Correlation of Functional and Structural Units in Cerebral Cortex

该提案是我们早期NIH R21项目的扩展，该项目探索了功能磁共振成像（fMRI）信号与潜在神经元结构之间的空间关系。在同一动物和皮层区域进行的高分辨率功能磁共振成像和组织学研究中，我们首次证明了组织功能磁共振成像信号在皮层第四层达到峰值。任何基于血流动力学的制图技术的空间特异性都受到潜在血管网络的约束；因此，两者之间的空间关系对于理解控制和限制这些映射技术的机制至关重要。目前对fMRI对比机制的理解，关于其血管起源，是基于许多假设和理论建模，但很少有实验验证存在，以支持或挑战这些模型。主要由于技术上的限制，目前对脑血管的认识仅限于大枕面和毛细血管水平。然而，关于连接这两组的中等大小的血管群，主要是皮质内血管，以及可能发生关键血流调节的地方，我们知之甚少。基于我们之前的发现，我们将探索功能磁共振成像信号与潜在血管组织的空间对应关系。为实现拟议的目标，将开展若干项多式联运发展。一种新的皮层血管（静脉和动脉）的活体可视化和分类方法将被开发。利用一种新的、独特的超高场（16.4 T / 26 cm）磁铁，高分辨率MRI采集方案结合离体微ct成像，可以在接近微观尺度的分辨率下对皮质血管系统进行详细、准确的3D建模。此外，还将开发分析工具，以提供血管模型的形态学描述和定量。利用这种独特的方法，刺激诱导的fMRI信号变化的空间分布将与同一动物和皮层区域内潜在的血管模型相关。几个假设将探讨关于功能磁共振成像信号和皮层血管形态，如血管大小和整个组织的空间分布。此外，通过刺激初级视觉皮层神经元群的子集，将生成眼优势和定向柱的3D功能图，并与血管模型相关联。我们将研究这些功能性皮质组件是否与特定的血管单位耦合。这些研究的结果将是双重的：首先，开发新的和独特的方法工具，将为探索血管模型提供途径。这些技术将应用于各种各样的应用，利用血管结构的知识；这些应用包括但不限于功能磁共振成像、脑血管疾病、癌症血管生成研究和脑热调节模型，准确的血管模型将极大地有利于这些研究。在第二个结果中，神经生理学研究和临床应用将受益；随着对血管形态和功能磁共振成像机制的进一步了解，我们可以预期功能磁共振成像信号对神经元活动部位的空间定位和空间特异性会增加。临床应用，如神经外科计划、癫痫和脑肿瘤切除都将受益于准确性的提高。此外，如果功能（神经元）和结构（血管）单位之间确实存在相关性，在未来，它可能被用作任何临床行为症状出现之前的脑部疾病诊断工具。与公共卫生相关：功能磁共振成像（fMRI）是一种可以无创地定位大脑活动区域的技术。大脑中神经元活动增加之后，血流会出现局部的小幅增加，这可以用功能磁共振成像（fMRI）来测量。虽然功能磁共振成像已经彻底改变了人类大脑的研究领域，但人们对这些基于血流动力学的信号的潜在血管起源知之甚少。利用强大的磁铁，这项研究旨在获得极高分辨率的皮质血管图像，生成血管树的三维模型，并将其与功能磁共振成像信号相关联。这些研究结果将极大地增强我们对血管网络的理解，并有利于包括功能磁共振成像、脑血管疾病和癌症血管生成在内的各种研究应用。

DESCRIPTION (provided by applicant): Correlation of Functional and Structural Units in Cerebral Cortex This proposal is an expansion of our earlier NIH R21 project that explored the spatial relationship between functional magnetic resonance imaging (fMRI) signals and the underlying neuronal architecture. In a combined high- resolution fMRI and histological study, conducted in the same animal and cortical region, we demonstrated for the first time that tissue fMRI signals peak at cortical layer IV. The spatial specificity of any hemodynamic-based mapping technique is bound by the underlying vascular network; therefore, the spatial relationship between the two is crucial for understanding the mechanisms governing and limiting these mapping techniques. The current understanding of the fMRI contrast mechanism, regarding its vascular origins, is based on numerous assumptions and theoretical modeling, but little experimental validation exists to support or challenge these models. Due to mainly technical limitations, the current knowledge of cerebral vasculature is limited to the large pial surface and capillary level vessels. However, little is known regarding the cluster of intermediate-sized, mainly the intracortical vessels, connecting these two groups and where, arguably, key blood flow regulation takes place. Building on our pervious findings, we will explore the spatial correspondence of fMRI signals with the underlying vascular organization. To accomplish the proposed goal several multimodal developments will be embarked on. A new method for in- vivo visualization and classification (veins and arteries) of cortical vessels will be developed. Utilizing a new and unique ultra high-field (16.4 T / 26 cm) magnet, a high-resolution MRI acquisition schemes combined with ex-vivo micro-CT imaging will enable detailed and accurate 3D modeling of cortical vasculature at resolution approaching the microscopic scale. In addition, analytical tools will be developed to provide morphological description and quantification of the vascular model. Capitalizing on this unique approach, the spatial distribution of stimulus-induced fMRI signal changes will be correlated with the underlying vascular model within the same animal and cortical region. Several hypotheses will be explored with respect to fMRI signals and the cortical vessel morphology such as vessels size and the spatial distributions throughout the tissue. Furthermore, by stimulating only subsets of the neuronal ensemble in primary visual cortex, 3D functional maps of ocular dominance and orientation columns will be generated and correlated with the vascular model. We will investigate whether these functional cortical assemblies are coupled to specific vascular units. The outcome of these studies will be twofold: initially, development of new and unique methodological tools that will provide ways for exploring vascular models. These techniques will be applied to a broad variety of applications that utilize knowledge of the vascular architecture; such application include, but not limited to, fMRI, cerebrovascular diseases, cancer angiogenesis research and models of cerebral thermal regulation all of which will greatly benefit from an accurate vascular model. In the second outcome, neurophysiology research and clinical applications will benefit; with better understanding of the vascular morphology and fMRI mechanism, one can expect the increase in spatial localization and spatial specificity of the fMRI signals to the site of neuronal activity. Clinical applications such as neurosurgery planning, epilepsy and brain tumor resections will all benefit from increased accuracy. Furthermore, if indeed a correlation between functional (neuronal) and structural (vascular) units exist, in the future, it may be used as a diagnostic tool for brain disorders prior to the appearance of any clinical behavioral symptoms. PUBLIC HEALTH RELEVANCE: Functional Magnetic Resonance Imaging (fMRI) is a technique that allows, noninvasively, the localization of active brain regions. Increased neuronal activity in the brain is followed by a small and localized increase in blood flow which can be measured using fMRI. While fMRI has revolutionized the field of human brain research, little is known about the underlying vascular origin of these hemodynamic-based signals. Using a powerful magnet, this study is aims to obtain extremely high-resolution images of cortical vessels, generate a 3-D model of the vascular tree and correlate it with the fMRI signals. The outcome of these studies will greatly enhance our understanding of the vascular network and benefit a variety of research applications including fMRI, cerebrovascular disease, and cancer angiogenesis.