Identification of Cortical Biomarkers for Seizure Risk in Childhood Epilepsy

 描述(申请人提供)：Catherine Chu博士是马萨诸塞州综合医院(MGH)的执业儿科癫痫专家和临床神经生理学家，其目标是开发一项独立的研究计划，利用非侵入性人体成像和神经生理记录来提高我们对大脑发育中癫痫发作风险的机制、疾病过程和指标的了解。朱博士建议研究最常见的儿童癫痫综合征，即伴有中央颞棘波的良性癫痫(BECTS)，使用新方法整合先进的神经成像、电生理学和信号处理技术，以确定癫痫发作风险的关键皮质生物标志物。尽管对这种疾病有丰富的临床经验，但确定谁将从抗癫痫药物(AED)治疗中受益以及何时停止治疗是安全的，仍然是一个挑战。其中三分之一的儿童只会有一次癫痫发作，而三分之二的儿童可能会在几年内反复发作。尽管不进行治疗或过早减量可能会导致癫痫发作，但长期接触AED会给30%-70%的接触AED的儿童带来认知副作用。需要一个生物标记物来隔离哪些儿童有持续癫痫发作的风险，以防止在这一大群儿童的认知、心理社会和行为成熟的关键年份过度或不足用药造成不必要的后果。由于癫痫发作被认为是由皮质兴奋性和连接性异常引起的，朱博士假设，使用现有的非侵入性技术对这些特性进行原则性测量将识别癫痫发作风险的临床相关生物标志物。朱博士已经得出了初步结果，支持她提出的方法的可行性。在麻省理工学院领先的翻译研究人员Kevin Staley博士、西德尼·卡什博士和Steven StuffleBeam博士的共同指导下，朱博士建议首先通过一项横断面研究评估患有癫痫活动期和缓解期的BECTS儿童，以使用先进的EEG和MRI技术确定癫痫风险的候选皮质生物标记物。然后，她将在最初评估一年后，通过重新研究横断面数据集中的受试者来评估将纵向数据添加到预测模型中的有效性。通过这些研究获得的知识将导致：1)量化与儿童癫痫发作风险增加相关的生理和解剖过程；2)确定可能与其他癫痫发作风险具有更广泛相关性的候选癫痫风险生物标记物；3)开发识别和量化这些过程的新工具和先进专业知识；以及4)R01资助的临床试验的初步数据，以测试儿童癫痫发作风险的非侵入性生物标记物。此建议书中概述的职业发展计划在出色的培训环境中为应聘者提供多模式成像技术、前瞻性临床研究和生物统计学方面的高级培训。她所拥有的专业知识 Will Development将使她在以患者为导向的研究中从事富有成效的独立职业生涯，在这一研究中，她可以专注于先进的成像技术，以解决儿科癫痫的紧迫和临床相关问题。

 DESCRIPTION (provided by applicant): Dr. Catherine Chu is a practicing pediatric epileptologist and clinical neurophysiologist at Massachusetts General Hospital (MGH), whose goal is to develop an independent research program utilizing non-invasive human imaging and neurophysiological recordings to improve our understanding of the mechanisms, disease process, and indicators of seizure risk in the developing brain. Dr. Chu proposes to study the most common pediatric epilepsy syndrome, benign epilepsy with Centro temporal spikes (BECTS) using novel methods to integrate advanced neuroimaging, electrophysiology, and signal processing techniques to identify key cortical biomarkers of seizure risk. Despite extensive clinical experience with this disease, it remains a challenge to determine who will benefit from antiepileptic drug (AED) treatment and when it is safe to discontinue. One- third of these children will have only a single seizure, while two-thirds may have recurrent seizures over several years. Although non-treatment or premature taper may result in seizures, chronic AED exposure introduces cognitive side effects in 30-70% of exposed children. A biomarker to isolate which children are at risk for ongoing seizures is needed to prevent the unnecessary consequences of over- or under-medication during critical years of cognitive, psychosocial and behavioral maturation in this large cohort of children. As seizures are thought to result from abnormal cortical excitability and connectivity, Dr. Chu hypothesizes those principled measures of these properties using available non-invasive techniques will identify clinically relevant biomarkers of seizure risk. Dr. Chu has developed preliminary results supporting the feasibility of her proposed approach. Under the joint mentorship of leading translational researchers Drs. Kevin Staley, Sydney Cash and Steven Stufflebeam at MGH, Dr. Chu proposes to first evaluate children with BECTS with active epilepsy and in remission in a cross-sectional study to identify candidate cortical biomarkers for seizure risk using advanced EEG and MRI techniques. She will then assess the utility of adding longitudinal data to the predictive models by re-studying th subjects in the cross sectional dataset one year after initial evaluation. The knowledge gained by these studies will lead to: 1) quantification of the physiological and anatomical processes associated with increased seizure risk in childhood epilepsy; 2) identification of candidate biomarkers of seizure risk which may have broader relevance to other epilepsies; 3) the development of novel tools and advanced expertise to identify and quantify these processes; and 4) preliminary data for an R01-funded clinical trial to test non- invasive biomarkers of seizure risk in childhood epilepsy. The career development program outlined in this proposal provides the candidate with advanced training in multimodal imaging techniques, prospective clinical research, and biostatistics in an outstanding training environment. The expertise that she will develop will position her for a productive independent career in patient-oriented research in which she can focus advanced imaging technologies to address pressing and clinically relevant questions in pediatric epilepsy.