Cerebral metabolism, EEG, and sleep cycling in critically ill neonates

描述（由申请人提供）：候选人：PI是一名委员会认证的儿童神经科医生和儿科医生，拥有临床神经生理学认证和临床研究设计和统计学硕士学位。她计划从事新生儿癫痫和脑病方面的临床研究。该项目从基金会和校内拨款中获得了初始资金，开始研究结合近红外光谱（NIRS）、传统脑电图（EEG）和振幅集成脑电图（EEG）作为癫痫发作和缺氧缺血性脑病新生儿脑功能和完整性的生物标志物。令人兴奋的初步结果导致了现在提出的新的假设和研究策略。关键的短期目标包括扩大PI的研究，将新生儿睡眠生理学和复杂信号分析技术纳入其中，这将需要额外的指导和培训。PI的长期目标是开发严格的多学科方法，以大大改善新生儿癫痫发作和脑病的评估和治疗。该奖项将使PI成为独立的临床研究人员，拓宽她的研究范围，纳入睡眠生理学，并组织新的合作，以创新最先进的分析方法。凭借K23奖项获得的专业知识，PI将成为一名独特的临床科学家，能够在新生儿学，临床神经生理学，神经学和睡眠医学的界面上追求关键问题。环境：PI将利用睡眠医学和新生儿神经病学的主要机构优势，以及她的导师与统计学和工程学同事的长期研究合作，创建一个独特的指导团队，坚定地致力于她的成功。密歇根大学医学院，儿科系和睡眠障碍中心为职业发展提供了一个特殊的环境。每个人都有长期的有影响力的临床和转化研究的历史，以及在初级教师职业发展中良好展示和富有成效的记录。职业发展计划：PI将受益于一个优秀的导师团队，包括睡眠医学，新生儿学，工程学和统计学的专家，以发展她的研究生涯在一个新的方向。Chervin博士是主要的导师，是睡眠障碍中心的主任，他将监督PI在多导睡眠图的理论、实践和解释方面的培训，并在方案的制定和实施方面提供帮助，以及向研究独立过渡的指导。巴克斯博士是联合导师，是新生儿科主任，也是PI目前资助研究的导师。他将在方案设计和实施方面发挥重要作用，并在新生儿神经病学和神经保护方面提供指导。顾问将在新生儿神经监测、统计和信号分析方面提供额外的专业知识。通过在密歇根大学著名的公共卫生学院、神经科学项目和统计咨询与研究中心的严格的研究生课程，以及研讨会和一对一的教学，PI将获得睡眠生理学、新生儿多导睡眠图、先进的信号处理和重复测量统计等方面的专业知识，以解决多种生理功能的复杂时间序列数据。研究计划：背景：新生儿癫痫发作的幸存者发生神经发育障碍的风险较高。不良结果背后的病理生理机制尚不清楚，但来自成人的数据表明，行为（睡眠）状态会影响癫痫发作的易感性，改变大脑代谢，并可能改变癫痫相关神经元损伤的易感性。我们建议使用最先进的技术来分析新生儿癫痫发作与睡眠生理学之间的复杂关系，包括脑电图（EEG）来评估癫痫发作负担，多导睡眠图（PSG）来表征生物行为状态，近红外光谱（NIRS）来评估大脑代谢。假设：1)新生儿睡眠-觉醒周期与脑代谢的可重复性变化有关。2)新生儿癫痫发作与代谢需求增加有关，在大脑代谢固有增加的行为状态下，代谢需求增加被放大。3)在癫痫发作的新生儿中，生物行为状态评估、脑代谢和癫痫发作负担能准确预测神经发育结局。目的：1)对50例危重新生儿在清醒、活跃和安静睡眠时的近红外光谱和脑电图进行跨通道分析。2)采用一致性、因果关系和定向传递函数来评估与清醒、主动和安静睡眠引起的癫痫发作相关的脑代谢改变。3)对新生儿癫痫发作幸存者进行18个月神经发育评估，确定PSG、NIRS和EEG对识别不良结局最高风险婴儿的预测价值。意义：量化新生儿癫痫发作、行为状态和脑代谢之间复杂的相互作用，将对高危人群不良后果的病理生理学产生新的见解，并可能导致新的诊断和治疗方法。PI将获得睡眠，新生儿神经学和信号处理方面的独特技能组合，这将使她能够开始一个成功的独立研究生涯，并有望改善高度脆弱的患者群体的健康。

DESCRIPTION (provided by applicant): Candidate: The PI is a board-certified child neurologist and pediatrician, with additional certification in clinical neurophysiology and a master's degree in clinical research design and statistics. She plans a clinical research career focused on neonatal seizures and encephalopathy. The PI secured initial funding from foundation and intramural grants to begin studies that combine near-infrared spectroscopy (NIRS), conventional electroencephalography (EEG), and amplitude-integrated EEG as biomarkers of brain function and integrity in neonates with seizures and with hypoxic ischemic encephalopathy. Exciting preliminary results led to the new hypotheses and research strategies now proposed. Key short-term goals include expansion of the PI's research to incorporate neonatal sleep physiology and complex signal analysis techniques, which will require additional mentorship and training. The PI's long-term goal is to develop rigorous multidisciplinary approaches that could substantially improve the evaluation and treatment of neonatal seizures and encephalopathy. This award will transition the PI to independence as a clinical researcher, broaden her research to incorporate sleep physiology, and assemble new collaborations to innovate state-of-the art analytic methods. With the expertise obtained through this K23 award, the PI will position herself as a clinical scientist uniquely able to pursue critical questions at the interface of neonatology, clinical neurophysiology, neurology, and sleep medicine. Environment: The PI will draw on major institutional strengths in sleep medicine and neonatal neurology, in addition to her mentor's long-standing research collaborations with colleagues in statistics and engineering, to create a unique mentoring team solidly committed to her success. The University of Michigan Medical School, Department of Pediatrics, and Sleep Disorders Center provide an exceptional environment for career development. Each has a long history of influential clinical and translational research, along with a well demonstrated and productive track record in junior faculty career development. Career Development Plan: The PI will benefit from an outstanding mentorship team, including experts in sleep medicine, neonatology, engineering, and statistics, to develop her research career in a novel direction. Dr. Chervin, primary mentor, is director of the Sleep Disorders Center and will oversee the PI's training in the theory, practice, and interpretation of polysomnography, and provide assistance with protocol development and implementation, along with guidance on transition to research independence. Dr. Barks, co-mentor, is director of Neonatology and serves as the PI's mentor for her currently funded studies. He will be instrumental in protocol design and implementation, and provide mentorship in aspects of neonatal neurology and neuroprotection. Consultants will offer additional expertise in neonatal neuromonitoring and in statistics and signal analysis. Through rigorous graduate-level course work at the University of Michigan's renowned School of Public Health, Neuroscience Program, and Center for Statistical Consultation and Research, as well as seminars and one-on-one teaching, the PI will gain expertise in sleep physiology, neonatal polysomnography, and the advanced signal processing and repeated measures statistics necessary to address complex time series data on multiple physiological functions. Research Plan: Background: Survivors of neonatal seizures are at high risk for neurodevelopmental disability. The pathophysiology underlying adverse outcomes is poorly understood, but data from adults suggest that behavioral (sleep) state influences susceptibility to seizures, alters cerebral metabolism, and could modify vulnerability to seizure-related neuronal injury. We propose to analyze the complex relationships between neonatal seizures and sleep physiology using state-of-the-art technology, including electroencephalography (EEG) to assess seizure burden, polysomnography (PSG) to characterize biobehavioral state, and near- infrared spectroscopy (NIRS) to evaluate cerebral metabolism. Hypotheses: 1) Neonatal sleep-wake cycling is associated with reproducible changes in cerebral metabolism. 2) Neonatal seizures are associated with increased metabolic demand, which is magnified during behavioral states with inherently increased cerebral metabolism. 3) Among neonates with seizures, biobehavioral state assessment, cerebral metabolism, and seizure burden can accurately predict neurodevelopmental outcome. Aims: 1) Perform cross-channel analyses of NIRS and EEG in 50 critically ill neonates during wakefulness, active and quiet sleep. 2) Employ measures of coherence, causality, and directed transfer functions to assess for altered cerebral metabolism associated with seizures arising from wakefulness, active and quiet sleep. 3) Perform 18-month neurodevelopmental assessments on survivors of neonatal seizures and determine the predictive value of PSG, NIRS, and EEG for identification of infants at highest risk for adverse outcomes. Significance: Quantification of the complex interplay between neonatal seizures, behavioral state, and cerebral metabolism will generate novel insight into the pathophysiology of adverse outcomes in high-risk individuals, and could lead to new diagnostic and therapeutic approaches. The PI will gain a unique combination of skills - in sleep, neonatal neurology, and signal processing - that will enable her to launch a successful independent research career with great promise to improve the health of a highly vulnerable patient population.