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于出现刻板的多关节运动模式，反映了失去独立的关节控制，以及脊柱反射的过度活动，包括伸展反射(痉挛)和屈曲撤退反射。卒中后出现异常协同效应和脊髓反射过度兴奋性之间的共性被认为是由于皮质脊髓和皮质球投射丢失后对脊髓的球脊髓单胺能驱动增加所致。球脊髓传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，以及由于出现刻板印象的协同运动模式而导致的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()来控制脊髓和/或脑干的神经兴奋性，来研究增加的球脊髓单胺能驱动对卒中后异常运动模式和脊髓反射表达的影响。我们的目的是：1)识别和量化卒中后脊髓去甲肾上腺素能输入增加的存在；2)阐明卒中后过度活跃的屈曲和拉伸反射的潜在机制；3)研究单胺能通路在等长和动态条件下卒中后偏瘫上肢异常肌肉和扭矩协同作用的表达中的作用。我们预测，通过给予去甲肾上腺素(NE)a-2激动剂(TIZ)抑制脑干单胺能通路以及脊髓II组和高阈值传入，将导致中风患者的不协调、屈曲反射和痉挛的减少。我们还预测，通过给予选择性的去甲肾上腺素a-1拮抗剂()来减少NE介导的运动神经元的兴奋，将导致意志力、痉挛和屈曲反射的幅度降低。由于缺乏脊柱上的影响，的管理预计上肢不协调将保持不变。这项研究所产生的知识试图揭示中风后存在协调失调和过度活跃的脊髓反射的主要机制。这些机制的确定可能会指导针对支持上肢不协调的球脊髓机制的新药理学药物的开发