Brain temperature and tissue microstructure in treatment-resistant epilepsy

难治性癫痫的脑温度和组织微观结构

• 批准号: 10671484
• 负责人: Ayushe Alicia Sharma
• 金额: $ 1.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671484
• 关键词: Affect; Aftercare; Anticonvulsants; Biochemical; Biometry; Blood - brain barrier anatomy; Brain; Cannabidiol; Data; Development; Diffusion; Epilepsy; Focal Seizure; Foundations; Freedom; Frequencies; Generations; Goals; Human; Image; Incidence; Magnetic Resonance Imaging; Maintenance; Maps; Measurement; Measures; Mentors; Mentorship; Methods; Multimodal Imaging; Neurites; Neurobiology; Pathologic; Patient imaging; Patients; Persons; Productivity; Reproducibility; Research; Research Training; Resistance; Scientist; Seizures; Severities; Solid; Structure; Temperature; Therapeutic Effect; Thermometry; Tissues; Training; Treatment Effectiveness; Visualization; career; density; experience; imaging modality; insight; magnetic resonance spectroscopic imaging; neuroimmunology; neuroinflammation; neuron loss; skills; tool; treatment response

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. .

项目总结/摘要 癫痫影响全球超过7000万人，全球每年新发病例240万例。在 在这些患者中，神经炎症（NI）是局灶性癫痫发作产生的关键病理因素， 上维护持续的NI降解血脑屏障，导致神经元死亡，并最终 降低癫痫发作阈值。找到成像和治疗NI的方法对于>30%的 使用标准抗癫痫药物无法实现无癫痫发作的难治性癫痫（TRE）患者 药物治疗大麻二酚（CBD）有效地降低了许多TRE患者的癫痫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。非典型的高脑温（>38°C）是一种 NI的生化后果的替代措施，并可能是一个有用的研究的影响， CBD对人的NI。脑温度可以通过体积磁共振无创测量 光谱成像和温度测量（MRSI-t）具有高重复性和再现性。该项目建立 我们使用磁共振成像-t进行大脑温度测绘的经验。在我们的初步研究中， 与TRE使用MRSI-t，并发现在参与发展的区域， 癫痫发作然而，到目前为止，还没有研究调查通过测量大脑温度是否升高。 MRSI-t表明潜在的组织损伤或这些升高是否在治疗后消退。在AIM 1中，我们 建议定义脑温度和微结构组织损伤之间的关系。 将使用通过神经突方向分析的多壳层扩散数据评估微观结构完整性 弥散和密度成像（NODDI），一个有前途的工具，已被组织病理学研究验证。 在AIM 2中，我们将在TRE患者中使用重复MRSI-t量化CBD诱导的脑温度变化。 我们假设，大脑温度升高与微结构损伤有关， CBD处理后温度畸变减少。拟议的研究将提供初步的见解 CBD如何在人类中发挥其治疗作用。该提案的长期目标是评估是否 通过MRSI-t测量的脑温度为可视化NI和评估NI提供了独特且有价值的信息。 TRE的治疗效果通过结合MRSI-t和NODDI，脑温度图的实用性将 使用已通过组织分析验证的成像方法进行评价。拟议的目标将是 与由Jerzy P. Szaflarski博士、Mark博士、 博尔丁和大卫·雷登医生培训计划将提高申请人在1）生物统计学，2） MRI方法，3）指导技能和专业发展，4）神经生物学和神经免疫学，以及 5)癫痫本建议书是指导培训的工具，将为技能提供坚实的基础 申请人作为一个富有成效的独立科学家的职业生涯所需要的。 .