Background/Readiness: The objective of this proposal is to maximize locomotor outcomes of patients following incomplete spinal cord injury (iSCI) through identification of rehabilitation strategies that maximize recovery. Specific training parameters, such as provision of large amounts of stepping, appears to facilitate locomotor function in patients with iSCI, although other factors may be critical. In this proposed phase II randomized clinical trial, the overarching hypothesis is that the "intensity" of locomotor practice, defined as power output and estimated using cardiopulmonary measures, is critical to maximizing walking outcomes. Performance of high intensity locomotor training increases the cardiovascular and neuromuscular demands, which results in physiological changes that facilitate greater locomotor performance in individuals with and without neurological injury. There are, however, limited data supporting its utility in patients with iSCI. Recent findings suggest a role for high-intensity stepping training in variable contexts, with gains in peak locomotor capacity as compared low-intensity variable training. Additional changes in cardiopulmonary function and neuromuscular coordination provide a mechanistic rationale for the utility of this strategy. Such changes are likely due to increased central (volitional) activation, and are in sharp contrast to the long-standing notion that high intensity training impairs motor function in neurological injury.

Despite these data, genotypic variations suggest specific caveats related to high intensity training. For example, many patients possess a single nucleotide polymorphism (SNP) variation in the brain derived neurotrophic factor (BDNF) gene that may impact the activity-dependent BDNF expression thought to contribute to neuroplasticity underlying improved performance. This single nucleotide polymorphism (SNP) can influential declarative memory, with recent data suggesting a potential impact on motor recovery after neurologic injury. Previous studies indicate limited BDNF increases in patients with this SNP during high intensity exercise, although the effects of locomotor recovery with repeated high-intensity training is unclear Hypothesis/Specific Aims: The primary hypotheses are that high intensity variable stepping can markedly improve locomotor performance as well as neuromuscular and cardiopulmonary function as compared to lower-intensity training in patients with chronic motor iSCI. It is believed that genotypic variations in the ability to synthesis activity dependent BDNF may modify the effects of high intensity training. Specific Aim 1: Test if high intensity stepping training in variable contexts results in greater locomotor gains as compared to lower intensity interventions. Specific Aim 2: Test the effects of these training strategies on neuromuscular and cardiopulmonary impairments. Specific Aim 3: Test the effects of the presence of the BDNF SNP on locomotor improvements in patients following high-intensity activities Study Design: This phase II, stratified, assessor- blinded randomized clinical trial will assess the effects 2 months (up to 30 sessions) of high- vs low-intensity variable stepping training on ambulatory patients with chronic (\> 1year) motor iSCI. Participants referred from outpatient therapy settings will undergo evaluation of locomotor performance, cardiopulmonary capacity, and neuromuscular coordination and impairments prior to and following each training paradigm, with 2-month follow-up assessments.

Clinical Impact: The application of high-intensity locomotor training in the clinical rehabilitation of patients with iSCI is extremely limited, despite data regarding the potential benefits in neurological intact individuals and patients with stroke. The clinical application of high-intensity training represents a simple, readily modified training parameter that can be readily implemented, and is in stark contrast to current clinical practice and challenge traditional dogma in rehabilitation medicine.