A Novel Wavelet Neurovascular Bundle for Real Time Detection of Injury in Neonatal Encephalopathy

用于实时检测新生儿脑病损伤的新型小波神经血管束

• 批准号: 10201762
• 负责人: LINA F CHALAK
• 金额: $ 34.28万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201762
• 关键词: Acute; Address; Aftercare; Ancillary Study; Asphyxia; Asphyxia Neonatorum; Biomedical Engineering; Birth; Blood Flow Velocity; Blood Pressure; Brain; Brain Death; Brain Injuries; Cerebral Palsy; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Trials; Cognitive; Coupling; Decision Making; Detection; Development; Devices; Dose; Electroencephalography; Enrollment; Erythropoietin; Evaluation; Global Change; Goals; Homeostasis; Hour; Impairment; Infant; Injury; Intervention; Knowledge; Life; Link; Logistic Models; Magnetic Resonance Imaging; Mathematics; Measurement; Measures; Mediating; Mediator of activation protein; Methodology; Mission; National Institute of Neurological Disorders and Stroke; Near-Infrared Spectroscopy; Neonatal Brain Injury; Neurocognitive; Neurological outcome; Neurons; Newborn Infant; Outcome; Patient Selection; Patients; Pediatric Neurology; Perfusion; Phase; Physiological; Placebos; Predictive Value; Public Health; Publishing; Randomized; Rewarming; Saline; Severities; Stratification; Structure; Surrogate Markers; System; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Trials; Time; Treatment Efficacy; angiogenesis; brain health; cerebral hemodynamics; cohort; disability; fetal; functional outcomes; hemodynamics; improved; natural hypothermia; neonatal encephalopathy; neonate; nervous system disorder; neurogenesis; neuroimaging; neuroprotection; neurovascular; neurovascular coupling; novel; outcome prediction; postnatal; predicting response; response; risk stratification; technology development; tool development

ABSTRACT Neonatal encephalopathy (NE) resulting from birth asphyxia constitutes a major global public health burden for millions of infants every year, and despite therapeutic hypothermia, half of neonates have poor neurologic outcomes. As new neuroprotective interventions are being studied in clinical trials, there is a critical need to establish physiological surrogate markers of therapeutic efficacy, to guide patient selection and/or to modify the therapeutic intervention. The challenge in the field of neonatal brain injury has been the difficulty to clinically discern the NE severity within the short therapeutic window after birth, or to analyze the dynamic aspects of the cerebral circulation in the NE sick newborns. The PI and her bioengineering team have developed a “wavelet neurovascular bundle” analytical system that can measure cerebral autoregulation (CA) and neurovascular coupling (NVC) at multiple time scales under dynamic, non-stationary clinical conditions. A real time evaluation of the coupling of cerebral blood flow and neuronal activity “neurovascular bundle” is therefore proposed in order to determine the severity of injury and identify infants that could potentially benefit from added therapies. The proposed approach not only has the ability to capture the evolving non-stationary aspects of the cerebral circulation, but can also quantify the magnitude and duration of the impaired hemodynamics in NE, and their effect on functional and structural outcomes. The PI has published her methodological technology development, together with preliminary observations linking the wavelet bundle measures to short- and long- term developmental outcomes following hypothermia. The long-term goal is to harness the technological advantages of the wavelet neurovascular bundle to optimize outcomes in asphyxiated newborns, by appropriately selecting patients for therapeutic trials and identifying the factors underlying responses to therapy. Erythropoietin (EPO), with postulated effects on cerebral blood flow, neurogenesis and angiogenesis, is currently being evaluated as a new adjunct therapy for moderate to severe NE (High dose EPO Asphyxia; NS092764 NCT02811263 NINDS1U01). The central hypothesis in this ancillary study at UT Southwestern is that the new wavelet neurovascular bundle measures will stratify the NE severity(Aim 1), identify the effects of EPO on CA/NVC during a new randomized neuroprotection trial of EPO + Hypothermia vs. Hypothermia alone (Aim 2), and predict short-term structural and long-term functional outcomes(Aim 3). To test this hypothesis, 100 newborns will be enrolled at UT Southwestern (30 non-treated mild NE and 70 moderate or severe NE who are randomized to treatment with EPO + Hypothermia or Hypothermia alone) and examined for developmental outcomes at 24months. New knowledge gained from the wavelet bundle will specifically provide:1) improved stratification of brain injury severity among newborns with NE, 2) understanding the effect of EPO on cerebral autoregulation and neuronal coupling, and 3) new bio-mediators that can predict responses to therapies in real time, aiming to improve brain outcomes as per NINDS mission.

摘要 由出生窒息引起的新生儿脑病（NE）构成了一个主要的全球公共卫生负担， 每年有数百万的婴儿，尽管有治疗性低温， 结果。由于新的神经保护干预措施正在临床试验中进行研究，因此迫切需要 建立治疗功效的生理学替代标志物，以指导患者选择和/或修改治疗效果。 治疗干预新生儿脑损伤领域的挑战一直是临床上难以 在出生后的短治疗窗内辨别NE的严重程度，或者分析NE的动态方面。 NE患儿的脑循环。PI和她的生物工程团队开发了一种“小波”， 神经血管束”分析系统，可以测量大脑自动调节（CA）和神经血管 偶联（NVC）在动态，非稳态临床条件下的多个时间尺度。真实的时间评估 脑血流和神经元活动的耦合的“神经血管束”，因此， 以确定损伤的严重程度，并确定可能从额外治疗中受益的婴儿。 所提出的方法不仅能够捕捉大脑的发展非平稳方面， 循环，但也可以量化的幅度和持续时间受损的血流动力学在NE，及其 对功能和结构结果的影响。PI发表了她的方法技术 发展，连同初步观察链接小波束措施，以短期和长期- 低温后的长期发育结果。长期目标是利用技术 小波神经血管束优化窒息新生儿结局的优势， 适当选择患者进行治疗试验，并确定对以下反应的潜在因素： 疗法促红细胞生成素（EPO），对脑血流、神经发生和血管生成具有假定作用， 目前正在评估作为一种新的辅助治疗中度至重度NE（高剂量EPO窒息; NS092764 NCT02811263 NINDS1U01）。UT Southwestern这项辅助研究的中心假设是 新的小波神经血管束测量将对NE严重程度进行分层（目的1），识别 在EPO +低温与单独低温的新随机神经保护试验中EPO对CA/NVC的影响 (Aim 2），并预测短期结构和长期功能结果（目标3）。为了验证这个假设， 将在UT Southwestern招募100名新生儿（30名未经治疗的轻度NE和70名中度或重度NE 随机接受EPO +低温或单独低温治疗），并检查 24个月时的发育结果。从小波束获得的新知识将具体地 提供：1）改善NE新生儿脑损伤严重程度的分层，2）了解NE的影响 促红细胞生成素对脑自动调节和神经元耦合的影响; 3）新的生物介质，可以预测反应 在真实的时间治疗，旨在改善大脑的结果，按照NINDS使命。