Amyotrophic lateral sclerosis (ALS) reduces connections between the cortical motor neurons that initiate movement and the spinal motor neurons that direct muscles to execute movement. This situation shares many key features with incomplete spinal cord injury (SCI). Accumulating evidence in SCI suggests that externally activating spared nerve circuits with electromagnetic stimulation augments neural transmission. With this goal, we developed a novel method of noninvasive cervical electrical stimulation (CES). CES activates multiple muscles on both upper limbs by triggering afferent sensory or efferent motor nerve roots depending on stimulus intensity. This proposal will investigate CES for its potential to strengthen residual circuits to the hands in ALS. To our knowledge, electrical spinal stimulation for ALS has never been tested or applied previously. Therefore, a pilot study is essential. This study will be performed in two stages: 1. Map CES circuit and synaptic targets: The experiments share a common structure comprising conditioning and test stimuli delivered at a range of intensities, sites, and interstimulus intervals. Hypotheses: Conditioning subthreshold CES will potentiate responses to TMS and peripheral nerve F-wave stimulation, indicating its potential to strengthen corticospinal and spinal motor circuit connections. Conditioning CES will reduce responses to peripheral nerve H-reflex stimulation, demonstrating its potential to reduce hyperactive afferent stretch reflexes (spasticity). 2. Determine parameters for combining CES with volitional movement: Volitional limb movements depend on the same corticospinal and motor neuron circuits as those activated by TMS and F-waves. Since preliminary data shows that subthreshold CES facilitates TMS responses, CES may also be able to facilitate volitional limb movements. Hypotheses: Subthreshold CES will facilitate concurrent arm and hand muscle activation, further indicating CES's ability to positively modulate motor circuits; high-intensity suprathreshold CES will transiently inhibit concurrent arm and hand muscle activation. If observed, this `spinal silent period' would shed insight into mechanisms underlying the `cortical silent period' noted when cortical TMS is delivered during volitional contraction. Successful completion of these experiments will: mechanistically elucidate CES circuit interactions; investigate the potential for CES to enhance concurrent volitional muscle activation; and establish CES as safe and feasible in the ALS population. Given the limited treatment options for ALS, any amount of progress would represent a meaningful step forward. Moreover, results of this pilot study could lead to direct translation for lasting clinical benefit by combining repetitive subthreshold CES with repetitive task-oriented physical exercise training in subsequent studies. CES would be compatible with other interventions, including medications and cell-based treatments. ALS has higher incidence in Veterans. Spinal stimulation has not been tested in ALS. Therefore, the proposed experiments will address important questions in an entirely unexplored context that strongly aligns with the mission of the RR&D service.

Public Health Relevance

Veterans are at higher risk than non-Veterans of falling ill with amyotrophic lateral sclerosis (ALS). This progressive disease leads to decreased connections in motor circuits between the brain and muscles. Though many drug and stem cell trials have occurred, almost no ALS studies have tried directly stimulating nerves with electrical energy. Electrical stimulation has shown promise for improving nerve transmission and function in other neurological diseases. The current proposal will now test this technique in ALS, using non-invasive electrical stimulation over the neck. Different stimulation parameters and combinations of stimulation with hand movements will be tested to for short-term effects on nerve transmission to the hands. These experiments will improve understanding of electrical stimulation in ALS, and may set the table for future treatments. Finding treatments for ALS is of special value to Veterans and their families, as all Veterans are at increased risk for this service-connected disease.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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Rehabilitation Research and Development SPiRE Program (RRDS)
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James J Peters VA Medical Center
United States
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