Monoaminergic Drive and Discoordination Following Stroke

中风后的单胺能驱动和协调障碍

• 批准号: 6969687
• 负责人: JULIUS P DEWALD
• 金额: $ 30.46万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969687
• 关键词: alpha adrenergic agent; alpha adrenergic receptor; amines; biological signal transduction; body movement; clinical research; clinical trials; clonidine; data collection methodology /evaluation; electromyography; human subject; human therapy evaluation; joints; medical complication; motor neurons; muscle relaxants; neuromuscular disorder chemotherapy; neurotransmitter antagonist; norepinephrine; outcomes research; reflex disorder; spinal reflex; stroke; stroke therapy

DESCRIPTION (provided by applicant): Movement discoordination following stroke is caused by the emergence of stereotypic multi-joint movement patterns, reflecting a loss of independent joint control, and hyperactivity of spinal reflexes including the stretch reflex (spasticity) and the flexion withdrawal reflex. The commonality between the emergence of abnormal synergies and spinal reflex hyperexcitability following stroke is postulated to arise from an increased bulbospinal monoaminergic drive to the spinal cord following a loss of corticospinal and corticobulbar projections. Evidence for increased bulbospinal input include increased motoneuron excitability, depressed short latency and enhanced long latency flexion reflexes, and a diminished capacity for selective movement due to the emergence of stereotypic synergic movement patterns. We propose to examine the effect of an increased bulbospinal monoaminergic drive on the expression of abnormal movement patterns and spinal reflexes following stroke by manipulating the neural excitability at the spinal cord and/or brainstem using either Tizanidine (TIZ) or Tamsulosin (TAM). It is our intention to: 1) identify and quantify the presence of increased noradrenergic input to the spinal cord following a stroke; 2) elucidate mechanisms underlying hyperactive flexion and stretch reflexes following stroke; 3) investigate the role of monoaminergic pathways in the expression of abnormal muscle and torque synergies under isometric and dynamic conditions in the paretic upper limb following stroke. We predict that inhibition of brainstem monoaminergic pathways as well as group II and high threshold afferents at the cord, through administration of a noradrenergic (NE) a-2 agonist (TIZ), will result in the reduction of discoordination, flexion reflexes and spasticity in individuals with stroke. We also predict that reduction of NE mediated excitation of motoneurons, through the administration of a selective NE a-1 antagonist (TAM), will result in the reduction of volitional strength, spasticity, and magnitude of the flexion reflex. Upper extremity discoordination is expected to remain unaltered by the administration of TAM because of its lack of supraspinal effects. The knowledge generated by this study seeks to reveal the primary mechanisms underlying the presence of discoordination and hyperactive spinal reflexes following stroke. The identification of these mechanisms may direct the development of novel pharmacological agents that target bulbospinal mechanisms underpinning upper extremity discoordination

描述（申请人提供）：中风后的运动不协调是由刻板的多关节运动模式的出现引起的，反映了独立关节控制的丧失，以及脊髓反射的过度活跃，包括牵张反射（痉挛）和屈曲撤回反射。中风后出现异常协同作用和脊髓反射过度兴奋之间的共同点被认为是由于皮质脊髓和皮质延髓投射丧失后球脊髓单胺能对脊髓的驱动增加而引起的。球脊髓输入增加的证据包括运动神经元兴奋性增加、短潜伏期抑制和长潜伏期屈曲反射增强，以及由于刻板协同运动模式的出现而导致选择性运动能力减弱。我们建议通过使用替扎尼定（TIZ）或坦索罗辛（TAM）操纵脊髓和/或脑干的神经兴奋性来检查球脊髓单胺能驱动增加对中风后异常运动模式和脊髓反射表达的影响。我们的目的是：1）识别并量化中风后脊髓去甲肾上腺素能输入增加的情况； 2）阐明中风后屈曲和牵张反射过度活跃的机制； 3）研究单胺能通路在中风后瘫痪上肢等长和动态条件下异常肌肉和扭矩协同表达中的作用。我们预测，通过给予去甲肾上腺素能 (NE) a-2 激动剂 (TIZ)，抑制脑干单胺能通路以及 II 组和高阈值传入神经，将导致患者的不协调、屈曲反射和痉挛减少。中风患者。我们还预测，通过施用选择性 NE a-1 拮抗剂 (TAM)，减少 NE 介导的运动神经元兴奋，将导致意志强度、痉挛和屈曲反射强度的降低。由于 TAM 缺乏脊髓上效应，预计上肢不协调不会因 TAM 的使用而改变。这项研究产生的知识旨在揭示中风后出现协调障碍和脊髓反射亢进的主要机制。这些机制的识别可能会指导针对支持上肢不协调的球脊髓机制的新型药物的开发