Blood Flow Regulation and Neuromuscular Function Post-Stroke

中风后的血流调节和神经肌肉功能

• 批准号: 10751266
• 负责人: Matthew Durand
• 金额: $ 67.31万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751266
• 关键词: Acetylcholine; Activities of Daily Living; Acute; Affect; Age; Area; Beds; Biological Availability; Blood Vessels; Blood flow; Clinical; Clinical Trials; Complex; Data; Double-Blind Method; Equilibrium; Exercise; Exposure to; Fatigue; Hyperemia; Impairment; Individual; Intervention; Ischemia; Leg; Lower Extremity; Mediating; Metabolic; Modality; Motor; Motor Neurons; Muscle; Muscle Contraction; Muscle Fatigue; Muscle Weakness; Nerve; Neural Inhibition; Neurologic; Nitric Oxide; Norepinephrine; Oxygen; Paresis; Performance; Perfusion; Persons; Play; Process; Randomized; Regulation; Rehabilitation therapy; Resistance; Rest; Role; Skeletal Muscle; Stimulus; Stroke; Sympathetic Nervous System; Testing; Tissues; Training; Vascular Endothelium; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Walking; Work; chronic stroke; functional disability; functional gain; improved; interest; ischemic conditioning; leg paresis; motor deficit; negative affect; neural; neuromuscular; neuromuscular function; post stroke; rehabilitation strategy; response; sex; stroke survivor; vasoconstriction

Increased neuromuscular fatigability (the acute, exercise induced reduction in force) is an understudied consequence of stroke. This is a clinically meaningful area of study because increased neuromuscular fatigability can negatively affect task endurance for activities like walking, and successful rehabilitation strategies require repeated levels of muscle activation and overload to cause functional gains in motor performance. In addition to decreased neural drive to motorneuron pools, recent data indicate that reduced blood flow to exercising paretic muscle may play a significant role in increased neuromuscular fatigability. Exercising muscles require adequate blood flow to match the increase in metabolic demand, and we have shown that stroke survivors have reduced blood flow to the leg muscles during exercise. During exercise, sympathetic nervous system activity increases in an activity-dependent manner, causing vasoconstriction in inactive muscle beds. In the active muscle, the release of local vasodilatory factors counteracts sympathetic vasoconstriction to maintain vascular tone. This process, called functional sympatholysis, has been postulated to be critical to muscle perfusion during exercise. Our central hypothesis is that in people with stroke functional sympatholysis is impaired and results in dysregulated blood flow during exercise, which exacerbates neuromuscular fatigability and limits motor function. We propose three specific aims. In Aim 1 we will establish impaired functional sympatholysis in chronic stroke survivors and determine the relationship with metrics of neuromuscular fatigue. We will test two hypotheses in Aim 1: 1) that functional sympatholysis during exercise is impaired in the paretic leg of chronic stroke survivors compared to the non-paretic leg and age- and sex-matched controls, and 2) stroke survivors with the highest degree of functional sympatholysis impairment will have greater paretic leg muscle fatigability, and both impaired modulation of motor unit firing rates and increased metabolite buildup in the muscle during exercise. In Aim 2 we will interrogate microvascular (dys)function in the lower extremity of chronic stroke survivors. We will test two hypotheses in Aim 2: 1) that compared age- and sex-matched controls, chronic stroke survivors will have reduced nitric oxide-mediated vasodilation to acetylcholine and an enhanced vasoconstrictor response to locally infused norepinephrine, and 2) that maximum dilation to acetylcholine in the affected leg will be positively associated with lower paretic muscle fatigability. Finally, in Aim 3 we will determine if a non-invasive intervention called ischemic conditioning (IC), which is known to improve muscle performance and vascular endothelial function, can improve functional sympatholysis, and if improvements in functional sympatholysis are associated with reduced paretic muscle fatigability. We will test two hypotheses in Aim 3: 1) that IC causes immediate and sustainable improvements in functional sympatholysis, and 2) that IC-induced improvements in functional sympatholysis are associated with improved muscle fatigue resistance, and both greater modulation of motor unit firing rates and less muscle metabolite buildup during fatiguing contractions.

神经肌肉疲劳性增加（运动引起的力的急性减少）是一个尚未得到充分研究的问题 中风的后果。这是一个具有临床意义的研究领域，因为神经肌肉的增加 疲劳会对步行等活动的任务耐力和成功的康复策略产生负面影响 需要重复水平的肌肉激活和超负荷才能导致运动表现的功能增益。在 除了运动神经元池的神经驱动力下降之外，最近的数据表明，流向运动神经元池的血流量减少 锻炼瘫痪肌肉可能在增加神经肌肉疲劳性方面发挥重要作用。锻炼肌肉 需要足够的血流量来匹配代谢需求的增加，我们已经证明中风 幸存者在运动时减少了腿部肌肉的血流量。运动时，交感神经 系统活动以活动依赖性方式增加，导致不活动的肌肉床血管收缩。在 活跃的肌肉，释放局部血管舒张因子抵消交感血管收缩以维持 血管张力。这个过程被称为功能性交感神经溶解，被认为对肌肉至关重要 运动时的灌注。我们的中心假设是，中风患者的交感神经功能是 受损并导致运动期间血流失调，从而加剧神经肌肉疲劳 并限制运动功能。我们提出三个具体目标。在目标 1 中，我们将建立受损的功能 慢性中风幸存者的交感神经并确定与神经肌肉疲劳指标的关系。 我们将在目标 1 中测试两个假设：1）运动期间的功能性交感神经在瘫痪患者中受损 慢性中风幸存者的腿与非麻痹腿以及年龄和性别匹配的对照组相比，以及 2) 中风 功能性交感神经损伤最严重的幸存者将有更大的瘫痪腿部肌肉 疲劳性，运动单位放电率调节受损和肌肉中代谢物积累增加 运动期间。在目标 2 中，我们将探讨慢性中风下肢的微血管（功能障碍）功能 幸存者。我们将测试目标 2 中的两个假设：1) 比较年龄和性别匹配的对照、慢性中风 幸存者将减少一氧化氮介导的乙酰胆碱血管舒张作用和增强的血管收缩作用 对局部输注去甲肾上腺素的反应，以及 2) 受影响腿部对乙酰胆碱的最大扩张将 与较低的麻痹性肌肉疲劳度呈正相关。最后，在目标 3 中，我们将确定是否采用非侵入性方法 称为缺血调节（IC）的干预措施，已知可以改善肌肉性能和血管 内皮功能，可以改善功能性交感神经，如果功能性交感神经的改善 与减少麻痹性肌肉疲劳有关。我们将测试目标 3 中的两个假设：1）IC 导致 功能性交感神经的立即和可持续的改善，以及 2) IC 引起的改善 功能性交感神经与改善的肌肉抗疲劳能力以及更大的调节有关 运动单位放电率的降低和疲劳收缩期间肌肉代谢物积累的减少。