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递有关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，如生态系统和气候。非线性系统比简单的线性系统具有更广泛的动态行为范围，包括多个状态和它们之间响应外源力的戏剧性转变。我们建议测试专注于潜在非线性行为表征的数学分析工具是否可以为评估人体肺循环提供新的指标。如果成功，这可能为疾病的早期检测和分类提供生物标志物，并为开发新的评估方法提供框架。该建议将1)我们的新型无创磁共振成像技术结合在一起，该技术使用动脉自旋标记，可以测量肺血流空间分布的波动；2)基于我们的合作者杉原博士开发的非线性预测，用于评估时间序列数据中潜在的非线性机制的数学工具。杉原博士此前曾表明，早产儿心率的非线性控制随着成熟而增强，并在脑死亡时消失，这表明非线性控制是健康人类心血管系统的一个关键特征。非线性预测产生了一组指标，这些指标提供了有关非线性相互作用类型的信息，所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。我们建议测试这种新方法的可行性，以评估健康人类受试者和那些已知的肺循环异常-以前的高原肺水肿（HAPE）患者的肺循环。在HAPE患者中，先前健康的个体在高原上出现浮肿性肺水肿。HAPE可能是致命的，但HAPE患者通过适当的治疗可以迅速恢复正常功能。我们将为未来的临床应用奠定基础，回答三个基本问题：新指标是否可重复？噪音和伪影的影响是什么？它们会以特定的方式对生理压力做出反应吗？他们能区分健康受试者和易患HAPE的受试者吗？我们将验证以下假设：健康人体肺循环表现出与非线性控制机制一致的行为模式，并且这种行为在生理挑战和HAPE易感受试者中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，他们将合作完成这项提案。相关性：该项目的成功完成将提供高回报：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基本上是沉默的，最终这项工作可能会为高危患者群体提供新的筛查工具，或者为靶向治疗确定人群的新方法。

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.