Effects of Remote Ischemic Conditioning on Hand Use in Individuals With Spinal Cord Injury and Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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Rehabilitation interventions such as physical training and neural stimulation after spinal cord injury (SCI) have been shown to increase neural plasticity. However, both physical training and neural stimulation require a large number of repetitions, and the retention of the intervention effects may be fleeting. In this proposal the investigators will test Remote ischemic conditioning (RIC), which has been shown to promote neural plasticity and has practical and theoretical advantages. RIC consists of transiently restricting blood flow to any 'remote' limb using a blood pressure cuff. This induces several of the body's systemic defensive reactions. RIC has been shown to improve motor learning. The investigators propose that RIC alters motor pathway excitability through a combination of systemic increases in plasticity-promoting factors and inhibition of inflammatory factors. The investigators have designed a clinical trial to test this hypothesis in 8 persons with SCI and 8 able-bodied controls. All participants will receive active/sham RIC plus a hand exercise. The investigators will measure effects on blood pressure, motor neuron excitability, and systemic inflammatory markers before and after RIC as well as after hand exercise. Starting July 2021, we will also enroll 5 individuals with Amyotrophic lateral sclerosis (ALS) in this study.

Detailed Description
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Most spinal cord injuries (SCI) are not full transections, indicating that there are residual nerve circuits after injury. Rehabilitation interventions after SCI, including physical training and neural stimulation, have been shown to reorganize motor pathways in the brain, corticospinal tract (CST), and at the spinal level; a process called neural plasticity. Functional improvement due to neural plasticity after SCI could be from enhanced excitability of residual neural circuits, or axon sprouting which has been shown in animal studies. However, both physical training and neural stimulation require a large number of repetitions, and the retention of the intervention effects may be fleeting. Therefore, the need remains for an effective approach to synergistically improve neuroplasticity in combination with other interventions. Remote ischemic conditioning (RIC) has been shown to promote neural plasticity and may have practical and theoretical advantages, which include: 1) RIC requires minimal equipment, (a timer and a manual blood pressure device); and 2) RIC has been shown to promote Hypoxia-inducible factor 1a (HIF-1a) and anti-inflammatory mediators which possibly promote neuroplasticity. In fact, One recent study has demonstrated in able-bodied subjects that introducing RIC before a motor learning intervention had a greater and longer-lasting effect on improving motor performance compared to sham conditioning prior to motor learning. In this proposed study, the investigators will investigate RIC coupled with physical training to promote neuroplasticity in hand muscles after cervical SCI. This will be the first study to introduce RIC in SCI population. The investigators hypothesize that RIC will acutely synergize with motor task training via increasing corticospinal excitability. Identifying the underlying mechanisms responsible for increasing corticospinal excitability, such as 1) increased cortical firing, 2) strengthened synaptic transmission, 3) improved spinal motor neuron recruitment or 4) other mechanisms is an important step for promotion of functional recovery after neurological injury. Aim 1: To determine the effects of active versus sham RIC prior to one bout of muscle contraction exercise on motor corticospinal excitability at the abductor pollicis brevis (APB) muscle. The investigators will also assess intra-cortical facilitation/inhibition and peripheral nerve conduction profiles to localize the level of changes in corticospinal excitability. Aim 2: To investigate effects of active versus sham RIC on systemic inflammatory mediators in individuals with SCI. Individuals living with SCI often show signs of chronic inflammation and other aspects of dysregulated immune system function. Studies in able-bodied adults have shown that a single application of RIC can suppress inflammatory gene expression in circulating leukocytes 15 min and 24h later. Upregulation of inflammatory cytokines is associated with decreased expression of genes that promote neuroplasticity, such as BDNF. Here, the investigators will determine if RIC decreases systemic inflammation in persons with chronic SCI, as it does in able-bodied individuals, by measuring a subset of inflammatory mediators in the blood pre- and post-RIC. Aim 3: To determine changes in heart rate (HR), blood pressure (BP) and oxygen saturation (SaO2) during active versus sham RIC in individuals with incomplete cSCI and able-bodied subjects. RIC has been shown to be safe in the healthy population as well as in individuals with heart disease and even critically ill patients with subarachnoid hemorrhage. However, there are no data describing the safety of RIC in persons with SCI. Damage to the autonomic nervous system (ANS) contributes to cardiovascular dysregulation and may alter physiological responses to RIC. In addition, the SCI population, particularly those with cervical SCI, has widespread sensory impairment, including a limited ability to feel pain/discomfort. The investigators will not only real-time record HR, BP and SaO2 responses during RIC, but also document the pain scale and any adverse effects of RIC in individuals with cSCI and able-bodied subjects.

Official Title
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Effects of Remote Ischemic Conditioning on Hand Use in Individuals With Spinal Cord Injury and Amyotrophic Lateral Sclerosis: A Preliminary Study

Conditions
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Spinal Cord Injuries, Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Other: Active Remote Ischemic Conditioning
* Other: Sham Remote Ischemic Conditioning
* Other: Isometric hand exercise


Participation Criteria
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Eligibility Criteria
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Able-bodied participants Age between 18 and 75 years; No known central or peripheral neurological disease or injury. SCI participants Inclusion Criteria: Age between 18 and 75 years; Chronic (more than 12 months since injury) motor-incomplete SCI between neurological levels C2-C8 Detectable F-wave responses of the left or right abductor pollicis brevis (APB) to median nerve stimulation; Detectable motor evoked potentials in left or right APB muscles to transcranial magnetic stimulation; Able to perform thumb-middle finger opposition pinch task with detectable APB EMG muscle activity. ALS participants Age between 21 and 75 years; Diagnosis of probable or definite ALS. Incomplete weakness of left or right wrist or hand muscles: score of 2, 3, or 4 (out of 5) on manual muscle testing of finger extension, finger flexion, or finger abduction. Detectable motor evoked potentials in left or right APB muscles to transcranial magnetic stimulation; Able to perform thumb-middle finger opposition pinch task with detectable APB EMG muscle activity. Exclusion Criteria: Multiple spinal cord lesions; History of seizures; Use of medications that significantly lower seizure threshold, such as amphetamines and bupropion; History of implanted brain/spine/nerve stimulators, aneurysm clips, or cardiac pacemaker/defibrillator; Any extremity soft tissue, orthopedic, or vascular condition or injury that may contraindicate RLIC (uncontrolled hypertension, peripheral vascular disease, hematological disease, severe hepatic or renal dysfunction); Any other contraindication to undergoing magnetic resonance imaging (except for claustrophobia); Clinically significant infection of any kind (urinary tract, pulmonary, skin or other) Significant coronary artery or cardiac conduction disease; Open skin lesions over the neck, shoulders, or arms; Pregnancy Unsuitable for study participation as determined by study physician. In addition, a medical record review will be conducted to identify any other medical concerns that might increase the risks associated with participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active RIC + isometric hand exercise<br>Subjects will receive an active remote ischemic conditioning (200mmHg cuff pressure) before an active isometric hand exercise. | Other: Active Remote Ischemic Conditioning<br>* The active RIC protocol involves 5 cycles of 5-min inflation and 5-min deflation on the non-target arm. The active RIC will be achieved via blood pressure cuff inflation to 200 mmHg.<br>Other: Isometric hand exercise<br>* Participants will be instructed to pinch a dynamometer with thumb and index finger at different intensities and durations. The intensities of pinch force will be 10%, 25%, and 50% of the maximal voluntary contraction (MVC). For each intensity, durations of 2, 4, and 6 s will be employed, which resulted in nine different combinations delivered in pseudorandom order. Participants will perform 2 sets of the isometric hand exercise (18 pinches in total). The interval between each pinch will be 2 seconds, with 30 second intervals between each set.<br>|
| Sham Comparator: Sham RIC + isometric hand exercise<br>Subjects will receive an sham remote ischemic conditioning (10 mmHg below the subjects' diastolic blood pressure) before an active isometric hand exercise. | Other: Sham Remote Ischemic Conditioning<br>* The sham RIC protocol involves 5 cycles of 5-min inflation and 5-min deflation on the non-target arm. The sham RIC will be achieved via blood pressure cuff inflation to 10 mmHg below the subjects' diastolic blood pressure which would not cause the blood occlusion.<br>Other: Isometric hand exercise<br>* Participants will be instructed to pinch a dynamometer with thumb and index finger at different intensities and durations. The intensities of pinch force will be 10%, 25%, and 50% of the maximal voluntary contraction (MVC). For each intensity, durations of 2, 4, and 6 s will be employed, which resulted in nine different combinations delivered in pseudorandom order. Participants will perform 2 sets of the isometric hand exercise (18 pinches in total). The interval between each pinch will be 2 seconds, with 30 second intervals between each set.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of Electromyographic responses after RIC plus hand isometric exercise | Response to electrical and magnetic stimulation will be measured via peak-to-peak amplitude (millivolts) in abductor pollicis brevis and first dorsal interosseous muscles. The changes of the electromyographic responses will be measured immediately after active/sham RIC plus isometric hand exercise in comparison with baseline measurement. The purpose is to investigate the synergic effects of RIC on hand isometric exercise. | Change in peak-to-peak amplitude between baseline measurement and immediately after completion of RIC plus isometric hand exercise. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of Electromyographic responses after RIC but before hand isometric exercise | Response to electrical and magnetic stimulation will be measured via peak-to-peak amplitude (millivolts) in abductor pollicis brevis and first dorsal interosseous muscles. The changes of the electromyographic responses will be measured immediately after active/sham RIC but before isometric hand exercise in comparison with baseline measurement. The purpose is to investigate whether RIC alone could change electromyographic responses. | Change in peak-to-peak amplitude between baseline measurement and immediately after completion of RIC. | 
| Changes of Electromyographic responses 15 mins after RIC plus hand isometric exercise | Response to electrical and magnetic stimulation will be measured via peak-to-peak amplitude (millivolts) in abductor pollicis brevis and first dorsal interosseous muscles. The changes of the electromyographic responses will be measured 15 mins after active/sham RIC plus isometric hand exercise in comparison with the measurement immediately after active/sham RIC plus isometric hand exercise. The purpose is to investigate whether the changes of electromyographic responses would last 15 mins. | Change in peak-to-peak amplitude between immediately after completion of RIC plus isometric hand exercise and 15 mins after completion of RIC plus isometric hand exercise. | 
| Inflammatory mediators: the intensity of the gene expression of Toll-like receptor (TLR) signal pathway. | The blood samples will be collected before and after RIC to analyze on the changes of inflammatory mediators on the intensity of the gene expression related to Toll-like receptor (TLR) signal pathway. | Change in mediator level between baseline measurement and immediately after completion of RIC. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remote ischemic conditioning, Neuroplasticity, transcranial magnetic stimulation