Monoaminergic Drive and Discoordination Following Stroke

中风后的单胺能驱动和协调障碍

• 批准号: 7435312
• 负责人: JULIUS P DEWALD
• 金额: $ 27.81万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7435312
• 关键词: Affect; Agonist; Automobile Driving; Autoreceptors; Brain Stem; Chronic; Condition; Coupling; Depressed mood; Development; Dyskinetic syndrome; Elbow; Foundations; Freedom; Generations; H-Reflex; Hyperactive behavior; Individual; Intention; Interneurons; Intervention; Isometric Exercise; Joints; Knowledge; Limb structure; Measures; Mediating; Motor; Motor Neurons; Movement; Muscle; Neurons; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Reflex action; Reliance; Role; Rotation; Shock; Shoulder; Source; Spinal; Spinal Cord; Stroke; System; Torque; Upper Extremity; Upper arm; Withdrawal; alpha 2 agonist; hemiparetic stroke; monoamine; noradrenergic; novel; receptor; relating to nervous system; spinal reflex; stretch reflex; tamsulosin; tizanidine; transmission process; vibration

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（由申请人提供）：卒中后的运动失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和脊髓反射的过度活跃，包括牵张反射（痉挛状态）和屈曲撤回反射。脑卒中后出现异常协同作用和脊髓反射性兴奋过度之间的共性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驱动脊髓增加所致。球脊髓输入增加的证据包括运动神经元兴奋性增加、短潜伏期降低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的选择性运动能力降低。我们建议检查的影响，增加球脊髓单胺能驱动器的表达异常运动模式和脊髓反射中风后操纵神经兴奋性在脊髓和/或脑干使用替扎尼定（TIZ）或坦索罗辛（TAM）。我们打算：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伸展反射的潜在机制; 3）研究卒中后麻痹上肢在等长和动态条件下单胺能通路在异常肌肉和扭矩协同作用表达中的作用。我们预测，抑制脑干单胺能通路，以及第二组和高阈值传入在脊髓，通过管理的去甲肾上腺素（NE）的α-2激动剂（TIZ），将导致减少失调，屈曲反射和痉挛的个人中风。我们还预测，减少NE介导的运动神经元的兴奋，通过管理的选择性NE a-1拮抗剂（TAM），将导致意志强度，痉挛，屈曲反射的幅度减少。由于缺乏脊髓上的作用，预计TAM给药后上肢不协调不会改变。本研究所产生的知识旨在揭示中风后存在不协调和脊髓反射亢进的主要机制。这些机制的确定可能会指导开发新的药理学药物，靶向支撑上肢不协调的球脊髓机制