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

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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.