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

摘要 由出生窒息引起的新生儿脑病(NE)构成全球主要公共卫生负担 每年有数以百万计的婴儿，尽管治疗过低体温，但有一半的新生儿神经功能不佳 结果。随着新的神经保护干预措施正在临床试验中研究，迫切需要 建立治疗效果的生理替代指标，以指导患者选择和/或修改 治疗性干预。新生儿脑损伤领域的挑战一直是临床应用的难点。 在出生后短的治疗窗口内辨别NE的严重性，或分析NE的动态方面 东北地区患病新生儿的脑循环。PI和她的生物工程团队已经开发出一种“小波 “神经血管束”分析系统可测量脑自动调节(CA)和神经血管 在动态、非静态临床条件下的多时间尺度的耦合(NVC)。实时评估 关于脑血流量和神经元活动的耦合，因此提出了“神经血管束” 以确定伤害的严重程度，并确定可能从增加的治疗中受益的婴儿。 所提出的方法不仅具有捕捉大脑进化中的非平稳方面的能力 但也可以量化NE血流动力学受损的程度和持续时间，以及他们的 对功能和结构结果的影响。私家侦探发表了她的方法论技术 发展，以及将小波束措施与短和长小波束措施联系起来的初步观察 体温过低后的足月发育结局。长期目标是利用技术 小波神经血管束在优化窒息新生儿预后方面的优势 适当地选择患者进行治疗试验，并确定潜在的反应因素 心理治疗。促红细胞生成素(EPO)，对脑血流、神经发生和血管生成有假定的作用， 目前正在评估作为一种新的辅助治疗中到重度NE(高剂量EPO窒息； NS092764 NCT02811263 NINDS1U01)。德克萨斯大学西南分校的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(目标1)，确定 一项新的随机神经保护试验中EPO对CA/NVC的影响 (目标2)，并预测短期结构和长期功能结果(目标3)。为了检验这一假设， 100名新生儿将在德克萨斯大学西南分校登记(30名未经治疗的轻度NE和70名中度或重度NE 他们被随机接受EPO低温治疗或仅接受低温治疗)并检查 24个月时的发育结果。从小波束中获得的新知识将具体 提供：1)改善NE新生儿脑损伤严重程度的分层，2)了解其影响 促红细胞生成素对大脑自我调节和神经元偶联的影响，以及3)可以预测反应的新生物介质 实时治疗，旨在根据NINDS任务改善大脑结果。

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.