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

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.

A comprehensive review of transcranial magnetic stimulation in secondary dementia

“…A common factor that seems to emerge is that the development of hyperexcitability/disinhibition of cortical circuits may be secondary to several noxious conditions, and, as such, it might represent a compensatory phenomenon that might prevent the development of an excitatory dysfunction; alternatively, it might be the consequence of a predominant impairment of inhibitory interneurons. This hypothesis contrasts with the view of hyperexcitability as a possible causative factor in some neurodegenerative disorders, such as AD and dementia in motor neuron diseases (Ranieri et al, 2020;Di Lazzaro et al, 2021). Interestingly, a hyperexcitability is also suggested in a few secondary dementias for which more homogeneous studies are available.…”

Abnormal sensorimotor cortex and thalamo-cortical networks in familial adult myoclonic epilepsy type 2: pathophysiology and diagnostic implications

“…Therefore, we suggest that implementing the systematic evaluation of cortical and subcortical circuits by using ad hoc TMS and SEP protocols might be of interest in the future investigation of the neural mechanisms underlying hyperexcitability of S1 and M1 in patients with amyotrophic lateral sclerosis. 61 Analogously, the application of these neurophysiological procedures in stroke patients might uncover the mechanisms of increased cortical excitability that are essential to boost synaptic plasticity and promote the reorganization of cortical networks in the recovery phase. 62 …”

Effect of whole-hand water flow stimulation on the neural balance between excitation and inhibition in the primary somatosensory cortex

“…The sensorimotor cortex hyperexcitability represents an important pathogenic mechanism underlying several neurological diseases such as familial adult myoclonic epilepsy type 2 (FAME2) ( Dubbioso et al, 2022 ), ALS ( Ranieri et al, 2020 ), dystonia ( Erro et al, 2018 ), fibromyalgia ( Lim et al, 2015 ), and schizophrenia ( Daskalakis et al, 2020 ). These diseases are typically caused by the abnormal neural balance between excitation and inhibition.…”