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（急性，运动诱导的力量减少）是研究的 中风的后果。这是一个临床上有意义的研究领域，因为神经肌肉增加 疲劳性可能会对步行和成功康复策略等活动等活动产生负面影响 需要重复水平的肌肉激活和过载以引起运动性能的功能增长。在 除了降低神经神经元池的神经驱动器外，最近的数据表明，血液流动降低 锻炼偏肌可能在增加神经肌肉疲劳性中起重要作用。锻炼肌肉 需要足够的血液流以符合代谢需求的增加，我们已经证明了中风 在运动过程中，幸存者的血液流向腿部肌肉。在锻炼过程中，交感神经 系统活性以活性依赖性的方式增加，从而导致无效肌肉床的血管收缩。在 活跃的肌肉，局部血管舒张因子的释放抵消了交感神经的血管收缩以维持 血管音。这个过程称为功能性交感解，已被认为对肌肉至关重要 运动过程中的灌注。我们的核心假设是，在中风的人中有交感神经解析是 锻炼过程中的受损并导致血流失调，这加剧了神经肌肉疲劳性 并限制运动功能。我们提出了三个具体目标。在AIM 1中，我们将建立功能受损 慢性中风幸存者中的交感解析，并确定与神经肌肉疲劳指标的关系。 我们将在目标1：1）中检验两个假设 与非幼稚的腿以及年龄和性别匹配的对照相比，慢性中风幸存者的腿和2）中风 功能性交感神经障碍最高的幸存者将具有更大的paret腿肌肉 疲劳性，并且均受损害运动单位发射速率的调节和肌肉中的代谢产物的增加 锻炼期间。在AIM 2中，我们将在慢性卒中下肢询问微血管（DYS）功能 幸存者。我们将在AIM 2：1）中测试两个假设，它们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血管舒张对乙酰胆碱和增强的血管收缩剂 对局部注入的去甲肾上腺素的反应，以及2）受影响腿中的最大扩张对乙酰胆碱的扩张将会 与较低的肌肉疲劳性呈正相关。最后，在AIM 3中，我们将确定是否无创 干预措施称为缺血条件（IC），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解，如果功能性交感解的改善是 与降低的肌肉疲劳性相关。我们将在AIM 3：1）中检验两个假设。 功能性交感解析的直接和可持续改进，以及2）IC引起的改进 功能性交感解论与改善肌肉疲劳性抗性有关，并且均更大的调节 在疲劳收缩期间，运动单位发射率和较少的肌肉代谢物积累。