Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Abstract

Key points •Amyotrophic lateral sclerosis (ALS) motoneurons become hypoexcitable with disease progression in experimental models, raising questions about the neural hyperexcitability supported by clinical observations. •A variant of the ∆F method, based on motor unit discharge frequency modulations during recruitment and derecruitment, has been developed to investigate the motoneuron capacity to self‐sustained discharge in patients. •The modulation of motor unit firing rate during ramp contraction and vibration‐induced recruitment are modified in ALS, suggesting lower motoneuron capacity to self‐sustained discharge, which is a sign of hypoexcitability. •∆F‐D decreases with functional impairment and its reduction is more pronounced in fast progressors. •In patients with ALS, motoneurons exhibit hypoexcitability, which increases with disease progression. Abstract Experimental models have primarily revealed spinal motoneuron hypoexcitability in amyotrophic lateral sclerosis (ALS), which is contentious considering the role of glutamate‐induced excitotoxicity in neurodegeneration and clinical features rather supporting hyperexcitability. This phenomenon was evaluated in human patients by investigating changes in motor unit firing during contraction and relaxation. Twenty‐two ALS patients with subtle motor deficits and 28 controls performed tonic contractions of extensor carpi radialis, triceps brachialis, tibialis anterior and quadriceps, aiming to isolate a low‐threshold unit (U1) on the electromyogram (EMG). Subsequently, they performed a stronger contraction or tendon vibration was delivered, to recruit higher threshold unit (U2) for 10 s before they relaxed progressively. EMG and motor unit potential analyses suggest altered neuromuscular function in all muscles, including those with normal strength (Medical Research Council score at 5). During the preconditioning tonic phase, U1 discharge frequency did not differ significantly between groups. During recruitment, the increase in U1 frequency (∆F‐R) was comparable between groups both during contraction and tendon vibration. During derecruitment, the decrease in U1 frequency (∆F‐D) was reduced in ALS regardless of the recruitment mode, particularly for ∆F‐R <8 Hz in the upper limbs, consistent with the muscle weakness profile of the group. ∆F‐D was associated with functional disability and its reduction was more pronounced in patients with more rapid disease progression rate. This in vivo study has demonstrated reduced motoneuron capacity for self‐sustained discharge, and further supports that motoneurons are normo‐ to hypoexcitable in ALS patients, similar to observations in experimental models.

Early Hypoexcitability in a Subgroup of Spinal Motoneurons in Superoxide Dismutase 1 Transgenic Mice, a Model of Amyotrophic Lateral Sclerosis

“…Direct lineage reprogramming also reveals hypo-activity of human ALS patients motor neurons (Liu et al, 2016). It is noteworthy that motoneurons recorded from ALS patients were hypoexcitable (Marchand-Pauvert et al, 2019). Hyperexcitability also develops in iPSC derived from ALS patients (Wainger et al, 2014) and was recorded in ALS patients (Vucic et al, 2014).…”

Neurophysiological Mechanisms Underlying Cortical Hyper-Excitability in Amyotrophic Lateral Sclerosis: A Review

“…Hence, despite variation in the morphological and functional properties of these neurons between species, lower MNs are directly or indirectly modulated by upper MNs via corticospinal descending projections from the motor cortex [ 41 , 42 , 43 , 44 ] and this influence from upper MNs are deleterious for lower MN survival in ALS [ 39 , 40 ]. A recent clinical study in ALS onset patients showing absence of hyper-excitability in spinal MNs [ 45 ] could possibly reflect a compensatory mechanism in the surviving MNs, given that not all lower MNs are hyper-excitable and their excitability status correlates with their survival [ 46 , 47 , 48 ]. Upper MN degeneration precedes lower MN loss [ 4 , 37 , 38 ], clearly implying the possibility of a dying forward influence in ALS.…”

Cortical hyperexcitability evolves with disease progression in ALS

“…Cortical hyperexcitability is heralded by reduction or absence of short‐interval intracortical inhibition (SICI), leading to disinhibition and hyperexcitability of the cortical motor neurons, 10 despite a recent study suggesting that spinal motor neuron excitability was normal or reduced in ALS 11 . Given that SICI is mediated by cortical inhibitory interneurons acting via GABA A receptors, 12 it has been surmised that dysfunction of these cortical inhibitory interneurons contributes to SICI abnormalities and thereby development of cortical hyperexcitability in ALS 13 .…”