Safety and feasibility of transcranial direct current stimulation in amyotrophic lateral sclerosis – a pilot study with a single subject experimental design

Madhavan, Sangeetha; Sivaramakrishnan, Anjali; Bond, Sam; Jiang, Qin Li

doi:10.1080/09593985.2018.1443536

Cited by 6 publications

(4 citation statements)

References 30 publications

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“…In the only study (94) in which cathodal tDCS of M1 was delivered for a prolonged time in a single subject, no effect on disease progression was observed. This was also the case of a single patient reported by Madhavan et al (96), treated for 4-week periods with either anodal, cathodal, or sham tDCS, and of two patients reported by Sivaramakrishnan et al (97), treated for 8 weeks with anodal tDCS of M1. The latter study also evaluated the feasibility of remotely supervised treatment, with therapists guiding caregivers through internet in the application of tDCS and reporting of adverse events.…”

Section: Non-invasive Electrical Stimulationsupporting

confidence: 62%

“…The 1-Hz rTMS showed promising results but it was tested only in a very preliminary study (87). Cathodal tDCS seems to be ineffective in preliminary observations (94,96,105), while a recent wider study suggests a functional effect of corticospinal tDCS (95) but limited by the fact that stimulation was applied only for 2 weeks (Table 1). Of note, with tDCS, individualized electric field modeling (192,193) could improve stimulation targeting and dosing of current density in target brain areas.…”

Section: Discussion and Perspectivementioning

confidence: 99%

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

et al. 2021

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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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Section: Non-invasive Electrical Stimulationsupporting

confidence: 62%

Section: Discussion and Perspectivementioning

confidence: 99%

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

et al. 2021

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“…Changes of ALSFRS-R in both patients were monitored before cathodal tDCS and during the period of cortical stimulation, and it determined that changes were similar before and during cathodal tDCS. Other clinical trials investigated the utility of tDCS based around the similar methodologies [144,145]. One trial included a single ALS patient, applied 12 sessions each of anodal, sham and cathodal tDCS for 4 weeks and measured changes of ALSFRS-R and mobility.…”

Section: Non-pharmacological Approachesmentioning

confidence: 99%

Neuronal Hyperexcitability and Free Radical Toxicity in Amyotrophic Lateral Sclerosis: Established and Future Targets

et al. 2022

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Amyotrophic lateral sclerosis (ALS) is a devastating disease with evidence of degeneration involving upper and lower motor neuron compartments of the nervous system. Presently, two drugs, riluzole and edaravone, have been established as being useful in slowing disease progression in ALS. Riluzole possesses anti-glutamatergic properties, while edaravone eliminates free radicals (FRs). Glutamate is the excitatory neurotransmitter in the brain and spinal cord and binds to several inotropic receptors. Excessive activation of these receptors generates FRs, inducing neurodegeneration via damage to intracellular organelles and upregulation of proinflammatory mediators. FRs bind to intracellular structures, leading to cellular impairment that contributes to neurodegeneration. As such, excitotoxicity and FR toxicities have been considered as key pathophysiological mechanisms that contribute to the cascade of degeneration that envelopes neurons in ALS. Recent advanced technologies, including neurophysiological, imaging, pathological and biochemical techniques, have concurrently identified evidence of increased excitability in ALS. This review focuses on the relationship between FRs and excitotoxicity in motor neuronal degeneration in ALS and introduces concepts linked to increased excitability across both compartments of the human nervous system. Within this cellular framework, future strategies to promote therapeutic development in ALS, from the perspective of neuronal excitability and function, will be critically appraised.

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“…No significant effect of tDCS on SICI or ICF was demonstrated in either group. Madhavan et al 73 applied anodal, cathodal and sham tDCS over the motor cortex in a single subject safety pilot, with no reported adverse effects. While electrode montages were consistent between studies, the application of 2 mA current raises concerns about blinding, while the number and duration of sessions differed significantly.…”

Section: Transcranial Direct Current Stimulationmentioning

confidence: 99%

Therapeutic non-invasive brain stimulation in amyotrophic lateral sclerosis: rationale, methods and experience

Edmond¹,

Stagg²,

Turner³

2019

J Neurol Neurosurg Psychiatry

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The neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) is characterised by increased cortical excitability, thought to reflect pathological changes in the balance of local excitatory and inhibitory neuronal influences. Non-invasive brain stimulation (NIBS) has been shown to modulate cortical activity, with some protocols showing effects that outlast the stimulation by months. NIBS has been suggested as a potential therapeutic approach for disorders associated with changes in cortical neurophysiology, including ALS. This article reviews NIBS methodology, rationale for its application to ALS and progress to date.

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Safety and feasibility of transcranial direct current stimulation in amyotrophic lateral sclerosis – a pilot study with a single subject experimental design

Abstract: This case study demonstrates the safety and feasibility of long-term facilitatory and inhibitory tDCS on a single participant with ALS. This study serves as a guideline for implementing tDCS in future ALS trials.

Cited by 6 publications

References 30 publications

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

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

Neuronal Hyperexcitability and Free Radical Toxicity in Amyotrophic Lateral Sclerosis: Established and Future Targets

Therapeutic non-invasive brain stimulation in amyotrophic lateral sclerosis: rationale, methods and experience

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