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

Abstract

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.

GABAergic changes in the thalamocortical circuit in Parkinson's disease

“…Furthermore, we were able to rule out that the correlation between GABA and disease severity was driven by age or by gray matter atrophy (see supplementary materials), and GABA/tCre values were comparable to similar studies, especially when considering participants within this age range (Gao et al, 2013;Geramita et al, 2011). According to recent consensus, MRS is most sensitive to extracellular unbound GABA, which is involved in tonic inhibition (Dyke et al, 2017;Rae, 2014;Stagg, 2014). This study relied on the ratio of GABA to creatine, which may have had mixed consequences; while we do not anticipate problems in our cortical voxels, there are reports of reduced thalamic creatine, which suggest that this may have led to reduced sensitivity for patient GABA reduction in our thalamic region of interest (as discussed above).…”

“…As MRS is sensitive to extracellular, unbound GABA (Dyke et al, 2017;Rae, 2014;Stagg, 2014)-which is involved in tonic rather than phasic inhibition-this method is appropriate to detect the predicted increase in tonic GABAergic tone in the thalamus in Parkinson's disease (Redgrave et al, 2010). Using magnetic resonance spectroscopy (MRS), here we aimed to clarify this issue by testing the effect of dopaminergic medication in carefully selected clinical phenotypes in Parkinson's disease, on GABA levels in the primary motor cortex, thalamus, and a control region in the visual cortex.…”

The dynamics of cortical GABA in human motor learning

“… a ; Dyke et al . ). However, a significant correlation between MRS GABA and tonic GABA has been observed (Stagg et al .…”

“… a ), although a more recent study has failed to replicate the relationship (Dyke et al . ). The metabolic GABA pool has no direct effect on neural signalling, although extracellular [GABA] is closely related to both metabolic and vesicular GABA levels.…”

The dynamics of cortical GABA in human motor learning

“…MRS measures of GABA concentration have been suggested to more closely represent the extracellular pool of GABA responsible for this tonic inhibitory activity, rather than the vesicular pool of GABA responsible for phasic signalling, which is bound to macromolecules and therefore may be less visible to MRS (Stagg et al 2011b,c). No correlations have been observed between MRS GABA and phasic GABA signalling using paired pulse TMS (Stagg et al 2011a;Dyke et al 2017). However, a significant correlation between MRS GABA and tonic GABA has been observed (Stagg et al 2011a), although a more recent study has failed to replicate the relationship (Dyke et al 2017).…”