Neurochemical Challenge in Human Stroke Recovery

人类中风康复中的神经化学挑战

• 批准号: 7162650
• 负责人: RONALD M LAZAR
• 金额: $ 34.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162650
• 关键词: Acute; Admission activity; Agonist; Anti-Cholinergics; Aphasia; Behavioral; Blood Vessels; Cerebrum; Cholinergic Agonists; Cholinergic Antagonists; Classification; Clinical; Cognitive; Cognitive deficits; Condition; Contralateral; Data; Enrollment; Event; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Human; Image; Impaired cognition; Infarction; Injury; Ipsilateral; Language; Left; Magnetic Resonance Imaging; Midazolam; Modeling; Motor; Neurotransmitters; Paresis; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Randomized; Recording of previous events; Recovery; Recovery of Function; Recruitment Activity; Role; Scopolamine; Score; Sedation procedure; Series; Side; Specificity; Stroke; Syndrome; System; Tail; Testing; Transient Ischemic Attack; Visual Perception; Visuospatial; aphasic; day; design; experience; hemiparesis; hemodynamics; motor deficit; neglect; neurochemistry; novel; post stroke; stroke recovery

DESCRIPTION (provided by applicant): Most patients who have a stroke recover at least some degree of function. PET and fMRI studies have shown new regions of activation in the contralateral and ipsilateral cortex after infarction, even 1 day after stroke onset. The mechanisms by which such regions come to assume new roles in these patients are largely unknown. The long-term objective of this proposal is to determine the neurochemical systems that underlie functional recovery after cerebral vascular events in humans. In a novel baseline-sedation-postsedation design, our preliminary data have shown that a brief challenge with short-acting, commonly-used agents with specific neurochemical effects can unmask former deficits in patients whose syndromes had subsided/recovered after stroke or TIA. Midazolam, a GABAA agonist, was more effective in re-inducing motor dysfunction, and scopolamine, an anticholinergic agent, re-elicited aphasia. Over the 5-year project period, we propose to use this "induced dysfunction" model to prospectively study stroke and TIA patients at acute admission with a uniform series of aphasia, left hemineglect and motor tests, and to administer midazolam or scopolamine sedation challenges at prescribed intervals. For Specific Aim 1 we will recruit 160 patients at post-stroke Day 6 who have demonstrated a predefined increase in function in at last 1 of the 3 assessment spheres. Among the 80 patients in each drug group, there will be 40 patients in the hemiparesis group and 40 patients in the combined cognitive group comprised of 20 aphasic patients (with and without paresis) and 20 with left hemineglect (with and without paresis). After being randomized either to midazolam or scopolamine, each patient will undergo drug challenge on Days 7 and 90, during which all three spheres will be evaluated. There will also be 12 normal subjects, 6 in each drug group, to serve as controls. For Specific Aim 2, we will enroll 40 patients with a clinical history of TIA with a negative image who experienced brief aphasia (20 patients) and/or right-sided weakness (20 patients) into each of the midazolam and scopolamine groups. Drug challenges will take place on Days 4 and 90. Our hypothesis is that a GABAA agonist will more likely re-induce former motor deficits and that an anticholinergic agent will more likely unmask aphasia or hemineglect. T-tests will provide 80% power at the .05 level (2-tailed) to show a .45 SD difference in the mean change scores in function from baseline to sedation conditions. Functional magnetic resonance imaging will take place in Specific Aim 3 for a subset of patients and for all of the normal controls from Specific Aims 1 and 2 using the sedation-testing paradigm to determine whether there is a systematic change in activation following injury from stroke or TIA.

描述（由申请人提供）：大多数中风的患者恢复至少一定程度的功能。 PET和FMRI研究表明，甚至在中风发作后1天，在梗塞后对侧和同侧皮层中的激活区域。这些地区在这些患者中扮演新角色的机制在很大程度上是未知的。该提案的长期目标是确定人类脑血管事件后功能恢复的基础的神经化学系统。在一种新颖的基线隔离式设计设计中，我们的初步数据表明，与具有特定神经化学作用的短效，常用的药物的短暂挑战可以揭示综合症在中风或TIA后消退/恢复的患者的旧缺陷。 Gabaa激动剂咪达唑仑在重新诱导运动功能障碍的情况下更有效，抗胆碱能剂的Scopolamine重新引起了人们的失语。在5年的项目期间，我们建议使用这种“诱发功能障碍”模型在急性入院中前瞻性地研究中风和TIA患者，并以一系列的失语症，左半障碍和运动测试，并在规定的间隔下对咪达唑仑或甲莫唑仑或施乳孢子型镇静挑战进行管理。对于特定目标1，我们将在第6天后招募160名患者，他们在3个评估领域中的最后1例表现出了预定义的功能增加。在每个药物组的80例患者中，偏瘫组中将有40例患者，共同认知组中将有40例患者，由20例失语症患者组成（有或没有瘫痪），而20例患者将有40例患者（有或不进行降低），左半障碍（有或没有释放）。在被随机分配给咪达唑仑或西番茄胺后，每个患者将在第7和90天接受药物挑战，在此期间，将对所有三个领域进行评估。每个药物组中还将有12个普通受试者，有6个作为对照。对于特定的目标2，我们将招募40名具有负面图像的TIA临床病史的患者，这些患者经历了短暂的失语症（20例）和/或右侧弱点（20例患者），并进入了每个咪达唑仑和scopolamine群体。毒品挑战将在第4天和第90天进行。我们的假设是，Gabaa激动剂将更有可能诱发以前的运动缺陷，并且抗胆碱能剂更有可能揭露失语症或偏爱。 t检验将在.05级别（2尾）提供80％的功率，以显示从基线到镇静条件的功能平均变化得分的.45 SD差异。功能性磁共振成像将在特定的目标3中为患者的一部分，以及使用镇静测试范式的特定目标1和2的所有正常对照组进行，以确定中风或TIA受伤后的激活发生了系统变化。