In vivo microstructural neuroimaging in infants at risk of developing neurocognitive delay or neurobehavioural disorders

Context of this research
Some babies are more likely than others to develop a range of problems in later childhood including poor attention, problems interacting with others or performing poorly when they go to school. It is possible that these problems are due to abnormalities in brain development or due to brain injury occurring before, or at the time of birth.
Aims
Our aims are to implement advanced imaging approaches to examine the brain in more detail than has previously been possible. We will study 3 groups of patients; infants who are born prematurely, infants who have abnormalities in the development of their heart (congenital heart disease, CHD) and infants who have a high risk of developing problems communicating and relating to others (as they have a sibling with this condition) . We will also collect imaging data in healthy babies who are born around their expected date of delivery (healthy term controls).
Methods
The imaging data we intend to collect is called diffusion magnetic resonance imaging (d-MRI). d-MRI provides objective measures which we can quantify, allowing us to compare patients and healthy controls. We will use d-MRI to obtain measures of the building blocks of the computational circuitry of the brain (known as neurites). These measures have not been previously studied in infants, but we believe they will provide important information on how brain circuitry is altered in our patients.
The babies will have a scan on a magnetic resonance imaging (MRI) scanner that we have placed in our neontatal intensive care unit. This means that we do not have to transport the babies to a different place in the hospital for them to have their scan. We are able to scan even the smallest and sickest babies safely using this scanner.
We will also assess the infants when they are 2 years of age. We will test their ability to perform a number of different tasks, which will highlight any problems they may have with cognition (how well they understand and follow instructions, and their ability to perform tasks), attention and how well they can interact with their families and other people. We will assess whether our d-MRI measures that we collect soon after birth correlate with these assessments at 2 years of age.
Expected outcomes from this research
We expect our methods to highlight differences in the brain between patients and healthy infants. If these measures are related to performance at 2 years of age, then these tools can be used to identify infants at risk of developing behavioural problems and problems that will lead to them performing poorly at school. This can improve the long-term outcome for these babies in 2 ways; children who may develop behavioural problems do much better if their therapy is started at an early age and treatments are now being developed which are aimed at reducing brain injury in these babies and we can use these imaging tools to test whether treatments have been effective. Ultimately, this could reduce the time taken for treatments to be widely used in clinical practice and, in this way, help to reduce the consequences of brain injury in babies.

Background: The underlying neural substrates for childhood neurocognitive and neourbehavioural disorders are not well defined. We will assess neurite morphology in 3 groups of at risk infants to increase our understanding of the microstructural neuropathology associated with these conditions and establish new imaging biomarkers to identify infants who will benefit from treatment and assess efficacy of potential treatments.
Aims: i. Assess neurite morphology (neurite density, Vic and orientation dispersion index, ODI) in 3 groups; preterm infants, infants with CHD and those at high risk of developing ASD, and compare these measures to those obtained in healthy controls. ii. Test the hypothesis that neurocognitive and neurobehavioural performance in these subjects at 2 years is associated with Vic and ODI measures in the early neonatal period.
Methods: We will study 100 infants born at <32 weeks GA within 2 weeks of birth and at term, 100 term born infants at risk of ASD, 35 infants with CHD and 35 term controls. Perinatal clinical data will be collected. MRI will be performed on a 3T system sited on the Neonatal Intensive Care Unit. The precise parameters for d-MRI will be optimised, but we will acquire a low b value and a high b value shell. Measures of Vic and ODI will be obtained using neurite orientation dispersion and density imaging (NODDI) analysis. Group-wise voxel based and machine learning based analyses of standard diffusion (fractional anisotropy, FA, mean diffusivity, MD, axial and radial diffusivity, AD and RD) and NODDI measures will be performed to i. compare subject groups to term controls ii. Correlate Vic, ODI, FA, MD, AD and RD with neurodevelopmental performance at 2.
Projected outputs: This work will provide improved imaging and analysis tools for the neonatal population, enhanced characterisation of brain development and injury and will facilitate the prediction of neurodevelopmental outcome and the testing of therapeutic interventions.

The principal non-academic beneficiaries of the proposed project are infants with acquired brain injury, in particular those with a poor neurodevelopmental prognosis, their families, short-term health providers who provide support for infants with perinatal brain injury and long-term health and education services that provide on-going support for these populations.

The incidence of preterm birth is increasing in the UK and preterm infants can suffer a range of neurological and cognitive disorders that impart a significant morbidity and can result in attentional and behavioural problems that adversely affect performance at school and into adult life. Cognitive and behavioural disorders associated with preterm birth now affect a large number of children and represent a tremendous human, emotional, social, and economic burden for their families and society.

Autism spectrum disorders and attention deficit hyperactivity disorder are associated with high levels of caregiver burden in adolescence and young adulthood (Cadman et al, 2012). Over the past decade, there has been an increasing awareness of these diseases. This may be due in part to better tools for diagnosis, which have contributed to enhance recognition of children with psychiatric disorders. However, the incidence of some disorders, like autism, appears to be increasing. Developing imaging tools that can identify infants at risk of developing neuropsychiatric disorders is important as an early diagnosis of neuropsychiatric disorders significantly improves outcome. This is particularly relevant now as treatments based on modulation of synaptic function have been proposed.

Preterm birth confers a significant economic and social cost across an entire lifetime, and reducing the burden of preterm brain injury may deliver significant cost improvements in health and social care. A model of the economic costs throughout childhood associated with prematurity, at 2006 prices, are estimated to be between £51 000 (at 37 weeks GA) and £151 000 (at < 27 weeks GA) (Petrou & Khan, 2012) and mean public sector costs for those preterm children with any neuropsychiatric diagnosis are approximately £2000/annum greater, again at 2006 prices, than preterm children without a neuropsychiatric disorder. This cost difference is increased in the presence of moderate cognitive impairment (Petrou et al, 2010).

Survivors of CHD are more likely to have specific learning difficulties and to require special education services. The economic burden of these impairments has not yet been defined in detail but it is clear that children who have neurocognitive deficits following mild HIE or CHD require increased community and school-based resources. By providing a mechanism to target therapies to those infants most likely to benefit and by offering the opportunity to assess efficacy of neuroprotection in the neonatal period, this project has the potential to reduce the economic burden related to morbidity associated with neonatal brain injury to the NHS and to education providers.

In addition, potential beneficiaries in the commercial private sector include pharmaceutical companies who are developing targeted therapies for neonatal brain injury. This project has the potential to deliver qualified biomarkers by the end of the 5 year period, which can then be employed in studies assessing neuroprotective treatments, enabling sample sizes in treatment trials to be reduced.

References
Cadmen et al. J Am Acad Child Adolesc Psychiatry 2012; 51: 879-888.
Petrou & Khan. Semin Fetal neonatal Med 2012; 17: 170-178
Petrou et al. Br J Psychiatry 2010; 197: 395-404