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作时脑功能和生理学的假设。 关于急性脑缺血生理学的知识，迄今为止几乎完全来自动物模型和细胞培养实验。 最近在建立人体溶栓和神经保护性卒中方案的有效性方面的挫折提出了一个问题，即我们对动物缺血级联反应的理解是否可以直接外推到预防人类卒中。 在人类中，临床中风发生在实验室之外，并且我们可以希望识别缺血的最早生理和临床表现，只有当患者在中风症状开始之后能够尽快到达神经科医生或MRI扫描仪时。该项目的协议提出了一种新的方法，我们的差距，在知识的最早表现的人类脑缺血。 我们将在两种临床环境中研究缺血的超急性期，这两种临床环境本身就是“自然实验“：第一，在患有不可手术的颈动脉海绵窦动脉瘤或头颈部肿瘤包裹颈动脉的患者中，如果治疗计划需要永久性伊卡牺牲，则需要伊卡的“测试闭塞”以评估他们对颈动脉闭塞的耐受性;第二，在我们机构进行常规测试的植入左心室辅助装置的心力衰竭患者中，通过暂时降低他们的机械泵的作用作为对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较高脑功能，并同时测量定量脑血流量、Willis侧支循环的改变和脑组织氧合，我们有机会开发出一种人体缺血模型，它可以开始研究人脑对缺血的早期反应与我们所知道的早期生理反应有多接近在动物中的局部缺血。 我们对接受伊卡试验闭塞的患者的研究也与颈动脉疾病引起的血流动力学卒中的临床实体有关，我们对心力衰竭患者的全脑灌注不足的研究直接与心脏骤停引起的脑缺血有关。 具体目标1是在已知的血流动力学条件下，确定早期缺血临床表现的发作和持续时间。 具体目标2和3是确定在脑灌注不足期间产生神经功能障碍的血液动力学和生理因素，具体目标4是使用来自脑灌注不足测试的行为和生理数据来预测需要永久性颈动脉闭塞的患者中随后的血液动力学缺血的风险。

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.