Peripheral Modulation of Muscle Stiffness and Spasticity

肌肉僵硬和痉挛的外周调节

• 批准号: 9462460
• 负责人: PREETI RAGHAVAN
• 金额: $ 25.32万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9462460
• 关键词: Adverse effects; Affect; Articular Range of Motion; Behavioral; Cerebrum; Charge; Connective Tissue; Contracture; Data; Double-Blind Method; Dyskinetic syndrome; Economic Burden; Elbow joint structure; Enzymes; Extracellular Matrix; FDA approved; Fascicle; Fibrosis; Glycosaminoglycans; Goals; Health Care Costs; Human; Hyaluronan; Hyaluronidase; Individual; Injection of therapeutic agent; Injury; Intramuscular; Intramuscular Injections; Isometric Exercise; Joints; Label; Lead; Left; Limb structure; Lubricants; Magnetic Resonance Imaging; Measures; Mediating; Membrane Potentials; Mission; Molecular Weight; Motor; Movement; Muscle; Muscle Contraction; Muscle Development; Muscle Fatigue; Muscle Fibers; Muscle Spasticity; Muscle Weakness; Muscular Atrophy; Nervous System Trauma; Normal saline; Outcome; Paralysed; Paresis; Participant; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Physiological; Placebos; Play; Polymers; Polysaccharides; Positioning Attribute; Posture; Protons; Public Health; Recombinants; Recovery of Function; Reflex action; Relaxation; Research; Resistance; Rest; Role; Rotation; Scientific Advances and Accomplishments; Sedation procedure; Slide; Spastic; Spinal; Spinal Cord; Stretching; Stroke; Tendon structure; Testing; Therapeutic; Time; Tissues; Triceps Brachii Muscle; Ultrasonography; United States National Institutes of Health; Upper Extremity; Viscosity; Visit; Wolves; arm; arm function; biceps brachii muscle; blind; central nervous system injury; disability; disability burden; efficacy testing; elastography; improved; mechanical properties; motor impairment; motor recovery; muscle stiffness; muscle strength; neuromechanism; novel; post stroke; randomized placebo controlled trial; relating to nervous system; response; soft tissue; spasticity; stretch reflex; transmission process

Upper limb muscle stiffness and spasticity after stroke are associated with reduced functional independence and a significant increase in health care costs. If left untreated, it leads to joint contractures, further disability, and increases the economic burden. Spasticity develops as a result of central nervous system injury, which leads to a velocity-dependent increase in stretch reflexes because of decreased cortical influence on the spinal cord. However, secondary changes within the muscles and connective tissue also contribute to muscle stiffness that increase the passive resistance to stretch. The precise non-neural mechanisms and their interaction with neural mechanisms are not well understood, and there are currently no approved medications for treatment of changes in muscle mechanical properties. We proposed the hyaluronan hypothesis, which postulates that the accumulation of hyaluronan within the extracellular matrix (ECM) of muscles promotes the development of muscle stiffness. Hyaluronan is a high molecular weight glycosaminoglycan (GAG) that acts as a lubricant to facilitate intramuscular and intermuscular sliding under physiological conditions. However, when its concentration is increased because of paresis and reduced mobility, it aggregates and makes the ECM hyper-viscous, which can lead to decreased sliding of the muscle fibers and fascicles, muscle shortening, and increased muscle stiffness. Untreated, the increased concentration of hyaluronan can lead to subsequent fibrosis and contracture. We have found that intramuscular injections of the FDA-approved enzyme hyaluronidase, which hydrolyzes long-chained hyaluronan polymers to smaller polymers, can reduce muscle stiffness and increase passive and active range of motion in patients with moderately-severe upper limb spasticity within a few days. Importantly, this effect persists for at least 3 months. These results suggest that reducing muscle hyaluronan concentrations with hyaluronidase is a feasible treatment for muscle stiffness. We now propose to identify the potential mechanisms and test the efficacy of using human recombinant hyaluronidase for treating muscle stiffness. Our central hypothesis is that hyaluronidase will enhance upper limb motor outcomes by modulating peripheral non-neural mechanisms, and reducing the GAG content and viscosity in muscles. We will conduct a proof-of-principle double-blind, randomized, placebo-controlled trial of human recombinant hyaluronidase injections in patients with post-stroke upper limb muscle stiffness to test this hypothesis. The specific aims are to: test the effect of hyaluronidase on upper limb motor outcomes (Aim 1); evaluate the effect of hyaluronidase on neural and non-neural components of muscle stiffness (Aim 2); and elucidate the effect of hyaluronidase on intramuscular GAG content quantified non-invasively by proton T1ρ relaxation mapping on muscle MRI (Aim 3). At its conclusion, this study will provide mechanistic and behavioral evidence for a novel, practical, and potentially transforming approach to treat muscle stiffness and reduce the burden of disability after neurological injury.

中风后上肢肌肉僵硬和痉挛与功能减退有关 独立性和医疗保健费用的大幅增加。如果不治疗，会导致关节挛缩， 这会加重残疾，增加经济负担。痉挛的发展是由于中枢神经系统 损伤，由于皮质影响减少，导致牵张反射的速度依赖性增加 在脊髓上。然而，肌肉和结缔组织内的继发性变化也有助于 肌肉僵硬，增加了对拉伸的被动阻力。精确的非神经机制及其 与神经机制的相互作用还不清楚，目前还没有批准的药物 用于治疗肌肉机械性能的变化。我们提出了透明质酸假说， 假设透明质酸在肌肉细胞外基质（ECM）中的积累促进了肌肉的生长， 肌肉僵硬的发展。Hybryonan是一种高分子量糖胺聚糖（GAG）， 在生理条件下促进肌肉内和肌肉间滑动的润滑剂。然而当 它的浓度增加，因为轻瘫和减少流动性，它聚集，使ECM 高粘性，这可能导致肌肉纤维和肌束的滑动减少，肌肉缩短，以及 增加肌肉僵硬。未经治疗，透明质酸浓度的增加可导致随后的 纤维化和挛缩。我们发现肌内注射FDA批准的酶 透明质酸酶能将长链透明质酸聚合物水解成较小的聚合物， 中重度上肢僵硬度及主、被动活动度增加 几天之内就会痉挛重要的是，这种影响至少持续3个月。这些结果表明 用透明质酸酶降低肌肉透明质酸浓度是治疗肌肉僵硬的可行方法。我们 现在建议鉴定潜在的机制并测试使用人重组 透明质酸酶用于治疗肌肉僵硬。我们的中心假设是透明质酸酶将增强上 通过调节外周非神经机制和降低GAG含量， 肌肉中的粘性。我们将进行一项双盲、随机、安慰剂对照试验， 在中风后上肢肌肉僵硬的患者中注射人重组透明质酸酶来测试这一点 假说.具体目的是：测试透明质酸酶对上肢运动结果的影响（目的1）; 评价透明质酸酶对肌肉僵硬的神经和非神经成分的影响（目的2）;以及 阐明透明质酸酶对通过质子T1ρ非侵入性定量的肌内GAG含量的影响 肌肉MRI弛豫映射（目的3）。在其结论，本研究将提供机制和行为 一种新的、实用的和潜在的治疗肌肉僵硬和减少肌肉僵硬的方法的证据。 神经损伤后的残疾负担。