A constant electric current of 1.5 mA was applied for 20 min for both conditions. The current was gradually increased and decreased during the first and last 15 s to avoid peripheral sensations.

Back to Top | Article Outline

Data analysis

For LICI, ratios of the conditioning stimulus over the TS were collected. The length of the CSP was manually evaluated and defined as the beginning of EMG activity suppression until the resumption of sustained EMG activity. Paired-sample t-tests were computed to evaluate the potential effect of tDCS on cortical excitability and inhibitory mechanisms. A P value less than 0.05 was considered significant. Participants were excluded from further analysis for a specific variable if the TMS data was ±2 SD from the mean. With this criterion one of the participants was excluded from LICI analysis.

Back to Top | Article Outline

Results

Anodal stimulation

Results of anodal stimulation are presented in Fig. 1 and Table 1. Anodal stimulation resulted in a 68% average increase in MEP size (pre: 1.14 mV; post: 1.92 mV), in which eight of 10 participants showed the effect. A paired-sample t-test revealed that this difference was significant [t(9)=2.67, P=0.026]. Duration of the CSP was shortened by an average of 12% (pre: 110 ms; post: 96 ms), in which nine of 10 participants showed the effect. A paired-sample t-test revealed that this difference was significant [t(9)=2.88, P=0.018]. Finally, anodal stimulation did not modulate the strength of LICI (pre: 0.59; post: 0.50) as shown by a paired t-test [t(8)=0.75, P=0.47].

Fig. 1

Fig. 1

Table 1

Table 1

Back to Top | Article Outline

Cathodal stimulation

Results of cathodal stimulation are presented in Fig. 2 and Table 2. Cathodal stimulation did not modulate MEP size [t(9)=0.12, P=0.90], CSP duration [t(9)=1.39, P=0.20] or LICI strength [t(9)=0.42, P=0.69].

Fig. 2

Fig. 2

Table 2

Table 2

Back to Top | Article Outline

Discussion

The main finding of the present study is that 20 min of anodal tDCS can significantly shorten the duration of the CSP. Conversely, despite an increase in corticospinal excitability reflected in greater MEP size, anodal tDCS failed to modulate LICI, another presumed measure of GABAB inhibition.

The present study is, to our knowledge, the first to show that anodal tDCS can reduce CSP duration. This is in contrast with a previous study, in which anodal tDCS failed to modulate CSP duration 7. This discrepancy could be due in part to differences in stimulation parameters and protocol. Indeed, in previous studies, stimulation intensity, duration and electrode sizes varied considerably from the ones used here (1.5 mA; 20 min, 25 cm2 for M1 stimulation and 35 cm2 for supraorbital stimulation). Moreover, participants in one of the studies suffered from chronic pain 6, hindering the generalizability of the results. The effect of cathodal stimulation on CSP is also unclear. Hasan et al. 9 reported that 9 min of cathodal tDCS could increase duration of the CSP in a sample of healthy participants, whereas another study 7 reported no impact of 10 min of cathodal tDCS on CSP duration in healthy participants. It should also be mentioned that the strength of the isometric muscle contraction was not adjusted post-tDCS in the present study. As such, tDCS may have modified absolute strength exerted by the participants and led to the increase in CSP duration.

Theoretically, an increase in excitability could be explained by either enhanced excitatory transmission, or a reduction of inhibitory transmission 15. A recent magnetic resonance spectroscopy study reported a decrease of GABA levels after tDCS, but no impact on glutamate 13, suggesting that intracortical inhibition rather than excitatory transmission could be specifically affected by tDCS and partially responsible for changes in cortical excitability. This is concordant with the reduction of GABAB synaptic activity observed here. The mechanism underlying this reduction of inhibitory transmission is thought to result from the modification of N-methyl-D-aspartate receptor activity and associated LTP mechanisms 2,15,16. Studies on motor learning point towards the involvement of intracortical inhibition in synaptic plasticity, as learning a motor sequence reduces GABA levels in M1, presumably through LTP 17. A recent TMS study also supports the close link between GABAB receptors and LTP as it was found that abnormal prolongation of the CSP in concussed athletes was linked to suppression of LTP plasticity 18.

Although both CSP and LICI have been linked to GABAB activity 12, anodal tDCS failed to modulate the strength of LICI. It has been shown previously that LICI and CSP measurements correlate, with increased CSP durations being associated with deeper LICI 19,20. In addition, parallel dysfunctions of CSP and LICI have been reported in individuals with succinic semialdehyde dehydrogenase deficiency 21. In this case, however, although LICI was reduced and CSP shortened, the two measures failed to correlate 21. Interestingly, correlations between LICI and CSP have also been reported in concussed athletes, but only at certain TMS intensities 20. Adding to the discrepancies, the GABAB agonist Baclofen has been shown to increase LICI without modulating CSP duration 11, and CSP and LICI values did not correlate in the present study. Anodal stimulation has been shown not to impact LICI in patients with chronic pain 6 although, as mentioned previously, study parameters differed significantly with those of our study. The present data thus suggest that anodal tDCS has a differential impact on LICI and CSP measures of GABAB-related activity, which could be due to different underlying mechanisms subtending both forms of inhibition. For example, the early part of the CSP is believed to rely on spinal inhibition 22, whereas LICI appears to be exclusively cortical 23. Intrasubject variability in MEP amplitude because of a relatively low number of pulses 19 may also be different for LICI and CSP, and increasing the number of MEPs could help stabilize the response and permit a better evaluation of the differential effects of anodal tDCS on LICI and CSP. Finally, the intersubject coefficients of variation were much higher for LICI compared with CSP, suggesting that LICI is more susceptible to differences between participants, which may partly explain the differential effects of tDCS on LICI and CSP.

The results of cathodal stimulation on intracortical inhibition are much more difficult to interpret. In contrast to most previous studies 24, cathodal tDCS failed to reduce MEP size. The absence of inhibitory effects following cathodal stimulation has been observed in several cognitive studies but more rarely in published studies of motor cortex excitability 24. Although the lack of significant results could in part be attributable to the limited statistical power of the small sample size, significant inhibitory cathodal effects on MEP size have been reported in studies with similar sample sizes 1. The absence of cathodal tDCS inhibition on corticospinal excitability suggests that the null CSP/LICI effect should be taken with caution, and further studies are needed to determine with certainty whether cathodal tDCS can reliably modulate GABAB-related intracortical inhibition.

Back to Top | Article Outline

Conclusion

Anodal tDCS can reduce CSP duration, suggesting that reduced GABAB-related inhibition may be implicated in the excitatory effect of anodal tDCS on the primary motor cortex. Cathodal stimulation, on the other hand, did not modulate MEP size or CSP duration.

Back to Top | Article Outline

Acknowledgements

This work was funded by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Fonds de Recherche du Québec – Santé.

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

References

1. Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000;527:633–639
2. Liebetanz D, Nitsche MA, Tergau F, Paulus W. Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. Brain. 2002;125:2238–2247
3. Stagg CJ, Nitsche MA. Physiological basis of transcranial direct current stimulation. Neuroscientist. 2011;17:37–53
4. Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron. 2010;66:198–204
5. Di Lazzaro V, Manganelli F, Dileone M, Notturno F, Esposito M, Capasso M, et al. The effects of prolonged cathodal direct current stimulation on the excitatory and inhibitory circuits of the ipsilateral and contralateral motor cortex. J Neural Transm. 2012 , DOI: 10.1007/s00702-012-0845-4
6. Antal A, Terney D, Kühnl S, Paulus W. Anodal transcranial direct current stimulation of the motor cortex ameliorates chronic pain and reduces short intracortical inhibition. J Pain Symptom Manage. 2010;39:890–903
7. Suzuki K, Fujiwara T, Tanaka N, Tsuji T, Masakado Y, Hase K, et al. Comparison of the after-effects of transcranial direct current stimulation over the motor cortex in patients with stroke and healthy volunteers. Int J Neurosci. 2012;122:675–681
8. Hummel F, Celnik P, Giraux P, Floel A, Wu W-H, Gerloff C, et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain. 2005;128:490–499
9. Hasan A, Nitsche MA, Herrmann M, Schneider-Axmann T, Marshall L, Gruber O, et al. Impaired long-term depression in schizophrenia: a cathodal tDCS pilot study. Brain Stimul. 2012;5:475–483
10. Ziemann U, Lönnecker S, Steinhoff BJ, Paulus W. The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res. 1996;109:127–135
11. McDonnell MN, Orekhov Y, Ziemann U. The role of GABAB receptors in intracortical inhibition in the human motor cortex. Exp Brain Res. 2006;173:86–93
12. Ziemann U. TMS and drugs. Clin Neurophysiol. 2004;115:1717–1729
13. Stagg CJ, Best JG, Stephenson MC, O'Shea J, Wylezinska M, Kincses ZT, et al. Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. J Neurosci. 2009;29:5202–5206
14. Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol. 1994;91:79–92
15. Reis J, Fritsch B. Modulation of motor performance and motor learning by transcranial direct current stimulation. Curr Opin Neurol. 2011;24:590–596
16. Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N, et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol. 2003;553:293–301
17. Floyer-Lea A, Wylezinska M, Kincses T, Matthews PM. Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning. J Neurophysiol. 2006;95:1639–1644
18. De Beaumont L, Tremblay S, Poirier J, Lassonde M, Théoret H. Altered bidirectional plasticity and reduced implicit motor learning in concussed athletes. Cereb Cortex. 2012;22:112–121
19. Farzan F, Barr MS, Levinson AJ, Chen R, Wong W, Fitzgerald PB, et al. Reliability of long-interval cortical inhibition in healthy human subjects: a TMS-EEG study. J Neurophysiol. 2010;104:1339–1346
20. De Beaumont L, Mongeon D, Tremblay S, Messier J, Prince F, Leclerc S, et al. Persistent motor system abnormalities in formerly concussed athletes. J Athl Train. 2011;46:234–240
21. Reis J, Cohen LG, Pearl PL, Fritsch B, Jung NH, Dustin I, et al. GABAB-ergic motor cortex dysfunction in SSADH deficiency. Neurology. 2012;79:47–54
22. Inghilleri M, Berardelli A, Cruccu G, Manfredi M. Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction. J Physiol. 1993;466:521–534
23. Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J. Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans. J Physiol. 1999;517:591–597
24. Jacobson L, Koslowsky M, Lavidor M. tDCS polarity effects in motor and cognitive domains: a meta-analytical review. Exp Brain Res. 2011;216:1–10
Keywords:

cortical silent period; γ-aminobutyric acid; transcranial direct current stimulation; transcranial magnetic stimulation

© 2013 Lippincott Williams & Wilkins, Inc.