Intermittent Hypoxia to Enhance Motor Function After Spinal Cord Injury

This study will examine if acute intermittent hypoxia (brief episodes of breathing lower oxygen), which has been shown to enhance plasticity and motor output, can enhance functional outcomes and muscle activation in individuals with spinal cord injury. Our aim is to assess breathing, sitting, standing and walking functional ability before and after acute intermittent hypoxia, compared to a sham treatment. This information may be useful in advancing rehabilitation for people with spinal cord injuries.

Recent evidence has shown that acute intermittent hypoxia can strengthen motor pathways after spinal cord injury, and enhance walking outcomes after walking rehabilitation compared to walking rehabilitation alone. A single session of acute intermittent hypoxia has also been shown to temporarily enhance breathing and limb strength in people with spinal cord injury. Further evidence supports the hypothesis that acute intermittent hypoxia acts on all motor pathways, and thus can enhance the strength of most muscles in the body. Spinal cord injury affects the trunk muscles that control respiration and posture. Decreased respiratory muscle function can lead to diseases of the respiratory system, which are the primary cause of death and significant cause of re-hospitalization after spinal cord injury. Deficits in postural muscle function affect one's ability to balance, safely maintain a seated position, or ambulate after spinal cord injury, severely impacting daily activities such as self-care and feeding skills. This study will test the hypothesis that a single session of acute intermittent hypoxia will increase strength and activation of the trunk muscles that control respiration and posture, leading to improved scores on functional assessments in individuals with chronic spinal cord injury. Our long term goal is to better understand the therapeutic potential of acute intermittent hypoxia combined with physical rehabilitation for individuals with chronic spinal cord injury.

Subjects will be asked to participate in two visits at least 7 days apart. Subjects will be assessed on various clinical outcomes before and after an exposure to one of two treatments. In one visit, subjects will be assessed before and after acute intermittent hypoxia, consisting of brief exposures of breathing low oxygen air, alternated with brief exposures to room air. In the other visit, subjects will be assessed before and after an exposure to a sham treatment, consisting of breathing brief exposures of normal oxygen air, alternated with brief exposures to room air. Subjects will undergo acute intermittent hypoxia or a sham treatment in a randomized order.

Subjects with chronic spinal cord injury will undergo an acute intermittent hypoxia protocol with low oxygen air (9-15% inspired oxygen.

Subjects with chronic spinal cord injury will undergo a sham placebo protocol with normal oxygen air (21% inspired oxygen).

During acute intermittent hypoxia, subjects will undergo 15 brief exposures (60-120 seconds) of low oxygen air (9-15% inspired oxygen) delivered by an air generator, alternated with 15 brief exposures (60-120 seconds) of ambient room air.

During sham intermittent hypoxia, subjects will undergo 15 brief exposures (60-120 seconds) of normal oxygen air (21% inspired oxygen) delivered by an air generator, alternated with 15 brief exposures (60-120 seconds) of ambient room air.

The degree to which subjects can independently perform certain tasks that require trunk muscles will be assessed with the Neuromuscular Recovery Scale. Four components of this standard, reliable and responsive clinical test of functional ability for people with SCI will be used. Standardized instructions will be provided to the subjects for each component. These components include: Sit - testing the subject's ability to sit tall with proper posture when the feet are flat on the floor. Reverse Sit-up - subjects will be asked to lower themselves from sitting up to lying supine on a mat as slowly and controlled as possible. Sit-up - the subject's ability to sit up from lying supine on a table while the feet are on the ground will be assessed. Trunk extension in sitting - while seated on a table with feet on the floor, subjects will be asked to lean forward with their arms hanging down, and then return to a seated position without using their hands.

An assessment of how much air a person can forcefully exhale after a maximal inspiratory effort. Tests are conducted using a digital spirometer or respiratory monitor.

An assessment of the pressure generated in the first 0.1 seconds of the participant's initiation of inhalation.Up to 10 trials of mouth occlusion pressure (P0.1) will be measured to ensure a valid measurement.

Assessed by asking subjects to remain sitting upright while a study staff member applies force to the participant's upper chest, shoulders, or back using a hand-held force meter to record the amount of resistance provided by the participant. Participants will be spotted as necessary by study staff in case the participant is unable to balance themselves during the test.

Activation and timing of activation of trunk and other accessory respiratory muscles will be measured using EMG, which are small sensors that attach to the skin.

Electrogoniometers, sensors used to calculate joint angles, may be placed on the hips or the trunk to allow for measurement of the angle of those segments during each assessment task.

An assessment of walking balance and fall risk based on the participant's ability to stand up from a seated position, walk 10 meters, turn around, return to their chair and sit down. This test will only be performed by subjects who can safely attempt it.

An assessment of walking speed over a distance of 10 meters. This test will only be performed by subjects who can safely attempt it.

An assessment of lower body strength and power which evaluates the maximum amount of times that a participant can safely stand up from a seated position and sit back down. This test will only be performed by subjects who can safely attempt it.

Inclusion criteria: Male or female, ages 18-65 Greater than 6 months post-spinal cord injury Spinal cord injury affecting segments between C4-T12 No other known neurological disorders Able to provide informed consent no severe musculoskeletal impairments, open wounds, or skin lesions that would limit participation in functional assessments. Exclusion criteria: Presence of a self-reported uncontrolled medical condition including, but not limited to: cardiovascular disease; sleep apnea; obstructive lung disease; severe neuropathic or chronic pain; severe recurrent autonomic dysreflexia Severe, untreated bladder or urinary tract infection Presence of severe musculoskeletal impairments, open wounds, or skin lesions that would limit participation in functional assessments Women who report being pregnant or test positive on a pregnancy test

Gonzalez-Rothi EJ, Lee KZ, Dale EA, Reier PJ, Mitchell GS, Fuller DD. Intermittent hypoxia and neurorehabilitation. J Appl Physiol (1985). 2015 Dec 15;119(12):1455-65. doi: 10.1152/japplphysiol.00235.2015. Epub 2015 May 21.

Hayes HB, Jayaraman A, Herrmann M, Mitchell GS, Rymer WZ, Trumbower RD. Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology. 2014 Jan 14;82(2):104-13. doi: 10.1212/01.WNL.0000437416.34298.43. Epub 2013 Nov 27.

Trumbower RD, Jayaraman A, Mitchell GS, Rymer WZ. Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehabil Neural Repair. 2012 Feb;26(2):163-72. doi: 10.1177/1545968311412055. Epub 2011 Aug 5.

Tester NJ, Fuller DD, Fromm JS, Spiess MR, Behrman AL, Mateika JH. Long-term facilitation of ventilation in humans with chronic spinal cord injury. Am J Respir Crit Care Med. 2014 Jan 1;189(1):57-65. doi: 10.1164/rccm.201305-0848OC.

Satriotomo I, Nichols NL, Dale EA, Emery AT, Dahlberg JM, Mitchell GS. Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons. Neuroscience. 2016 May 13;322:479-88. doi: 10.1016/j.neuroscience.2016.02.060. Epub 2016 Mar 2.