Effects of Remote Ischemic Conditioning on Hand Use in Individuals With Spinal Cord Injury and Amyotrophic Lateral Sclerosis
Condition: Spinal Cord Injuries; Amyotrophic Lateral Sclerosis
MeSH terms: Spinal Cord Injuries; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Wounds and Injuries
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Active Remote Ischemic Conditioning; Sham Remote Ischemic Conditioning; Isometric hand exercise
Intervention type(s): Other; Other; Other
Intervention description(s): 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.; 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.; 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.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Remote ischemic conditioning; Neuroplasticity; transcranial magnetic stimulation