Time Domian Electron Paramagnetic Resonance Imaging

a)确定和固有的空间、光谱（生理）和时间分辨率，并与MRI图像共同配准。在多模态成像过程中，不同的成像方式（如MRI、EPRI、PET等）衍生出不同的方面，可能需要对这些具有不同内在分辨率特征的图像进行共配准，以帮助在分辨率更高的MRI图像基础上解释EPRI图像。我们严格审查了决定EPRI内在分辨率的因素，并开发了图像形成策略，以优化EPRI数据集，以获得最佳的空间、时间和光谱（生理）分辨率。这使我们第一次能够研究肿瘤的生理波动以及抗血管生成药物在减少这种波动方面的作用。此外，成像实验的优化使得能够在1周至10天的时间内连续监测肿瘤生理变化，从而有可能评估对治疗的反应变化。b)肿瘤中pO2绝对定位的成像策略。EPRI的pO2映射工作最初是从使用滤波反投影方法的图像生成和重建方法开始的。然而，由于该技术固有的较差的空间分辨率和广泛的EPR共振，我们采用了使用单点成像（SPI）策略的傅立叶成像方法，但使用静态磁场梯度。通过这种方法，我们能够实现有用的空间和生理分辨率。然而，使用SPI模式的EPRI固有的磁化率不均匀性使得使用不同扫描仪甚至使用相同扫描仪的不同谐振器获得的成像结果难以比较。为了克服这一困难，我们开发了一种新的图像形成策略，利用SPI的傅立叶图像编码方法在EPRI中实现电子自旋回波检测。脉冲序列使用LabView平台上设计的脉冲编程器开发，时间分辨率为1ns，脉冲宽度可以以20ns的步长递增。使用回声检测生成图像，我们能够获得幻影物体和体内绝对pO2的图像，这些图像不受与磁场不均匀性相关的伪影的影响。c)大尺寸物体成像策略：虽然所开发的图像形成和重建方法将适用于小动物的组织氧成像，甚至适用于人类可触及的肿瘤，如乳房、头颈部、前列腺等，但在深部肿瘤中绘制pO2需要使用功率可能超过允许水平的射频（RF）激发。为了开发用于人类深部肿瘤的射频激励策略，我们结合了固态核磁共振波谱和手机工业中使用的技术，使用具有恒定振幅但不同相位的低激励功率的定制脉冲序列。这样的脉冲序列使用的射频峰值功率比传统方法低几个数量级，但仍然可以检测到EPRI信号。为了实现这一点，我们集成了一个具有83 ps时间分辨率的任意波形发生器和一个恢复时间为50 ns的发送/接收开关。有了这种能力，我们正在评估与检测灵敏度相关的方面，以了解将这种技术用于人类使用的下一步步骤。d) EPRI对肿瘤生理动力学的评估。在制定图像形成策略，将肿瘤pO2的三维图像时间减少到小于3分钟后，我们在30分钟的时间窗口内进行了肿瘤氧成像，以检查肿瘤区域的氧波动。我们首次表明，在肿瘤中存在氧气状态反映典型循环缺氧行为的区域和慢性缺氧区域。e)抗血管生成药物治疗时肿瘤生理的时间分布。利用EPR监测suntinib治疗时肿瘤pO2和血容量变化的能力，我们发现在开始治疗后的一段时间内，肿瘤pO2短暂升高，同时血管密度下降，这与血管再正常化的假设一致。

a) Determining and intrinsic spatial, spectral (physiologic) and temporal resolution of EPRI and co-registration with images from MRI. In a multimodality imaging process where different aspects are derived with various imaging modalities such as MRI, EPRI, PET etc, co-registration of these images with different intrinsic resolution characteristics may be required to help in interpreting the EPRI images based on the better resolved MRI images. We have critically examined factors involved in determining the intrinsic resolution in EPRI and developed image formation strategies to optimize the EPRI data sets for optimal spatial, temporal and spectral (physiologic) resolutions. This allowed for the first time to examine physiological fluctuations in tumors and the effect of anti-angiogenic drugs in minimizing such fluctuations. Further, optimization of imaging experiments allowed the capability to serially monitor changes in tumor physiology over a period of 1 week-10days making it possible to evaluate changes in response to treatment. b) Image formation strategies for absolute pO2 mapping in tumors. The pO2 mapping efforts with EPRI initially started with image formation and reconstruction approaches using filtered back-projection methods. However with the poor spatial resolution inherent with this technique with the broad EPR resonances, we resorted to a Fourier imaging approach using the Single Point Imaging (SPI) strategy yet using static magnetic field gradients. With this approach, we were able to realize useful spatial and physiologic resolutions. However, the magnetic susceptibility inhomogeneity inherent with the EPRI using the SPI modality makes it difficult to compare imaging results obtained with different scanners or even different resonators with the same scanners. To overcome this difficulty, we have developed a novel image formation strategy by implementing Electron Spin Echo detection in EPRI with the Fourier image encoding approach of SPI. Pulse sequences were developed using a puklse programmer designed on a LabView platform with a time resolution of 1 ns and pulse widths which can be incremented in 20 ns steps. Images were generated using the echo detection and we were able to obtain images of absolute pO2 in phantom objects and in vivo which were not subject to artifacts associated with magnetic field inhomogeneities. c) Strategies for imaging larger sized objects: While the image formation and reconstruction approaches developed will be applicable for imaging tissue oxygen in small animals and even accessible tumors in humans such as in breast, head and neck, prostate etc, mapping pO2 in deep seated tumors requires the use of radiofrequency (RF) excitation at powers which may exceed the permitted levels. To develop RF excitation strategies for human applications in deep seated tumors, we have incorporated techniques utilized in solid state NMR spectroscopy and cell phone industry to use tailored pulse sequences which have constant amplitude but different phases with low excitation power. Pulse sequences such as this use RF peak powers several orders of magnitude lower than conventional methods and yet can detect EPRI signals. To enable this, we have incorporated an arbitrary wave form generator with a 83 ps time resolution and a transmit/receive switch with a recovery time of 50 ns. With this capability, we are evaluating aspects related to sensitivity of detection to understand the next steps in implementing this technique for human use. d) Assessment of dynamics in tumor physiology by EPRI. After developing image formation strategies to minimize the time taken for a 3-d image of tumor pO2 to be less than 3 minutes, we have conducted tumor oxygen imaging in a time window of 30 minutes to examine regions of tumor for fluctuations in oxygen. We show for the first time that there exist in tumors, regions where oxygen status reflects behaviour typical of cycling hypoxia and regions which are chronically. e) Temporal profile of tumor physiology when treated with anti-angiogenic drugs. Using the capability of EPR to monitor changes in tumor pO2 and blood volume when treated with suntinib, we found that there is a period aft6er initiating treatment where there is a transient increase in tumor pO2 with an accompanying decrease in blood vessel density consistent with the hypothesis of vascular re-normalization.