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.

Public Health Relevance

Background: Newborn infants with seizures are at high risk death or developmental disabilities, such as cerebral palsy and mental retardation. The reasons for poor outcomes are not well understood. Information from adults suggests that behavioral (sleep) state influences vulnerability to seizures, changes brain metabolism, and could be related to brain injury caused by seizures. We plan to analyze the relationships between neonatal seizures and sleep physiology using state-of-the-art technology, including electroencephalography (EEG) to assess seizure burden, polysomnography (PSG) to characterize sleep-wake states, and near-infrared spectroscopy (NIRS) to evaluate brain metabolism. Hypotheses: 1) Neonatal sleep-wake cycling is associated with reproducible changes in brain metabolism. 2) Neonatal seizures are associated with increased metabolic demand in the brain. 3) Among neonates with seizures, sleep-wake state assessment, brain metabolism, and seizure burden can accurately predict developmental outcome. Aims: 1) Perform analyses of NIRS and EEG in 50 critically ill neonates during wakefulness, active and quiet sleep. 2) Use advanced statistical measures to assess for changes in brain metabolism associated with seizures arising from wakefulness, active and quiet sleep. 3) Perform 18-month developmental assessments on survivors of neonatal seizures and determine the predictive value of PSG, NIRS, and EEG for identification of infants at highest risk for poor outcomes. Career Development: Through formal course work, seminars, and one-on-one teaching, the principal investigator will gain expertise in neonatal sleep physiology, polysomnography, and the advanced signal processing and repeated measures statistics necessary to address complex time series data on multiple physiological functions. Significance: Analyzing the interplay between neonatal seizures, sleep-wake state, and brain metabolism will lead to new understanding of the reasons for poor developmental outcomes in high-risk individuals, and could lead to diagnostic and therapeutic advances. The principal investigator 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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HD068402-02
Application #
8249781
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Raju, Tonse N
Project Start
2011-04-03
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$133,920
Indirect Cost
$9,920
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Glass, Hannah C; Wusthoff, Courtney J; Shellhaas, Renée A et al. (2014) Risk factors for EEG seizures in neonates treated with hypothermia: a multicenter cohort study. Neurology 82:1239-44
Shellhaas, Renée A; Burns, Joseph W; Wiggins, Stephanie A et al. (2014) Sleep-wake cycling and cerebral oxygen metabolism among critically ill neonates. J Child Neurol 29:530-3
Szymczak, Stacy E; Shellhaas, Renée A (2014) Impact of NICU design on environmental noise. J Neonatal Nurs 20:77-81
Shellhaas, Renée A; Burns, Joseph W; Barks, John D E et al. (2014) Quantitative sleep stage analyses as a window to neonatal neurologic function. Neurology 82:390-5