Modeling of transient oxygen delivery in the brain

描述(由申请人提供)：摘要：短暂的神经活动以复杂但稳定的形式触发血管反应。这种血流动力学响应函数(HRF)被广泛应用于常用的成像方法，如功能磁共振成像(FMRI)和基于反射的光学成像。正确解释和利用这些成像技术需要对HRF有详细的了解。此外，由于大脑是持续活跃的，瞬时反应可能对健康大脑的正常功能很重要。对HRF的更好理解将使依赖于大脑中明显明显的“休息状态”或“默认模式”活动的研究工作成为可能。最后，脑血管病理可能会影响这种瞬时反应，因此对其正常特征的更全面的了解应该能够使其作为早期或现有病理的诊断而进行研究。HRF的生理学和物理学还没有被很好地理解。已经开发了一个标准模型，该模型结合了一个非线性顺应元件(气球)来解释流动和体积的变化。然而，气球模型的一些具体预测还没有得到实验证实，现在对这个问题存在很大争议。我们发展了一个新的模型，它结合了线性流动描述和一维对流扩散氧传输。流动模型包含了流动血液的惯性动力学，在机械调节血流反应的较大小动脉中不应忽略这一点。我们的完整模型为使用极谱探头进行的组织氧测量提供了非常精确的拟合，从而导致短暂(几秒)的神经刺激事件。该模型还解释了静息功能磁共振成像中的神经血管偶联现象。我们建议对我们的模型进行进一步的开发和测试。具体地说，我们希望提高其血管内氧浓度预测的质量，并能够检查氧质量平衡问题。目标1是以几种方式扩展模型：通过添加从血红蛋白中解离氧气的动力学，以及通过添加术语来处理替代的氧气运输机制，例如内皮组织的氧气消耗。目标2是通过拟合使用极谱探头获得的额外组织氧测量来进一步测试我们的模型。目标3是使用双光子光学成像来测量小动脉和毛细血管的血流速度，以及它们如何在短暂的神经刺激后发生变化。我们将使用我们的线性流动模型以及以前的非线性模型来测试这些测量结果的拟合程度。拟议的工作将进一步审查我们的模型，使其成为主流，作为对脑血管血流动力学的简单但强大的分析性描述。 公共卫生相关性：我们需要更好地了解氧气从血液到脑组织的转移，无论是在稳态新陈代谢过程中，还是作为短暂的神经刺激的结果。这种理解对于正确使用和解释依赖神经血管耦合的脑成像技术以及诊断和治疗脑血管疾病至关重要。我们建议进一步开发一种新的向脑组织瞬时输送氧气的模型，并针对短暂的神经刺激引起的组织氧和血流变化的精确局部测量来测试该模型的预测。

DESCRIPTION (provided by applicant): Summary Brief periods of neural activity trigger a vascular response with a complex but stable form. This hemodynamic response function (HRF) is extensively exploited in popular imaging methods such as functional magnetic resonance imaging (fMRI) and reflectance based optical imaging. Proper interpretation and utilization of these imaging techniques requires a detailed understanding the HRF. Moreover, because the brain is continually active, transient responses are likely to be important in normal function of the healthy brain. Better understanding of the HRF will enable research efforts that rely on "resting-state" or "default-mode" activity that is clearly evident in the brain. Finally, cerebrovascular pathology is likely to affect such transient responses, so a more complete understanding of their normal character should enable their investigation as diagnostics of incipient or extant pathology. The physiology and physics of the HRF are not well understood. A standard model has been developed that incorporates a non-linear compliant element (balloon) to explain flow and volume changes. However, some specific predictions of the balloon model have not been confirmed experimentally, and there is now great controversy on the subject. We have developed a new model that combines a linear flow description with one-dimensional convection-diffusion oxygen transport. The flow model includes the inertial dynamics of moving blood, which should not be neglected in the larger arterioles that mechanically mediate the flow response. Our full model has provided remarkably accurate fits to tissue oxygen measurements performed with polarographic probes consequent to brief (few second) neural stimulation events. This model also provides an explanation for the neurovascular coupling utilized in resting-state fMRI. We propose further development and testing of our model. Specifically, we want to improve the quality of its intravascular oxygen concentration predictions, and to enable examination of oxygen mass-balance issues. Aim 1 is to expand the model in several ways: by adding the dynamics of oxygen dissociation from hemoglobin, and by adding terms to deal with alternative oxygen transport mechanisms such as oxygen consumption by endothelial tissue. Aim 2 is to further test our model by fitting additional tissue oxygen measurements obtained using polarographic probes. Aim 3 is to use two-photon optical imaging to measure flow speeds in small arterioles and capillaries, and how they change consequent to brief neural stimulation. We will test how well these measurements are fit by our linear flow model as well as previous non-linear models. The proposed work will further vet our model, bringing it into the mainstream as a simple but powerful analytic description for cerebrovascular hemodynamics. PUBLIC HEALTH RELEVANCE: We need a better understanding of oxygen transfer from blood to brain tissue, both during steady-state metabolism and as a consequence of brief neural stimulation. Such understanding is critical to the proper use and interpretation of brain imaging techniques that rely on neurovascular coupling, as well as the diagnosis and treatment of cerebrovascular diseases. We propose further development of a novel model for the transient delivery of oxygen to brain tissue, together with efforts that test the model's predictions against precise local measurements of tissue oxygen and blood flow changes induced by brief neural stimulation.