Localizing epileptic networks using novel 7T MRI glutamate imaging

 描述(申请人提供)：全世界有6500万人患有癫痫，其中三分之一的人有无法通过药物控制的癫痫发作。定位癫痫发作在大脑中的位置可以极大地改善这些患者的癫痫手术和抗癫痫装置的结果。不幸的是，目前的临床成像技术不能识别大约三分之一的定位相关癫痫患者的癫痫发作区域。这项建议应用了一种新的7T磁共振技术，GluCEST，它以高分辨率成像兴奋性神经递质谷氨酸，以定位癫痫网络。谷氨酸被广泛认为是癫痫发作发生的中心，初步数据表明，这项技术可以识别其他技术未定位的患者的癫痫发作产生区域。GluCEST将在有病变和非皮损性癫痫的大队列患者和对照组中获得。磁共振波谱将用于验证GluCEST衍生的谷氨酸措施，并调查被认为存在于致痫区域的兴奋性/抑制性错配。我们希望证明GluCEST可以在有或没有当前临床影像上存在病变的颞叶和新皮质癫痫患者中识别癫痫网络。拟议的工作将产生新的科学结果，有可能改善耐药癫痫的治疗，促进我们对其潜在机制的了解，并迅速转化为床边。GluCEST有可能提高癫痫手术的准确性和结果，并成为评估新治疗策略的有价值的生物标记物。同样重要的是，拟议的项目旨在为候选人提供关键的职业发展培训，他是宾夕法尼亚大学癫痫学部的神经学助理教授。这项提议建立在候选人对癫痫多模式成像的既定兴趣以及她先前接受的翻译研究培训的基础上。候选人将得到经验丰富的资深教员跨学科团队的指导，团队成员包括：(1)主要导师John Detre博士，他是世界著名的神经成像专家，对开发这项工作中使用的新技术至关重要；(2)Brian Litt博士，他是一位在临床癫痫方面拥有丰富经验的知名研究员，正在开发定位癫痫网络、癫痫手术和植入性脑设备的新技术；以及(3)Ravinder Reddy博士，他是多核磁共振成像和光谱技术方面的资深研究专家。这些教师和Davis博士的其他导师将确保本意见书中提出的研究和培训经验将使她能够作为一名临床医生-科学家建立一个独立的研究计划，开发和应用多模式成像技术来研究癫痫。

 DESCRIPTION (provided by applicant): Epilepsy affects 65 million people worldwide, one-third of who have seizures that cannot be controlled by medications. Localizing where seizures are generated in the brain can dramatically improve outcome from epilepsy surgery and anti-seizure devices in these patients. Unfortunately current clinical imaging techniques are unable to identify the seizure-generating region in approximately one-third of patients with localization related epilepsy. This proposal applies a novel 7T MRI technique, GluCEST, which images the excitatory neurotransmitter glutamate at high resolution, to localize epileptic networks. Glutamate is widely believed to be central to seizure-generation, and preliminary data indicates that this technique can identify seizure generating regions in patients not-localized by other techniques. GluCEST will be obtained in large cohort patients with lesion and nonlesional epilepsy and in control subjects. Magnetic resonance spectroscopy will be used to validate GluCEST derived glutamate measures and to investigate excitatory/ inhibitory mismatch thought to be present in epileptogenic regions. We expect to demonstrate that GluCEST can identify the epileptic network in patients with temporal lobe and neocortical epilepsies both with and without lesions present on current clinical imaging. The proposed work will produce novel scientific results with the potential to improve treatment for medication-resistant epilepsy, advance our knowledge of its underlying mechanisms, and to be quickly translated to the bedside. GluCEST has the potential to improve accuracy and outcome from epilepsy surgery, and to become a valuable biomarker for assessing novel treatment strategies. Equally important, the proposed project is designed to provide critical career development training to the candidate, an Assistant Professor of Neurology in the Epilepsy Division at the University of Pennsylvania. The proposal builds upon the candidate's established interest in multimodality imaging in epilepsy and her prior training in translational research. The candidate will be mentored by an experienced interdisciplinary team of senior faculty, led by: (1) primary mentor Dr. John Detre, a world renowned expert in neuroimaging who has been critical to development of the novel technique utilized in this work, (2) Dr. Brian Litt, an established investigator with tremendous experience i clinical epilepsy, developing new technologies to localize epileptic networks, epilepsy surgery and implantable brain devices, and (3) Dr. Ravinder Reddy, an established investigator expert in multinuclear magnetic resonance imaging and spectroscopic techniques. These faculty, together with Dr. Davis's other mentors, will assure that the research and training experience proposed in this submission will enable her to establish an independent research program as a clinician-scientist developing and applying multimodality imaging techniques to investigate epilepsy.