Cortical tonic GABAergic inhibition – preliminary insights from MR Spectroscopy of subacute stroke

Objectives: Stroke unleashes a complex series of repair-related neural events that leads to acute functional impairment and, over a longer time-frame, results in the specific functional outcome for individual patients. A major repair-related mechanism is the decrease in tonic $\gamma-$aminobutyric acid (GABA) mediated inhibition. On a physiological level, a reduction of tonic inhibition (or disinhibition) within the motor system for example, augments plastic properties of the neural circuits resulting in creation of newly available networks and strengthening the existing ones, all to generate a motor output to the impaired arm. Our current knowledge derives largely from animal models, mainly rodents. Invivo evaluation of the nature of this type of inhibition in stroke patients is lacking; it remains difficult to discern whether such changes are functionally relevant in humans. Design: We assessed tonic GABAergic inhibition, using noninvasive MR Spectroscopy (MEGA-sLASER, 3T Siemens) measurements of GABA levels (a validated index of such inhibition in living human brain), in 3 subcortical stroke patients (66.3 [10.1] (mean [SD]) years old, 2 males, mildly impaired, NIHSS=6 for all; 22.2 [2.0] days after stroke onset). We selected the subacute phase of stroke to capture the profound changes of tonic GABAergic inhibition, as established in animal models. We selected patients with subcortical stroke to assess this mechanism in spared, viable cortices. We focused on 2 motor areas that play a major role in arm motor recovery after stroke, primary motor (M1) and premotor (PM) cortices. Note that patient’s recruitment has been stopped during the study due to COVID-19 pandemic. The stability of GABA measurements in these 2 areas was tested in 3 healthy controls (24.7 [4.0] yrs old, 2 women, both in the follicular phase of the menstrual cycle) at 23.7 [0.6] h interval. MEGA□sLASER parameters, processing, analysis, and voxel positioning were the same for both time points. The coefficient of variation (CoV = SD/mean of test-retest) was calculated for each area. Results: Relative to matched controls, we found a trend toward higher GABA levels in all areas (left M1 in control vs. M1 in injured hemisphere, ipsilesional, in stroke: $2.0 \pm 0.2$ vs $2.2 \pm 0.2, \mathrm{p}=0.2$, a 10% increase; left PM vs. ipsilesional PM: 1.9 [0.1] vs. 2.3 [0.2], p=0.08, 21% increase; right M1 vs. contralesional M1: 2.0 [0.5] vs. 2.2 [0.3], p=0.6, 10% increase; right PM vs. contralesional PM, 1.9 [0.2] vs. 2.2 [0.3], p=0.2, 16% increase). The differences in M1 GABA levels reported in patients compared with controls felt out (higher) of the range of normal GABA variability in the human brain (coefficient of variance, left M1, CoV 2.5-7.1%; right M1, 6.2-8.7%) while those in PM felt within this range (left PM, 11.1-20.4%; right PM, 15.724.3%). Due to the small sample size, the relationships between GABA levels and hand impairment were not assessed. Conclusions: Our preliminary data have shown there is a trend toward increased tonic GABAergic inhibition in motor areas, primarily in M1, early after stroke. If this trend is further demonstrated in larger sample size, this knowledge will provide evidence whether such mechanism is a robust biological substrate to drive functional improvements early after stroke.