Effects of Breathing Mild Bouts of Low Oxygen on Limb Mobility After Spinal Injury

Foundation Wings For Life, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Accumulating evidence suggests that repeatedly breathing low oxygen levels for brief periods (termed intermittent hypoxia) is a safe and effective treatment strategy to promote meaningful functional recovery in persons with chronic spinal cord injury (SCI). The goal of the study is to understand the mechanisms by which intermittent hypoxia enhances motor function and spinal plasticity (ability of the nervous system to strengthen neural pathways based on new experiences) following SCI.

Accumulating evidence suggests that repeatedly breathing low oxygen levels for brief periods (termed intermittent hypoxia) is a safe and effective treatment strategy to promote meaningful functional recovery in persons with chronic spinal cord injury. Repetitive exposure to mild hypoxia triggers a cascade of events in the spinal cord, including new protein synthesis and increased sensitivity in the circuitry necessary for breathing and walking. Recently, the investigators demonstrated that daily (5 consecutive days of) intermittent hypoxia stimulated walking enhancement in persons with chronic spinal cord injury. Despite these exciting findings, important questions remain. First, does intermittent hypoxia improve walking recovery by increasing strength or muscle coordination or both? Understanding its mechanisms will allow us to best apply intermittent hypoxia in the clinic. Second, initial studies indicate that the beneficial effects of intermittent hypoxia are greatest when intermittent hypoxia is used just prior to task training and that the benefits are greatest for the practiced task. The investigators will explore this possibility by examining the effects of intermittent hypoxia on walking ability and force production when applied alone and when applied in combination with walking training or strength training. The investigators expect to observe the greatest improvements in walking ability in those individuals receiving intermittent hypoxia with walking training and the greatest improvements in strength in response to intermittent hypoxia with strength training. Third, studies suggest that intermittent hypoxia induces spinal plasticity by increasing the expression of a key plasticity-promoting protein, brain-derived neurotrophic factor (BDNF). Mutations in the BDNF gene have been shown to impair BDNF functionality. Thus, the investigators will also explore the impact of BDNF polymorphisms on responsiveness to intermittent hypoxia therapy.

Subjects with chronic, motor-incomplete SCI receive acute intermittent hypoxia (AIH) with walking practice, then AIH with strength practice and compare their efficacy on enhancing strength and/or walking performance.

Subjects with chronic, motor-incomplete SCI receive AIH with strength practice, then AIH with walking practice and compare their efficacy on enhancing strength and/or walking performance.

Participants will breathe intermittent low oxygen via air generators. The generators will fill reservoir bags attached to a non-rebreathing face mask. Oxygen concentration will be continuously monitored to ensure delivery of fraction of inspired oxygen (FiO2) = 0.10±0.02 (hypoxia). Participants will receive treatment on 5 consecutive days.

Baseline, immediately after intervention (day 1 and day 5), and at follow-ups (one week and two weeks)

Strength will be assessed as the maximum isometric torque produced by the ankle and measured by a 6 degrees-of-freedom (DOF) load cell.

Baseline, immediately after intervention (day 1 and day 5), and at follow-ups (one week and two weeks)

Baseline, immediately after intervention (day 1 and day 5), and at follow-ups (one week and two weeks)

Inclusion Criteria: Age 18 and 75 years (the latter to reduce likelihood of heart disease) Medical clearance to participate Lesion at or below C2 and above T12 with non-progressive etiology Classified as motor-incomplete with visible volitional leg movement Injury greater than 1 year Exclusion Criteria: Concurrent severe medical illness (i.e., infection, cardiovascular disease, ossification, recurrent autonomic dysreflexia, unhealed decubiti, and history of pulmonary complications) Pregnant women because of the unknown affects of AIH on pregnant women and fetus History of seizures, brain injury, and/or epilepsy Undergoing concurrent physical therapy Diabetes Cirrhosis Caffeine and/or NSAID allergies or intolerances

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