Is there hope that transpinal direct current stimulation corrects motoneuron excitability and provides neuroprotection in amyotrophic lateral sclerosis?

Abstract

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Non-Invasive Transcutaneous Spinal DC Stimulation as a Neurorehabilitation ALS Therapy in Awake G93A Mice: The First Step to Clinical Translation

“…As spinal anodal stimulation increases MN excitability [ 16 , 17 ] with effects that could be sustained for weeks [ 18 ], and MN hyperexcitability has been reported in symptomatic SOD mice [ 35 ], anodal stimulation could therefore accelerate the neurodegeneration process and lead to shortened survival of SOD mice. Interestingly, the negative anodal survival trend contradicts the prediction that anodal stimulation would have beneficial effects on G93A mice [ 20 ]. However, many factors could explain this discrepancy between this prediction by Baczyk, Krutki and Zytnicki [ 20 ] and our results: (1) Timepoint : In order to be clinically relevant, our study was completed at symptom onset (P90–P105), whereas Baczyk, Krutki and Zytnicki [ 20 ] study targeted a pre-symptomatic timepoint (around P50–P60).…”

“…Interestingly, the negative anodal survival trend contradicts the prediction that anodal stimulation would have beneficial effects on G93A mice [ 20 ]. However, many factors could explain this discrepancy between this prediction by Baczyk, Krutki and Zytnicki [ 20 ] and our results: (1) Timepoint : In order to be clinically relevant, our study was completed at symptom onset (P90–P105), whereas Baczyk, Krutki and Zytnicki [ 20 ] study targeted a pre-symptomatic timepoint (around P50–P60). It is highly likely that excitability changes are dynamic throughout disease progression [ 44 ].…”

“…Therefore, increasing MN excitability with anodal stimulation could be beneficial earlier in the disease but harmful by symptom onset. Furthermore, the prediction of Baczyk, Krutki and Zytnicki [ 20 ] of beneficial anodal effects in ALS was not based on survival or behavioral experiments but rather was based on cellular data that anodal stimulation enhanced synaptic inputs to MNs and evoked MN hyperexcitability, along with the prediction that these effects would have a beneficial treatment outcome. Extrapolating the individual MN effects to predict the overall treatment outcome relies on filling gaps in the field’s knowledge of the import of the hypo- and hyperexcitability seen throughout disease progression—that is to say, which is the disease mechanism and which is the protective, compensatory mechanism.…”

“…For example, sDCS was suggested by computational models to effectively regulate the dendritic PICs of MNs [ 15 ]. Additionally, recent in vivo studies show subcutaneous spinal DC stimulation (ssDCS) modulates measured electrophysiological properties, resulting in altered excitability of spinal MNs, during and beyond the stimulation period [ 16 , 17 , 18 , 19 , 20 , 21 ].…”

“…Specifically, we used daily sessions of non-invasive transcutaneous spinal DC stimulation (tsDCS) with the goal of inducing lasting excitability changes in lumbar spinal MNs to affect motor function loss and survival in ALS via anodal (dorsal-to-ventral) or cathodal (ventral-to-dorsal) stimulation. Due to the physics of the polarizations induced across MNs in the stimulated region [ 15 ], it is expected that the cathodal and anodal orientations will have opposing effects (hyper or hypo-excitation), a phenomenon supported by measured MN changes in previous studies [ 16 , 19 , 20 ]. We hypothesized, therefore, that these opposing effects would make one orientation beneficial and the other harmful to symptom progression.…”