Oscillating gradient diffusion MRI and quantitative susceptibility mapping in the epileptogenic brain

摘要 癫痫是一种严重的神经系统疾病，涉及衰弱的癫痫发作，影响超过1%(6500万)的 世界人口。导致癫痫的一连串大脑结构和生理变化仍在继续 以保持人们对此的了解。由于癫痫直到癫痫发作后才能在患者中发现，洞察力 在癫痫发生过程中引发的大脑病理变化，包括神经退行性变，胶质细胞增生症， 钙化和树突损伤几乎完全来自已建立的啮齿动物模型。一位少校 靶向干预的早期诊断和发展的局限性是缺乏可靠的标记物 癫痫的发病过程，终点组织学对癫痫的进展提供了严重有限的洞察 不同脑区的致痫变化。R21计划旨在研究活体定量磁共振 使用1)振荡梯度扩散磁共振成像(OG-dMRI)的对比机制；以及2)定量磁性 药敏图谱(QSM)，实现无创、灵敏、有针对性的特异性检测 匹罗卡品癫痫持续状态大鼠模型的脑内微结构致痫后遗症。 此外，我们将结合3D扫描电子显微镜，阐明其微观结构基础 OG-DMRI和QSM结果验证MR对比剂机制作为特定癫痫发生的标志物 导致病理性后遗症。 我们将在三个具体目标中针对这些目标：1)研究振荡和脉冲梯度dMRI 海马神经元和树突状变性的检测，这是 癫痫的发生；2)研究进行性钙化和铁沉积在体内的检测 以及，3)阐明OG-dMRI的微结构基础和起源； QSM表现采用3D连续块面扫描电子显微镜和组织病理学分析。这个 在此R21项目中开发的关键创新技术将建立高度具体、量化和 基于MRI的内源性标记物，用于靶向检测大脑中的微结构过程，这将 允许对癫痫发生过程中发生的进行性病变进行非侵入性成像。这个项目 将产生对深入了解癫痫的发展和进展至关重要的技术和数据 并进一步阐明脑部dmri和qsm表现的潜在病理相关性。 导致癫痫的大脑。

Summary Epilepsy is a severe neurological disorder involving debilitating seizures that affects over 1% (65 million) of the world’s population. The cascade of alterations in brain structure and physiology leading to epilepsy continues to remain poorly understood. Since epilepsy is not detected in patients until after the onset of seizures, insights into pathologic changes triggered in the brain during epileptogenesis, which include neurodegeneration, gliosis, calcification, and dendritic damage, are almost exclusively gained from established rodent models. A major limitation in early diagnosis and development of targeted intervention is the lack of reliable markers of the epileptogenic process, with end-point histology providing severely limited insight into the progression of epileptogenic changes across brain areas. This R21 proposal aims to investigate in vivo quantitative MR contrast mechanisms using, 1) oscillating gradient diffusion MRI (OG-dMRI); and 2) quantitative magnetic susceptibility mapping (QSM), to achieve non-invasive, sensitive, and targeted detection of specific microstructural epileptogenic sequelae across the brain in the pilocarpine rat model of status epilepticus. Further, in combination with 3D scanning electron microscopy, we will elucidate the microstructural basis of OG-dMRI and QSM findings to validate the MR contrast mechanisms as markers of specific epileptogenesis- induced pathologic sequelae. We will target these goals in three specific aims: 1) to investigate oscillating- and pulsed-gradient dMRI for detection of hippocampal neuronal and dendritic degeneration, which is one of the main hallmarks of epileptogenesis; 2) to investigate in vivo detection of progressive calcification and iron deposits in the epileptogenic thalamus using QSM; and, 3) to elucidate the microstructural basis and origins of OG-dMRI and QSM findings using 3D serial block-face scanning electron microscopy and histopathological analyses. The key innovative techniques developed in this R21 project will establish highly-specific, quantitative, and endogenous MRI-based markers for targeted detection of microstructural processes in the brain, which will allow non-invasive imaging of progressive pathological changes occurring during epileptogenesis. This project will produce techniques and data crucial to afford insights into the development and progression of epilepsy in the brain, and further, to elucidate the underlying pathological correlates of both dMRI and QSM findings in the epileptogenic brain.