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; 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（由申请人提供）：中风后的运动脱节是由刻板印象的多接头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柱反射的过度活跃，包括拉伸反射（痉挛）和屈曲屈服反射。假定，在皮质脊髓和皮质骨阳极投影丧失后，引起脊髓的球脊髓单胺能驱动到脊髓的增加，引起了异常协同效应与脊柱反射过度兴奋性之间的共同点。球囊输入增加的证据包括运动神经元的兴奋性增加，短潜伏期和增强的长潜伏期屈曲反射以及由于刻板印象的协同运动模式的出现而导致选择性运动的能力降低。我们建议通过使用Tizanidine（TIZ）或TAMSULOSIN（TAMSULOSIN（TAM）（TAM）（TIZ）（TIZ）（TIZ）（TIZ）（TIZ）（TIZ）（TIZ）（TIZ）（TIZ）（TAM），通过操纵脊髓和/或脑干的神经兴奋性来检查中风后异常运动模式和脊柱反射的表达的影响。我们的目的是：1）识别和量化中风后脊髓上甲肾上腺素能输入增加的存在； 2）阐明中风后多动屈曲和拉伸反射的机制； 3）研究单胺能途径在中风后的坐骨上肢和动态条件下，单胺能途径在异常肌肉和扭矩协同作用中的作用。我们预测，通过给药（NE）A-2激动剂（TIZ），抑制脑干单胺能途径以及II组和高阈值传入，将导致脱节，屈曲反射和中风患者的屈曲反射和频繁性。我们还预测，通过选择性的NE A-1拮抗剂（TAM），NE介导的运动神经元的激发的减少将导致屈曲反射的自愿强度，痉挛和幅度的降低。由于缺乏脊柱上的效应，预计上肢的脱节预计将不改变。这项研究产生的知识旨在揭示中风后脱节和脊柱反射过度的主要机制。这些机制的识别可能会导致针对上肢脱节的基础的新型药理学剂的发展