Probing Intra-voxel Tissue Heterogeneity Using MRI

摘要 生物组织是异质的，特别是在微观尺度上(例如，~10m)。学位 在组织特征、疾病诊断和治疗中起着非常重要的作用 监测治疗效果。例如，在癌症中，肿瘤内的异质性已被确定为 癌症分期和个体化治疗中最重要的因素，如以下几项所示 在影响力很大的期刊上发表的最新论文。组织异质性有多种来源，例如 遗传学、表观遗传学、生理学和病理学，所有这些都会导致特定的结构异质性 空间尺度。因此，研究组织结构的异质性可以提供一个独特的途径来探索 潜在的生物过程。不幸的是，目前人类核磁共振成像的空间分辨率远未达到 足以在微观水平上显示组织结构的异质性(例如，~5-50m)。努力实现 进一步提高分辨率面临着严峻的技术挑战。另一种策略是使用 目前的空间分辨率，但专注于通过链接宏观体素级别来提取子体素信息 对反映组织结构异质性的微观体素内物理过程的测量。 使用一种基于分数阶微积分(FROC)的新扩散模型，我们的小组得到了其他人的响应， 观察到越来越多的证据表明宏观扩散参数之间存在联系 以及微观体素内组织的异质性。拟议项目的总体目标是进一步 开发和验证这一有前景的扩散成像技术，并证明一组FROC 参数可以表征受试者体素内组织的异质性。 该项目的科学前提是微观结构的异质性是一个重要的组织 特征和基于FROC模型的先进扩散磁共振成像可以无创地评估 微观结构的异质性，导致了新的成像标志物。我们的中心假设是扩散 在高b值的组织中的行为可以通过不均匀的扩散过程来表征，并且 扩散异质性的程度可以直接与体素内组织结构的异质性联系起来。这个 该项目有四个具体目标。首先，我们将优化一种高分辨率扩散成像技术，以 能够准确测量体素内扩散的异质性。第二，我们将概括中华民国 扩散模型不仅在空间上而且在时间上解释体素内扩散的异质性。第三, 使用前两个目标中的技术，我们将演示基于MRI的 身体体素内扩散异质性和基于组织学的结构异质性 患有神经胶质瘤的大脑。最后，我们将把演示扩展到对60名脑瘤患者的活体研究。 使用立体定向活组织检查。总而言之，该项目将解决一个重大的未得到满足的需求，这是非常重要的 在生物科学和临床医学，尤其是癌症方面的重要性。

ABSTRACT Biological tissues are heterogeneous, particularly at a microscopic scale (e.g., ~10m). The degree of tissue heterogeneity plays a very important role in tissue characterization, disease diagnosis, and monitoring treatment efficacy. In cancer, for example, intra-tumor heterogeneity has been identified as one of the most important factors in cancer staging and individualized treatment, as demonstrated in a number of recent papers in high-impact journals. Tissue heterogeneity arises from a variety of origins, such as genetics, epigenetics, physiology, and pathology, all of which lead to structural heterogeneity at a specific spatial scale. Studying tissue structural heterogeneity, therefore, can provide a unique avenue to probe the underlying biological processes. Current spatial resolution for human MRI, unfortunately, is far from adequate to visualize tissue structural heterogeneity at a microscopic level (e.g., ~5-50 m). Efforts to further improve the resolution face formidable technical challenges. An alternative strategy is to use the present spatial resolution, but focus on extracting sub-voxel information by linking a macroscopic voxel-level measurement to a microscopic intra-voxel physical process that reflects tissue structural heterogeneity. Using a novel diffusion model based on fractional order calculus (FROC), our group, echoed by others, has observed an increasing number of evidences suggesting a link between a macroscopic diffusion parameter and microscopic intra-voxel tissue heterogeneity. The overarching goal of the proposed project is to further develop and validate this promising diffusion imaging technique, and demonstrate that a set of FROC parameters can enable characterization of intra-voxel tissue heterogeneity in human subjects. The scientific premise of the project is that microstructural heterogeneity is an important tissue feature and that advanced diffusion MRI based on the FROC model can non-invasively assess microstructural heterogeneity, leading to new imaging markers. Our central hypothesis is that diffusion behavior in tissues at high b-values can be characterized by a heterogeneous diffusion process, and the degree of diffusion heterogeneity can be directly linked to intra-voxel tissue structural heterogeneity. The project has four Specific Aims. First, we will optimize a high-resolution diffusion imaging technique to enable accurate measurement of intra-voxel diffusion heterogeneity. Second, we will generalize the FROC diffusion model to account for intra-voxel diffusion heterogeneity not only spatially but also temporally. Third, using the techniques in the first two aims, we will demonstrate the possible relationship between MRI-based intra-voxel diffusion heterogeneity and histology-based structural heterogeneity on postmortem human brains with glioma. Finally, we will extend the demonstration to in vivo studies on sixty brain tumor patients using stereotactic biopsies. Taking together, the project will address a significant unmet need that is of great importance in biological sciences and clinical medicine, especially cancer.