Investigating newborn brain function and behaviour associated with prematurity and brain injury

Lifelong neurodisability remains a major problem in sick newborn babies with brain injury. With a growing number of babies surviving with significant problems in later life, this will place an enormous physical, psychological and financial burden on the individual, their families and wider society.

Conventional brain scans rely on the detection of abnormal brain structure to diagnose brain injury; however, some children who develop significant learning difficulties or behavioural problems will have normal brain scans. The ability to assess brain function and neurological behaviour at an early stage will allow for accurate identification of high-risk babies at an early stage to ensure that appropriate therapies are started in a timely manner.

This project aims to investigate the brain function and behaviour of healthy and high-risk babies such as those born extremely premature or diagnosed with brain injury such as hypoxic-ischaemic encephalopathy. The research will be carried out at the Cambridge Centre for Perinatal Neuroscience in collaboration with the UCL Biomedical Optics Research Laboratory. A novel cap suited for babies has been designed with optical and electrical sensors that will non-invasively monitor blood flow and electrical brain activity simultaneously at the cot-side while the baby sleeps in the Evelyn Perinatal Imaging Centre or on the neonatal intensive care unit. In the healthy adult brain, studies have shown the presence of baseline brain activity known as resting state functional connectivity (RSFC). In babies the development of RSFC is not so clear but has been shown to be incomplete in some babies born prematurely or with brain injury. Studying RSFC will therefore help us to further understand newborn brain development. This cap uses the combined techniques of diffuse optical imaging (DOI) with electroencephalography (EEG). This technology is safe and has been used by the research group in previous studies in small, sick newborn babies demonstrating its feasibility in practice.

In order to fully understand newborn brain function, it is also important to assess the behaviour of the babies. The Neonatal Behavioral Assessment Scale (NBAS) is a standardised, clinical examination of infant neurology and behaviour. Infant behaviour is observed while they are awake or asleep; by their reaction to different sounds and objects; and how they interact with people's faces and voices. Different patterns of behaviour can indicate varying levels of brain function. Poor performance is associated with increased risk of adverse cognitive and behavioural outcome in early childhood.

Babies will also be enrolled into a follow-up programme to compare early functional and behavioural measures with longer-term neurodevelopment.

This project will represent the first comprehensive investigation of brain function and behaviour in babies. The overall aim of this study is to understand better the relationship between RSFC and behaviour as measures of brain function in the newborn. By comparing differences between healthy and high-risk infants, it will be possible to demonstrate the effects of prematurity and structural brain injury on brain function. The ultimate aim is to use this information to develop indicators of early abnormal function in babies with brain injury which will allow clinicians to initiate early treatment and support.

Conventional brain-imaging techniques detect structural pathological lesions, however subtle injury can occur undetected leading to lifelong neurodisability. Improving our understanding of infant brain function (resting-state functional connectivity) and behaviour will provide a more comprehensive picture of infant neurodevelopmental potential.

The project aims to investigate early development of brain function and behavior in infants to develop a clinical biomarker for brain injury.

A novel cap with optical and electrical sensors will be placed on the infant's head while remaining in their cot. This cap uses the combined techniques of diffuse optical imaging (DOI) with electroencephalography (EEG) to non-invasively monitor RSFC within the haemodynamic and electrical brain signals. This technology is safe and has been used by the research group previously to study seizure activity in the newborn and more recently to investigate RSFC.

The Neonatal Behavioral Assessment Scale (NBAS) is a standardised, clinical examination of infant neurology and behaviour. Poor performance is associated with increased risk of adverse cognitive and behavioural outcome in early childhood and will be used to evaluate behaviour in this study. Infants will be enrolled into a follow-up programme to compare early functional and behavioural measures with longer term neurodevelopment.

Three distinct studies will be carried out on different cohorts of infants for the following objectives
1. To establish a normal reference of RSFC: healthy term and near-term infants
2. To investigate the impact of extreme prematurity on behaviour and formation of RSFC: infants <32 weeks gestation
3. To investigate the impact of brain injury on behaviour and formation of RSFC: preterm and term infants with evidence of acquired brain injury

By demonstrating the effects of prematurity and brain injury on RSFC and behaviour, it will be possible to produce biomarkers for clinical application.

ACADEMIC IMPACT:

NEUROSCIENCE
Cambridge University is as one of the world centres for neuroscience research. The Cambridge Centre for Perinatal Neuroscience has an active programme of research focusing on brain injury and brain-imaging systems. This project is unique as it is one of the first to explore the relationship between brain structure, function and behaviour. The outcomes will therefore add a significant contribution to neonatal research, and generate potential future projects and scientific advancements in neonatal neuroscience.

The project also delivers to a wide academic field by inherently bridging distinct disciplines of psychological, clinical and physical sciences leading to future collaborations. Current collaborations that will benefit include the Autism Research Centre and Birkbeck BabyLab. The development of infant behaviour patterns with functional (ie RSFC) brain maps would contribute to the work of both groups looking into infant brain development. Functional brain injury and multimodal brain-imaging technology can be translated to research in adults with brain injury and contribute to the work of the Wolfson Brain Imaging Centre, Department of Clinical Neuroscience. The output of this work will also contribute to the Brazelton Centre which has an active programme of research in infant behaviour promoting positive healthy parent-infant relationship.

OPTICAL RESEARCH
The unique headgear design suitable for babies will allow for comprehensive multimodal functional brain-imaging in the clinical setting. The international optical community would therefore benefit from the innovative techniques of this research. Working closely with the UCL Biomedical Optics Lab will help refine their technology leading to further advances such as the development of a 3D optical brain-imaging system.

CLINICAL ACADEMIC TRAINING
The Clinical Academic Training Office has helped support my academic development in my ACF. Being awarded the Evelyn Research Training Fellowship for the first year of my PhD reflects their support and encouragement. To succeed with a further fellowship for the following 2 years of my PhD will help encourage other trainees pursuing a clinical academic career.

SOCIETAL AND ECONOMIC IMPACT:

NEONATAL MEDICINE
In England and Wales, the cost of prematurity to the public sector in 2006 was estimated at £2.9 billion, equivalent to 2.9% of the annual NHS budget. With a growing number of babies surviving with neurodisability, this places an enormous physical and financial burden on their families and society. Identifying high-risk infants early on will allow for early intervention and efficient use of resources to optimise neurodevelopmental potential. The East of England Perinatal Network has a dedicated Neonatal Neuroprotection team supporting units in the region. The team leads an award winning service in coordinated cooling treatment for infants with brain injury. The output of this research would provide clinicians with a tool to monitor brain injury and generate a robust biomarker for neuroprotective therapies such as this to help improve long-term outcomes. The team would support me in disseminating my findings and recommendations to clinical and managerial healthcare professionals across the region.

COMMERCIALISATION
There is real potential from this research to deliver a clinically valuable output to a vulnerable patient group. The UCL BORL are actively engaged with UCL Enterprise which will allow for public engagement and commercialisation of the multimodal system to ensure a positive impact will be translated into improved patient care.

CHARITIES
The Evelyn Imaging Centre was funded by the Evelyn Trust. The research of the group including this project will appeal to the public as most families can relate to the issues addressed. This will help further publicise the charity and attract potential trustees who may want to contribute to help with future medical research.