Effects of Remote Ischemic Conditioning on Hand Use in Individuals With SCI and ALS

Overview

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.

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 brain-derived neurotrophic factor (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 cervical SCI 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 cervical SCI and able-bodied subjects.