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大范围的全身压力下保持恒定。有效的“自我调节”通过脑血管阻力变化来维持脑血流，充分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，因为过少的血流会引起缺血，而过多的血流会升高颅内压。对脑血流速度的逐拍评估表明，脑血流不仅在几分钟和几小时内受到调节，而且在几次心跳的较短时间尺度上也受到调节。压力变化在短至15秒（即~0.07 Hz）的时间内被衰减，并且随着时间的延长，这种衰减会逐渐增大。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却很少。该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生成反应在脑血流的短期调节中的作用。我们假设交感神经在高频率（即更快的压力变化）的脑血流调节中起主导作用，内皮一氧化氮在低频率（即较慢的压力变化）的调节中起很小的作用，血管肌源性的作用在低频率的自我调节中起主导作用。更全面地了解大脑自动调节的控制器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）。这些症状的罪魁祸首可能是大脑自身调节功能障碍。因此，作为一个额外的目标，我们将表征症状性和无症状性TBI的脑血流自动调节，并评估脑血流自动调节与TBI症状之间的关系。我们假设在有症状的TBI患者中，交感神经控制下的脑血管自身调节功能（较短时间尺度）会受损，而在一氧化氮和肌原性控制下的自身调节功能（较长时间尺度）将保持完整。为了验证我们的假设，我们将在包含人类脑血流自动调节的频率范围内产生系统压力变化，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来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我调节能力的影响。此外，为了确定这些反应与非脑动脉床有何不同，我们将评估在相同条件下肱血流量和全身血压之间的关系。从这项工作中，我们将能够构建人类大脑自动调节的生理学的全面图景，并测试可能导致创伤性脑损伤常见症状的病理生理学。公共相关性：在大范围的血压范围内保持脑流量恒定对健康至关重要，因为过少的脑流量可能导致脑死亡，而过高的脑流量可能会增加脑压力。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却很少。因此，本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改变的贡献的信息，这些改变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.