AIH for Spinal Cord Repair

February 13, 2024 updated by: VA Office of Research and Development

Repetitive Acute Intermittent Hypoxia for Spinal Cord Repair

Contusive cervical spinal cord injury (cSCI) impairs upper limb function (reach-and-grasp) which limits daily-life activities and thus decreases the quality of life. Promoting neuroplasticity may support upper limb recovery after SCI. Repetitive exposure to acute intermittent hypoxia (rAIH) combined with motor training promotes recovery of motor function after SCI; however, the overall effects of rAIH/training are limited. The investigators will use an adult rat model of long-term contusive cSCI to study novel approaches to enhance the effect of rAIH/training on forelimb function and study the neuronal substrate underlying the effects. The findings will be used to direct the development of more effective rAIH/training approaches for people with contusive, functionally incomplete, cSCI. Because deficits in upper limb function are a major problem after stroke, amyotrophic lateral sclerosis, multiple sclerosis, and other motor disorders, this work may also be relevant for patients with other types of central nervous system (CNS) lesions.

Study Overview

Detailed Description

The overall goal is to develop effective, clinically applicable, approaches to restore upper limb function (reach-and-grasp) after chronic contusive cervical spinal cord injury (cSCI). Impairments in upper limb function significantly reduce the quality of life for people with cSCI. Reach-and-grasp actions in animals and humans are largely controlled by the corticospinal tract (CST). The investigators argue that promoting plasticity within the CST may support the recovery of upper limb function after cSCI. Repetitive exposure to acute intermittent hypoxia (rAIH) combined with motor training is a safe, minimally invasive, treatment that elicits neuroplasticity resulting in improved recovery after cSCI, but its overall effects remain limited. The main goals are to: 1) enhance rAIH/training-induced aftereffects on forelimb function and increase the understanding of the neuronal substrates in an adult rat model of chronic contusive cSCI, and 2) use this knowledge to guide the development of more effective rAIH/training approaches to improve upper limb function in humans with chronic contusive cSCI.

In Specific Aim 1, using an adult rat model of chronic contusive cSCI, the investigators will investigate the effects of rAIH frequency and dose on rAIH/training-mediated functional recovery of the impaired forelimb. Also, the investigators will combine rAIH/training with N-methyl-D-aspartate receptor (NMDA)-mediated synaptic plasticity through D-cycloserine treatment and study the effects on recovery of forelimb function. Immunocytochemistry with imaging techniques will be used to assess structural neuronal plasticity in the CST after rAIH/training. In Specific Aim 2, in people with chronic incomplete cSCI, guided by the findings in Specific Aim 1, the investigators will study the effects of rAIH frequency and concurrent D-cycloserine treatment on rAIH/training-mediated upper limb function recovery. The investigators will comprehensively analyze the effects of rAIH on the strength of electrophysiological and functional aftereffects in the upper limb.

The proposed research will provide new knowledge on rAIH/training-mediated functional and anatomical aftereffects (Specific Aim 1), which will be used to develop effective rAIH/training protocols for people with contusive, functionally incomplete, cSCI (Specific Aim 2). The data from the investigators' experiments may lead to clinically applicable approaches that improve arm and hand function recovery after chronic contusive cSCI, which would positively impact the quality of life of Veterans with cSCI. The relevance of this proposal is emphasized by the limited efficacy of current strategies to improve upper limb function after cSCI.

Study Type

Interventional

Enrollment (Estimated)

90

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Illinois
      • Hines, Illinois, United States, 60141-3030
        • Recruiting
        • Edward Hines Jr. VA Hospital, Hines, IL
        • Principal Investigator:
          • Martin Oudega, PhD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Male and females Veterans between 18-85 years
  • Chronic cSCI (1 yr of injury)
  • Cervical injury at C8 or above
  • Sensory function: impaired (score of 1) but not absent (score of 0) or intact (score of 2) innervations in dermatomes C6, C7 and C8 during light touch and pin prick stimulus using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) sensory scores
  • Motor function: Able to grasp small objects with one hand and able to perform a visible precision grasp between the index finger and thumb
  • Motor scores ISNCSCI: 1 to 4 but not 5 on finger flexors and finger abductors on the hand tested.

    • These criteria were selected to ensure that hand impairment will not interfere with the ability to perform training and proposed tests

Inclusion criteria for controls:

  • Male and females (18-80 years)
  • Right handed
  • Able to complete precision and power grips

Exclusion Criteria:

  • Uncontrolled medical problems including pulmonary, cardiovascular or orthopedic disease
  • Any debilitating disease prior to the SCI that caused exercise intolerance
  • Premorbid, ongoing major depression or psychosis, altered cognitive status
  • History of head injury or stroke
  • Metal plate in skull
  • History of seizures
  • Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold such as antipsychotic drugs

    • chlorpromazine
    • clozapine
    • or tricyclic antidepressants
  • Pregnant females
  • Ongoing cord compression or a syrinx in the spinal cord or who suffer from a spinal cord disease as spinal stenosis, spina bifida or herniated cervical disk
  • AIH Exclusion Criteria (in addition to the above listed exclusion criteria):

    • resting heart rate > 120 bpm
    • resting systolic blood pressure >180 mmHg
    • resting diastolic blood pressure >100 mmHg
    • self-reported history of unstable angina or myocardial infarction within the previous month
    • resting SpO2 > or equal to 95%
    • cardiopulmonary complications such as COPD

Exclusion criteria for healthy controls:

  • Same as for SCI individuals

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: hypoxia plus training
combined hypoxia treatment with exercise training
intermittent cycles of normoxia-hypoxia
bimanual massed practice training
Sham Comparator: sham hypoxia plus training
combined sham hypoxia treatment with exercise training
bimanual massed practice training
intermittent cycles of sham hypoxia
Experimental: hypoxia plus training plus NMDA agonist
combined hypoxia treatment with exercise training and with NMDA agonist treatment
intermittent cycles of normoxia-hypoxia
bimanual massed practice training
NMDA agonist treatment
Other Names:
  • NMDA agonist
Placebo Comparator: hypoxia plus training plus sham NMDA agonist
combined hypoxia treatment with exercise training and with sham NMDA agonist treatment
intermittent cycles of normoxia-hypoxia
bimanual massed practice training
sham-NMDA agonist treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in grip strength
Time Frame: baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week
Grip strength will be measured using a hand-held dynamometer, with an average force (measured in dynes) taken over the course of three trials. A rest break is provided between trials. Strength testing will be completed bilaterally.
baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week
Change in pinch strength
Time Frame: baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week
Pinch strength will be assessed using a digital pinch gauge (unit of Force= Newton). The minimum value of zero will be assigned when a participant cannot actively squeeze the pinch meter between the thumb and index finger. The mean value of total of 3 trials will be assessed, with a rest break provided between trials.
baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week
Change in motor evoked potential size
Time Frame: 30 minutes before and 30 minutes after intervention
Resting and active motor thresholds (RMT and AMT) will be tested in each of the muscles using a stimulator.
30 minutes before and 30 minutes after intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Martin Oudega, PhD, Edward Hines Jr. VA Hospital, Hines, IL

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 25, 2020

Primary Completion (Estimated)

February 10, 2025

Study Completion (Estimated)

February 10, 2025

Study Registration Dates

First Submitted

December 12, 2018

First Submitted That Met QC Criteria

December 17, 2018

First Posted (Actual)

December 19, 2018

Study Record Updates

Last Update Posted (Actual)

February 15, 2024

Last Update Submitted That Met QC Criteria

February 13, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on SCI

Clinical Trials on hypoxia

3
Subscribe