Acute Intermittent Hypoxia and Body Weight Supported Treadmill Training for Incomplete Spinal Cord Injury Patients
Acute Intermittent Hypoxia and Body Weight Supported Treadmill Training: a Potential Therapy for Incomplete Spinal Cord Injury Patients
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Currently, there is no "cure" for spinal cord injuries (SCI). Although the scientific understanding of central nervous system (CNS) regeneration has advanced greatly in the past twenty years, there are still many unknowns with regard to inducing successful regeneration, especially with chronic SCI. A more realistic approach, based on currently available knowledge, to improve the quality of life for a large proportion of the paralyzed population may be to develop treatments that elicit partial functional recovery based on neuroplastic potential of spared neural pathways. In this scenario, acute intermittent hypoxia (AIH) enhances the inherit capacity for neuroplasticity and strengthens surviving synaptic inputs onto spinal motorneurons, which trigger functional recovery following SCI in rats and humans AIH-induced neuroplasticity has been extensively studied in phrenic motor nuclei (C3-C5) through phrenic nerve recording preparations (Mitchell, 2007). Briefly, moderate AIH (3, 5-min hypoxic episodes; PaO2 35-45 mmHg; 5-min intervals) elicits phrenic long term facilitation (pLTF), a type of memory present in the cervical spinal cord. The mechanism of AIH-induced pLTF is that episodic hypoxia activates raphe serotonergic neurons that project to phrenic motor nuclei. Spinal serotonin release during hypoxic episodes subsequently activates serotonin type 2 (5-HT2) receptors coupled to Gq protein on or near phrenic motor neurons, and initiates intracellular cascades that underlie pLTF . pLTF requires spinal 5-HT2 receptor activation , new synthesis of brain-derived neurotrophic factor (BDNF) and activation of its high-affinity receptor tyrosine kinase (TrkB) followed by ERK MAP kinase signaling. Although downstream signaling events from ERK are less clear, it is speculated that glutamate receptors are phosphorylated, increasing glutamatergic transmission and perhaps insertion within phrenic motor neurons, thereby establishing LTF.
Longer time domains of AIH, for example, daily acute intermittent hypoxia (i.e. dAIH, 10 episodes per day, 7 days) have shown to strengthen synaptic pathways to spinal motorneurons and increase respiratory and locomotor recovery after cervical SCI in unanesthetized rats. This functional improvement is accompanied by increased BDNF and TrkB levels within cervical (C7) motor nuclei innervating the forelimb. Although the detailed mechanisms of the functional recovery in somatic thoracic or lumbar motorneurons have not been verified, it has been proposed that the same serotonin-dependent mechanisms facilitate motor output in respiratory and non-respiratory motor nuclei.
The use of dAIH to improve limb function in humans with incomplete, chronic SCI has shown promising results. A single presentation of AIH (15, 1-minute episodes of 9% O2 alternating with 1-minute of 21% O2) in incomplete, chronic (>1 year) spinal cord injury patients, classified as C or D according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), increases the ability to voluntarily generate plantar flexion 4 h post-hypoxia. In a randomized, double-blind, placebo-controlled, crossover design study, the impact of daily AIH (15 episodes per day, 90 sec 9% O2, 60 sec normoxic interval, 5 consecutive days) combined with walking training was studied in 19 chronic, incomplete SCI patients (ISNCSCI D). Daily AIH alone increased walking speed 18% three days after treatment (10 m walk test); whereas dAIH combined with walking training improved both walking speed and distance (37%) after 5 days and 1 week post-dAIH. Importantly, no changes in cognitive function was observed after dAIH, suggesting that this moderate dose of AIH is safe in humans.
Although dAIH (5 consecutive days of AIH) has demonstrated beneficial effects in incomplete SCI patients, its effect last only up to one week; therefore, is important to design extended protocols maintaining the initial functional effect of dAIH over time. Repetitive AIH (rAIH) consisting of AIH three times per week (3×wAIH) for 10 weeks have demonstrated to increase respiratory function and maintain the increased functional effect elicited by dAIH in unanesthetized rats. Moreover, rAIH increases the expression of key molecules involved in AIH-induced spinal plasticity in unanesthetized rats. Therefore, repetitive AIH may represent a safe and effective strategy to enhance functional recovery after chronic incomplete spinal cord injuries.
The protocol of intermittent hypoxia proposed in this project corresponds to a moderate dose of intermittent hypoxia, which is the equivalent of climbing a mountain at 5000 meters altitude. Abundant literature has demonstrated that moderate AIH (≥ 9% O2, < 15 cycles/day) have several multi-systemic beneficial effects: reduces arterial hypertension, strengthens innate immune responses, reduces inflammation, reduces body weight, increases aerobic capacity, improves glucose tolerance, increases bone mineral density, enhances spatial learning and memory, rescues ischemia-induced memory impairment, reduces symptoms of depression, improves post-ischemic recovery of myocardial contractile function, and increases respiratory capacity in chronic obstructive pulmonary disease. Moreover, moderate repetitive AIH improves respiratory and somatic function after SCI, without adverse consequences such as hypertension, neuronal cell loss and/or reactive gliosis or systemic inflammation. Therefore, the potential beneficial effects of AIH are not only limited to spinal cord injuries but include a wide scope of clinical conditions.
Combinatorial therapies, one of them being an activity-based training, can augment plasticity after incomplete SCI. In rats with incomplete SCI, dAIH combined with ladder walking leads to near complete recovery of ladder walking ability. Moreover, dAIH and overground walking improve walking speed and distance in incomplete SCI patients ISNCSCI D. Research studies in animals and humans have found that retraining after SCI using the intrinsic physiologic properties of the nervous system can facilitate the recovery of function. This potential for retraining is based on activity-dependent plasticity driven by repetitive task-specific sensory input to spinal networks.
The most prominent and well-developed activity-based therapy (physical rehabilitation) to date is locomotor training. The fundamental principles of locomotor training are built on the premise of robustly approximating the sensorimotor experience of walking through repetitive practice including: 1) maximize load bearing by the lower extremities and minimize load bearing by the upper extremities, 2) optimize the sensory cues for walking, 3) optimize the kinematics (i.e., trunk and extremities) for each motor task, and 4) maximize recovery strategies and minimize compensatory mechanisms. The fundamental mechanisms supporting this intervention have been derived largely from studies conducted in spinalised animals. Specifically, treadmill training increases axonal regrowth and collateral sprouting proximal to the lesion site in mice (Goldshmit et al., 2008), phosphorylation of Erk1/2 in the motor cortex as well as the spinal cord injury area (Oh et al., 2009), expression of brain-derived neurotrophic factor (BDNF) in the spinal cord, ameliorates muscle atrophy in moderate contused SCI rats, and alters properties of spinal motor neurons. Body weight-supported treadmill training (BWSTT) is based on optimizing sensory inputs relevant to step training, repeated practice, and possible optimization of neuroplasticity. Uncontrolled studies in acute and chronic SCI patients show within-subject improvements in walking ability using BWSTT. Investigators propose that BWSTT therapy provide a behavioral therapy that independently supports positive outcomes.
AIH combined with body weight-assisted training represents a simple and safe, non-pharmacological method for enhancing neuroplasticity in the spinal cord and thus, improving walking function in patients with incomplete spinal cord injuries. At the cellular level, both BWSTT and AIH increase the expression of BDNF. BDNF has a wide repertoire of neurotrophic and neuroprotective properties in the CNS and the periphery; namely, neuronal protection and survival, neurite expression, axonal and dendritic growth and remodeling, neuronal differentiation and synaptic plasticity such as synaptogenesis in arborizing axon terminals, and synaptic transmission efficacy. Thus, BWSTT may serve as a catalyst in tandem with repetitive AIH that when combined develop an even better response.
Currently, there are no approved therapies for chronic SCI; therefore, the approach represents a promising new strategy to enhance function in patients with sub-acute and chronic SCI, where the potential for further functional gains is limited.
Investigators propose a triple blind (patients, outcome assessors and stadistician) randomized, placebo-controlled study testing the combined effect of intermittent hipoxia and body weight-supported treadmill training in incoplete spinal cord injury patients.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Santiago, Chile, 8320000.
- Instituto de Rehabilitación Infantil Teletón
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Metropolitana
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Santiago, Metropolitana, Chile, 9160000
- Hospital Mutual de Seguridad
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients ≥ 18 years-old from "Instituto Teletón Santiago" and "Hospital Clínico Mutual de seguridad".
- C5 to T12 spinal cord injury, classified as ISNCSCI grades C and D
- Traumatic and non-traumatic, non-progressive lesions
- Onset > 6 months
- Ability to ambulate with or without assistive devices
- Ability to follow verbal or visual commands
- Signed informed consent
Exclusion Criteria:
- Orthopedic injuries that are unstable
- Osteoporosis with high risk of pathological fracture
- Cutaneous lesions and/or pressure ulcers
- Joint contractures
- Cardiopulmonary diseases
- Body weight exceeding 150 Kg
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Experimental: Acute Intermittent Hypoxia Arm
AIH protocol: it consists of 15, 90-second hypoxic episodes (FiO2=0.09)
interspersed with 15, 90-second normoxic intervals (FiO2=0.21)
for a total time of 45 minutes.
This protocol will be repeated every day for 5 consecutive days and then 3 times per week for 3 weeks.
Total time: 4 weeks.
After this AIH protocol, patients will received body weight-assisted treadmill training (BWSTT) for 45 minutes.
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Patients will breath 9% oxigen for 1.5 minutes interspersed with 1.5 minutes of 21% oxigen (normoxia), 15 times for a total of 45 minutes.
Patient´s gait will be trained through a weight-assisted treadmill (BWSTT).
All recruited patients will start BWSTT at a speed of 0.6 km/hr.
The physical therapist will manually correct posture to assure an adequate gait, increasing the speed of treadmill progressively depending upon the patient progress and tolerance.
This training will be done immediately after the protocol of AIH or Sham and it will last 45 minutes.
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Placebo Comparator: Normoxia Arm
Sham protocol: it consists of continuous normoxia (FiO2=0.21)
for 45 minutes for 5 consecutive days and then 3 times per week for 3 weeks.
Total time: 4 weeks.After this AIH protocol, patients will received body weight-assisted treadmill training (BWSTT) for 45 minutes.
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Patient´s gait will be trained through a weight-assisted treadmill (BWSTT).
All recruited patients will start BWSTT at a speed of 0.6 km/hr.
The physical therapist will manually correct posture to assure an adequate gait, increasing the speed of treadmill progressively depending upon the patient progress and tolerance.
This training will be done immediately after the protocol of AIH or Sham and it will last 45 minutes.
It consists of continuous normoxia (FiO2=0.21)
for 45 minutes for 5 consecutive days and then 3 times per week for 3 weeks.
Total time: 4 weeks.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Gait Speed With 10-Meter Walk Test
Time Frame: Change from baseline in gait speed five days after daily IH.
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The 10-meter walk test measures the time (in seconds) that it takes a patient to walk 10m.
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Change from baseline in gait speed five days after daily IH.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Gait Endurance With the 6-Minute Walk Test
Time Frame: Change from baseline in gait indurance five days after daily IH.
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The 6-Minute Walk Test measures the distance (in meters) a patient is able to walk over 6 minutes.
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Change from baseline in gait indurance five days after daily IH.
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Gait Speed With the Timed up and go Test
Time Frame: Change from baseline in gait speed five days after daily IH.
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The timed up and go test measures the time (in seconds) it takes the patient to stand-up from a seated position in a chair, walk 3 meters at a comfortable and safe pace, turn, walk back to the chair and sit down.
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Change from baseline in gait speed five days after daily IH.
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Percentage of Subjects With Worsening Muscle Tone on the Ashworth Scale
Time Frame: Muscle tone at week 4.
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The Ashworth Scale assess muscle tone.
It is a 5-points scale ranging from 0 (no increase in muscle tone) to 4 (limb rigid in flexion or extension).
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Muscle tone at week 4.
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Percentage of Subjects With Worsening Pain Perception on the "The Visual Analog Test"
Time Frame: Pain perception at week 4
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The visual analog test assess general pain intensity.
It is a 10-score scale ranging from no pain (score 0) to unbearable pain (score 10).
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Pain perception at week 4
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Learning and Memory With the Rey-Osterrieth Complex Figure (ROCF) Test
Time Frame: Episodic visual memory at week 4.
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The ROCF is a neuropsychological instrument used for assessment of episodic visual memory. Z score ranges from -2 (worse outcome), -1, 0, 1 and 2 (best outcome). The normal population range is between -1 and 1. Z score was calculated with the following formula: Z score = (direct score-average for a particular age range)/standard deviation |
Episodic visual memory at week 4.
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Learning and Memory With the Complutense Verbal Learning Test (TAVEC)
Time Frame: Episodic verbal memory at week 4.
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The TAVEC is the Spanish version of the California Verbal Learning Test and is used for the assessment of episodic verbal memory. Z score ranges from -2 (worse outcome), -1, 0, 1 and 2 (best outcome). The normal population range is between -1 and 1. Z score was calculated with the following formula: Z score = (direct score-average for a particular age range)/standard deviation |
Episodic verbal memory at week 4.
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Angela A Navarrete-Opazo, MD, PhD, Instituto de Rehabilitación Infantil Teletón
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 0027
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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