Brain, Immunity and Psychopathology following very Preterm birth (BIPP)

Importance

Thirteen million infants are born prematurely every year and approximately one quarter are at risk of developing mental health problems. These problems continue into adult life and encompass a variety of diagnoses including anxiety and depression.

It is therefore a public health priority to address the long-term consequences of prematurity. Researchers believe that mental health difficulties associated with prematurity could be at least partly explained by differences in neurodevelopment: the life-long process by which the brain grows and adapts to change. However, we do not know how specific patterns of brain maturation make premature children more likely to experience mental health problems compared to term-born children. We also do not know if the stress caused by premature birth and by the procedures received during neonatal intensive care change the way premature babies respond to stress. Responding to stress triggers a response in the system dedicated to fight infections in our body (i.e., the immune system). This response is exaggerated in people with a variety of mental health problems. Therefore, it is possible that prematurity and an altered immune response interact with an underlying vulnerability in the brain of premature children, giving rise to mental health problems.

To date, brain development and its relationship with the immune system and mental health has never been studied in premature children. This is what BIPP plans to do. If our results show that alterations in immune system activation have long-term effects on brain development, we can reasonably think that new treatments targeting the immune system could foster resilience and improve the mental health problems experienced by so many premature children.

BIPP - Our Study

BIPP's key research goal is to generate new information about brain development and immune system activation in relation to mental health problems in premature children. BIPP has the big advantage that all children we will study at 9 years of age have already been studied three times in the past, at around the time of birth, at 2 and at 4-6 years of age. Information collected on these children is unique in that only very few centres worldwide have studied the long-term effects of prematurity in such detail. We will access the wealth of data provided by the previous assessments at no cost to the MRC.

The ultimate aim of the study is to identify those children who could benefit from interventions to prevent mental health problems from arising, and before they become overt. Provision of effective interventions to protect mental health at an early stage has the potential to place vulnerable children onto healthy developmental trajectories, hence avoiding severe distress to children and their families and expense to society at large.

We will study 240 children who were born prematurely (< 32 weeks of gestation) who are part of on-going follow-up studies we are conducting at King's College London. We will also study a group of 120 age and sex-matched controls recruited from local schools.

Planned work comprises the following:

1. Identifying those children who are vulnerable to developing mental health problems by studying specific patterns of brain development from the neonatal period to childhood. Children will be assessed with age-appropriate tests and a high-resolution brain scan which does not use radiation and gives detailed pictures of the brain that cannot be obtained in any other way.

2. Studying patterns of immune system activation from the neonatal period to childhood and their links to brain development and mental health. We will measure immune response by collecting a small blood sample.

3. Using existing and new data to study whether we can identify specific pathways that lead children to experiencing mental health problems, in order to develop interventions to prevent such problems early in life.

Infants born very preterm (i.e., born before 32 weeks of gestation) are at high risk of long-term psychiatric illness. BIPP will map the trajectories of brain growth and function that underlies the risk of psychopathology associated with very preterm birth from foetal life to childhood, study the role of genetic and environmental factors, and test the hypothesis that alterations in brain development and psychopathology are caused in part by immune activation in the perinatal period and/or later childhood. The study will be carried out in the largest and most comprehensively phenotyped sample of children who were born very preterm that has been studied longitudinally to age 4-6 years as part of the NIHR-funded Evaluation of Preterm Imaging Study (ePrime). BIPP will collect new cognitive, MRI, immune and psychopathology data in 240 very preterm children at age 9. 120 controls matched 2:1 by age, sex and socio-economic status will be also studied.

Firstly, we will provide an unprecedented longitudinal characterisation of brain development with structural and functional magnetic resonance imaging (MRI), and define how this relates to psychopathology, assessed with clinical, dimensional and trait measures. Secondly, we will determine whether peripheral cellular mediators of immune activation, assessed perinatally and in childhood, relate to structural and functional brain alterations and psychopathology. Thirdly, we will integrate these data with other cognitive and psychosocial measures and delineate biologically and clinically meaningful neurodevelopmental trajectories - from foetal life to childhood - to map phenotypic heterogeneity onto alterations in underlying pathophysiology.

The results of the study will inform the development and implementation of neurobehaviourally-informed preventative interventions and will facilitate the identification of new pharmaceutical and behavioural targets for improving the mental health outcomes of very preterm children.

Academic impact
1) Our study will map for the first time the neurobiological and molecular mechanisms that underlie the relationship between very preterm birth and psychopathology from foetal life to age 9.
2) Our work will be the first to determine whether peripheral cellular mediators of immune activation, assessed perinatally and in childhood, relate to structural and functional brain alterations and psychopathology in very preterm children.
3) By using longitudinal multimodal neuroimaging to predict psychopathology in childhood we will validate various imaging modalities as potential biomarkers of psychiatric vulnerability in very preterm children.
4) Our work will study specific neurodevelopmental trajectories from foetal life to childhood that can help identifying those children who are most vulnerable to psychopathology, in order to develop preventative interventions.
5) Training. We will recruit new research associates and provide them with comprehensive training in multidisciplinary neurodevelopmental research.

Societal impact
The proposed study has the potential to improve the quality of life and health of preterm children as, despite a great deal of on-going research, the causes underlying the cognitive and behavioural difficulties associated with very preterm birth remain unclear. Furthermore, at present there are no established preventative strategies to address the psychiatric
problems of preterm children and to provide necessary family support. As early interventions appear to diminish the adverse long-term consequences of some neurodevelopmental conditions (1), the establishment of criteria to identify target groups for intervention will be important in the medium term for shaping and enhancing the effectiveness of public
health strategies policies, standards, guidelines and care pathways for improving preterm children's long-term sequelae.

Furthermore, our research could 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 and psychiatric disorders (e.g., MIND, Autism Speaks). We envisage the results of the study will be highlighted in the media, thus contributing to increasing public awareness of the long-term consequences of very preterm birth.

Economic impact
The economic cost of childhood behavioural problems has been estimated as ranging from £11,030 to £59,130 per child per annum (2). Provision of preventative interventions at an early stage of development has the potential to place children at high risk of psychiatric disorder onto healthy developmental trajectories, hence avoiding significant later distress and expense to both the specific individual and society.

In summary, our work will have important implications for children at high risk of developing psychopathology and their families, mental health professionals, educators and society at large. Our work is perfectly aligned with the MRC "Mental health and wellbeing" area of high strategic priority as it will explore the risk factors for poor mental health in preterm school- aged children, with an emphasis on linking neurodevelopmental mechanisms with behaviour and its associated cognitive processes. The work is also aligned with the MRC "Strategy for Lifelong Mental Health Research", where "mental health research which focuses on children and young adults" is advocated, stressing the "need to better understand the early manifestations, resilience and the impact of the biological, social and environmental drivers of disorders" "and engage cutting edge informatics technology and analytics expertise".

References
1. Halperin JM, et al. Preventive interventions for ADHD: a neurodevelopmental perspective. Neurotherapeutics. 2012;9(3):531-541.
2. Suhrcke M, et al. Economic aspects of mental health in children and adolescents. WHO Regional Office for Europe; 2008.