Imaging Nonlinear Control of the Pulmonary Circulation with Proton MRI

描述(由申请人提供)：越来越多的证据表明，系统中的波动可能传达关于系统健康状况的关键信息。非线性科学的发展为许多不同系统的动力学提供了新的见解，例如生态系统和气候。与简单的线性系统相比，非线性系统具有更广泛的动态行为范围，包括多个状态以及它们之间响应外力的戏剧性转变。我们建议测试专注于描述潜在的非线性行为的数学分析工具是否可以为评估人类肺循环提供新的度量标准。如果成功，这可能会为疾病的早期发现和分类提供生物标志物，并为开发新的评估方法提供一个框架。这一建议结合了1)我们使用动脉自旋标记的新型无创磁共振成像技术，该技术允许测量肺血流空间分布的波动，以及2)基于我们的合作者Sugihara博士开发的非线性预测来评估时间序列数据中潜在的非线性机制的数学工具。杉原博士此前曾证明，早产儿对心率的非线性控制随着发育成熟而增强，并在脑死亡中消失，这表明非线性控制是健康的人类心血管系统的关键特征。非线性预测产生一套衡量标准，提供有关非线性相互作用的类型、涉及的相互作用因素的数量，甚至因素之间相互作用的强度的信息。我们建议在健康人和已知肺循环异常的人中测试这种新方法的可行性，这些人是既往的高原肺水肿(HAPE)患者。Hape是一名先前健康的个体，在海拔高度发展为粉红色肺水肿。HAPE可能是致命的，但HAPE患者经过适当的治疗后迅速恢复正常功能。我们将为未来的临床应用奠定基础，回答三个基本问题：新的指标是可重复的吗？噪声和伪影的影响是什么？它们会以特定的方式改变以回应生理压力吗？他们是否将健康的受试者与易患HAPE的受试者区分开来？我们将测试这样一种假设，即健康的人的肺循环表现出符合非线性控制机制的行为模式，并且这种行为可以通过生理挑战和Hape易感受试者以可重复的方式改变。我们的团队由来自磁共振成像、非线性预测、肺血管疾病和生理学的专家组成，他们将就这项提议进行合作。相关性：该项目的成功完成将提供高额回报：为评估肺血管疾病的全新手段奠定基础。由于肺血管疾病在进展之前在很大程度上是沉默的，这项工作最终可能导致一种新的高危患者群体筛查工具，或者一种识别人群进行靶向治疗的新方法。

DESCRIPTION (provided by applicant): There is growing evidence that the fluctuations in a system may convey critical information about the health of the system. Developments in nonlinear science have provided new insights on the dynamics of many different systems, such as ecological systems and climate. Nonlinear systems have the potential for a much wider range of dynamic behavior than simple linear systems, including multiple states and dramatic transitions between them in response to exogenous forces. We propose to test whether the mathematical analysis tools focused on characterization of underlying nonlinear behavior can provide new metrics for evaluating the human pulmonary circulation. If successful, this may provide biomarkers for the early detection and classification of disease, and a framework for developing new methods of evaluation. This proposal brings together 1) our novel noninvasive magnetic resonance imaging technique using arterial spin labeling that allows measurement of fluctuations in the spatial distribution of pulmonary blood flow and 2) mathematical tools for assessing underlying nonlinear mechanisms in time series data based on nonlinear forecasting developed by our collaborator Dr. Sugihara. Dr. Sugihara has previously shown that nonlinear control of heart rate of pre-term infants increased with maturation, and was lost in brain death suggesting that nonlinear control is a critical feature of a healthy human cardiovascular system. Nonlinear forecasting yields a set of metrics that provide information on the type of nonlinear interactions, the number of interacting factors involved, and even the strength of interactions between factors. We propose to test the feasibility of this new approach for evaluating the pulmonary circulation in healthy human subjects and those with a known abnormality of the pulmonary circulation-previous sufferers of high altitude pulmonary edema (HAPE). In HAPE a previously healthy individual, develops a florid pulmonary edema at altitude. HAPE may be fatal, but HAPE patients rapidly regain normal function with decent and treatment. We will lay a foundation for future clinical applications, answering three basic questions: Are the new metrics reproducible? What are the effects of noise and artifact. Do they change in specific ways in response to physiological stressors? Do they distinguish healthy subjects from those susceptible to HAPE? We will test the hypothesis that the healthy human pulmonary circulation exhibits patterns of behavior consistent with nonlinear control mechanisms and that this behavior is altered in a reproducible way by physiological challenges and in HAPE susceptible subjects. Our team is composed of experts from MR imaging, Nonlinear Forecasting, Pulmonary Vascular Disease, and Physiology who will collaborate on this proposal. Relevance: Successful completion of this project will provide a high reward: a foundation for an entirely new means of evaluating pulmonary vascular disease. Since pulmonary vascular disease is largely silent until it is advanced, ultimately this work may lead to a new screening tool for high-risk patient populations, or a new way of identifying populations for targeted therapies.