Hyperexcitability, neurodegeneration, and disease progression in amyotrophic lateral sclerosis

The real problem with developing effective therapies for amyotrophic lateral sclerosis (ALS) reflects the fact that the cause and the pathophysiology of the disease remain to be determined. Furthermore, it would seem that at least from a modeling perspective, there is no simple cause-effect process to explain the triggering of disease. Indeed, it seems that multiple hits to the human nervous system determine whether an individual develops ALS, even in those who carry genetic mutations linked to ALS. As such, when considering gene–environment interactions, the etiology of ALS appears heterogenous, with environmental factors potentially uncovering a genetic susceptibility. Adding to the further complexity of ALS, the disease appears relatively unique in terms of spread across both compartments of the human nervous system. Involvement of the upper and lower motor neurone systems remain key features in reaching a diagnosis of ALS, although it is accepted that upper motor neuron signs may not be clinically evident. Recent years have witnessed the focus shift toward cortical involvement in ALS, albeit with acceptance that lower motor neurons have critical functions including the maintenance of breathing, and thereby determine patient survival. Of relevance to the discussion of the lower motor neurone, and specific roles within a complex and more complete motor system, the present issue of Muscle & Nerve includes an elegant study that investigates the impact of disease on motor unit behavior. Specifically, Noto and colleagues have investigated motor unit firing rates in ALS using high-density surface electromyography, with a decomposition analysis. Consistent with the progressive nature of ALS, there were overall, fewer motor units evident in the cohort of 19 ALS patients, when compared to healthy controls. More critically, Noto and colleagues determined higher motor unit firing rates in ALS patients, with lower recruitment thresholds, changes that the authors interpreted as being consistent with hyperexcitability. This study contributes further data to the accumulating role of an evolution of hyperexcitability in ALS, in this case at a peripheral neuromuscular level, an evolution that warrants attention, offering potential therapeutic intervention in this most treatment-resistant of diseases. When considering pathophysiological processes linked to ALS, an excitotoxicity cascade has been implicated as one of many potential mechanisms of neurodegeneration and disease spread. Specifically, activation of glutamate receptors may lead to dysfunction and ultimately failure of motor neurones to undertake key tasks, with consequent progressive disability and patient death, most typically linked to respiratory failure. Post-mortem examinations have identified degeneration of the corticospinal tract, from a cortical level through to the spinal cord, with involvement of anterior horn cells, and ultimately the loss of control for voluntary movements. Linking disease pathology to brain function, the glial-specific glutamate transporter GLT-1 appears reduced in ALS patient brains and spinal cords, such that excess glutamate alters function of cortical cells, rendering the brain hyperexcitable in ALS patients during the course of their disease. But the brain and spinal cord are not alone in being hyperexcitable in ALS – the entire neural axis appears to be altered from a functional perspective, with further supportive evidence provided by the Noto study. At the level of the peripheral nerve, studies have identified widespread dysfunction in axonal ion channels, reflected by an increase in persistent sodium (Na) conductances, combined with abnormalities of fast paranodal and internodal slow potassium (K) channel function, all contributing to hyperexcitability, likely further contributing to the generation of common patient symptoms such as cramps and fasciculation. While turning to central function, short-interval intracortical inhibition (SICI) may also become significantly reduced in ALS patients, most prominently in those with limb-onset disease. Underlying these changes, SICI reflects activation of inhibitory interneuronal basket cells located in layer IV of the pre-central cortex acting via γ-aminobutyric acid sub-type A (GABA-A) receptors, combined with the effects of refractoriness of interneuronal axonal circuits and synaptic inhibition, particularly during the early phase of SICI. So a reduction in SICI would suggest that alteration in interneuronal function is at least a contributing factor to the advent of cortical hyperexcitability. In consort with changes in intracortical inhibition, the duration of the cortical silent period typically becomes reduced in ALS, while there is also a lowering of resting motor threshold, changes in brain function consistent with a transformation toward cortical hyperexcitability. Eventually with progressive disease and loss of corticospinal projections, the motor pathways in patients with advanced disease become relatively inexcitable, consistent with neuronal death and significant disease burden, and thereby patient disability. Taken together, the presence of hyperexcitability is now well established in ALS, across both upper and lower motor neuron compartments of the nervous system, with cortical hyperexcitability an early feature of the disease. While the motor cortex does not control muscles directly, it critically coordinates muscle synergies during movement. Impairment of List of abbreviations: ALS, amyotrophic lateral sclerosis; Ca, calcium; GABA-A, γ-aminobutyric acid sub-type A; GLT-1, glial-specific glutamate transporter; K, potassium; Na, sodium; SICI, short interval intracortical inhibition; TDP-43, TAR DNA-binding protein 43. Received: 10 April 2023 Revised: 25 April 2023 Accepted: 26 April 2023