Increased GABA Contributes to Enhanced Control over Motor Excitability in Tourette Syndrome

Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4, 5, 6, 7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8, 9, 10, 11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. 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 [14]—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

Activity or Connectivity? Evaluating neurofeedback training in Huntington's disease

Non-invasive methods, such as neurofeedback training (NFT), could support cognitive symptom management in Huntington’s disease (HD) by targeting brain regions whose function is impaired. The aim of our single-blind, sham-controlled study was to collect rigorous evidence regarding the feasibility of NFT in HD by examining two different methods, activity and connectivity real-time fMRI NFT. Thirty-two HD gene-carriers completed 16 runs of NFT training, using an optimized real-time fMRI protocol. Participants were randomized into four groups, two treatment groups, one receiving neurofeedback derived from the activity of the Supplementary Motor Area (SMA), and another receiving neurofeedback based on the correlation of SMA and left striatum activity (connectivity NFT), and two sham control groups, matched to each of the treatment groups. We examined differences between the groups during NFT training sessions and after training at follow-up sessions. Transfer of training was measured by measuring the participants’ ability to upregulate NFT target levels without feedback (near transfer), as well as by examining change in objective, a-priori defined, behavioural measures of cognitive and psychomotor function (far transfer) before and at 2 months after training. We found that the treatment group had significantly higher NFT target levels during the training sessions compared to the control group. However, we did not find robust evidence of better transfer in the treatment group compared to controls, or a difference between the two NFT methods. We also did not find evidence in support of a relationship between change in cognitive and psychomotor function and NFT learning success. We conclude that although there is evidence that NFT can be used to guide participants to regulate the activity and connectivity of specific regions in the brain, evidence regarding transfer of learning and clinical benefit was not robust. Although the intervention is non-invasive, given the costs and absence of reliable evidence of clinical benefit, we cannot recommend real-time fMRI NFT as a potential intervention in HD

Activity or connectivity? A randomized controlled feasibility study evaluating neurofeedback training in Huntington's disease

Non-invasive methods, such as neurofeedback training, could support cognitive symptom management in Huntington’s disease by targeting brain regions whose function is impaired. The aim of our single-blind, sham-controlled study was to collect rigorous evidence regarding the feasibility of neurofeedback training in Huntington’s disease by examining two different methods, activity and connectivity real-time functional MRI neurofeedback training. Thirty-two Huntington’s disease gene-carriers completed 16 runs of neurofeedback training, using an optimized real-time functional MRI protocol. Participants were randomized into four groups, two treatment groups, one receiving neurofeedback derived from the activity of the supplementary motor area, and another receiving neurofeedback based on the correlation of supplementary motor area and left striatum activity (connectivity neurofeedback training), and two sham control groups, matched to each of the treatment groups. We examined differences between the groups during neurofeedback training sessions and after training at follow-up sessions. Transfer of training was measured by measuring the participants’ ability to upregulate neurofeedback training target levels without feedback (near transfer), as well as by examining change in objective, a priori defined, behavioural measures of cognitive and psychomotor function (far transfer) before and at 2 months after training. We found that the treatment group had significantly higher neurofeedback training target levels during the training sessions compared to the control group. However, we did not find robust evidence of better transfer in the treatment group compared to controls, or a difference between the two neurofeedback training methods. We also did not find evidence in support of a relationship between change in cognitive and psychomotor function and learning success. We conclude that although there is evidence that neurofeedback training can be used to guide participants to regulate the activity and connectivity of specific regions in the brain, evidence regarding transfer of learning and clinical benefit was not robust

Activation induced changes in GABA: functional MRS at 7 T with MEGA-sLASER

Functional magnetic resonance spectroscopy (fMRS) has been used to assess the dynamic metabolic responses of the brain to a physiological stimulus non-invasively. However, only limited information on the dynamic functional response of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, is available. We aimed to measure the activation-induced changes in GABA unambiguously using a spectral editing method, instead of the conventional direct detection techniques used in previous fMRS studies. The Mescher-Garwood-semi-localised by adiabatic selective refocusing (MEGA-sLASER) sequence was developed at 7 T to obtain the time course of GABA concentration without macromolecular contamination. A significant decrease (−12±5%) in the GABA to total creatine ratio (GABA/tCr) was observed in the motor cortex during a period of 10 minutes of hand-clenching, compared to an initial baseline level (GABA/tCr = 0.11±0.02) at rest. An increase in the Glx (glutamate and glutamine) to tCr ratio was also found, which is in agreement with previous findings. In contrast, no significant changes in NAA/tCr and tCr were detected. With consistent and highly efficient editing performance for GABA detection and the advantage of visually identifying GABA resonances in the spectra, MEGA-sLASER is demonstrated to be an effective method for studying of dynamic changes in GABA at 7 T

Alterations in the microstructure of white matter in children and adolescents with Tourette syndrome measured using tract-based spatial statistics and probabilistic tractography

Tourette syndrome (TS) is a neurodevelopmental disorder characterised by repetitive and intermittent motor and vocal tics. TS is thought to reflect fronto-striatal dysfunction and the aetiology of the disorder has been linked to widespread alterations in the functional and structural integrity of the brain. The aim of this study was to assess white matter (WM) abnormalities in a large sample of young patients with TS in comparison to a sample of matched typically developing control individuals (CS) using diffusion MRI. The study included 35 patients with TS (3 females; mean age: 14.0 ± 3.3) and 35 CS (3 females; mean age: 13.9 ± 3.3). Diffusion MRI data was analysed using tract-based spatial statistics (TBSS) and probabilistic tractography. Patients with TS demonstrated both marked and widespread decreases in axial diffusivity (AD) together with altered WM connectivity. Moreover, we showed that tic severity and the frequency of premonitory urges (PU) were associated with increased connectivity between primary motor cortex (M1) and the caudate nuclei, and increased information transfer between M1 and the insula, respectively. This is to our knowledge the first study to employ both TBSS and probabilistic tractography in a sample of young patients with TS. Our results contribute to the limited existing literature demonstrating altered connectivity in TS and confirm previous results suggesting in particular, that altered insular function contributes to increased frequency of PU

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

Summary: Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2 and 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4, 5, 6 and 7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8, 9, 10 and 11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12 and 13]. 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 [14]—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

Comparing GABA-dependent physiological measures of inhibition with proton magnetic resonance spectroscopy measurement of GABA using ultra-high-field MRI

Imbalances in glutamatergic (excitatory) and GABA (inhibitory) signalling within key brain networks are thought to underlie many brain and mental health disorders, and for this reason there is considerable interest in investigating how individual variability in localised concentrations of these molecules relate to brain disorders. Magnetic resonance spectroscopy (MRS) provides a reliable means of measuring, in vivo, concentrations of neurometabolites such as GABA, glutamate and glutamine that can be correlated with brain function and dysfunction. However, an issue of much debate is whether the GABA observed and measured using MRS represents the entire pool of GABA available for measurement (i.e., metabolic, intracellular, and extracellular) or is instead limited to only some portion of it. GABA function can also be investigated indirectly in humans through the use of non-invasive transcranial magnetic stimulation (TMS) techniques that can be used to measure cortical excitability and GABA-mediated physiological inhibition. To investigate this issue further we collected in a single session both types of measurement, i.e., TMS measures of cortical excitability and physiological inhibition and ultra-high-field (7 T) MRS measures of GABA, glutamate and glutamine, from the left sensorimotor cortex of the same group of right-handed individuals. We found that TMS and MRS measures were largely uncorrelated with one another, save for the plateau of the TMS IO curve that was negatively correlated with MRS-Glutamate (Glu) and intra-cortical facilitation (10ms ISI) that was positively associated with MRS-Glutamate concentration. These findings are consistent with the view that the GABA concentrations measured using the MRS largely represent pools of GABA that are linked to tonic rather than phasic inhibition and thus contribute to the inhibitory tone of a brain area rather than GABAergic synaptic transmission