Simultaneous PET/fMRI to map cocaine's pharmacokinetic-vascular coupling

描述（由申请人提供）：问题：功能性磁共振成像（fMRI）越来越多地用于研究可卡因和其他药物对大脑功能的影响。然而，很少有人知道如何在大脑中的区域摄取和清除可卡因的时间过程与功能磁共振成像信号的区域动态变化。在这里，我们提出了一种新的，尖端的成像方法，同时使用正电子发射断层扫描（PET）和功能磁共振成像捕捉可卡因的动力学和功能性血流动力学反应，它在同一成像会话。目的：本提案的总体目标是优化我们实验室开发的PET/MRI仪器的空间和时间分辨率，以研究可卡因的药代动力学和可卡因对大脑中BOLD反应的药效学效应，同时使用PET和fMRI。方法：将定制高性能梯度线圈插入物，以适应小型化、MRI兼容PET摄像机。将优化MRI脉冲序列参数，以最大化MRI采集速率并最小化MRI梯度脉冲对PET采集的干扰。[11 C]可卡因将用于监测可卡因在大鼠大脑中的药代动力学，并确定药物摄取和清除率如何改变功能磁共振成像信号。假设：（1）MRI兼容的PET仪器将耐受超快MRI梯度脉冲;（2）仅在梯度脉冲的短暂上升时间内，MRI才会干扰PET采集;（3）功能性MRI信号仅会因[11 C]可卡因的有效剂量而改变，并将随药物摄取和清除率的变化而变化。成果：我们的双模态方法将允许标记药物和其他生化标记物与血流动力学反应一起同时映射。所提出的技术利用了PET的独特能力来绘制药物浓度的瞬间变化，以及fMRI以无与伦比的时间和空间分辨率捕获血流动力学反应的能力。因此，提出的PET/fMRI多模态方法代表了一个量子飞跃，桥接药物药代动力学及其对大脑活动的影响，通过在同一动物中同时进行这两种测量的能力，通过fMRI激活来测量。好处：这项新技术将为大脑中的药物作用如何转化为区域大脑活动的变化提供一个新的视角。这些研究的知识将弥合可卡因药代动力学PET结果与所观察到的血管fMRI反应之间的现有差距。这将为未来的人类研究奠定基础，以确定可卡因对血管和行为影响的潜在机制。

DESCRIPTION (provided by applicant): Problem: Functional magnetic resonance imaging (fMRI) is being increasingly used to study the effects of cocaine and other drugs on brain function. However, little is known about how the time course of regional uptake and clearance of cocaine in the brain relates to regional dynamic changes in fMRI signals. Here we propose a novel, cutting-edge imaging approach using simultaneous positron emission tomography (PET) and fMRI to capture both the kinetics of cocaine and the functional hemodynamic response to it in the same imaging session. Purpose: The overall goal of this proposal is to optimize the spatial and temporal resolution of the PET/MRI instrument developed in our laboratory to study the pharmacokinetics of cocaine and the pharmacodynamic effects of cocaine on BOLD responses in the brain, simultaneously with PET and fMRI. Methods: A high-performance gradient coil insert will be customized to fit a miniaturized, MRIcompatible PET camera. MRI pulse sequence parameters will be optimized to maximize the MRI acquisition rate and minimize the interference of MRI gradient pulses on PET acquisition. [11C]Cocaine will be used to monitor the pharmacokinetics of cocaine in the rat brain and determine how the rate of drug uptake and clearance alters the fMRI signal. Hypothesis: (1) The MRI-compatible PET instrument will tolerate ultra-fast MRI gradient pulses; (2) Only during the brief rise time of gradient pulses MRI will interfere PET acquisition; and (3) the fMRI signal will only be altered by the pharmacologically active dose of [11C]cocaine and will vary as a function of the rate of drug uptake and clearance. Outcomes: Our dual-modality approach will allow simultaneous mapping of labeled drugs and other biochemical markers together with the hemodynamic response. The proposed technology capitalizes on the unique ability of PET to map the moment-by-moment changes of drug concentration and the ability of fMRI to capture hemodynamic responses with unparalleled temporal and spatial resolution. Thus the proposed PET/fMRI multimodality approach represents a quantum leap bridging drug pharmacokinetics and its affects on brain activity as measured by fMRI-activation through the ability to make both of these measurements in the same animal simultaneously. Benefits: This new technology will provide a novel perspective on how drug actions in the brain translate into changes in regional brain activity. Knowledge from these studies will bridge the existing gap between PET findings of cocaine pharmacokinetics and the observed vascular fMRI responses. This will lay the groundwork for future studies in humans to pinpoint the mechanisms underlying the vascular and behavioral effects of cocaine.