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

描述（由申请人提供）：脑灌注通过脑血管阻力的反调节变化在广泛的全身压力范围内保持恒定。有效的“自动调节”通过脑血管阻力变化来维持脑血流，脑血管阻力变化完全抵消动脉压的持续变化。这种机制对神经生理健康至关重要，因为流量太少可能导致缺血，而流量太多可能升高颅内压。对脑血流速度的逐搏评估表明，脑血流不仅在几分钟和几小时内受到调节，而且在更短的时间尺度上（仅几次心跳）也受到调节。压力变化在短至15秒的时间段内被衰减（即，~0.07 Hz），并且这种阻尼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，但关于其潜在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、内皮源性一氧化氮和血管肌源性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下占主导地位（即，更快的压力变化），内皮一氧化氮的作用在较低频率的调节中起很小的作用（即，压力变化较慢），而血管肌源性作用是较低频率下自动调节的主要影响因素。对脑自动调节控制器的更全面了解将允许识别许多病理生理条件下的缺陷。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，我们将表征脑血流自动调节在有症状和无症状TBI和评估脑血流自动调节和症状TBI之间的关联。我们假设，脑血管自动调节功能交感神经控制下（较短的时间尺度）将在TBI患者的症状受损，而自动调节功能下的一氧化氮和肌源性控制（较长的时间尺度）将保持不变。为了验证我们的假设，我们将在包括人类脑血流自动调节的频率范围内产生全身压力变化，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，并确定交感神经α-肾上腺素能阻滞、一氧化氮合酶阻滞和钙通道阻滞对脑血管系统自动调节能力的影响。此外，为了确定这些反应与非脑动脉床的反应有何不同，我们将评估在相同条件下肱动脉血流量与体循环血压之间的关系。从这项工作中，我们将能够构建一个全面的图片生理学基础的大脑自动调节在人类和测试的病理生理学，可能是常见的创伤性脑损伤的症状。公众相关性：在大范围的血压下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的压力。尽管脑血管的这种功能至关重要，但关于其潜在机制的信息很少。因此，拟议的研究将探索各种控制系统在脑血流调节中的作用，并提供有关它们对脑血流变化的贡献的信息，这些脑血流变化可能是创伤性脑损伤后症状的基础。

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.