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.

增加神经肌肉的疲劳性(急性运动导致的力量减少)是一个研究较少的问题。 中风的后果。这是一个有临床意义的研究领域，因为增加了神经肌肉 疲劳感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，才能导致运动能力的功能性提高。在……里面 除了运动神经元池的神经驱动力减少外，最近的数据表明， 锻炼偏瘫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，我们已经证明了中风 幸存者在运动过程中减少了腿部肌肉的血流量。在运动中，交感神经紧张 系统活动以依赖活动的方式增加，导致非活动肌肉床的血管收缩。在……里面 活跃的肌肉，局部血管扩张因子的释放抵消交感神经血管收缩的维持 血管张力。这一过程被称为功能性交感神经溶解，一直被认为对肌肉至关重要 在运动过程中进行灌流。我们的中心假设是，在中风患者中，功能性交感神经松解症是 在运动中受损并导致血流失调，从而加剧神经肌肉的疲劳性 并限制运动功能。我们提出了三个具体目标。在目标1中，我们将建立受损的功能 慢性卒中存活者的交感神经溶解，并确定与神经肌肉疲劳指标的关系。 我们将验证目标1：1中的两个假设，即运动中的功能性交感神经溶解在偏瘫患者中受到损害 慢性中风幸存者的小腿与非瘫痪小腿以及年龄和性别匹配的对照组进行比较，以及2)中风 功能性交感神经损害程度最高的幸存者将有更多的瘫痪腿部肌肉 疲劳性，以及运动单位放电率的调节和肌肉中代谢物积聚的增加 在锻炼的时候。在目标2中，我们将询问慢性卒中患者肢体的微血管功能。 幸存者。我们将测试目标2：1中的两个假设，将年龄和性别匹配的对照组、慢性中风 幸存者将减少一氧化氮介导的血管扩张为乙酰胆碱和增强的血管收缩 对局部注射去甲肾上腺素的反应，以及2)受影响腿对乙酰胆碱的最大扩张将 与较低的瘫痪肌肉疲劳性呈正相关。最后，在目标3中，我们将确定非侵入性 被称为缺血调节(IC)的干预措施，众所周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溶解，如果功能性交感神经溶解的改善 与瘫痪肌肉的疲劳性降低有关。我们将在目标3：1)中测试IC导致的两个假设 立即和可持续的改善功能性交感神经溶解，以及2)IC诱导的 功能性交感神经溶解与肌肉疲劳抵抗力的提高有关，两者都有更大的调制作用 运动性收缩时运动单位的发射率和较少的肌肉代谢物积聚。