The Influence of Primary Motor Cortex Inhibition on Upper Limb Impairment and Function in Chronic Stroke: A Multimodal Study

Abstract

Background. Stroke is a leading cause of adult disability owing largely to motor impairment and loss of function. After stroke, there may be abnormalities in γ-aminobutyric acid (GABA)-mediated inhibitory function within primary motor cortex (M1), which may have implications for residual motor impairment and the potential for functional improvements at the chronic stage. Objective. To quantify GABA neurotransmission and concentration within ipsilesional and contralesional M1 and determine if they relate to upper limb impairment and function at the chronic stage of stroke. Methods. Twelve chronic stroke patients and 16 age-similar controls were recruited for the study. Upper limb impairment and function were assessed with the Fugl-Meyer Upper Extremity Scale and Action Research Arm Test. Threshold tracking paired-pulse transcranial magnetic stimulation protocols were used to examine short-and long-interval intracortical inhibition and late cortical disinhibition. Magnetic resonance spectroscopy was used to evaluate GABA concentration. Results. Short-interval intracortical inhibition was similar between patients and controls (P = .10). Long-interval intracortical inhibition was greater in ipsilesional M1 compared with controls (P < .001). Patients who did not exhibit late cortical disinhibition in ipsilesional M1 were those with greater upper limb impairment and worse function (P = .002 and P = .017). GABA concentration was lower within ipsilesional (P = .009) and contralesional (P = .021) M1 compared with controls, resulting in an elevated excitation-inhibition ratio for patients. Conclusion. These findings indicate that ipsilesional and contralesional M1 GABAergic inhibition are altered in this small cohort of chronic stroke patients. Further study is warranted to determine how M1 inhibitory networks might be targeted to improve motor function.

A Systematic Review of Long-Interval Intracortical Inhibition as a Biomarker in Neuropsychiatric Disorders

“…Mooney et al compared chronic stroke patients and HC based on LICI and investigated its correlation with GABA concentration measured with magnetic resonance spectroscopy. LICI was found to be enhanced in chronic stroke patients relative to HC in the ipsilesional motor cortex (p < 0.001), whereas there was no significant association between LICI and metabolite concentrations in stroke patients and HC (142).…”

“…Studies have presented mixed results in stroke. Studies that found alterations in LICI discussed the methodological differences (using single ISI vs. using range of ISI) as an explanation for the discrepancy between studies (142). On the other hand, it has been consistently shown that LICI has not changed after interventions.…”

Recent advances in the role of excitation–inhibition balance in motor recovery post-stroke

“…Multimodal studies are vital to interpret the potentially conflicting results between modalities. A recent study using both TMS and MRS described no significant differences in TMS-derived measurements of GABA A activity between patients and controls 57 . However, the authors reported a significant reduction in [GABA] in both hemispheres in the same patients.…”

“…TMS studies have shown that, as in the early stages of stroke recovery, overall cortical excitability is decreased in the ipsilesional hemisphere compared to both the contralesional hemisphere and healthy age-matched controls 50 . A number of human MRS studies have demonstrated a decrease in [GABA] in the ipsilesional hemisphere at rest in chronic stroke patients 55 – 57 . However, GABA A -mediated inhibition measured using SICI does not differ significantly between the ipsilesional hemisphere and either the contralesional hemisphere or healthy age-matched controls 50 .…”

“…One promising avenue for future research highlighted by Mooney and colleagues was the role of the GABA B receptor in the excitation–inhibition balance in chronic stroke. TMS measures of GABA B -mediated inhibition have been found to be higher in the ipsilesional hemisphere, and late cortical disinhibition (LCD), a measure of presynaptic GABA B receptors normally present in healthy adults 64 , had an inhibitory effect in the ipsilesional hemisphere in chronic stroke 57 . LCD was the only metric that correlated with clinical impairment and functional scores, possibly suggesting a central role for GABA B signalling.…”