Increased GABA contributes to enhanced control over motor excitability in Tourette syndrome

Abstract

Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics and associated with cortical-striatal-thalamic-cortical circuit dysfunction, hyperexcitability within cortical motor areas, and altered intracortical inhibition. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals, who exhibit enhanced control over their volitional movements. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of γ-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)--a region strongly associated with the genesis of motor tics in TS--are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Results of Brain Imaging Analyses (A) The fMRI BOLD signal associated with a bimanual sequential finger-thumb opposition task (tap > rest contrast) for a single representative participant that, for presentation purposes only, has been spatially smoothed. (B) Mean GABA/NAA ratios for the Tourette syndrome (TS) and control group (CS) for each ROI. For the SMA ROI only, GABA concentrations are elevated relative to controls (∗p < 0.05). Error bars are standard deviation. (C) Scatterplot showing the negative association (r = −0.63, p 

Figure 2

Association between SMA GABA Concentration and Motor Excitability Individual levels of GABA concentration within the SMA ROI are inversely related to motor excitability immediately prior (81%–100%) to the execution of volitional movements. Motor excitability was measured by recording motor evoked potentials from the right hand following single-pulse TMS delivered to the left primary motor cortex. See Supplemental Information for further details.

Figure 3

Association between SMA GABA Concentration and WM Microstructure (Ai and Aii) An example ROI located in the SMA, displayed in the axial (Ai) and sagittal (Aii) planes. (Aiii) Fibers tracked from the SMA region (red) and the location of the 6 mm3 ROI located within the body of the corpus callosum where the fibers cross between the hemispheres (blue). (Aiv) Confirmation that fibers tracked from the central 6 mm3 ROI located within the corpus callosum terminate within the SMA. (B) Scatterplot showing the significant positive association (r = 0.87, p