The dynamics of cortical GABA in human motor learning

Abstract

The ability to learn novel motor skills is both 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 7T MR 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, baseline M1 GABA was strongly predictive of 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 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.Funding informationJ.K.:Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship (204696/Z/16/Z). C.J.S.: Wellcome Trust/Royal Society Henry Dale Fellowships (102584/Z/13/Z).

Regulation of perceptual learning by chronic chemogenetic manipulation of parvalbumin-positive interneurons

“…This possibility is in agreement with the biphasic model of skill learning described by Vinogradov et al (2012). In this model, Phase 1 is characterized by rapid improvements in behavior, which have been associated with downregulation of cortical inhibition in animal models (Sale et al, 2010) and in humans (Kolasinski et al, 2019). In light of previous findings that transient specific manipulation of PV+ interneurons affects the initial rate of learning (Letzkus et al, 2011;Donato et al, 2013;Wolff et al, 2014), our results add to the mounting evidence indicating that suppression of PV+ cells is necessary for the initiation of learning (Hu et al, 2014).…”

Effects of Transcranial Direct Current Stimulation on GABA and Glutamate in Children: A Pilot Study

“…No relationship between changes in Glx and task performance post-intervention nor between GABA or Glx and change in PPT score 6 weeks after stimulation and training was observed. These results are in accordance with adult studies that report no significant relationship between change in motor skill and concentration of Glx in the motor cortex contralateral to the hand executing the task (33). However, adult studies have reported a relationship between task improvement and GABA changes in the tDCS targeted cortex (i.e.…”

“…Additionally, this is the first-time metabolites have been measured in a control population after a multiday protocol with a followup assessment. Previous studies in adults have illustrated that GABA decreases (33,46) and glutamate increases (47), with skill acquisition and improved function in the region responsible for the skill execution, the M1. It has been suggested that tDCS facilitates changes in GABA and glutamate to augment learning.…”

“…However, adult studies have reported a relationship between task improvement and GABA changes in the tDCS targeted cortex (i.e. right sensorimotor GABA changes and left hand training and task performance) (25,33). This dissimilarity suggests that neurochemistry in the pediatric and adult brain respond in different ways during motor learning, warranting further investigation.…”

Transcranial Direct Current Stimulation Modulates GABA Levels Beyond the Stimulated Region: Perspectives for Stroke Rehabilitation

“…Recently, it has become apparent that tDCS applied to M1 affects motor learning, possibly by altering GABA concentrations. In healthy participants, GABA concentration decreases in the M1 during motor learning (Kolasinski et al, 2018), and anodal tDCS can enhance cortical excitability while decreasing GABA concentration in M1 (Stagg et al, 2011a). Furthermore, Stagg et al (2011a) found a positive correlation between the magnitude of the tDCS-induced GABA decrease in M1 and the degree of motor learning.…”