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.

Hippocampal and striatal responses during motor learning are modulated by prefrontal cortex stimulation

“…It is worth noting that the learning-specific GABA+ effect in the DLPFC was observed under the effect of facilitatory stimulation, which might suggest that stimulation potentiated the neural plasticity processes mentioned above. Although this interpretation is speculative given the absence of a stimulation by task interaction, it is in line with previous studies describing increases and decreases of M1 GABA levels after inhibitory [e.g., cTBS or cathodal transcranial direct current stimulation (tDCS); (Bachtiar et al, 2018;)] and facilitatory [e.g. anodal tDCS; (Bachtiar et al, 2018(Bachtiar et al, , 2015Stagg, Best, et al, 2009)] stimulation of M1, respectively.…”

“…Based on models suggesting that hippocampo-prefrontal networks exert control processes over sensorimotor-striato-cortical networks during MSL (Albouy, King, et al, 2013), we expected that facilitatory iTBS and inhibitory cTBS of the DLPFC would repress and facilitate, respectively, the development of striato-motor activity during sequence learning as compared to random practice. With respect to the effects on GABA, previous MRS studies have shown that M1 GABA levels can be altered by both M1 brain stimulation (Bachtiar et al, 2018;Bachtiar, Near, Johansen-Berg, & Stagg, 2015;Marjańska et al, 2013;Stagg, Bachtiar, & Johansen-Berg, 2011;Stagg, Best, et al, 2009; and motor learning (Floyer-Lea, Wylezinska, Kincses, & Matthews, 2006;Kolasinski et al, 2018;Sampaio-Baptista et al, 2015).…”

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

“…Sehm et al 2012showed that bilateral mon-tage modulated network connectivity in the primary motor, secondary motor, and prefrontal areas, whereas unilateral montage affected prefrontal, parietal, and cerebellar areas; these findings indicated that the modulated networks differed between bilateral and unilateral tDCS. Thus, although Bachtiar et al (2018) demonstrated that both bilateral and unilateral tDCS decrease M1 GABA levels, this result might have been mediated by different underlying physiological mechanisms operative in bilateral versus unilateral montages. Further studies are needed to investigate the influence of electrode position (particularly with regard to polarity and current flow direction) on the tDCSinduced physiological effect.…”

“…For bilateral stimulation, Bachtiar et al (2018) found that GABA concentration decreased only in the cathodetargeted M1. Although bilateral tDCS is theoretically a sum of anodal and cathodal tDCS, this result indicates that the physiological effects of bilateral stimulation were not simply the sum of the constituent unilateral montages (anodal and cathodal tDCS).…”

“…In a recent report in The Journal of Neuroscience, Bachtiar et al (2018) examined the effect of anodal, cathodal, and bilateral tDCS on neurochemical changes in M1 using two-voxel magnetic-resonance spectroscopy (MRS). Briefly, current was delivered via electrodes applied over the M1 of 12 healthy participants.…”