Localizing epileptic networks using novel 7T MRI glutamate imaging

 描述（由申请人提供）：癫痫影响全球6500万人，其中三分之一的癫痫发作无法通过药物控制。定位癫痫发作在大脑中产生的位置可以显着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无法识别大约三分之一的癫痫患者的癫痫发生区域。该建议应用了一种新的7 T MRI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神经元生成的核心，初步数据表明，该技术可以识别其他技术无法定位的患者癫痫发作发生区域。GluCEST将在大队列病变性和非病变性癫痫患者以及对照受试者中获得。磁共振波谱将用于验证GluCEST衍生的谷氨酸测量，并研究认为存在于致癫痫区域的兴奋性/抑制性失配。我们希望证明GluCEST可以识别颞叶和新皮质癫痫患者的癫痫网络，无论是否存在当前临床成像上的病变。 拟议的工作将产生新的科学成果，有可能改善耐药性癫痫的治疗，提高我们对其潜在机制的认识，并迅速转化为临床应用。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志物。 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，宾夕法尼亚大学癫痫科神经病学助理教授。该提案建立在候选人对癫痫多模态成像的既定兴趣以及她之前在转化研究方面的培训基础上。候选人将由资深教师组成的经验丰富的跨学科团队指导，由以下人员领导：（1）主要导师John Detre博士，世界著名的神经影像学专家，他对这项工作中使用的新技术的开发至关重要，（2）Brian Litt博士，一位在临床癫痫方面具有丰富经验的知名研究者，开发新技术来定位癫痫网络，癫痫手术和植入式大脑设备，以及（3）Ravinder Reddy博士，多核磁共振成像和光谱技术方面的既定研究专家。Davis的其他导师，将确保本提交文件中提出的研究和培训经验将使她能够建立一个独立的研究计划，作为临床科学家开发和应用多模态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.