Learning a novel motor skill is dependent both on regional changes within the primary motor cortex (M1) contralateral to the active hand and also on modulation between and within anatomically distant but functionally connected brain regions. Interregional changes are particularly important in functional recovery after stroke, when critical plastic changes underpinning behavioral improvements are observed in both ipsilesional and contralesional M1s. It is increasingly understood that reduction in GABA in the contralateral M1 is necessary to allow learning of a motor task. However, the physiological mechanisms underpinning plasticity within other brain regions, most importantly the ipsilateral M1, are not well understood. Here, we used concurrent two-voxel magnetic resonance spectroscopy to simultaneously quantify changes in neurochemicals within left and right M1s in healthy humans of both sexes in response to transcranial direct current stimulation (tDCS) applied to left M1. We demonstrated a decrease in GABA in both the stimulated (left) and nonstimulated (right) M1 after anodal tDCS, whereas a decrease in GABA was only observed in nonstimulated M1 after cathodal stimulation. This GABA decrease in the nonstimulated M1 during cathodal tDCS was negatively correlated with microstructure of M1:M1 callosal fibers, as quantified by diffusion MRI, suggesting that structural features of these fibers may mediate GABA decrease in the unstimulated region. We found no significant changes in glutamate. Together, these findings shed light on the interactions between the two major network nodes underpinning motor plasticity, offering a potential framework from which to optimize future interventions to improve motor function after stroke.SIGNIFICANCE STATEMENT Learning of new motor skills depends on modulation both within and between brain regions. Here, we use a novel two-voxel magnetic resonance spectroscopy approach to quantify GABA and glutamate changes concurrently within the left and right primary motor cortex (M1) during three commonly used transcranial direct current stimulation montages: anodal, cathodal, and bilateral. We also examined how the neurochemical changes in the unstimulated hemisphere were related to white matter microstructure between the two M1s. Our results provide insights into the neurochemical changes underlying motor plasticity and may therefore assist in the development of further adjunct therapies.

Stroke is a leading cause of long-term disability, with around three-quarters of stroke survivors experiencing motor problems. Intensive physiotherapy is currently the most effective treatment for post-stroke motor deficits, but much recent research has been targeted at increasing the effects of the intervention by pairing it with a wide variety of adjunct therapies, all of which aim to increase cortical plasticity, and thereby hope to maximize functional outcome. Here, we review the literature describing neurochemical changes underlying plasticity induction following stroke. We discuss methods of assessing neurochemicals in humans, and how these measurements change post-stroke. Motor learning in healthy individuals has been suggested as a model for stroke plasticity, and we discuss the support for this model, and what evidence it provides for neurochemical changes. One converging hypothesis from animal, healthy and stroke studies is the importance of the regulation of the inhibitory neurotransmitter GABA for the induction of cortical plasticity. We discuss the evidence supporting this hypothesis, before finally summarizing the literature surrounding the use of adjunct therapies such as non-invasive brain stimulation and SSRIs in post-stroke motor recovery, both of which have been show to influence the GABAergic system.

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Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships across multiple behavioural, anatomical and biological domains. Surprisingly, we find support for predicted relationships between FA and behaviour only in one of three pre-registered tests. We also find no evidence for consistent multimodal signatures across neuroimaging markers with different biological sensitivity, which suggests there is no common biological substrate for WM-behaviour relationships. These results demonstrate that FA-behaviour relationships from the literature may not be easily generalisable across domains. They also highlight a broad heterogeneity in WM's relationship with behaviour, indicating that variable biological effects may be shaping their interaction.

Background: Transcranial direct current stimulation (tDCS) has been used to enhance motor and language rehabilitation following a stroke. However, improving the effectiveness of clinical tDCS protocols depends on understanding how a lesion may influence tDCS-induced current flow through the brain. Objective: We systematically investigated the effect of brain lesions on the magnitude of electric fields (e-mag) induced by tDCS. Methods: We simulated the effect of 630 different lesions - by varying lesion location, distance from the region of interest (ROI), size and conductivity - on tDCS-induced e-mag. We used current flow models in the brains of two participants, for two commonly used tDCS montages, targeting either primary motor cortex (M1) or Brocas area (BA44) as ROIs. Results: The effect on absolute e-mag change was highly dependent on lesion size, conductance and distance from ROI. Larger lesions, with high conductivity, close to the ROI caused e-mag changes of more than 30%. The sign of this change was determined by the location of the lesion. Specifically, lesions located in-line with the predominant direction of current flow increased e-mag in the ROI, whereas lesions located in the opposite direction caused a decrease. Conclusions: These results demonstrate that tDCS-induced electric fields are profoundly influenced by lesion characteristics. This highlights the need for individualised targeting and dose control in stroke. Additionally, the variation in electrical fields caused by assigned conductance of the lesion underlines the need for improved estimates of lesion conductivity for current flow models.

Baclofen is a GABA B agonist prescribed as a treatment for spasticity in stroke, brain injury and multiple sclerosis patients, who are often undergoing concurrent motor rehabilitation. r Decreasing GABAergic inhibition is a key feature of motor learning and so there is a possibility that GABA agonist drugs, such as baclofen, could impair these processes, potentially impacting rehabilitation. r Here, we examined the effect of 10 mg of baclofen, in 20 young healthy individuals, and found that the drug impaired retention of visuomotor learning with no significant effect on motor sequence learning. r Overall baclofen did not alter transcranial magnetic stimulation-measured GABA B inhibition, although the change in GABA B inhibition correlated with aspects of visuomotor learning retention. r Further work is needed to investigate whether taking baclofen impacts motor rehabilitation in patients.

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