Cortical excitability stratifies neurochemical profiles in amyotrophic lateral sclerosis

Abstract Transsynaptic deficits arising from an imbalance in excitatory/inhibitory inter-neuronal circuitry has been extensively shown to underlie the phenomena of altered cortical motor excitability in patients with amyotrophic lateral sclerosis (ALS), with glutamate-induced excitotoxicity believed to represent a primary mechanism of ALS pathogenesis. In-vivo evidence of glutamate abnormality in ALS patients, however, remains inconsistent, likely reflecting heterogeneity in the severity of underlying cortical dysfunction. The current study assessed the utility of short interval intracortical inhibition (SICI), a validated marker of upper motor neuron (UMN) dysfunction in ALS, to stratify cortical motor metabolite abnormalities, as determined by proton magnetic resonance spectroscopy (1H-MRS). Serial 1H-MRS data was acquired over 2.5 years for 2 ALS participants with contrasting profiles of progressive motor dysfunction as a pilot study. Longitudinal monitoring of these participants demonstrated stable cortical motor metabolite concentrations in the participant with lower motor predominant disease presentation but progressive changes in Glx and NAA concentrations in the participant with a classical ALS presentation. Fifty-four participants (34 ALS; 20 Control) were prospectively recruited for a formal study. All patients underwent threshold tracking transcranial magnetic stimulation (TMS) and were classified as having high (>5.5%; H-SICI) or low (≤5.5%; L-SICI) cortical motor inhibition. Matching 3T single-voxel 1H-MRS data were acquired from the hand region of the motor cortex for all participants at baseline, with a subset of patients (N=10) longitudinally assessed at 6-months. Dissociable patterns of pathological change in N-acetylaspartate (NAA) and Glutamate-Glutamine (Glx)/NAA metabolites were observed at baseline and longitudinally in ALS. At baseline, L-SICI ALS participants with increased cortical motor excitability demonstrated a significant bilateral reduction in NAA and elevated Glx/NAA metabolite concentrations (p-values<0.03), contrasting to H-SICI ALS participants where the neurochemical concentration was preserved. At follow-up, H-SICI patients demonstrated a trend towards elevated Glx and Glx/NAA in the left motor cortex (p-values≤0.06). In contrast, L-SICI patients demonstrated stable concentrations of Glx but further reductions in NAA ratio (p=0.04). Cortical excitability and brain neurochemical profile abnormalities reflect evolving states of upper motor neuron dysfunction in ALS. Elevated Glx/NAA metabolite concentration underlies greater cortical motor dysfunction in ALS. Longitudinal 1H-MRS holds potential prognostic utility for clinical monitoring of ALS disease trajectory.