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

Mechanisms of Intermittent Hypoxia-induced Motor Recovery in Persons With 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 (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.

Study Overview

• Status: Recruiting
• Conditions: Spinal Cord Injuries
• Intervention / Treatment: Other: AIH; Other: Walk; Other: Strength

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stella Barth, BA; Phone Number: 617-952-6822; Email: sbarth@partners.org
• Study Contact Backup: Name: Randy D Trumbower, PT, PhD; Phone Number: 617-952-6951; Email: randy.trumbower@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Cambridge, Massachusetts, United States, 02138
      • Recruiting
      • Spaulding Rehabilitation Hospital
      • Contact: Randy D Trumbower, PT, PhD; Phone Number: 617-952-6951; Email: randy.trumbower@mgh.harvard.edu
      • Contact: Melissa DeChellis, BA; Phone Number: (617) 952-6953; Email: mpierre19@partners.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: AIH/Walk; 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.	Other: AIH; 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.; Other Names: Acute Intermittent Hypoxia; Other: Walk; 30 minutes of walking practice consisting of 5 repetitions of 6-minute walks
Active Comparator: AIH/Strength; 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.	Other: AIH; 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.; Other Names: Acute Intermittent Hypoxia; Other: Strength; 30 minutes of isometric ankle plantar flexion torque practice broken into 3 sets of 10 repetitions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in overground walking endurance	Endurance will be measured as the distance walked during 2 min and 6 min (6MWT).	Baseline, immediately after intervention (day 1 and day 5), and at follow-ups (one week and two weeks)
Change in muscle strength	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in overground walking speed	Speed will be assessed by the time required to walk 10 meters (10MWT).	Baseline, immediately after intervention (day 1 and day 5), and at follow-ups (one week and two weeks)

Collaborators and Investigators

• Sponsor: Spaulding Rehabilitation Hospital
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Foundation Wings For Life
• Investigators: Principal Investigator: Randy D Trumbower, PT, PhD, Harvard Medical School (HMS and HSDM)

Publications and helpful links

General Publications

• 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.
• Hayes HB, Chvatal SA, French MA, Ting LH, Trumbower RD. Neuromuscular constraints on muscle coordination during overground walking in persons with chronic incomplete spinal cord injury. Clin Neurophysiol. 2014 Oct;125(10):2024-35. doi: 10.1016/j.clinph.2014.02.001. Epub 2014 Feb 14.
• Hoffman MS, Golder FJ, Mahamed S, Mitchell GS. Spinal adenosine A2(A) receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia. J Physiol. 2010 Jan 1;588(Pt 1):255-66. doi: 10.1113/jphysiol.2009.180075. Epub 2009 Nov 9.
• Baker-Herman TL, Fuller DD, Bavis RW, Zabka AG, Golder FJ, Doperalski NJ, Johnson RA, Watters JJ, Mitchell GS. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci. 2004 Jan;7(1):48-55. doi: 10.1038/nn1166. Epub 2003 Dec 14.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): May 1, 2024

Study Registration Dates

• First Submitted: November 20, 2014
• First Submitted That Met QC Criteria: December 23, 2014
• First Posted (Estimated): December 24, 2014

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: breathing; walking; strength; acute intermittent hypoxia; incomplete spinal cord injury
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Trauma, Nervous System; Spinal Cord Diseases; Spinal Cord Injuries
• Other Study ID Numbers: 2017P001940a; 1R01HD081274-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes