Development of Brain Connectivity in the Human Fetus

描述（由申请人提供）：我们建议使用磁共振成像（MRI）和组织学来确定离体人胎脑中放射状通路、丘脑-皮质纤维、短距离和长距离皮质-皮质纤维和皮质传出投射纤维的发育时间过程。磁共振纤维束成像的一个主要挑战是在相互交叉的位置区分不同的纤维束。当两个或多个纤维束在一个体素内交叉时，常规扩散张量成像（DTI）通常无法分辨具有峰值水扩散的多个角度。这会导致错误，例如当存在光纤交叉点时遗漏光纤交叉点或错误连接不正确的光纤束。为了克服这个问题，我们的同事开发了高角分辨率技术。他们解决了水的扩散角沿着60-200方向和检测的水扩散光谱中的多个峰的存在下，纤维交叉。然而，即使有了这些高分辨率的技术，当人们试图应用这些技术来确定胎儿大脑发育中的纤维通路时，还有一个额外的问题。由于髓鞘形成是不完整的，并且髓鞘形成的模式在发育过程中动态变化，因此对人类胎儿大脑进行准确的纤维束成像一直具有挑战性。我们最近表明，这个问题可以克服与HARDI和DSI进一步细化扫描条件和数据分析技术。我们现在能够在不使用水扩散各向异性阈值的情况下在发育中的大脑中进行纤维束成像。这使我们能够在发育中的大脑中可视化详细的连贯结构，即使是在髓鞘形成较低的区域。这个R21建议利用这些最新的技术发展来解决人类神经科学发展中的一个重要问题，即人类胎儿大脑中纤维通路发展的时间过程。虽然这个问题已经解决了其他人与扩散纤维束成像，这些研究到目前为止，使用DTI与不完整的路径跟踪。因此，我们对人脑纤维发育的时空过程仍然知之甚少。我们相信，我们的技术发展将使我们能够证明，重要的发展问题，可以解决在离体制剂。对于这第一个系统的高分辨率研究纤维发育在整个人类胎儿大脑，我们将使用死后样本。这种方法将提供具有高信噪比的关键规范性数据，因为运动伪影将完全不存在。此外，我们将能够通过与组织学比较来验证我们的纤维束成像结果。正如提案中所讨论的，我们认为这项研究在围产期脑损伤或畸形以及理解影响出生后高级认知功能的折叠/连接的微妙异常方面具有重要的临床应用潜力。 公共卫生相关性：我们建议使用磁共振成像（MRI）和组织学来确定大脑连接和脑回形成的发展的时间过程。由于这将是第一次系统地高分辨率研究整个人类大脑中的纤维发育，结果应该会导致一种新的，精确的空间，纤维发育的时间图，并允许纤维和脑回发育的精确比较，这不仅有助于基础神经科学，而且有助于准确诊断和理解围产期脑损伤或畸形

DESCRIPTION (provided by applicant): We propose to use magnetic resonance imaging (MRI) and histology to determine the time course of development of radial pathways, thalamo-cortical fibers, short- and long-range cortico-cortical fibers and cortical efferent projection fibers in the brain of the human fetus ex vivo. Amajor challenge in MR tractography is to distinguish different fiber tracts at locations where they cross one another. When two or more fiber tracts cross within a voxel, conventional diffusion tensor imaging (DTI) often fail to resolve the multiple angles with peak water diffusion. This leads to errors such as missing fiber crossings when they exist or misconnecting incorrect fiber tracts. To overcome this problem, our colleagues have developed high-angular resolution techniques. They resolve the water diffusion angles along 60-200 directions and detect fiber crossings by the presence of multiple peaks in the water diffusion spectrum. Even with these high-resolution techniques, however, there is an additional problem when one tries to apply these techniques to determine the fiber pathways in developing fetal brains. Because myelination is incomplete, and the pattern of myelination dynamically changes during development, accurate tractography on human fetal brains has been challenging. We have recently shown that this problem can be overcome with HARDI and DSI by further refining scanning conditions and data analysis technique. We are now able to perform tractography in the developing brain without using a water diffusion anisotropy threshold. This has enabled us to visualize detailed coherent structures in the developing brain even in the areas with low myelination. This R21 proposal takes advantage of these recent technical developments to address an important issue in developmental human neuroscience, namely the time course of development of fiber pathways in human fetal brains. Although this issue has been addressed by others with diffusion tractography, these studies thus far have used DTI with incomplete pathway tracking. Therefore, we still know very little about the spatio-temporal course of fiber development in human brain. We believe that our technical developments will enable us to demonstrate that important developmental issues can be addressed in ex vivo preparations. For this first systematic high-resolution study of fiber development in the whole human fetal brain, we will use postmortem samples. This approach will provide crucial normative data with high signal-to-noise ratios, since movement artifact will be completely absent. Moreover, we will be able to validate our tractography results by comparing with histology. As discussed in the proposal, we believe that this research has potential for important clinical applications in perinatal brain injury or malformation as well as understanding of subtle abnormality of folding/connectivity that affect higher cognitive functions after birth. PUBLIC HEALTH RELEVANCE: We propose to use magnetic resonance imaging (MRI) and histology to determine the time course of development of brain connectivity and gyral formation. As this will be the first systematic high-resolution study of fiber development in the whole human brain, the results should lead to a novel, precise spatio-temporal maps of fiber development and allow precise comparison of fiber and gyral development that will contribute not only for basic neuroscience but also for accurate diagnose and understanding of the implications of abnormal folding and connectivity in infants with perinatal brain injury or malformation.