| ALS and frontotemporal dementia | Rare Neurological Diseases  

Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter.

This article provides a comprehensive review of the studies using non-invasive brain and spinal stimulation in motor neuron disease, with a focus on amyotrophic lateral sclerosis, to discuss potential therapeutic applications. The authors examined the strengths and weaknesses of the studies conducted to date, suggesting that targeted, individualized, home-based treatments would be desirable in the near future.

The ‘‘cortico-motoneuronal” hypothesis, underlying amyotrophic lateral sclerosis (ALS) pathogenesis, proposes that there is an initial hyperexcitability of upper motor neurons (UMN) located in the primary motor cortex (M1) that drives secondary degeneration of the lower motor neurons (LMN) via an anterograde glutamatergic mechanism. The clinical correlates of altered excitability of the UMN, and in turn of the LMN, are represented by profuse fasciculations, hyperreflexia and spasticity (1). Neurophysiological studies, using standard as well as more advanced techniques, have demonstrated that UMN hyperexcitability may be the result of disinhibition within M1 due to degeneration of inhibitory GABAergic circuits, along with increased cortical excitability secondary to hyperactivity of excitatory cortical interneurons (2). In the case of LMN, a decrease in spinal inhibitory activity has been demonstrated, which translates into a dysfunction of the reciprocal inhibition of the activity of antagonist-agonist muscles. In this context, non-invasive brain and spinal stimulation techniques have been exploited in motor neuron disease (MND) with multiple objectives: from diagnostic to therapeutic purposes (3).

In the present systematic review (3), Di Lazzaro et al. considered how neuromodulation can now be employed to treat MND, with particular attention to ALS, considering the electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques.

This review article includes repetitive transcranial magnetic stimulation methods (i.e., low frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation (tDCS) as well as experimental findings with the novel approach of trans-spinal direct current stimulation (tsDCS). The authors also discussed the trials that have been performed, their strengths and weaknesses. Finally, they concluded that, despite the promising results, further studies are necessary to validate these methods, suggesting the use of targeted, individualized and home-deliverable treatments for future advancements.

Key Points:

  1. Non-invasive brain and spinal stimulation techniques have been investigated as a potential treatment in motor neuron disease, especially in amyotrophic lateral sclerosis.
  2. These methods aim to counteract glutamate-mediated excitotoxicity that leads to motor neuron degeneration.
  3. Despite the promising results, targeted, individualized and home-deliverable treatments are critical challenges to further validate these methods.


  1. Eisen A, Weber M. The motor cortex and amyotrophic lateral sclerosis. Muscle Nerve. 2001 Apr;24(4):564-73.
  2. Geevasinga N, Menon P, Özdinler PH, Kiernan MC, Vucic S. Pathophysiological and diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol. 2016 Nov;12(11):651-661.
  3. Di Lazzaro V, Ranieri F, Bączyk M, de Carvalho M, Dileone M, Dubbioso R, Fernandes S, Kozak G, Motolese F, Ziemann U. Novel approaches to motoneuron disease/ALS treatment using non-invasive brain and spinal stimulation: IFCN handbook chapter. Clin Neurophysiol. 2023 Dec 26;158:114-136.

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