Neonatal Medicine

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

Newborn babies are at high risk of brain damage if they are born too early or if they suffer a shortage of oxygen during birth at the right age. Our aim is to discover treatments to reduce or prevent this damage. ||We have been successful in finding a treatment for oxygen starvation at birth, showing with our collaborators around the world that cooling a baby to 34oC after asphyxia reduces brain damage. This treatment is being studied further but is the first time a therapy has been found which reduces brain damage in babies. It is simple and cheap and can be used around the world, and is hopefully the beginning of a series of new therapies for these unfortunate children.||Preterm brain injury is less well understood, but we have been developing new ways of taking pictures of the brain to uncover what the problems are. Using new computational techniques we now understand the problems well enough to plan for a trial next year of a treatment to reduce brain damage in preterm babies.

Technical Summary

The goal of the programme is to reduce the number of newborn infants who leave intensive care with neurodevelopmental impairment. MR imaging is a core technology which is used: (a) for discovery of the phenotype of brain abnormalities; and (b) the assessment of interventions to reduce brain injury. The programme is broadly divided between studies of preterm infants which have previously been largely observational and are now moving to interventions for the first time, and studies of term infants suffering perinatal asphyxia in which there is a longstanding interest in interventions. These projects involve close collaboration with other groups and the development of new computational and mathematical approaches to image analysis as well as laboratory studies to discover novel diagnostic and therapeutic approaches. The programme benefits from the installation in 2006 of a new State-of-the-Art 3.0T MR scanner within the neonatal intensive care unit at Hammersmith Hospital with funding from MRC and SRIF2.||A major programme for the group has been the study of hypothermic neural rescue therapy after birth asphyxia. In 2005 we reported for the first successful neuroprotection study in newborn infants and currently lead the MRC TOBY phase III trial of total body hypothermia after asphyxia. The discovery of a successful treatment for neonatal brain injury is a significant step forward.||Following a programme of laboratory studies in collaboration with Prof Nick Franks and Prof Mervyn Maze we are preparing for a phase II trial to study the benefit of adding xenon to hypothermia, using an MR imaging biomarker outcome we have previously qualified. This trial is planned to minimize the long lead time in testing potential therapies and capitalise on our combined strengths in imaging, neuroprotection and anaesthetics.||The preterm imaging programme has successfully implemented novel approaches including deformation based morphometry, allometric scaling analysis, tract-based spatial statistics and probabilistic diffusion tractography to show abnormalities in growth and development in preterm infants which mirror neurological outcomes, being both sexually dimorphic and dependent on the severity of prematurity. We are now in a position to test interventions in this group and are funded by the MRC Experimental Medicine call to test the neuroprotective value of melatonin using an MR imaging biomarker. We are working on further approaches to understanding growth and development in this population, developing an automated brain atlas and measures of connectivity which will offer metrics for further studies. ||The group benefits from very close collaborative relationships with other scientists within the MRC CSC and Imperial College, but also with the Hammersmith Hospital Trust Neonatal Unit which allows a partnership that underpinned the installation and use of the unique neonatal MR system within the intensive care unit, funded by Imperial College, MRC and external funds. This facility is the only one of its type in the world and allows data to be acquired that is not available elsewhere.

Publications

10 25 50
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Aljabar P (2010) Combining morphological information in a manifold learning framework: application to neonatal MRI. in Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention

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Allievi AG (2013) An fMRI compatible wrist robotic interface to study brain development in neonates. in Annals of biomedical engineering

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Atkinson D (2006) Nonlinear phase correction of navigated multi-coil diffusion images. in Magnetic resonance in medicine

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Atkinson J (2008) Cortical vision, MRI and developmental outcome in preterm infants. in Archives of disease in childhood. Fetal and neonatal edition

 
Guideline Title IPG347 Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury
Description NICE guideline
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Our work on hypothermia has been the subject of a review by NICE to which we contributed expert guidance. On 17-12-09 NICE held a public hearing and the preliminary guidance is that the treatment should become part of normal NHS practice. In March 2010 formal guidance was published stating that hypothermia should become standard of care. The British Association of Perinatal Medicine simultaneously issued guidelines for the general application of the therapy across the UK.
URL http://www.nice.org.uk/ipg347
 
Description National Institute of Health, USA
Geographic Reach North America 
Policy Influence Type Membership of a guideline committee
Impact NIH workshops to formulate guidelines for: (i) therapeutic hypothermia, (ii) perinatal stroke, and (iii) neonatal hypoglycaemia. Influential in US practice and research agenda
 
Description Action Medical Research, Project Grant
Amount £124,308 (GBP)
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Action Medical Research, Project Grant
Amount £148,510 (GBP)
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 10/2013
 
Description Applied Programme Grant RP-PG-0707-10154 Evaluation of MR imaging to predict neurodevelopmental impairment in preterm infants
Amount £2,600,000 (GBP)
Funding ID RP-PG-0707-10154 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2009 
End 07/2015
 
Description Chain Florey Clinical Training Fellowship (with Imperial College)/Medical Research Council (MRC) and NIHR Imperial College BRC
Amount £75,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Imperial Biomedical Research Centre
Sector Public
Country United Kingdom
Start 03/2008 
End 02/2011
 
Description Development Pathway Funding Scheme
Amount £548,666 (GBP)
Funding ID MR/N027949/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description EPSRC Pathways to Impact
Amount £51,170 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start  
 
Description EPSRC Project Grant EP/F011830/1 Computational Morphometry of the Developing Cortex
Amount £273,740 (GBP)
Funding ID EP/F011830/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 06/2008 
End 05/2011
 
Description EPSRC healthcare partnership EP/I000445/1 Computer aided diagnosis of neurological damage to improve care for infants born prematurely
Amount £706,635 (GBP)
Funding ID EP/I000445/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start  
 
Description European Society for Pediatric Research Consolidator Grant
Amount € 75,000 (EUR)
Organisation European Society Paediatric Research 
Sector Charity/Non Profit
Country Switzerland
Start 02/2018 
End 02/2019
 
Description HEFCE New Blood Senior Lecturership
Amount £500,000 (GBP)
Organisation Higher Education Funding Council for England 
Sector Public
Country United Kingdom
Start 09/2009 
End 08/2013
 
Description HEFCE Strategic Research Infrastructure Fund (2)
Amount £1,000,000 (GBP)
Organisation Higher Education Funding Council for England 
Sector Public
Country United Kingdom
Start  
 
Description Imperial College Biomedical Research Centre
Amount £120,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Imperial Biomedical Research Centre
Sector Public
Country United Kingdom
Start  
 
Description Imperial College Biomedical Research Centre
Amount £177,877 (GBP)
Organisation National Institute for Health Research 
Department NIHR Imperial Biomedical Research Centre
Sector Public
Country United Kingdom
Start  
 
Description MRC Project Grant
Amount £1,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2009 
End 08/2011
 
Description Medical Research Council (MRC) MD/PhD studentship
Amount £75,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
End 06/2013
 
Description PROJECT GRANT
Amount £174,035 (GBP)
Funding ID GN2630 
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 10/2020
 
Description Programme Grant
Amount £1,097,179 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Project Grant
Amount £77,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 08/2013
 
Description Senior Investigator Award
Amount £75,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description Wellcome Centre
Amount £12,100,395 (GBP)
Funding ID 203148/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2017 
End 07/2022
 
Description Wellcome Trust Value in People Award
Amount £50,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title Brain Atlas 
Description We have developed a registerable labelled brain atlas for 2 year old children which has been made freely available to researchers on our website www.brain-development.org This has now been extended to include a term and 1 year old atlas again to be made available freely on the webpage 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2008 
Provided To Others? Yes  
Impact In use by other research groups 
URL http://www.brain-development.org
 
Title Computational Atlas of the preterm heart 
Description A computational atlas of the newborn heart from 28 to 44 weeks of gestation. This allows precise analysis of normal and normal development and the effects of preterm birth, fetal compromise or other conditions. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact This atlas will be made available as soon as peer review publication is completed 
 
Title Labelled Brain Atlas 
Description A labelled registerable brain atlas made freely available on our website www.brain-development.org, available for use with out 4D brain atlas 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2008 
Provided To Others? Yes  
Impact in use in further studies 
URL http://www.brain-development.org
 
Title MRI methods research software 
Description Source code for MRI methods developed as part of research project 
Type Of Material Improvements to research infrastructure 
Year Produced 2016 
Provided To Others? Yes  
Impact Dissemination of research software that is being used by others in the field 
URL http://mriphysics.github.io/
 
Description Brain Atlas 
Organisation Imperial College London
Department Department of Computing
Country United Kingdom 
Sector Academic/University 
PI Contribution Construction of a labelled brain atlas for 2 year olds. This was a PhD stipend for a project
Collaborator Contribution Expertise in image registrationExpertise in Brain Atlas Construction
Impact Made available on our website: www.brain-development.org Publication: 18234511 Further funding obtained and in progress
 
Description Brain Atlas 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution Construction of a labelled brain atlas for 2 year olds. This was a PhD stipend for a project
Collaborator Contribution Expertise in image registrationExpertise in Brain Atlas Construction
Impact Made available on our website: www.brain-development.org Publication: 18234511 Further funding obtained and in progress
 
Description Collaboration on fMRI in newborn infants 
Organisation Radboud University Nijmegen
Department Donders Institute for Brain, Cognition and Behaviour
Country Netherlands 
Sector Academic/University 
PI Contribution We initiated the project and collect and analyse the data
Collaborator Contribution Expertise in statistical interpretation of MR image data
Impact Doria et al PNAS 2010. Disciplines involved. Clinical Medicine, Neonatal Intensive Care, Imaging Physics, Clinical Neuroscience, fMRI, Statistics
Start Year 2009
 
Description Department of Bioengineering, Imperial College London 
Organisation Imperial College London
Department Department of Bioengineering
Country United Kingdom 
Sector Academic/University 
PI Contribution We have a collaboration with Dr Etienne Burdet in the development of haptic devices for study and treatment of preterm infants, currently focusing on creation of somatosensory stimuli for fMRI studies
Collaborator Contribution Delivery of a device for somatosensory stimulation of preterm infants and collaborations on haptic devices
Impact 19854281 Multidisciplinary involving neonatal medicine, computational neuroscience, bioengineering, MRI
Start Year 2007
 
Description Department of Computing, Imperial College London 
Organisation Imperial College London
Department Department of Computing
Country United Kingdom 
Sector Academic/University 
PI Contribution We have a longstanding collaboration with Prof Daniel Rueckert and many joint projects and publications.
Collaborator Contribution Prof Rueckert has essential expertise in image analysis that underpins our MR imaging programme. We have been able to do research using grants on which he was PI funded by EPSRC.
Impact 18234511 18979782 17919930 17888685 17696128 17344066 17633705 18044561 16675269 20969966 20451627 20510375 20879376 20079440
 
Description Division of Neurosciences, Imperial College London 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We have a collaboration with Dr Christian Beckman, developing fMRI technques for preterm infants
Collaborator Contribution Dr Christian Beckman has provided essential expertise for fMRI studies in preterm infants.
Impact 19854281 21041625 Multidisciplinary involving neonatal medicine, computational neuroscience, cognitive neuroscience, MRI
Start Year 2007
 
Description Guy's and St Thomas' NHS Foundation Trust 
Organisation Evelina London Children's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Installation and use of a new neonatal MRI scanner in the Neonatal Intensive Care Unit of St Thomas' Hospital. We have moved our research group to this site and formed a new strategic alliance between our University (King's College London) and the Trust
Collaborator Contribution Infrastructure support
Impact New MR scanner and multidisciplinary group which uses this for research and clinical practice. This involves neonatal medicine, physics, computer science and neuroscience as well as cardiology and psychiatry
Start Year 2012
 
Description Imaging Genetics 
Organisation Duke-NUS Graduate Medical School
Country Singapore 
Sector Academic/University 
PI Contribution We have developed imaging genetics methods which combine the large MRI and genomic datasets to allow biologic inference from imaging datasets. Using this approach we have discovered new genes and biologic pathway involved in brain development and preterm brain injury. Our contributions have been to lead the project, define the medical problems, acquire and analyse the images, and to carry out the analysis
Collaborator Contribution We had no skills in genomics, and our partners have provided this to the programme.
Impact Multidisciplinary involving neuroscience, neonatology, imaging, genomics, statistics. Outputs include: Krishnan et al, Nature Communications 2017; Krishnan et al PNAS 2017
Start Year 2011
 
Description Imaging Genetics 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We have developed imaging genetics methods which combine the large MRI and genomic datasets to allow biologic inference from imaging datasets. Using this approach we have discovered new genes and biologic pathway involved in brain development and preterm brain injury. Our contributions have been to lead the project, define the medical problems, acquire and analyse the images, and to carry out the analysis
Collaborator Contribution We had no skills in genomics, and our partners have provided this to the programme.
Impact Multidisciplinary involving neuroscience, neonatology, imaging, genomics, statistics. Outputs include: Krishnan et al, Nature Communications 2017; Krishnan et al PNAS 2017
Start Year 2011
 
Description Imaging Physics, MRC Clinical Sciences Centre 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution We have a longstanding collaboration with Prof Jo Hajnal and many joint projects, grants and publications.
Collaborator Contribution Prof Hajnal provides essential expertise without which our MR imaging programme could not function, stretching from supervising the installation of our MR scanner to pulse-programming and image analysis
Impact 19926413 19564309 18952670 18687746 18234511 18222994 17919930 17888685 17698966 17696128 17606564 17344066 17403847 17174575 17633705 18044561 16675269 16882805 16866579 16551994 16452356 20969966 20451627 20510375 20879376 20079440 20971721
 
Description Imperial College Healthcare Trust 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Most of our research is clinical investigation of sick newborn infants which uses the MR scanner sited within the Neonatal Intensive Care Unit at Hammersmith Hospital. We funded and run the scanner and the research, but without the active collaboration of the clinical staff and the NHS Trust this work could not happen. This is a strong symbiotic relationship which is at the core of our programme and my research team is heavily involved in the provision of clinical services.
Collaborator Contribution Essentail collaborative infrastructure for clinical studies of sick preterm infants
Impact 19926413 19896902 19854281 19564309 19302092 18952670 18687746 18234511 18222994 17919930 17888685 17698966 17696128 17606564 17344066 17403847 17174575 17633705 18044561 16820391 16675269 16882805 16866579 16551994 16452356
 
Description National Perinatal Epidemiology Unit 
Organisation University of Oxford
Department National Perinatal Epidemiology Unit Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution We have a longstanding collaboration with the NPEU, and this has led to substantial funded projects: these projects are initiated by our group and NPEU provides the expertise and facilites of a Clinical Trials Unit. 1. The MRC funded Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), which was jointly led by our group (joint PI D Azzopardi) and the NPEU (Joint PI P Brocklehurst). This has now reported (Azzopardi et al N Engl J Med 2009) 2. The MRC funded TOBY childrens study, led by our group (PI Azzopardi), 6 year follow up of the TOBY subjects, in progress. 3. MRC funded study of Xenon as a neuroprotectant for neonatal encephalopathy, led from our group (PI Azzopardi). In progress 4. NIHR Applied Programme Grant: Evaluation of MR imaging for preterm infants (PI Edwards).
Collaborator Contribution NPEU provide clinical trials unit facilites and skills for a series of projects 1. The MRC funded Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), which was jointly led by our group (joint PI D Azzopardi) and the NPEU (Joint PI P Brocklehurst). This has now reported (Azzopardi et al N Engl J Med 2009) 2. The MRC funded TOBY childrens study, led by our group (PI Azzopardi), 6 year follow up of the TOBY subjects, in progress. 3. MRC funded study of Xenon as a neuroprotectant for neonatal encephalopathy, led from our group (PI Azzopardi). In progress 4. NIHR Applied Programme Grant: Evaluation of MR imaging for preterm infants (PI Edwards).
Impact 19797281 19060009 17392043 16492950
 
Description Perinatal Imaging, MRC Clinical Sciences Centre 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution We have a longstanding collaboration with Prof Mary Rutherford and many joint projects, grants and publications.
Collaborator Contribution We work together in neonatal MR imaging.
Impact 19926413 19896902 19564309 18952670 18687746 18334617 18222994 17919930 17888685 17698966 17696128 17344066 17403847 17174575 17633705 18044561 16675269 16882805 16866579 16551994 16452356 20969966 20879376 20510375 20451627 19896902
 
Title Xenon as an Organ protectant 
Description Xenon gas is a powerful protector of tissues after hypoxic injury 
IP Reference WO2007039731 
Protection Patent granted
Year Protection Granted 2007
Licensed No
Impact We are running a clinical trial
 
Title Hypothermic Neural Rescue Therapy for Perinatal Asphyxia 
Description Hypothermic neural rescue therapy reduces death and disability in infants suffering birth asphyxia and reduces cerebral palsy in survivors. This is the first effective treatment for this serious condition and provides not only a clinical therapy but proof of principle that neural rescue is practical and signposts the way for future research. This programme of work included a const benefit analysis which showed that hypothermia is cost effective. Hypothermia has now been reviewed by NICE and preliminary advice is that it should be introduced into the NHS as a normal therapy. 
Type Therapeutic Intervention - Physical
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2010
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Hypothermic neural rescue reduces death and disability in infants suffering birth asphyxia with a numbers needed to treat of 9, and reduces the incidence of cerebral palsy and other neurological deficits in survivors. It is now actively being rolled out across the NHS and the wider world. It was declared by NICE to be standard of care for the NHS is 2010 
URL https://clinicaltrials.gov/show/NCT01092637
 
Description Television and radio interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact We have given several media interviews and had filming on our unit with respect to our research outputs. This includes BBC News, Today Programme, Womens Hour

Difficult to ascertain
Year(s) Of Engagement Activity 2007,2008