Regional glutamate but not GABA concentration scales with TMS-based measures of cortical excitability – a combined 7T MR spectroscopy and TMS study of the human primary motor hand area

Introduction: Magnetic resonance spectroscopy (MRS) can be used to probe regional levels of glutamate and GABA in the human brain. However, little is known about how local neuro-transmitter levels are related to measures of excitation and inhibition measured using transcranial magnetic stimulation (TMS).
Aim: We examined the relationship between glutamate and GABA concentrations measured from the primary sensorimotor hand area (SM1-HAND) using 7T MRS and regional inhibition and facilitation probed using TMS.
Methods: 20 healthy volunteers (median age 43.5 years, range: 24-68 years) underwent single-voxel 7T MRS of the right and left SM1-HAND to measure regional concentrations of glutamate and GABA. Single- and paired-pulse TMS was used to obtain short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We tested for relationships between regional neurotransmitter levels and MEP amplitudes of SICI, ICF and ‘test’ stimulations at 120% RMT in two mixed linear models.
Results: The model that incorporated all acquired motor evoked potential (MEP) amplitudes in the SICI/ICF model yielded an interaction between glutamate concentration and stimulation condition (P=0.029). Post-hoc assessments showed that ICF and “Test” MEP amplitudes more negatively associated with glutamate concentration than SICI MEP amplitudes (ICF: -1.83 [-3.32--0.35] log(%), P=0.015, Test MEP: -1.62 [-3.09--0.16] log(%), P=0.03). We found a similar interaction when modelling MEP amplitudes normalized to “Test” amplitudes (P=0.014). Since MEP amplitudes were now normalized to the “Test” MEP response, higher glutamate levels were associated with less SICI with no effect of ICF (P=0.014). There were no effects of GABA on MEP amplitudes in any of the conditions, nor were there any relationship between glutamate/GABA ratios and ICF/SICI ratios.
Conclusion: Local glutamate levels measured with 7T MRS reflect corticospinal excitability and the relative strength of intracortical inhibition. Further research is needed to determine the functional implications of these findings.