The dynamics of cortical GABA in human motor learning

Abstract

Key points: The ability to learn new motor skills is supported by plasticity in the structural and functional organisation of the primary motor cortex in the human brain. Changes inhibitory to signalling by GABA are thought to be crucial in inducing motor cortex plasticity. This study used magnetic resonance spectroscopy (MRS) to quantify the concentration of GABA in human motor cortex during a period of motor learning, as well as during a period of movement and a period at rest. We report evidence for a reduction in the MRS-measured concentration of GABA specific to learning. Further, the GABA concentration early in the learning task was strongly correlated with the magnitude of subsequent learning: higher GABA concentrations were associated with poorer learning. The results provide initial insight into the neurochemical correlates of cortical plasticity associated with motor learning, specifically relevant in therapeutic efforts to induce cortical plasticity during recovery from stroke.

Abstract: The ability to learn novel motor skills is a central part of our daily lives and can provide a model for rehabilitation after a stroke. However, there are still fundamental gaps in our understanding of the physiological mechanisms that underpin human motor plasticity. The acquisition of new motor skills is dependent on changes in local circuitry within the primary motor cortex (M1). This reorganisation has been hypothesised to be facilitated by a decrease in local inhibition via modulation of the neurotransmitter GABA, but this link has not been conclusively demonstrated in humans. Here, we used 7 T magnetic resonance spectroscopy to investigate the dynamics of GABA concentrations in human M1 during the learning of an explicit, serial reaction time task. We observed a significant reduction in GABA concentration during motor learning that was not seen in an equivalent motor task lacking a learnable sequence, nor during a passive resting task of the same duration. No change in glutamate was observed in any group. Furthermore, M1 GABA measured early in task performance was strongly correlated with the degree of subsequent learning, such that greater inhibition was associated with poorer subsequent learning. This result suggests that higher levels of cortical inhibition may present a barrier that must be surmounted in order to achieve an increase in M1 excitability, and hence encoding of a new motor skill. These results provide strong support for the mechanistic role of GABAergic inhibition in motor plasticity, raising questions regarding the link between population variability in motor learning and GABA metabolism in the brain.

Keywords: GABA; Motor cortex; Plasticity.

Figure 1. Experimental design and MRS data acquisition

A, MRS data were acquired in six independent blocks during a concurrent task which differed across the three experimental groups: the Learning group performed a 16‐button press, repeating serial reaction time task; the Movement group performed a serial reaction time task without a repeating sequence; the Rest group passively observed a video. B, the Learning group performed the same 16‐button press sequence with three repeats per epoch (48 s), with each epoch separated by a 12 s rest period. MRS data were acquired in each block (64 averages) and analysed using LCModel (Provencher, 2001). C, representative acquisition from one participant in one M1 block, including model fit. D, M1 mRS voxels were centred over the left (contralateral) hand knob illustrated in as heatmaps in the three experimental groups: colour bars represent the number of participants.

Figure 2. Learning of motor sequence serial reaction time task

Group mean response time data showing a decrease in response times in the Learning SRTT as the participants learned the four‐button 16‐press sequence (magenta). No equivalent learning was observed in the Movement group SRTT of equivalent duration, which contained no repeating sequence (blue). Two‐way mixed ANOVA: experimental group (Learning or Movement) as between‐subjects factor and time (blocks 1–6) as within‐subjects factor: F _(1.49,31.24) = 10.52, p = 0.001, partial η² = 0.334 (Greenhouse–Geisser corrected). This effect was driven by a reduction in response time in the Learning group (simple main effect of block: F _(1.4,14.0) = 9.33, p = 0.005, partial η² = 0.483, Greenhouse–Geisser corrected). ^* p < 0.05 Bonferroni‐adjusted post hoc pairwise comparison compared with block 1. Within‐subject standard error bars calculated across each group (Cousineau, 2005).

Figure 3. Motor learning is associated with a reduction in motor cortex GABA concentrations

Group mean GABA:tCr and Glu:tCr concentrations presented normalised to block 1 for six serial MRS acquisitions measured during task performance. During motor sequence learning, a reduction in the concentration of motor cortex GABA:tCr is observed (pink) that is not seen in a motor task of equivalent duration lacking a learnable sequence (blue), nor during a passive resting task of the same duration (green). Two‐way mixed ANOVA with one factor of experimental group (Learning, Movement, or Rest) and one factor of block (1–6): F _(10,155) = 2.03, p = 0.034, partial η² = 0.116. This effect was driven by a drop in GABA:tCr concentration in the Learning group (simple main effect of block: F _(5,50) = 4.16, p = 0.003, partial η² = 0.294). Equivalent measures of glutamate showed no evidence of a change specific to the Learning group: a two‐way mixed ANOVA revealed no significant interaction between experimental group (Learning, Movement or Rest) and time on Glu:tCr: F _(10,155) = 0.780, p = 0.648, partial η² = 0.048. ^* p < 0.05 Bonferroni‐adjusted post hoc pairwise comparison compared with block 1. Mixed ANOVAs were conducted using raw non‐normalised data; for visualisation purposes only, data were normalised to block 1. Within‐subject standard error bars were calculated across each group (Cousineau, 2005).

Figure 4. Early concentrations of GABA:tCr are correlated with the magnitude of subsequent motor learning

A, a positive correlation was observed between the concentration of GABA:tCr in motor cortex and the reduction in response time due to learning, defined as the difference between median performance in sequence blocks 4–6 and sequence block 1, normalised to sequence block 1. B, early concentrations of GABA:tCr are also strongly correlated with the percentage change in reaction time in the best block, defined as the block (from blocks 2–6) in which the median reaction time was lowest. The same pattern was not observed with equivalent concentrations of excitatory glutamate (Glu:tCr). ^*The correlation of GABA:tCr with learning and task performance differed significantly from equivalent correlations between Glu:tCr and the same behavioural measures: Hittner's Z p < 0.05.