The Physiological Basis of Functional MRI

描述（由申请人提供）：我们的总体目标是建立一种量化单个受试者大脑状态变化的新方法，一种用于评估药物效果或跟踪疾病进展和治疗反应的临床应用范例。该方法建立在先前支持期间与定量fMRI方法相关的几个发展的基础上，用于测量脑血流量（CBF）和脑氧代谢率（cro2）：在校准的BOLD方法中开发一种替代校准方法，不需要吸入特殊气体混合物；一系列研究表明，单独的BOLD反应对于检测导致对标准刺激引起的生理反应变化的大脑状态变化相对不敏感；还有一项关于咖啡因效应的研究表明，定量功能磁共振成像方法能够检测到CBF和cmr2的基线和激活反应的实质性变化，而这些变化基本上是单独使用BOLD无法检测到的。基于这项工作，我们提出了一套四项指标，反映基线CBF和cmor2及其对标准刺激（类似于“压力测试”）的反应，可以在20分钟内无创获得，无需特殊气体混合物。该项目的目标是通过测试这些指标追踪个体受试者大脑状态变化的能力，为这种方法的临床应用奠定基础。目的1将测试基于测量基线状态下松弛率R2'的校准新方法，该方法与标准高碳酸血症挑战基本相同，可用于量化cmoro2对刺激的反应。目的2将通过背靠背试验和间隔约1个月的研究，在健康人群中检验这四个指标的可重复性。目标3是一个盲法测试案例，以检测这些指标在个体基础上检测咖啡因导致的大脑状态变化的能力。这项工作将建立这些指标的敏感性和可靠性，以跟踪个体受试者的大脑状态变化，作为未来集中临床应用评估药物效应（例如，识别应答者，或量化对疾病的影响），确定疾病进展或评估治疗效果的基础。

DESCRIPTION (provided by applicant): Our overall goal is to establish a new methodology for quantifying changes in brain state in single subjects, a paradigm for clinical applications in assessing the effects of a drug or for following the progression of disease and the response to therapy. The method builds on several developments during the previous period of support related to quantitative fMRI methods to measure cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2): the development of an alternative approach to calibration in the calibrated BOLD method that does not require inhalation of special gas mixtures; a series of studies showing that the BOLD response alone is relatively insensitive for detecting a change in brain state that leads to a change in the evoked physiological response to a standard stimulus; and a particular example study of caffeine effects showing that quantitative fMRI methods are able to detect substantial changes in both baseline and activation responses of CBF and CMRO2 that were essentially undetected by BOLD alone. Based on this work we propose that a set of four metrics, reflecting baseline CBF and CMRO2 and their responses to a standard stimulus (analogous to a 'stress test'), can be acquired noninvasively and without requiring special gas mixtures in ~20 min. The goal of the project is to establish a basis for clinical applications of this approach by testing the ability of these metrics to track brain state changes in individual subjects. Aim 1 will test that the new approach to calibration based on measuring the relaxation rate R2' in the baseline state gives essentially the same required information as the standard hypercapnia challenge for quantifying the CMRO2 response to a stimulus. Aim 2 will test the reproducibility of the four metrics in a healthy population in both back to back test and in studies ~1 month apart. Aim 3 is a blinded test case of the ability of these metrics to detect changes in brain state due to caffeine on an individual basis. This work will establish the sensitivity and reliability of these metrics for following brain state changes in individual subjecs as a basis for future focused clinical applications in assessing drug effects (e.g., identifying responders, or quantifying the effect on disease), for determining the progression of disease, or for assessing the effect of therapy.