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

Abstract

Spinal direct current stimulation (sDCS) modulates motoneuron (MN) excitability beyond the stimulation period, making it a potential neurorehabilitation therapy for amyotrophic lateral sclerosis (ALS), a MN degenerative disease in which MN excitability dysfunction plays a critical and complex role. Recent evidence confirms induced changes in MN excitability via measured MN electrophysiological properties in the SOD1 ALS mouse during and following invasive subcutaneous sDCS (ssDCS). The first aim of our pilot study was to determine the clinical potential of these excitability changes at symptom onset (P90-P105) in ALS via a novel non-invasive transcutaneous sDCS (tsDCS) treatment paradigm on un-anesthetized SOD1-G93A mice. The primary outcomes were motor function and survival. Unfortunately, skin damage avoidance limited the strength of applied stimulation intensity, likewise limiting measurable primary effects. The second aim of this study was to determine which orientation of stimulation (anodal vs cathodal, which are expected to have opposing effects) is beneficial vs harmful in ALS. Despite the lack of measured primary effects, strong trends in survival of the anodal stimulation group, combined with an analysis of survival variance and correlations among symptoms, suggest anodal stimulation is harmful at symptom onset. Therefore, cathodal stimulation may be beneficial at symptom onset if a higher stimulation intensity can be safely achieved via subcutaneously implanted electrodes or alternative methods. Importantly, the many logistical, physical, and stimulation parameters explored in developing this novel non-invasive treatment paradigm on unanesthetized mice provide insight into an appropriate and feasible methodology for future tsDCS study designs and potential clinical translation.

What Else Can Be Done by the Spinal Cord? A Review on the Effectiveness of Transpinal Direct Current Stimulation (tsDCS) in Stroke Recovery

“…Indeed, according to the earliest reports [ 14 , 15 , 16 ], all the results in animal studies confirmed that both anodal and cathodal tsDCS induce local and cortical plastic changes [ 38 , 39 , 40 , 41 , 42 , 43 ] in rat motoneurons, which considerably outlast the time of polarization [ 38 , 39 , 40 , 41 , 42 ]. Most studies found a depolarization and, thus, an increase of motor responses following cathodal tsDCS, and a hyperpolarization and, thus, a decrease of motor responses following anodal tsDCS [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. In the authors’ hypothesis, cathodal tsDCS increases evoked synaptic transmission, and, by depolarizing cell bodies, it augments motoneuron activity through induction of calcium release [ 14 , 15 , 16 , 38 ], while anodal tsDCS exerts opposite effects [ 43 , 44 ].…”

“…Indeed, according to the earliest reports [14][15][16], all the results in animal studies confirmed that both anodal and cathodal tsDCS induce local and cortical plastic changes [38][39][40][41][42][43] in rat motoneurons, which considerably outlast the time of polarization [38][39][40][41][42]. Most studies found a depolarization and, thus, an increase of motor responses following cathodal tsDCS, and a hyperpolarization and, thus, a decrease of motor responses following anodal tsDCS [38][39][40][41][42][43][44].…”

“…In the authors’ hypothesis, cathodal tsDCS increases evoked synaptic transmission, and, by depolarizing cell bodies, it augments motoneuron activity through induction of calcium release [ 14 , 15 , 16 , 38 ], while anodal tsDCS exerts opposite effects [ 43 , 44 ]. Fewer studies found facilitatory effects after anodal tsDCS [ 39 , 40 , 41 , 42 ] calling into question the distinction between motoneuron firing induced by intracellular stimulation and the firing induced by synaptic activation. Indeed, only in the first case, the anodic current depolarizes the cell membrane since it directly influences the cell body bypassing the synaptic system [ 39 , 40 , 41 , 42 ].…”

“…Fewer studies found facilitatory effects after anodal tsDCS [ 39 , 40 , 41 , 42 ] calling into question the distinction between motoneuron firing induced by intracellular stimulation and the firing induced by synaptic activation. Indeed, only in the first case, the anodic current depolarizes the cell membrane since it directly influences the cell body bypassing the synaptic system [ 39 , 40 , 41 , 42 ].…”

“…As reported in Table 1 , we identified the effects of tsDCS on motor improvement in animals in seven out of seventeen studies. Some studies showed increased motor neuron responses after cathodal tsDCS and decreased responses after anodal tsDCS applied over the thoracic-lumbar [ 38 ] and cervical regions [ 44 ] while some others showed a facilitation of motoneuron responses after anodal tsDCS, while cathodal effects were not significant [ 39 , 40 , 41 , 42 ]. In the Song and Martin study [ 43 ], both cathodal and anodal tsDCS immediately increased spontaneous motor unit firing during stimulation, but the administration of the L-type calcium channel blocker Nimodipine decreased motor responses only after cathodal tsDCS.…”