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 μ m）。程度 组织异质性在组织表征、疾病诊断和 监测治疗效果。例如，在癌症中，肿瘤内异质性已被确定为一种 癌症分期和个体化治疗中最重要的因素之一，正如一些研究所证明的那样， 近期发表在高影响力期刊上的论文组织异质性的来源多种多样，例如 遗传学，表观遗传学，生理学和病理学，所有这些都导致了特定的结构异质性。 空间尺度因此，研究组织结构异质性可以提供一种独特的途径来探索组织结构的异质性。 潜在的生物过程。不幸的是，目前人类MRI的空间分辨率还远远不够。 足以在微观水平上显现组织结构异质性（例如，~5-50 μ m）。努力 进一步提高分辨率面临巨大的技术挑战。另一种策略是使用 目前的空间分辨率，但侧重于提取亚体素信息，通过链接一个宏观体素水平 将测量结果转化为反映组织结构异质性的微观体素内物理过程。 使用基于分数阶微积分（FROC）的新型扩散模型，我们的团队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的联系 和微观体素内组织异质性。拟议项目的总体目标是进一步 开发和验证这种有前途的扩散成像技术，并证明，一套FROC 参数可以使得能够表征人类受试者体内的体素内组织异质性。 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，并且基于FROC模型的高级扩散MRI可以无创评估 显微结构的异质性，导致新的成像标记。我们的核心假设是， 在高b值的组织中的行为可以通过非均匀扩散过程来表征， 扩散异质性的程度可以直接与体素内组织结构异质性相关联。的 项目有四个具体目标。首先，我们将优化高分辨率扩散成像技术， 能够精确测量体素内扩散异质性。其次，我们将推广FROC 扩散模型，以不仅在空间上而且在时间上解释体素内扩散异质性。第三、 使用前两个目标中的技术，我们将证明基于MRI的 死后人体三维体素内扩散异质性和基于组织学结构异质性 患有神经胶质瘤的大脑最后，我们将扩展到六十个脑肿瘤患者的体内研究 使用立体定向活检。总的来说，该项目将解决一个重大的未满足的需求， 在生物科学和临床医学，特别是癌症中的重要性。

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.