Converging lines of evidence derived from genetic¹, postmortem², and animal³ studies implicate γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, in the pathophysiology of Tourette's Syndrome (TD), an inherited neurodevelopmental disorder of childhood onset characterized by multiple motor tics and at least one vocal tic. In addition, two studies have examined in vivo concentrations of brain GABA in TD, with findings showing: 1) decreased GABA in the right sensorimotor cortex of children with TD⁴; and 2) elevated GABA within the supplementary motor area in adolescents with TD⁵. Continued examination of the role of GABA in TD holds merit for improving our understanding of the neurobiology of TD and informing treatment. Toward this end, the present study used ¹H MRS to measure GABA levels in two brain regions that have been strongly implicated in TD², the anterior cingulate cortex (ACC) (Fig. 1A) and the striatum (Fig. 1B), for adolescents with TD and healthy controls (HC). Based on prior preclinical data, we hypothesized that adolescents with TD would have significantly lower ACC and striatal GABA than HC. We further explored associations between GABA concentrations and tic severity, expecting that greater severity would be associated with lower GABA levels.

A. Patient Population. We enrolled 17 psychotropic medication-free adolescents with TD and 36 HC, ages 12-21. TD diagnoses were established with the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS), administered by board-certified child and adolescent psychiatrists with expertise in TD. The Yale Global Tic Severity Scale (YGTSS) evaluated tic severity.

B. In Vivo Brain GABA Measurements by ¹H MRS. All in vivo brain GABA spectra were recorded in 15 min. from single 2.5x2.5x3.0-cm3 ACC and 1.5x2.0x3.0-cm3 striatal voxels on a GE 3.0 T MR system, using the standard J-edited spin echo difference method and an 8-channel phased-array head coil with TE/TR 68/1500 ms and 290 interleaved excitations (580 total). Fig. 1 illustrates the editing method and the resulting difference spectrum, which includes a co-edited glutamate+glutamine (Glx) resonance. The areas under the GABA and Glx peaks were obtained by frequency-domain spectral fitting (Fig. 1D) and expressed as ratios relative to the area of simultaneously acquired unsuppressed voxel tissue water (W) peak.

C. Statistical Methods. Analysis of covariance compared TD and HC participants on mean levels of GABA relative to unsuppressed voxel tissue water (GABA/W), controlling for demographic variables that showed group differences (e.g., sex, ethnicity). The associations of GABA/W with tic severity were assessed using correlational analyses.

We obtained ACC GABA spectra in 15 TD participants and 36 HC and striatal GABA spectra in 15 TD participants and 16 HC. As shown in Fig. 2, ACC GABA/W was lower (F = 5.10, p = .03) in TD participants (.00254 ± .00039) than in HC (.00285 ± .00044) Moreover, ACC GABA/W was positively correlated with total tic severity (r = .55, p = .05). For striatal GABA/W, there were no significant group differences (TD = .00363 ± .00039 versus HC = .00388 ± .00045; F = 2.44, p = .13), nor was striatal GABA/W significantly associated with tic severity.As hypothesized, GABA spectra in the ACC was lower in individuals with TD than healthy comparisons. However, there were no group differences in striatal GABA spectra. Within the TD group, there was relationship between tic severity and ACC GABA spectra (but not striatal GABA), but this association was in the opposite direction as expected. These findings could potentially reflect incorporation of compensatory mechanisms in the ACC (a region associated with more “top-down” cognitive control) to regulate or suppress tics. Our finding of lower GABA in adolescent TD is consistent with a pathophysiological role for dysregulated ACC neurotransmitter function, and provides further evidence for possible dysfunction of the central GABAergic system in TD. Further research is needed to elucidate GABA’s role and mechanisms of action in various components of the cortico-striato-thalamo-cortical circuit, as well as the ways in which these systems may be affected by compensatory mechanisms.