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开始时大脑功能和生理的假设。到目前为止，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。最近在建立人类溶栓和神经保护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推断出人类卒中的预防。在人类中，临床中风发生在实验室之外，我们只能希望在中风症状开始后尽快找到神经科医生或核磁共振扫描仪，以确定缺血的最早生理和临床表现。这个项目中的方案提供了一种新的方法来填补我们对人类脑缺血最早表现的知识空白。我们将在两种被称为“自然实验”的临床环境中研究缺血的超急性期：首先，对于无法手术的颈动脉海绵状动脉瘤或包裹颈动脉的头颈部肿瘤患者，如果治疗计划需要永久性的ICA牺牲，他们需要“测试闭塞”颈动脉以评估他们对颈动脉闭塞的耐受性；第二，在心力衰竭患者中，他们使用植入式左心辅助装置，通过暂时减少他们的机械泵的动作来耐受心输出量的减少，以此来测试自然心功能。通过监测这两组患者在故意、可逆性脑低灌流期间的较高大脑功能，并同时测量定量脑血流量、Willis侧支循环的变化和脑组织氧合，我们有机会开发出一种人类缺血模型，该模型可以开始研究人类大脑对缺血的早期反应与我们所知的动物对缺血的早期生理反应有多么接近。我们对接受颈内动脉测试性闭塞的患者的研究也与颈动脉疾病引起的血液动力学卒中的临床实体有关，而我们对心力衰竭患者整体低灌注量的研究直接与心脏骤停所致的脑缺血有关。具体目的1是在已知的血流动力学条件下，建立早期缺血临床表现的发病和持续时间进程。具体目标2和3是确定在脑低灌流时是什么血液动力学和生理因素导致神经功能障碍，而具体目标4是利用脑低灌流试验的行为和生理数据来预测那些需要永久性颈动脉闭塞的患者随后发生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.