Structural and functional fronto-hippocampal maturation and neurodevelopmental outcome following very preterm birth in adulthood

Premature birth is a major public health problem, costing the UK £939m a year. Babies who are premature may suffer many adversities after birth. As they grow up some appear to be at risk of problems relating to health, cognition and behaviour, while others are resilient. These differences may be related to neurodevelopment, the life-long process by which the brain grows and adapts to change. We will work with a unique cohort of individuals who were born prematurely and who have been taking part in a follow-up study from birth to age 19. They are now 28-33 years old. First, we will assess their cognition (including learning disabilities, memory and attention) and mental health, suspecting that many people may be "suffering in silence" with difficulties which are not recognised. Second, we propose to use various neuroimaging techniques to examine how the brain changes as people grow into adults. The aim of the study will be to define for the first time the patterns of brain growth that make a person at risk of poor outcome, as well as those that are associated with developmental resilience. In the future, this information will enable us to develop treatments to reduce or prevent long-term disability in people born prematurely.

Individuals who were born very preterm are at greater risk of brain damage and consequent neurological disorders, neuropsychological, and behavioural impairments in childhood and later in life. A number of studies to date have used MRI at term to predict childhood outcome, but little is known about the nature and course of neurodevelopment in preterm individuals when they reach adulthood. We propose to study 153 individuals who were born very preterm (VP; <33 weeks of gestation) in 1979-1984, with varying degrees of neonatal distress, for whom we have acquired detailed longitudinal neuroimaging and developmental data from birth up to adolescence, and 89 age matched controls. This will allow us to undertake the first study on how VP birth affects the longitudinal trajectories of brain development from mid-adolescence (14-15 years) to adulthood (28-33 years), and to determine the relationship between brain maturational patterns, cognition and behaviour. As functional and structural alterations in frontal, temporal and hippocampal regions have been described in VP samples and have been associated with neurodevelopmental outcome, we will specifically focus on studying maturation in these brairegions. We propose a multimodal neuroimaging study, which will use voxel-based morphometry, region of interest volumetric and shape analysis, diffusion and functional MRI and a novel technique (mcDESPOT), which will allow us for the first time to assess myelin fraction in a VP sample in adulthood. We hypothesise that VP individuals will show altered dynamic sequences of brain maturation (slower growth rates and accelerated cortical thinning) in frontal and temporal brain regions compared to controls from mid-adolescence to adulthood. We further hypothesise that exaggerated or/and dysregulated dynamic patterns of frontal and temporal maturation will be associated with neurodevelopmental "risk", while early alterations which normalize by adulthood will be associated with "resilience"

According to the definition of Pathways to Impact by Research Councils UK, it is paramount to invest in the best research, people and infrastructure, with the aim of enhancing the impact of funding on society.

The current study provides a unique opportunity to investigate the long-term neurodevelopmental impact of very preterm birth, which currently represents approximately 1-2% of all live births. Access to our longitudinal cohort, on which much information has already been gathered, will allow us to link later-life structural and functional brain changes to perinatal variables and measures of behavioral, cognitive and neurological development in childhood and adolescence.

This study will improve the health and well-being of preterm individuals by identifying strong predictors of outcome, as at present it is not possible to do this solely on clinical grounds. Our study will fall under the remit of a recent White Paper released by the March of Dimes, which advocates to prioritise the development of strategies for reducing disability related to preterm birth.
In terms of possible contribution of this study to enhance the quality of life of preterm individuals, we believe our results could guide the development of remediation strategies to be implemented at those individuals at risk of developing cognitive and behavioural problems at younger ages. The planning and elaboration of preventative and remediation strategies partly based on the results of the current study could attract further R&D funding.

Strategies aimed at attenuating or even preventing long-term disability could improve the quality of life of very preterm individuals and shape and enhance the effectiveness of public services (e.g., preventing academic difficulties using adaptive cognitive intervention programs). This study could also potentially be of clinical importance, as recent research suggests that the initiation of treatment before the onset of psychiatric disorder (e.g., psychosis) may prevent or delay the development of the disorder.
Therefore, in the medium term, our research could have an impact on the care management of preterm populations as described in policies, standards, guidelines and care pathways and inform the work of associated carers and therapists, centres that provide facilities and services, charities / associations that help, support, advise and campaign for those with neurodevelopmental disorders (e.g., British Neuroscience Association).

At a local level, our study will recruit new research associates and provide them with comprehensive training in multidisciplinary neurodevelopmental research, and one researcher will have the opportunity of receiving state-of-the-art training in longitudinal neuroimaging analysis at UCLA, where one of our collaborators is based (Prof Thompson), benefiting from an existing exchange program between our centre and UCLA. At a global level, our results will extend existing knowledge on the life-long patterns of brain maturation following very preterm birth, up to an age that has never been investigated before. Thus, our study will contribute to increasing public awareness and understanding of the long-term consequences of very preterm birth. Please refer to previous section on 'Communication plans' for details on our plans for engagement, communication and dissemination about our research and its outcomes.