Unraveling the superficial white matter of the primate brain: Tracer-based histology and dMRI tractography validation

摘要 在这项为期5年的R 01资助中，题为“揭开灵长类动物大脑表面的白色物质：基于示踪剂的 组织学和弥散MRI纤维束成像验证，”我们将绘制灵长类动物的浅表白色物质（SWM 用实验性束示踪法对大脑进行了研究。我们将使用这些地面实况信息来验证高- 在同一恒河猴中进行基于体内高分辨率和超高分辨率离体扩散MRI（dMRI）的纤维束成像 猕猴SWM是位于前脑的大脑皮层和大脑皮层之间的连续层。 潜在的白色物质关联途径。它包括连接大脑皮层区域的轴突， 包括脑沟下的U形纤维（U纤维）。这种轴突层在广泛的 神经系统疾病，如自闭症谱系障碍、多发性硬化症和阿尔茨海默病，以及 SWM的知识对于准确解释基于dMRI的纤维束成像是必不可少的。关键是， SWM的基本连接神经解剖学在很大程度上是未知的，因为我们无法可视化 人类大脑中轴突的特定起源、终止和轨迹。我们对人类SWM的了解 因此，连接神经解剖学几乎完全来自非- 人类灵长类动物（NHP）模型，但NHP SWM的全面研究，从起源到轨迹， 终止，尚未执行。因此，人类SWM连接和组织的知识可以 通过NHP中的侵入性管道追踪研究得到改善。拟议研究的目标是开展 第一个详细的神经解剖学研究的SWM在NHP的大脑，与dMRI验证在NHP和翻译 to human人的brains脑.为了实现这一目标，我们将使用一系列组织学技术与dMRI结合 使用马萨诸塞州总医院（MGH）Connectom扫描仪获得的扫描，以产生上级质量 dMRI数据。我们将首先对研究文献进行数据挖掘， 恒河猴的SWM连接。我们还将研究潘迪亚-罗什档案，一个巨大的集合， 神经解剖学的情况下，已形成的基础数据的白色物质连接在NHP。我们将 利用这个档案来绘制SWM在额叶脑区的组织。我们将使用现代 组织学方法，包括基于免疫学的组织清除和神经解剖束追踪，以询问 SWM的结构、地形和连通性，从而产生地面实况数据。我们将执行 在我们进行神经解剖束示踪实验的相同动物中进行体内和离体dMRI， 允许直接比较组织学和基于神经成像的连通性。而且还要 将dMRI数据传播给神经成像界，并举办一场竞赛，以确定最佳的 SWM的纤维束成像方法最后，我们将把SWM神经解剖学的知识翻译到人脑中。 使用基于同源性的比较与人类连接组计划数据集。这些数据将提供 SWM连接的基础事实，并用于改善NHP和人脑中的dMRI纤维束成像。

Abstract In this 5 year R01 grant entitled “Unraveling the superficial white matter of the primate brain: Tracer-based histology and diffusion MRI tractography validation,” we will map superficial white matter (SWM) in the primate cerebrum using experimental tract tracing methods. We will use this ground truth information to validate high- resolution in vivo and ultra-high resolution ex vivo diffusion MRI (dMRI) based tractography in the same rhesus macaque monkeys. The SWM is a continuous layer located between the cerebral cortex of the forebrain and the underlying white matter association pathways. It comprises axons that interconnect cerebral cortical areas, including U-shaped fibers (U-fibers) under the cerebral sulci. This axonal layer plays a role in a broad range of neurological conditions such as autism spectrum disorder, multiple sclerosis, and Alzheimer’s disease, and knowledge of the SWM is essential for accurately interpreting dMRI-based tractography. Critically, the fundamental connectional neuroanatomy of the SWM is largely unknown due to our inability to visualize the specific origins, terminations, and trajectories of axons in the human brain. Our knowledge of human SWM connectional neuroanatomy is thus derived almost exclusively from experimental tract tracing results in the non- human primate (NHP) model, but comprehensive studies of the NHP SWM, from origin through trajectory to termination, have not been performed. Therefore, knowledge of human SWM connectivity and organization can be improved by invasive tract tracing studies in the NHP. The goal of the proposed research is to carry out the first detailed neuroanatomical study of the SWM in the NHP brain, with dMRI validation in the NHP and translation to human brains. To achieve this goal, we will use a range of histological techniques in conjunction with dMRI scans obtained with the Massachusetts General Hospital (MGH) Connectom scanner to produce superior quality dMRI data. We will first datamine the research literature to produce a compendium of existing knowledge of SWM connectivity in the rhesus monkey. We will also examine the Pandya-Rosene Archive, a vast collection of neuroanatomy cases that has formed the foundation of data on white matter connections in the NHP. We will utilize this archive to chart the organization of the SWM in frontal brain areas. We will then use modern histological methods, including CLARITY-based tissue clearing and neuroanatomical tract tracing, to interrogate the structure, topography, and connectivity of the SWM, and thereby produce ground truth data. We will perform in vivo and ex vivo dMRI in the same animals in which we perform neuroanatomical tract tracing experiments, allowing for direct comparisons between histological and neuroimaging-based connectivity. Moreover, we will disseminate the dMRI data to the neuroimaging community and host a competition to determine the optimal tractography method for SWM. Finally, we will translate knowledge of SWM neuroanatomy to the human brain using homologically based comparisons with Human Connectome Project datasets. These data will provide ground truth of SWM connectivity and serve to improve dMRI tractography in NHP and human brains.