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: 7912984
• 负责人: J ANDREW TAYLOR
• 金额: $ 35.96万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912984
• 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）：通过脑血管阻力的反调节变化，脑灌注在广泛的全身压力下保持恒定。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。这种机制对于神经生理健康至关重要，因为流量太少可能导致缺血，而流量太多可能会升高颅内压。对脑血流速度的逐次评估表明，脑血流不仅在几分钟和几小时内受到调节，而且在仅几次心跳的较短时间范围内受到调节。压力变化在短至 15 秒（即约 0.07 Hz）的时间内受到阻尼，并且这种阻尼在较长的时间段内逐渐变大。尽管这种自动调节能力至关重要，但有关其潜在生理机制的信息却很少。本研究的具体目的是探讨α-肾上腺素能交感血管收缩、内皮源性一氧化氮和血管生肌反应在脑血流短期调节中的作用。我们假设交感神经在脑血流调节中的作用在较高频率（即较快的压力变化）下占主导地位，内皮一氧化氮的作用在较低频率（即较慢的压力变化）的调节中起较小作用，血管生肌作用是 对大脑自动调节控制器的更全面的了解将有助于识别许多病理生理状况中的缺陷。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)。这些症状的罪魁祸首可能是大脑自动调节功能障碍。因此，作为另一个目标，我们将表征有症状和无症状 TBI 中的脑血流自动调节，并评估脑吹血流自动调节与 TBI 症状之间的关联。我们假设有症状的 TBI 患者在交感神经控制（较短的时间尺度）下的脑血管自动调节功能将受损，而在一氧化氮和肌源性控制（较长的时间尺度）下的自动调节功能将保持完整。为了检验我们的假设，我们将产生一系列频率的全身压力变化，包括人类脑血流自动调节，从 10 秒波动到低至 50 秒波动。我们将通过线性和非线性分析评估脑血流量和全身血压之间的关系，并确定交感α-肾上腺素能阻断、一氧化氮合酶阻断和钙通道阻断对脑血管系统自动调节能力的影响。此外，作为检查以确定这些反应与非脑动脉床有何不同，我们将评估在这些相同条件下肱血流量和全身血压之间的关系。通过这项工作，我们将能够全面了解人类大脑自动调节的生理学，并测试可能是创伤性脑损伤常见症状的病理生理学。公众相关性：在较宽的血压范围内保持脑流量恒定对健康至关重要，因为流量太少可能导致脑死亡，而流量太多可能会增加大脑压力。尽管脑血管的这种功能至关重要，但有关其潜在机制的信息却很少。因此，拟议的研究将探讨各种控制系统在脑血流调节中的作用，并提供有关它们对脑血流变化的贡献的信息，而脑血流变化可能是创伤性脑损伤后症状的基础。