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

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, n...

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Autores principales: Ranieri, Federico, Mariotto, Sara, Dubbioso, Raffaele, Di Lazzaro, Vincenzo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892772/
https://www.ncbi.nlm.nih.gov/pubmed/33613416
http://dx.doi.org/10.3389/fneur.2020.605335
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author Ranieri, Federico
Mariotto, Sara
Dubbioso, Raffaele
Di Lazzaro, Vincenzo
author_facet Ranieri, Federico
Mariotto, Sara
Dubbioso, Raffaele
Di Lazzaro, Vincenzo
author_sort Ranieri, Federico
collection PubMed
description 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.
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spelling pubmed-78927722021-02-20 Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability Ranieri, Federico Mariotto, Sara Dubbioso, Raffaele Di Lazzaro, Vincenzo Front Neurol Neurology 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. Frontiers Media S.A. 2021-02-05 /pmc/articles/PMC7892772/ /pubmed/33613416 http://dx.doi.org/10.3389/fneur.2020.605335 Text en Copyright © 2021 Ranieri, Mariotto, Dubbioso and Di Lazzaro. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Ranieri, Federico
Mariotto, Sara
Dubbioso, Raffaele
Di Lazzaro, Vincenzo
Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability
title Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability
title_full Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability
title_fullStr Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability
title_full_unstemmed Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability
title_short Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability
title_sort brain stimulation as a therapeutic tool in amyotrophic lateral sclerosis: current status and interaction with mechanisms of altered cortical excitability
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892772/
https://www.ncbi.nlm.nih.gov/pubmed/33613416
http://dx.doi.org/10.3389/fneur.2020.605335
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