Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability.

Federico Ranieri,Vincenzo Di Lazzaro,Sara Mariotto,Raffaele Dubbioso

doi:10.3389/fneur.2020.605335

Abstract

In the last 20 years, several modalities of neuromodulation, mainly based on non-invasive brain stimulation (NIBS) techniques, have been tested as a non-pharmacological therapeutic approach to slow disease progression in amyotrophic lateral sclerosis (ALS). In both sporadic and familial ALS cases, neurophysiological studies point to motor cortical hyperexcitability as a possible priming factor in neurodegeneration, likely related to dysfunction of both excitatory and inhibitory mechanisms. A trans-synaptic anterograde mechanism of excitotoxicity is thus postulated, causing upper and lower motor neuron degeneration. Specifically, motor neuron hyperexcitability and hyperactivity are attributed to intrinsic cell abnormalities related to altered ion homeostasis and to impaired glutamate and gamma aminobutyric acid gamma-aminobutyric acid (GABA) signaling. Several neuropathological mechanisms support excitatory and synaptic dysfunction in ALS; additionally, hyperexcitability seems to drive DNA-binding protein 43-kDA (TDP-43) pathology, through the upregulation of unusual isoforms directly contributing to ASL pathophysiology. Corticospinal excitability can be suppressed or enhanced using NIBS techniques, namely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as well as invasive brain and spinal stimulation. Experimental evidence supports the hypothesis that the after-effects of NIBS are mediated by long-term potentiation (LTP)-/long-term depression (LTD)-like mechanisms of modulation of synaptic activity, with different biological and physiological mechanisms underlying the effects of tDCS and rTMS and, possibly, of different rTMS protocols. This potential has led to several small trials testing different stimulation interventions to antagonize excitotoxicity in ALS. Overall, these studies suggest a possible efficacy of neuromodulation in determining a slight reduction of disease progression, related to the type, duration, and frequency of treatment, but current evidence remains preliminary. Main limitations are the small number and heterogeneity of recruited patients, the limited “dosage” of brain stimulation that can be delivered in the hospital setting, the lack of a sufficient knowledge on the excitatory and inhibitory mechanisms targeted by specific stimulation interventions, and the persistent uncertainty on the key pathophysiological processes leading to motor neuron loss. The present review article provides an update on the state of the art of neuromodulation in ALS and a critical appraisal of the rationale for the application/optimization of brain stimulation interventions, in the light of their interaction with ALS pathophysiological mechanisms.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the cortical, brainstem, and spinal motor neurons, leading to death due to respiratory failure usually within 3–5 years of symptom onset
Regardless of the underlying mechanisms, studies of riluzole have suggested a utility of transcranial magnetic stimulation (TMS) in assessing biological effectiveness of compounds at an early stage of drug development. These results suggest that non-invasive in vivo monitoring of cortical function, and short-interval” intracortical inhibition (SICI), may be an effective biomarker used to monitor the effects of novel therapeutics in a clinical trial setting
Findings of studies on the clinical effects of non-invasive brain stimulation (NIBS) in ALS patients suggest a possible efficacy in determining a slight reduction of disease progression, related to the duration and frequency of treatment

Summary

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the cortical, brainstem, and spinal motor neurons, leading to death due to respiratory failure usually within 3–5 years of symptom onset. The activity of CSNs and interneurons is regulated by several afferent projections from distant structures by means of different neurotransmitters Neuropathological studies on both ALS patients and mouse models have shown impairment of serotoninergic, dopaminergic, noradrenergic, histaminergic, and cholinergic systems, variably characterized by loss of neurons, altered expression of transporters and receptors, or TDP-43 inclusions [reviewed in Brunet et al [52]]. One study [101] confirmed, in a sample of 10 ALS subjects, the physiological inhibitory effect of cTBS on M1 excitability observed in the healthy population, by showing a cumulative increase of motor threshold and a reduction of FIGURE 1 | Schematic representation of mechanisms implicated in the origin of hyperexcitability in ALS and of proposed sites of interaction of different techniques of stimulation of the corticospinal system. Cortical subdural stimulation was initially tested by Sidoti and Agrillo [98] in four patients who underwent bilateral M1

Hz 20 Hz cTBS 5 Hz

Findings

DISCUSSION AND PERSPECTIVE