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R01基金中，题为“解开灵长类动物大脑的浅层白质：基于示踪剂” 组织学和弥散磁共振纤维束成像验证：“我们将绘制灵长类动物的浅表白质图。 采用实验性的脑束示踪方法。我们将使用这一地面事实信息来验证高- 同一只恒河猴体内分辨率和超高分辨率体外扩散磁共振成像(DMRI)研究 猕猴。SWM是位于前脑皮质和大脑皮质之间的连续层 潜在的脑白质关联途径。它由相互连接大脑皮层区域的轴突组成， 包括大脑沟下的U形纤维(U形纤维)。这一轴突层在广泛的 神经疾病，如自闭症谱系障碍、多发性硬化症和阿尔茨海默病，以及 SWM知识对于准确解释基于dMRI的气管造影术是必不可少的。关键的是， SWM的基本神经解剖学尚不清楚，这是因为我们无法将 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于非神经束实验追踪结果 人类灵长类动物(NHP)模型，但对NHP SWM从起源到轨迹再到 终止，尚未执行。因此，有关人力SWM连接和组织的知识可以 通过国家卫生计划中的侵入性途径追踪研究加以改进。拟议研究的目标是开展 首次对NHP脑中的SWM进行了详细的神经解剖学研究，并在NHP和翻译中进行了dMRI验证 人类的大脑。为了实现这一目标，我们将结合dmri使用一系列的组织学技术。 使用马萨诸塞州综合医院(MGH)Connectom扫描仪获得的扫描可产生卓越的质量 DMRI数据。我们将首先对研究文献进行数据挖掘，以形成现有知识的概要。 恒河猴的SWM连通性。我们还将研究Pandya-Rosene档案馆，这是一个巨大的收藏 神经解剖学案例构成了NHP中脑白质连接数据的基础。我们会 利用这个档案来绘制大脑前部SWM的组织结构图。然后我们将使用现代的 组织学方法，包括基于清晰度的组织清除和神经解剖束追踪，以审问 SWM的结构、地形和连通性，从而产生地面真实数据。我们将表演 在体内和体外进行神经解剖学轨迹追踪实验的同一动物体内和体外的dMRI， 允许在组织学和神经成像的连接性之间进行直接比较。此外，我们还将 将dMRI数据传播给神经成像社区，并举办一场比赛，以确定最佳 用于SWM的光刻法。最后，我们将把SWM神经解剖学的知识转化到人脑中 使用基于同源的与人类连接组项目数据集的比较。这些数据将提供 这是SWM连通性的基础事实，并有助于改进NHP和人脑中的dMRI轨迹成像。

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.