GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement

Abstract

Background and objective: γ-Aminobutyric acid (GABA) is the dominant inhibitory neurotransmitter in the brain and is important in motor learning. We aimed to measure GABA content in primary motor cortex poststroke (using GABA-edited magnetic resonance spectroscopy [MRS]) and in relation to motor recovery during 2 weeks of constraint-induced movement therapy (CIMT).

Methods: Twenty-one patients (3-12 months poststroke) and 20 healthy subjects were recruited. Magnetic resonance imaging structural T1 and GABA-edited MRS were performed at baseline and after CIMT, and once in healthy subjects. GABA:creatine (GABA:Cr) ratio was measured by GABA-edited MRS. Motor function was measured using Wolf Motor Function Test (WMFT).

Results: Baseline comparison between stroke patients (n = 19) and healthy subjects showed a significantly lower GABA:Cr ratio in stroke patients (P < .001) even after correcting for gray matter content in the voxel (P < .01) and when expressing GABA relative to N-acetylaspartic acid (NAA; P = .03). After 2 weeks of CIMT patients improved significantly on WMFT, but no consistent change across the group was observed for the GABA:Cr ratio (n = 17). However, the extent of improvement on WMFT correlated significantly with the magnitude of GABA:Cr changes (P < .01), with decreases in GABA:Cr ratio being associated with better improvements in motor function.

Conclusions: In patients 3 to 12 months poststroke, GABA levels are lower in the primary motor cortex than in healthy subjects. The observed association between GABA and recovery warrants further studies on the potential use of GABA MRS as a biomarker in poststroke recovery.

Keywords: GABA; constraint-induced movement therapy; magnetic resonance spectroscopy; rehabilitation; stroke.

Figure 1

Example of magnetic resonance spectrography voxel placement in the affected hemisphere.

Figure 2

Example of a filtered difference spectrum in a patient. Arrow indicating the GABA (γ-aminobutyric acid) peak at 3 ppm.

Figure 3

GABA:Cr (mean, SEM) was significantly lower in patients post stroke and prior to CIMT, compared to healthy subjects Abbreviations: GABA, γ-aminobutyric acid; Cr, creatine; SEM, standard error of the mean; CIMT, constraint-induced movement therapy. ***P<0.001

Figure 4

Larger motor improvements (WFMT) were associated with smaller or even negative GABA:Cr fractional changes (R = –0.61, P = .009). Arrow indicating the patient with a lesion in the hand area. Abbreviations: WFMT, Wolf Motor Function Test; GABA, γ-aminobutyric acid; Cr, creatine.

Figure 5

Examples of stroke location and possible changes in M1 GABA (γ-aminobutyric acid) levels after a small subcortical stroke (A) or a large stroke extending into cortex (B). (A1) Beneficial decrease in GABA as a compensatory phenomenon facilitating or maintaining motor recovery. (A2) Maladaptive pattern of GABA increase as a part of a learned nonuse pattern. (B1) Disturbed interhemispheric inhibition leading to a high inhibitory drive from unaffected to affected hemisphere. (B2) Decrease in GABA levels due to loss of GABA neurons in the affected M1 cortex. In case A2 and B1, a training-induced drop in M1 GABA could be associated with a large improvement in motor function after constraint-induced movement therapy (CIMT).