The Homeostatic Interaction Between Anodal Transcranial Direct Current Stimulation and Motor Learning in Humans is Related to GABAA Activity

Ugwechi Amadi, Claire Allman, Heidi Johansen-Berg, Charlotte J Stagg, Ugwechi Amadi, Claire Allman, Heidi Johansen-Berg, Charlotte J Stagg

Abstract

Background: The relative timing of plasticity-induction protocols is known to be crucial. For example, anodal transcranial direct current stimulation (tDCS), which increases cortical excitability and typically enhances plasticity, can impair performance if it is applied before a motor learning task. Such timing-dependent effects have been ascribed to homeostatic plasticity, but the specific synaptic site of this interaction remains unknown.

Objective: We wished to investigate the synaptic substrate, and in particular the role of inhibitory signaling, underpinning the behavioral effects of anodal tDCS in homeostatic interactions between anodal tDCS and motor learning.

Methods: We used transcranial magnetic stimulation (TMS) to investigate cortical excitability and inhibitory signaling following tDCS and motor learning. Each subject participated in four experimental sessions and data were analyzed using repeated measures ANOVAs and post-hoc t-tests as appropriate.

Results: As predicted, we found that anodal tDCS prior to the motor task decreased learning rates. This worsening of learning after tDCS was accompanied by a correlated increase in GABAA activity, as measured by TMS-assessed short interval intra-cortical inhibition (SICI).

Conclusion: This provides the first direct demonstration in humans that inhibitory synapses are the likely site for the interaction between anodal tDCS and motor learning, and further, that homeostatic plasticity at GABAA synapses has behavioral relevance in humans.

Keywords: GABA; Homeostatic plasticity; Motor learning; Non-invasive brain stimulation (NIBS).

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Supplementary Figure 1
Supplementary Figure 1
Figure 1
Figure 1
Schematic of experimental design. All subjects participated in all four experimental sessions, the order of which was counterbalanced across the group and all sessions were separated by at least 1 week. TMS blocks, consisting of 30 single pulses at MT1mV, 15 paired pulses with a 1 ms ISI and 15 paired pulses with a 2.5 ms ISI were acquired at the beginning, mid-point and end of each session. In the 20 min between TMS blocks, subjects had either anodal tDCS (A), sham tDCS (S) or no stimulation, while performing the motor learning task (T) or sitting quietly with their right hands relaxed.
Figure 2
Figure 2
Motor learning task. Reaction times during the learning blocks of the motor task. Offline tDCS (A-T) led to decreased learning compared to online tDCS (AT-0) and control (S-ST). The two blocks containing random sequences (before Block 1 and after Block 13) have been excluded. Error bars ±1 SEM.
Figure 3
Figure 3
Effects of tDCS and Motor Learning on cortical excitability A. Anodal tDCS increases cortical excitability. Change in cortical excitability, expressed as a ratio of post-stimulation to pre-stimulation MEP size, where higher numbers reflect greater excitability. Anodal tDCS at rest (A-0) increases MEP size, an effect that is not seen if stimulation is applied concurrently with task performance (AT-0). * P < 0.05 B. Task performance decreases cortical excitability. Change in excitability, expressed as a ratio of post- to pre- task performance MEP size, where higher numbers reflect greater excitability. Performance of the task alone (S-ST) decreases MEP size, an effect that is not present if anodal tDCS is applied prior to (A-T) or concurrent with (AT-0) task performance. Error bars ±1 SEM, *P < 0.05.
Figure 4
Figure 4
Task performance increases GABAA-synaptic inhibition. Changes in inhibition expressed as a ratio of post- to pre- task performance 2.5ms SICI. Anodal tDCS applied prior to task performance (A-T), increases task-related GABAA activity as measured by 2.5ms SICI. Note that lower values reflect greater inhibition. Error bars ±1 SEM, * P < 0.05.
Figure 5
Figure 5
Worsening of learning after anodal tDCS is inversely related to increase in GABAA activity in the same period. The decrease in learning of the motor task when task performance was preceded by anodal tDCS (A-T) is correlated with the increase in 2.5 ms SICI seen over the same period (r = −0.69, P = 0.009), such that subjects who showed a less detrimental behavioral effect of prior anodal tDCS (i.e. those who were presumably able to induce more LTP-like plasticity during the task) were those in whom the increase in GABAA activity was greatest over the same time period.

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