Development of a cot-side optical biomarker of brain tissue health following neonatal hypoxic-ischaemic brain injury.

在英国，每1000个足月新生儿中有1-2个会出现分娩过程中导致缺氧（出生窒息）和随后的脑损伤（新生儿脑病或NE）的问题。当长期缺氧以满足大脑的代谢需求时，婴儿的健康就处于极大的危险之中。围产期脑损伤仍然是新生儿死亡的一个重要原因，并与包括认知障碍、智力迟钝在内的长期神经残疾有关，占脑瘫儿童的15%至28%。监测脑血流量、氧输送和脑组织代谢率的紧密平衡是患者诊断和护理的主要目标。临床医生目前无法在婴儿床边连续无创地监测受伤大脑的生化状态。临床迫切需要尽早发现那些风险最大的新生儿，以及那些可能受益于辅助治疗和/或重定向临床护理以实现有效康复的新生儿。早期检测和评估脑神经状态和结果需要敏感、稳健和易于测量的生物标志物。我们建议采用一种新的、创造性的方法来监测新生儿的大脑，并将有用的信息传递给医生。我们将首先开发一种全新的便携式，非侵入性脑监测仪器，它将允许在重症监护病房的床边监测出生窒息的婴儿。这将为我们如何指导脑损伤婴儿的管理开辟新的可能性。这种新仪器将结合两种利用光来监测大脑的技术。第一种技术是宽带近红外光谱（或宽带NIRS），它使用低亮度的近红外光来测量大脑中氧气和血液的分布，以及细胞的能量工厂线粒体是如何利用氧气的。第二种技术被称为漫射相关光谱学，它使用单一波长（颜色）的近红外激光来测量红细胞的运动，从而量化脑血流量。特别是，该仪器将能够通过测量线粒体中的一种酶细胞色素-c氧化酶的电化学状态来监测非侵入性脑血流量、脑氧水平和脑组织的代谢状态。我们将在实验室中使用人类新生儿的大型动物模型来评估该仪器和测量；之后，我们将继续进行新生儿重症监护病房的临床评估研究。该系统/仪器将专门用于帮助医生量化损伤的严重程度，优化治疗的类型和持续时间，最大限度地降低进一步损伤大脑的风险，从而提高婴儿康复的可能性。除了建立这种新的神经监测仪器，我们还将开发计算机程序，这对于从大脑的测量信号中提取相关信息至关重要。这将包括开发实时测量的程序，并结合大脑的计算机模型来帮助我们理解测量信号的含义和关系。我们在这种类型的转化研究方面有着悠久而成功的记录，即针对医疗保健中的特定应用，将新型脑成像技术的硬件和软件工程相结合，并将其引入临床应用。我们已经组建了一个多学科的团队来应对这个雄心勃勃的项目的挑战，包括工程师、临床医生和物理学家，我们已经吸引了一个工业项目合作伙伴的兴趣，对我们开发的系统进行潜在的商业开发。

Problems during birth leading to a lack of oxygen (birth asphyxia) and subsequent brain injury (neonatal encephalopathy or NE) occur in 1-2 per 1000 full term births in the UK. An infant's health is in great danger when there is a prolonged lack of oxygen delivery to meet the metabolic demand of the brain. Perinatal brain injury remains a significant cause of neonatal mortality and is associated with long-term neurological disabilities including cognitive impairment, mental retardation and accounts for 15 to 28% of children with cerebral palsy. Monitoring the tight balance of brain blood flow, oxygen delivery and brain tissue metabolic rate is a major aim in patient diagnosis and care. Clinicians currently cannot monitor the biochemical status of theinjured brain continuously and non-invasively at the infant's cot-side. There is an urgent clinical need to detect as early as possible those neonates at most risk and who may benefit from adjunct therapies and/or redirection of clinical care for effective rehabilitation. Early detection and assessment of brain neurological status and outcome requires sensitive, robust and easy to measure biomarkers. We are proposing to take a new and creative approach to the way in which the neonatal brain is monitored and useful information is delivered to doctors. We will first develop an entirely novel portable, non-invasive brain monitoring instrument, which will allow birth asphyxiated infants to be monitored at the cot-side in the intensive care unit. This will open up new possibilities for how we guide the management of babies with brain injury. This new instrument will be based on integrating two technologies that use light to monitor the brain. The first technique is broadband near-infrared spectroscopy (or broadband NIRS) and uses low light levels of near-infrared light to measure the distribution of oxygen and blood in the brain, and how oxygen is being utilised by mitochondria the power factory of cells. The second technique is called diffuse correlation spectroscopy and uses a single wavelength (colour) of near-infrared laser light to measure the movement of the red blood cells and hence quantify brain blood flow. In particular this instrument will be able to monitor non-invasively brain blood flow, brain oxygen levels and the metabolic status of the brain tissue by measuring the electrochemical status of cytochrome-c-oxidase, an enzyme in the mitochondria. We will evaluate this instrument and measurement in the lab using a large animal model of the human neonate; after which we will move on to clinical evaluation studies in the neonatal intensive care unit. The system/instrument will be specifically designed to help doctors to quantify the injury severity and optimise the type and duration of therapies, minimise the risk of further injury to the brain, and thus improve the likelihood of the infant's recovery. In addition to building this new neuromonitoring instrument, we will also develop computer programmes which are essential to extract the relevant information from the measured signals from the brain. This will involve developing routines for delivering measurements in real time, and incorporating a computer model of the brain to help us understand the meaning and relationships of our measured signals.We have a long and successful track record of this type of translational research, i.e. the combined approach of hardware and software engineering of novel brain imaging technologies targeted at specific applications in healthcare, and introduction into clinical use. We have assembled a multidisciplinary team to meet the challenges of this ambitious project including engineers, clinicians and physicists, and we have attracted the interest of an industrial project partner for potential commercial exploitation of our developed systems.