Modulating Regional Motor Cortical Excitability with Noninvasive Brain Stimulation Results in Neurochemical Changes in Bilateral Motor Cortices

Abstract

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.

Keywords: DTI; GABA; M1; MRS; plasticity; tDCS.

Figure 1.

A, Schematic outlining the protocol of the 7 T MRS sessions. B, Representative spectrum from one acquisition block from one voxel, as analyzed by LCModel, showing the raw data (red) as well as the individual metabolite fits (colored lines) and the residual noise (black). Inset shows the location of both voxels from which MRS was acquired.

Figure 2.

Percentage change in GABA during and after anodal(A), cathodal (B), and bilateral (C) stimulation relative to sham stimulation. Brain images show the location of MRS voxels and stimulation. Red indicates anode placement, blue cathode placement, and gray no electrode placement. *Significant main effect of condition for each sham versus real stimulation comparison of the baselined GABA concentrations. Error bars indicate SEM. A, Decrease in GABA was observed in both stimulated and nonstimulated M1s in response to anodal tDCS (right M1, n = 12; left M1, n = 9). B, Significant decrease in GABA was observed only within the nonstimulated right M1 in the cathodal tDCS condition (right M1, n = 10; left M1, n = 7). C, Significant decrease in GABA was observed only within the cathode-targeted right M1 in response to bilateral tDCS condition (right M1, n = 10; left M1, n = 8).

Figure 3.

A, M1–M1 CC mask. The M1–M1 tract is shown in yellow and the M1–M1 CC in green. B, Cathodal tDCS-induced GABA change within right M1 correlates with FA in the M1–M1 CC mask. No significant relationship between M1–M1 CC FA and change in GABA in right M1 was demonstrated during either anodal or cathodal tDCS.