Spinal Cord Associative Plasticity for Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is more prevalent in Veterans than civilians, leading to ALS being considered a Service-Connected condition by the VA. ALS features incomplete degeneration of upper and lower motor neuron pathways within the spinal cord, a circumstance resembling that of spinal cord injury (SCI). Transcutaneous spinal cord stimulation (TSCS) has demonstrated remarkable potential to activate damaged circuits after SCI to improve motor and autonomic function. Partly funded by a prior RR&D SPiRE award (RX002527), we have preliminary data demonstrating that pairing subthreshold cervical TSCS pulses with suprathreshold transcranial magnetic stimulation (TMS) pulses can enhance hand muscle motor evoked potentials when the cortical pulse reaches the cervical spinal cord 0-5 milliseconds prior to the spinal pulse. This evidence for immediate facilitation of the response to one pair of pulses suggests that if given repetitively, this approach could mediate spinal cord associative plasticity (SCAP) outlasting the period of paired stimulation. We propose that increasing neural plasticity in this manner could be applied as a method to strengthen volitional (cortical) motor output and/or to 'prime' weakened circuits for improved responses to task-oriented exercise. Both exercise and neuromodulation are understudied in ALS. Though not likely to cure the underlying disease mechanism, these approaches have the potential to mediate symptomatic benefit. We strive to find better ways to conduct disease-oriented research that may provide direct clinical benefit to research participants with ALS and simultaneously increase scientific understanding. Additionally, most ALS clinical study entry criteria heavily favor those at earlier stages of disease. Strict entry criteria are understandable from the scientific perspective. However, we have repeatedly observed the frustration and rejection felt by individuals with ALS who cannot enter clinical trials. Our proposed study does not restrict entry by time since symptom onset. We thereby hope to produce more generalizable knowledge by performing a phased study: 1. Optimization: SCAP synaptic pairing interval and repetitive frequency pattern will be individually optimized to enhance hand muscle excitability and dexterity. We hypothesize that pairs of stimuli with TMS arriving at the cervical spinal cord up to 2 ms prior to TSCS, delivered in an ‘intermittent theta burst’ pattern, will produce the strongest facilitation of hand neural circuits. 2. Consolidation: Two-week programs of SCAP alone versus exercise alone versus SCAP plus task- oriented hand exercise will be compared. We hypothesize that the combined intervention will result in greater and longer lasting physiological and clinical benefits than either modality by itself. There are currently no clinical studies in the world involving magnetic brain paired with phasic electrical spinal stimulation for ALS. Therefore, safety needs to be meticulously tracked. Aside from detailed clinical safety measures, we will analyze serum biomarkers drawn at baseline and various stages of the study to better understand whether baseline levels of neurodegenerative, excitotoxic, inflammatory, and neurotropic biomarkers associate with either beneficial or detrimental responses to SCAP and exercise interventions.