Brain temperature and tissue microstructure in treatment-resistant epilepsy

项目摘要/摘要 全世界有7000多万人患有癫痫，全球每年新增病例240万例。在……里面 在这些患者中，神经炎症(NI)是局灶性癫痫产生和发作的关键病理因素 维修。持续的NI会降低血脑屏障，导致神经元死亡，最终 降低癫痫发作阈值。对于30%的人来说，找到成像和治疗医院感染的方法尤其重要 无法通过标准的抗癫痫药物实现癫痫自由发作的难治性癫痫(TRE)患者 药物。大麻二醇(CBD)有效地降低了许多TRE患者的发作频率和严重程度， 尽管人们对它如何发挥这些好处知之甚少。异常高的大脑温度(&gt；38°C)是一种 NI生化后果的替代测量，可能有助于研究NI的影响 人体NI上的CBD。利用体积磁共振无创测量脑温 光谱成像和测温(mrsi-t)，重复性和再现性高。此项目构建 关于我们使用mrsi-t进行大脑温度测绘的经验。在我们的初步研究中，我们将患者 使用mrsi-t与tre进行比较，并在参与脑部发育的区域发现异常高的脑温。 癫痫发作。然而，到目前为止，还没有研究调查大脑温度的升高是否由 MRSI-t提示潜在的组织损害或这些隆起在治疗后是否消失。在目标1中，我们 提出定义脑温度与微结构组织损伤的关系。 将使用轴突取向分析的多壳层扩散数据来评估微观结构的完整性 弥散和密度成像(NODI)是一种很有前途的工具，已被组织病理学研究证实。 在AIM 2中，我们将在TRE患者中使用重复的MRSI-t来量化CBD引起的脑温度变化。 我们假设大脑温度升高与微结构损伤有关，而这些 经CBD治疗后，体温像差减少。拟议的研究将提供初步的见解 研究CBD如何在人类身上发挥其治疗效果。这项提案的长期目标是评估 Mrsi-t测量的脑温为医院感染的可视化和评估提供了独特而有价值的信息。 Tre的治疗效果。通过结合MRSI-t和NODI，大脑温度图的实用将 使用已通过组织分析验证的成像方法进行评估。拟议的目标将是 与Jerzy P.Szaflarski博士赞助的正式研究培训计划一起完成，Mark博士 博尔丁和大卫·雷登博士。培训计划将加强申请者在1)生物统计学方面的专业知识，2) 核磁共振方法，3)指导技能和职业发展，4)神经生物学和神经免疫学，以及 5)癫痫。这项建议是一种指导培训的工具，将为技能提供坚实的基础 申请人作为一名多产、独立的科学家的职业生涯所需的。 。

PROJECT SUMMARY/ABSTRACT Epilepsy affects over 70 million people worldwide with a global incidence of 2.4 million new cases per year. In many of these patients, neuroinflammation (NI) is a key pathological contributor to focal seizure generation and maintenance. Sustained NI degrades the blood–brain barrier, leads to neuronal death, and ultimately decreases seizure threshold. Finding ways to image and treat NI is especially important for the >30% of patients with treatment-resistant epilepsy (TRE) who cannot achieve seizure freedom with standard antiseizure medications. Cannabidiol (CBD) effectively reduces seizure frequency and severity in many TRE patients, though how it exerts these benefits is poorly understood. Atypically high brain temperature (>38°C) is a surrogate measure for the biochemical consequences of NI, and may be a useful for studying the effects of CBD on human NI. Brain temperature can be non-invasively measured by volumetric magnetic resonance spectroscopic imaging and thermometry (MRSI-t) with high repeatability and reproducibility. This project builds on our experience using MRSI-t for brain temperature mapping. In our preliminary studies, we imaged patients with TRE using MRSI-t and found atypically high brain temperature in regions involved in the development of seizures. To date, however, no study has investigated whether elevations in brain temperature measured by MRSI-t indicate underlying tissue damage or whether these elevations resolve after treatment. In AIM 1, we propose to define the relationship between brain temperature and microstructural tissue damage. Microstructural integrity will be assessed using multi-shell diffusion data analyzed by neurite orientation dispersion and density imaging (NODDI), a promising tool that has been validated by histopathological studies. In AIM 2, we will quantify CBD-induced changes in brain temperature using repeated MRSI-t in TRE patients. We hypothesize that elevated brain temperature is associated with microstructural damage, and that these temperature aberrations decrease after treatment with CBD. The proposed research will provide initial insights into how CBD exerts its therapeutic effects in humans. The long-term goal of this proposal is to assess whether brain temperature measured by MRSI-t offers unique and valuable information for visualizing NI and evaluating treatment effectiveness in TRE. By combining MRSI-t and NODDI, the utility of brain temperature mapping will be evaluated using an imaging method that has been validated by tissue analyses. The proposed aims will be completed in conjunction with a formal research training plan sponsored by Dr. Jerzy P. Szaflarski, Dr. Mark Bolding, and Dr. David Redden. The training plan will enhance the applicant’s expertise in 1) biostatistics, 2) MRI methods, 3) mentorship skills and professional development, 4) neurobiology and neuroimmunology, and 5) epilepsy. This proposal is a vehicle for mentored training that will provide a solid foundation for the skills needed for the applicant’s career as a productive, independent scientist. .