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

Lead Research Organisation: King's College London
Department Name: Psychosis Studies

Abstract

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.

Technical Summary

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

Planned Impact

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.

Publications

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Budisavljevic S (2016) Heritability of the limbic networks. in Social cognitive and affective neuroscience

 
Description Participation in NICHD (USA) meeting aimed at developing research strategic plans for individuals with cerebral palsy
Geographic Reach North America 
Policy Influence Type Participation in a advisory committee
 
Description Participation in NICHD (USA) meeting aimed at developing research strategic plans for survivors of preterm birth
Geographic Reach North America 
Policy Influence Type Participation in a advisory committee
 
Description Research Grant
Amount £185,999 (GBP)
Funding ID GN2606 
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 03/2021
 
Description Adults Born Preterm International Collaborative Network 
Organisation McMaster University
Department Faculty of Health Sciences
Country Canada 
Sector Academic/University 
PI Contribution This is an international data sharing initiative investigating various areas of functioning in adults who were born very preterm. I am leading the Executive Function analysis group.
Collaborator Contribution Each Centre is leading one theme. All collaborating partners are contributing to the Initiative with sharing published data when available.
Impact This collaboration is multi disciplinary. Disciplines involved include paediatrics, psychology, psychiatry, neurology, respiratory medicine, health economics.
Start Year 2013
 
Description Adults Born Preterm International Collaborative Network 
Organisation Norwegian University of Science and Technology (NTNU)
Department Department of Laboratory Medicine, Children's and Women's Health (LBK)
Country Norway 
Sector Academic/University 
PI Contribution This is an international data sharing initiative investigating various areas of functioning in adults who were born very preterm. I am leading the Executive Function analysis group.
Collaborator Contribution Each Centre is leading one theme. All collaborating partners are contributing to the Initiative with sharing published data when available.
Impact This collaboration is multi disciplinary. Disciplines involved include paediatrics, psychology, psychiatry, neurology, respiratory medicine, health economics.
Start Year 2013
 
Description Adults Born Preterm International Collaborative Network 
Organisation University College London
Department Institute for Women's Health
Country United Kingdom 
Sector Academic/University 
PI Contribution This is an international data sharing initiative investigating various areas of functioning in adults who were born very preterm. I am leading the Executive Function analysis group.
Collaborator Contribution Each Centre is leading one theme. All collaborating partners are contributing to the Initiative with sharing published data when available.
Impact This collaboration is multi disciplinary. Disciplines involved include paediatrics, psychology, psychiatry, neurology, respiratory medicine, health economics.
Start Year 2013
 
Description Adults Born Preterm International Collaborative Network 
Organisation University of Helsinki
Department HUS Children's Hospital
Country Finland 
Sector Hospitals 
PI Contribution This is an international data sharing initiative investigating various areas of functioning in adults who were born very preterm. I am leading the Executive Function analysis group.
Collaborator Contribution Each Centre is leading one theme. All collaborating partners are contributing to the Initiative with sharing published data when available.
Impact This collaboration is multi disciplinary. Disciplines involved include paediatrics, psychology, psychiatry, neurology, respiratory medicine, health economics.
Start Year 2013
 
Description Adults Born Preterm International Collaborative Network 
Organisation University of Warwick
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution This is an international data sharing initiative investigating various areas of functioning in adults who were born very preterm. I am leading the Executive Function analysis group.
Collaborator Contribution Each Centre is leading one theme. All collaborating partners are contributing to the Initiative with sharing published data when available.
Impact This collaboration is multi disciplinary. Disciplines involved include paediatrics, psychology, psychiatry, neurology, respiratory medicine, health economics.
Start Year 2013
 
Description Bar Ilan University Israel 
Organisation Bar-Ilan University
Country Israel 
Sector Academic/University 
PI Contribution This collaboration was established with the award of a Lectureship Award by the British Council. The aims of the collaboration are the following: 1. Establishing a new research network to study the early life antecedents of later emotion regulation problems in typically and atypically developing children. This activity will be the main purpose of the visit and will involve several meetings with Prof. Geva and her research team and colleagues in order to develop ideas and discuss optimal research methodologies. 2. Forming a sustainable UK-Israel scientific partnership with the establishment of an Erasmus Plus agreement between Bar-Ilan University, Israel and King's College London, UK. Dr. Nosarti and Prof. Geva will complete all paperwork and meet with the appropriate International Exchange Officers to discuss details of the scheme. Erasmus Plus offers lecturers' mobility as well as students'. This option will be explored in order to arrange for Prof. Geva to spend a period of time at King's College London in the near future to develop the joint funding call further, thus facilitating long lasting cooperation initiated by the UK-Israel Science Lectureship Scheme. 3. Delivering lectures to both undergraduate and postgraduate students. 4. Teaching new techniques/research methods that are not available in their host laboratories. One of Dr. Nosarti's current research interests is dynamic resting state functional connectivity, which refers to patterns of brain communication that change over time, and can be investigated by quantifying variability in the strength or spatial organization of functional connectivity among brain regions. Dr Nosarti will deliver a series of workshops an analysis of dynamic resting state functional connectivity using a sliding window approach. Workshops on probabilistic tractography will be also offered. 5. Visiting collaborating sites and collegues in relevant clinical settings (Sheba medical center, Asaf-Harofeh, Sourasky medical Center) as well as discussing possible collaborations with other groups at Bar-Ilan University.
Collaborator Contribution please see above
Impact Lectureship Award by the British Council (£ 1850)
Start Year 2016
 
Description Erasmus + University of Padova 
Organisation University of Padova
Country Italy 
Sector Academic/University 
PI Contribution This collaboration has been facilitate by the establishment of an Erasmus + scheme whereby postgraduate students from the University of Padova have spent periods of 6 months contributing to analysis of data acquired as part of this project.
Collaborator Contribution Please see above, my partners have selected excellent students to take part in research.
Impact The following papers have been co-authored by collaborators from the University of Padova (*): Caldinelli C*, Froudist-Walsh S, Karolis V, Tseng CE, Allin MP, Walshe M, Cuddy M, Murray RM, Nosarti C. White matter alterations to cingulum and fornix following very preterm birth and their relationship with cognitive functions. Neuroimage. 2017 Apr 15;150:373-382. A multimodal imaging study of recognition memory in very preterm born adults. Tseng CJ, Froudist-Walsh S, Brittain PJ, Karolis V, Caldinelli C*, Kroll J, Counsell SJ, Williams SC, Murray RM, Nosarti C. Hum Brain Mapp. 2017 Feb;38(2):644-655. doi: 10.1002/hbm.23405. Epub 2016 Sep 20. Altered resting-state functional connectivity in emotion-processing brain regions in adults who were born very preterm. Papini C*, White TP, Montagna A*, Brittain PJ, Froudist-Walsh S, Kroll J, Karolis V, Simonelli A*, Williams SC, Murray RM, Nosarti C. Psychol Med. 2016 Oct;46(14):3025-3039. Socio-Emotional Development Following Very Preterm Birth: Pathways to Psychopathology. Montagna A*, Nosarti C. Front Psychol. 2016 Feb 12;7:80. The case of late preterm birth: sliding forwards the critical window for cognitive outcome risk. Mento G*, Nosarti C. Transl Pediatr. 2015 Jul;4(3):214-8.
Start Year 2013
 
Description Monash Prof Peter Anderson 
Organisation Monash University
Country Australia 
Sector Academic/University 
PI Contribution We are carrying out a mate-analysis of mental health outcomes in adults who were born very preterm / with a very low birth weight
Collaborator Contribution please see above
Impact none yet
Start Year 2013
 
Description SPARC collaboration with Prof Cota Navin Gupta 
Organisation Indian Institute of Technology Guwahati
Country India 
Sector Academic/University 
PI Contribution Government of India - Scheme for Promotion of Academic and Research Collaboration (SPARC) Title of Project: Data driven neuro-behavioural clusters in adults who were born very preterm using multivariate analysis Thrust Area: Emergent areas of Impact Sub-domain: Artificial Intelligence and Cognitive Science Abstract: We propose to apply and validate a family of multivariate methods to structural magnetic resonance imaging (sMRI) datasets of adults who were born very preterm (< 33 weeks of gestation) and healthy controls. Multivariate approaches such as Source Based morphometry (SBM) and Biclustered Independent Component Analysis (BICA) are ideally suited for identifying complex and weak effects from high dimensional datasets, while simultaneously performing data reduction procedures. Previous brain structural imaging studies in samples of individuals who were born very preterm born used grey matter volumes and showed both increases (i.e. in frontal and lateral parieto-temporal areas) and decreases (i.e. in subcortical and medial temporal regions) compared to healthy controls. Application of SBM to very preterm and healthy controls data will not only highlight group differences but also robustly capture complex relationships between these brain regions (i.e. independent components in multivariate context) and preserve spatial correlation. Data-driven clinical subtyping in psychiatric cohorts using sMRI data was recently suggested using BICA. Data driven neuro-behavioural clusters will be obtained using BICA on sMRI data from the very preterm cohort only, using two brain regions which show group differences and the highest effect size from SBM. Considering the same two regions, BICA will also be applied to healthy controls cohort only. This work will also validate existing and research new methods to obtain subgroup specific component maps. My research team will provide neuroimaging and outcome data.
Collaborator Contribution Our partners will provide novel analytical techniques.
Impact This scheme has just been funded.
Start Year 2019
 
Description SPRING 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution I am on the advisory board of SPRING, an MRC-funded project on preterm birth and genetics (PI: Anita Thapar)
Collaborator Contribution please see above
Impact multi-disciplinary collaboration, no outputs yet
Start Year 2016
 
Description Consultation about adolescent mental health with Sparkle and Dark Theatre Company 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I have been discussing issues relating to adolescent mental health and brain development for a new production entitled I am beast; with the Company Director and performers. This performance features an adolescent girl who experiences psychiatric problems and is described on the Theatre Company's website as a "stunning exploration of the power of grief and childish imagination".
Year(s) Of Engagement Activity 2015
URL http://www.sparkleanddark.com/#!i-am-beast/cprp
 
Description Creative Intersections 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We took a particular text related transformation and change from a work by the Cardboard Citizens and converted it into numerical data by using an analysis of the words/spaces/letters. We then took this data and turned it into sets of 3 co-ordinates that can be used as Talairach and Tournoux's co-ordinates to describe the location of human brain structures independent of individual differences). We then mapped the obtained locations in the brain (informed by the co-ordinates) to the specific functions they underlie (e.g. movement of right arm, speech, emotion, etc). In order to do this we used a public access electronic database that maps structure to function. We worked with a writer, Marina Benjamin who created a whole new story based on transformation and change and the brain functions identified through this process.
More information can be found @
https://creativeintersections.wordpress.com/what-have-we-been-doing/

A public event took place at the Royal Society of Arts in Nov 2012 where we presented the results of our collaboration. There were approxiamately 50 participants, artists, academics and members of the general public. A blog on this event can be found @
http://www.sarahfarrugia.com/2012/11/creative-intersections.html
Year(s) Of Engagement Activity 2012,2013,2014
URL https://creativeintersections.wordpress.com
 
Description New Scientist 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I worked with a freelance journalist, Linda Geddes, to prepare a feature article entitled Premature birth: How its effects can stay with you for life. Participants from the MRC funded study were also interviewed and their experiences were reported in the article.
Year(s) Of Engagement Activity 2016
URL https://www.newscientist.com/article/2077401-premature-birth-how-its-effects-can-stay-with-you-for-l...
 
Description Pint of Science - public engagement event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Pint of Science is a worldwide science festival which brings researchers to local pub/cafe to share their scientific discoveries with the public. We will be speaking at a 'Beautiful Mind' event on May 12th 2020, talking about our research (premature children, psychological and cognitive development and neural correlates, etc) to a lay audience in a pub setting.
Year(s) Of Engagement Activity 2020
 
Description School visit and presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We have established links with Our Lady of Grace Catholic Infant School in London where we recruit control participants for our study. We invited parents to attend a workshop presenting our research.
Year(s) Of Engagement Activity 2018
 
Description Talk at the NHS South West Neonatal Network entitled YOUR PREMATURE BABY AT HOME A DAY FOR PARENTS 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact I did two talks for the NHS South West Neonatal Network in 2016, in Bristol and Plymouth. These were part of conferences for parents of babies who were born premature. I talked about the importance of play and engaged parents to consider activities that aimed at supporting their children's learning and development. The feedback from these talks were very positive and I will consider doing more in the near future.
Year(s) Of Engagement Activity 2016
URL http://www.swneonatalnetwork.co.uk/parents-families/2016-parent-conference/
 
Description Visit and presentation to Westminster Academy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We presented our work to 6th formers attending Westminster Academy in London. Whilst students may not benefit directly from this research, this pathway will help inform students about health care research and may help to enthuse the next generation of potential scientists and health care workers.
Year(s) Of Engagement Activity 2018