Exploring the Physiology of Short-term Control of Cerebral Blood Flow in Humans

探索人类脑血流短期控制的生理学

• 批准号: 7677469
• 负责人: J ANDREW TAYLOR
• 金额: $ 35.5万
• 依托单位: SPAULDING REHABILITATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677469
• 关键词: Adrenergic Agents; Autonomic Dysfunction; Beds; Blood; Blood Flow Velocity; Blood Pressure; Blood Vessels; Blood flow; Brain; Brain Death; Brain Injuries; Calcium Channel; Cardiovascular system; Cerebrovascular Circulation; Cerebrum; Conscious; Craniocerebral Trauma; Data; Dizziness; Dysautonomias; Event; Frequencies; Functional disorder; Headache; Health; Homeostasis; Hour; Human; Injury; Intracranial Pressure; Ischemia; Left; Nerve Fibers; Neurons; Nitric Oxide; Nitric Oxide Synthase; Patients; Perfusion; Peripheral; Physiological; Physiology; Play; Post-Concussion Syndrome; Recovery; Regulation; Research; Resistance; Risk; Role; Symptoms; System; TBI Patients; Testing; Time; Traumatic Brain Injury; Vasoconstrictor Agents; Work; adrenergic; base; cerebrovascular; experience; novel; pressure; response; vasoconstriction

DESCRIPTION (provided by applicant): Cerebral perfusion is maintained constant over a wide range of systemic pressures via counter-regulatory changes in cerebrovascular resistance. Effective "autoregulation" maintains cerebral blood flow via cerebrovascular resistance changes that fully counteract sustained changes in arterial pressure. This mechanism is critical to neurophysiologic health since too little flow could cause ischemia whereas too much could raise intracranial pressure. Beat-by-beat assessment of cerebral blood flow velocity has shown that cerebral flow is regulated not just over minutes and hours but also on shorter time scales of only a few beats. Pressure changes are damped over periods as short as 15 seconds (i.e., ~0.07 Hz) and this dampening is progressively greater over longer time periods. Despite the critical importance of this autoregulatory capacity, there is very little information on the underlying physiologic mechanisms. The specific aims of the proposed research are to explore the roles of alpha- adrenergicsympatheticvasoconstriction,endothelial-derivednitricoxide,andvascularmyogenicresponsesinthe short-term regulation of cerebral blood flow. We hypothesize that the sympathetic role in cerebral flow regulation is predominant at higher frequencies (i.e., faster pressure changes), the endothelial nitric oxide role plays a small role in regulation at lower frequencies (i.e., slower pressure changes), and the vascular myogenic role is a predominanteffectorofautoregulationattheselowerfrequencies.Morecompleteunderstandingofthecontrollers for cerebral autoregulation will allow identification of deficits in a number of pathophysiologic conditions. One especially relevant example is traumatic brain injury(TBI)that results in post-concussion symptoms. A likely culprit for these symptoms is cerebral autoregulatory dysfunction. Therefore, as an additional aim, we will characterize cerebral blood flow autoregulation in symptomatic and asymptomatic TBI and evaluate the association between cerebral blow flow autoregulation and symptoms in TBI. We hypothesize that cerebrovascular autoregulatory function under sympathetic control (shorter time scales ) will be impaired in TBI patients with symptoms, whereas autoregulatory function under nitric oxide and myogenic control (longer time scales) will remain intact. To test our hypotheses, we will generate systemic pressure changes across a range of frequencies that encompass cerebral blood flow autoregulation in humans, from 10 second fluctuations down to as low as 50 second fluctuations. We will assess the relationship between cerebral blood flow and systemic blood pressure via both linear and non-linear analyses and determine the effects of sympathetic alpha-adrenergic blockade, of nitric oxide synthase blockade, and of calcium channel blockade on the autoregulatory capacity of the cerebral vasculature. In addition,as a check to determine how these responses differ from non-cerebral arterial beds, we will assess the relation between brachial blood flow and systemic blood pressure under these same conditions. From this work, we will be able construct a comprehensive picture of the physiology that underlies cerebral autoregulation in humans and test the pathophysiology that may underlie symptoms common to traumatic brain injury. PUBLIC RELEVANCE: Maintaining brain flow constant over a wide range of blood pressures is critical to health since too little flow could cause brain death whereas too much could raise the pressure on the brain. Despite the fact that this function of the brain blood vessels is of critical importance, there is very little information on the underlying mechanisms. Therefore, the proposed research will explore the roles of various control systems in the regulation of brain blood flow and provide information on their contribution to alterations in brain blood flow that may underlie symptoms after traumatic brain injury.

描述(由申请人提供)：通过脑血管阻力的逆调节变化，脑血流灌注在广泛的全身压力范围内保持恒定。有效的“自动调节”通过脑血管阻力的变化来维持脑血流量，从而完全抵消动脉压的持续变化。这一机制对神经生理学健康至关重要，因为太少的血流量可能会导致缺血，而太多的血流量可能会升高颅内压。对大脑血流速度的逐拍评估表明，大脑血流不仅在几分钟和几个小时内受到调节，而且还在较短的时间尺度上进行调节，只有几个心跳。压力变化在短至15秒(即约0.07赫兹)的时间段内被抑制，并且这种抑制在较长的时间段内逐渐增大。尽管这种自我调节能力至关重要，但关于潜在的生理机制的信息很少。本研究的具体目的是探讨α-肾上腺素能交感血管收缩、内皮细胞衍生的一氧化氮和血管发生反应在脑血流短期调节中的作用。我们假设在较高频率(即较快的压力变化)下，交感神经在脑血流调节中起主导作用，在较低频率(即较慢的压力变化)下，内皮细胞的一氧化氮作用在调节中起很小的作用，而血管的生肌作用是一种predominanteffectorofautoregulationattheselowerfrequencies.Morecompleteunderstandingofthecontrollers，因为脑自动调节将允许在许多病理生理条件下识别缺陷。一个特别相关的例子是导致脑震荡后症状的创伤性脑损伤(TBI)。这些症状的一个可能的罪魁祸首是大脑自动调节功能障碍。因此，作为一个额外的目标，我们将表征有症状和无症状的脑外伤患者的脑血流自动调节，并评估脑血流自动调节与脑外伤症状之间的关系。我们假设，有症状的脑外伤患者在交感神经控制(较短时间尺度)下的脑血管自我调节功能将受损，而在一氧化氮和肌源性控制(较长时间尺度)下的自我调节功能将保持不变。为了验证我们的假设，我们将在一系列频率范围内产生系统性压力变化，这些频率包括人类脑血流自动调节，从10秒的波动到低至50秒的波动。我们将通过线性和非线性分析来评估脑血流和全身血压之间的关系，并确定交感α-肾上腺素能受体阻滞剂、一氧化氮合酶阻滞剂和钙通道阻滞剂对脑血管自我调节能力的影响。此外，为了确定这些反应与非脑动脉床的不同之处，我们将评估在相同条件下臂动脉血流和全身血压之间的关系。通过这项工作，我们将能够构建一幅全面的人类大脑自我调节基础的生理学图景，并测试可能导致创伤性脑损伤常见症状的病理生理学。公众关注：在大范围的血压范围内保持脑血流恒定对健康至关重要，因为太少的血压可能导致脑死亡，而太多的血压可能会增加大脑的压力。尽管脑血管的这一功能至关重要，但对其潜在机制的信息很少。因此，这项拟议的研究将探索各种控制系统在脑血流调节中的作用，并提供有关它们在脑创伤后可能导致症状的脑血流变化中的作用的信息。