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

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.

Intrapartum-related events are the 4th leading cause of childhood mortality worldwide. Infants exposed to a perinatal insult typically present with neonatal encephalopathy (NE) that is treated with hypothermia, which prevents adverse outcome in only ~50% of infants. There is an urgent clinical need to detect those neonates at most risk and who may benefit from adjunct therapies. We aim to address this by developing a novel optical instrumentation that will allow non-invasive, in-vivo, at the cot-site measurements of brain oxygenation, blood flow, metabolic rate of oxygen and mitochondrial function. This instrument will use: (1) broadband near-infrared spectroscopy or Broadband NIRS that has the capacity to measure brain vascular oxygenation and mitochondrial function. By measuring the light attenuation at many different near-infrared (NIR) wavelengths, one can estimate the vascular haemoglobin oxygenation and the redox state of mitochondrial respiratory chain enzyme, cytochrome-c-oxidase (CCO). (2) diffuse correlation spectroscopy or DCS has the capacity to measure cerebral blood flow (CBF). DCS uses a single wavelength of NIR light that measures brain blood flow by quantifying temporal fluctuations of light fields emerging from the tissue surface.
Measurements of brain tissue CCO with Broadband NIRS and of CBF with DCS have been successfully but independently applied to monitor NE. For the first time we will combine them into a single instrument. The measurements will then be integrated using our computational model of brain tissue physiology. We will assess the instrument through a series of hypoxic-ischaemic studies in the neonatal preclinical model and validate its predictive capacity to quantify the level of brain injury using a series of multimodal measurements (MRS, EEG, Histology). Finally we will move beyond of proof-of-principle to a clinical observational study in NE infants both during the acute (Days 1-3) and post-acute phases (Days 4-7).

Healthcare: Millions of babies around the world suffer brain injuries due to events around the time of birth. Neonatal encephalopathy (NE), the clinical manifestation of disordered brain function in newborns occurs in 1-3 per 1000 live term births in the UK, with 5-10 times higher rates in resource poor settings. NE is the 4th leading cause of death in children and accounts for 50 million disability life adjusted years. Many surviving infants have long-term health and social care needs with substantial resource implications for the NHS.
The primary focus of the management of NE is to reduce on-going brain injury, which is essentially hypoxic-ischaemic in nature, and thereby improve outcome. To achieve this is important to monitor a range of variables related to cerebral haemodynamics, oxygenation and metabolism, and which can be used to identify important physiological events. Our proposed instrument will be able to deliver such measurements and help in the management of NE with the aim of identifying the most severe affected babies that can be helped with adjunct therapies. This research has the potential to revolutionise the pathophysiological assessment of NE. We believe that this work will also transform the trajectory of neurotherapeutic developments, allowing early individualised assessment and a shift towards individually tailored therapies.
Understanding the physiological mechanisms controlling cerebral substrate/oxygen delivery and utilization, and their derangement, is crucial to understanding the pathophysiology of brain injury and its response to treatment. Tools which enable these mechanisms to be characterised from measured neuromonitoring signals can be used to inform optimised and individualised patient management strategies in a broad range of clinical scenarios. In particular it is important to deconstruct the mechanisms and components of haemodynamic, oxygenation and metabolic regulation. This information can then be used to guide individualised treatment strategies and develop novel therapies.
In this proposal we will focus on delivering a solution for the management of NE patients in the neonatal neurocritical care, but our non-invasive brain monitoring, is readily transferrable to other clinical areas and scenarios such as stroke units and the perioperative period. In particular we already have established collaborations with neuro-surgeons and neuro-anaesthetists investigating traumatic brain injury and stroke.
Medical technology: The healthcare decision support market is already a major growth area in health informatics, with a market value of approximately $201.7 million at the end of 2012; it has been forecast to grow to $239 billion by 2019.
Medical technology industries would benefit from a clinically effective tool for the non-invasive assessment of brain injury pathophysiology. A successful outcome to our project would be to explore a commercial market for a combination of a non-invasive neuromonitoring array and model-based data interpretation, and ensure that the UK takes a lead in development of the emerging industry. Development of this impact would require further industrial or translational resourcing, but would have the potential to have significant healthcare and economic benefits in the medium term (3-5 years after the completion of the project).