HUMAN BRAIN FUNCTION IN INDUCED CEREBRAL HYPOPERFUSION

该项目的总体目标是测试关于人类脑缺血发病时大脑功能和生理的假设。迄今为止，关于急性脑缺血的生理学知识几乎完全来自动物模型和细胞培养实验。最近在人类溶栓和神经保护中风方案中建立疗效的挫折提出了一个问题，即我们对动物缺血性级联的理解是否可以直接推断到人类中风的预防。在人类中，临床中风发生在实验室之外，我们希望只有在中风症状开始后患者能够尽快找到神经科医生或MRI扫描仪时，才能识别出缺血的最早生理和临床表现。该方案在这个项目提出了一个新的途径，我们的知识差距在人类脑缺血的最早表现。我们将在两种临床环境中研究缺血的超急性期，这两种临床环境使其成为“自然实验”：首先，在无法手术的颈动脉海绵动脉瘤或头颈部肿瘤包围颈动脉的患者中，如果治疗计划需要永久牺牲颈动脉，则需要对颈动脉进行“测试闭塞”以评估其对颈动脉闭塞的耐受性；其次，在心力衰竭患者植入左心室辅助装置，在我们的机构例行测试他们的能力，以容忍减少心输出量暂时减少机械泵的行动，作为天然心脏功能的测试。通过监测这两组患者在有意的、可逆的脑灌注不足期间的高级脑功能，同时定量测量脑血流量、威利斯络圈的改变和脑组织氧合，我们有机会开发一个人类缺血模型，可以开始解决人类大脑对缺血的早期反应与我们所知道的动物对缺血的早期生理反应有多接近。我们对ICA试验性闭塞患者的研究也关系到颈动脉疾病引起的血流动力学卒中的临床实体，我们对心力衰竭患者整体灌注不足的研究直接关系到心脏骤停引起的脑缺血。具体目的1是确定已知血流动力学条件下早期缺血临床表现的发病时间和持续时间。具体目的2和3是确定脑低灌注时哪些血流动力学和生理因素导致神经功能障碍，具体目的4是利用脑低灌注试验的行为和生理数据来预测需要永久性颈动脉闭塞的患者后续血流动力学缺血的风险。

The overall goal for the project is to test assumptions about brain function and physiology at the onset of cerebral ischemia in humans. Knowledge about the physiology of acute brain ischemia to date has been generated almost exclusively from animal models and cell culture experiments. Recent frustrations in establishing efficacy in thrombolytic and neuroprotective stroke protocols in humans has raised questions as to whether our understanding of the ischemic cascade in animals can be extrapolated directly to the prevention of human stroke. In humans, clinical stroke occurs outside the laboratory and we can hope to identify the earliest physiologic and clinical manifestations of ischemia only as quickly as the patient can reach a neurologist or an MRI scanner after symptoms of a stroke begin. The protocol in this project presents a new approach to our gap in knowledge of the earliest manifestations of human cerebral ischemia. We will study the hyperacute phase of ischemia in two clinical settings that lend themselves as "natural experiments:" first, in patients with inoperable carotid cavernous aneurysms or head and neck tumors encasing the carotid who require "test occlusions" of the ICA to assess their tolerance to carotid occlusion should the treatment plan require permanent ICA sacrifice; second, in cardiac failure patients with implantable left ventricular assist devices who are tested routinely at our institution for their ability to tolerate reduction in cardiac output by temporarily reducing the action of their mechanical pumps as a test of native heart function. By monitoring higher cerebral function in these two groups of patients during intentional, reversible cerebral hypoperfusion and simultaneously measuring quantitative cerebral blood flow, alterations in circle of Willis collaterals, and brain tissue oxygenation, we have an opportunity to develop a human model of ischemia that can begin to address how closely the human brain's early response to ischemia matches what we know of the early physiologic responses to ischemia in animals. Our study of patients undergoing test occlusions of the ICA also bears on the clinical entity of hemodynamic stroke from carotid artery disease, and our study of global hypoperfusion in the heart failure patients bears directly on cerebral ischemia from cardiac arrest. Specific aim 1 is to establish the time course of the onset and persistence of the clinical manifestations of early ischemia under known hemodynamic conditions. Specific aims 2 and 3 are to determine what hemodynamic and physiologic factors produce neurologic dysfunction during cerebral hypoperfusion, and Specific aim 4 is to use the behavioral and physiologic data from the cerebral hypoperfusion testing to predict risk for subsequent hemodynamic ischemia in those patients in whom permanent carotid artery occlusion is required.