Neonatal Imaging
Neonatal Imaging represents an unusual multidisciplinary grouping of researchers based at mainly at the Hammersmith Campus who combine skills from basic physics through computational visualisation to clinical paediatrics to exploit the potential of these advances to understand disorders of the developing brain.
Research Objectives
Newborn infants are at high risk of brain damage, particularly if born preterm. The group has developed and used magnetic resonance (MR) imaging to study the diseases of newborn infants The primary object of the group is to understand the causes and consequences of neurodevelopmental impairment in the newborn to allow strategies can be devised to reduce the level of neurodevelopmental impairment. To achieve this we have developed a highly multidisciplinary approach and have seamless links and shared personnel with other relevant research groups such as the Weston Group for Neonatal Research (led by David Edwards), Imaging Physics (Jo Hajnal), Pediatric Neurology (Frances Cowan) and Computing (Daniel Rueckert).
Background
Problems at birth are a major health problem in both the developed and the developing world, and affected infants are drawn disproportionally from disadvantaged populations. Birth trauma remains a major cause of death in developing countries, and preterm deliveries are commoner amongst the poor and the unemployed, with teenage pregnancy and in stressed or poorly educated mothers. Indeed, a major international survey found that unequal income distribution and lack of political representation was more strongly associated with low birthweight and infant mortality than any other health outcome. Worldwide these problems reach epidemic proportions, and in countries where modern facilities are available about 7% of all infants require some form of neonatal intensive care. There is a pressing need for social and political as well as medical reasons to address the problems of neonatal disease.
Birth asphyxia in mature infants remains a significant cause of neurodevelopmental impairment, accounting for some 20% of cases of cerebral palsy in the developed world and more in poorer countries. Pre-term birth has a profound effect on the developing brain, particularly with extreme prematurity: half of all infants born at 25 weeks of less show impaired neurodevelopment at 30 months of age and even in less immature infants neurological and psychiatric deficits are common in the teenage years. In a minority this is a predominantly motor impairment, but in the remainder the impairment is neurocognitive and behavioural.
The Neonatal MR Imaging group aims to undertake translational research which brings together the most advanced imaging technology and techniques for the benefit of vulnerable newborn infants. The group is highly collaborative and it provides a central resource and impetus for a larger group of researchers looking into specific diseases in the newborn.
The group has a particular emphasis on the causes and consequences of brain damage in the newborn, but imaging is valuable for addressing many problems, and members are therefore involved with collaborators in studies of several organ systems and diseases, including neonatal lung and intestinal disease, molecular imaging, neonatal fat distributions, fetal imaging and non-clinical studies in animal models.
RECENT ACHIEVEMENTS
Brain damage and neurodevelopmental abnormalities in preterm infants
1. Development and use of a dedicated MR imaging facility
A central achievement for the group has been to establish the systems and skills to allow MR imaging of the most immature and vulnerable newborn infant. We have a long record of studying infants who require intensive care, and since the early 1990’s have been able to obtain images from infants undergoing mechanical ventilation. However, these systems were not safe or robust enough to allow us to examine the very smallest preterm infants who are at the highest risk of neurological problems. In 1996 we therefore established the worlds first dedicated neonatal MR scanner in a suite within the neonatal intensive care unit, allied to full intensive care facilities such as: advanced mechanical ventilation; inotropic support; and nitric oxide administration. This unparalleled facility has allowed us to collect a unique set of images of preterm infants from the age of viability onwards.
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Our current prototype neonatal MRI system developed in association with OMT and Philips Medical Systems |
We have undertaken studies to demonstrate the safety of the system, and made comparisons between MR, ultrasound images and histopathological findings. These showed that MR images were not surprisingly much more sensitive to abnormality than the commonly used ultrasound methods, and that it detected the majority of the lesions seen in pathological specimens. It was clear that the commonly accepted classification of brain lesions based on ultrasound appearances and used by neonatal researchers needed review, and that the neonatal MR system provided the appropriate tool to do this.
With this preliminary work completed we moved to substantive studies. Our first aim was to define the phenotype of brain abnormality in an unselected population of preterm infants, and to examine the timing of lesions in relation to parturition. We therefore undertook a large cohort study of consecutive patients born before 32 weeks gestation, imaged immediately after birth and then serially. We collected up to seven MR studies between delivery and term corrected age from 160 subjects, with the median age of the first image being less than 48 hours after birth. A large amount of collateral information, including DNA and placental biopsies, was collected on these infants, and survivors are currently undergoing detailed neurological and cognitive follow-up at the age of six years.
This cohort study demonstrated that: (1) the classical pathologies of periventricular leucomalacia and parenchymal intraventricular haemorrhage were very uncommon. (2) Abnormalities, often characteristic of longterm problems were seen on 2/3 of the first scans, ie within hours of birth, and appeared to have originated during intrauterine life. (3) By the corrected age of term over 80% of infants have abnormalities on the MR image, almost always diffuse excessive high signal intensity in the white matter and dilated lateral ventricles (Fig 1). Focal lesions, even where they had existed on early scans were often absent. These results demonstrated that studies using single MR images of preterm infants at term would be unlikely to define the nature of brain lesions precisely, and that the phenomenology of abnormality changed as the brain developed.
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Fig 1 MR image from preterm infant showing severe diffuse white matter abnormality, particularly in regions shown by arrows. |
It was essential to determine whether the diffuse excessive high signal intensity seen in these infants in the later images represented brain injury. Serena Counsell therefore used diffusion weighted imaging to measure apparent diffusion coefficients in white matter in several brain regions in normal controls, preterm infants with diffuse excessive high signal intensity, and preterm infants with periventricular leucomalacia, a characteristically diffuse severe form of injury. We found that the apparent diffusion coefficients values in the diffuse signal regions were similar to those in infants with periventricular leucomalacia and significantly higher than controls, strongly implying that the diffuse high signal represented tissue damage.
This success has led to funding being made available from the MRC, the Strategic Research Infrastructure Fund, and from charitable donors to upgrade the facility to a new state of the art 3.0 T MRI system in 2005. This is the only dedicated neonatal 3.0T system in the world, and the group has already shown that the 3.0T scanner is able to provide images of far higher quality and scientific richness.
2. Infection, inflammation and immunity in preterm brain damage.
Several studies had suggested that high levels of pro-inflammatory cytokines, notably interleukin 6, in amniotic fluid or fetal blood was associated with periventricular leucomalacia on cranial ultrasound scanning or with poor neurological outcome in preterm infants. These studies lacked force because the measures were not robust. Ultrasound is highly insensitive in this context, and neurological outcome cannot distinguish between antenatal events and the rigours of intensive care to which all these infants are subjected. Equally, measurements of cytokine concentrations in blood or amniotic fluid had the disadvantage that inflammation is part of normal parturition and these measures do not give definite evidence of infections
We addressed the problem using the neonatal MR imaging resource. We examined umbilical blood and placental samples from 50 infants and reasoned that if prolonged infection was associated with brain injury there would be immunological memory of the infecting agent. Dr Philip Duggan, a joint PhD student with Prof Robert Lechler’s group in the Department of Immunology, Imperial College, having confirmed that harvested cells were of fetal not maternal origin, measured the percentage of CD45RO+ve T lymphocytes (which reflect immunoigical memory for antigen) in the fetal blood. He found that higher concentrations were significantly associated with abnormalities on the first brain image (Fig 2). In studies being prepared for publication he repeated this with other markers of T cell activation, CD69 and CD25 and found that these markers also predicted abnormalities on the first image. Together with confirmation that pro-inflammatory cytokines were increased in these infants these data provide the best available evidence that intrauterine infection is associated with brain lesions in preterm infants.
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Fig 2. Increased concentrations of inflammatory cytokines and CD45RO+ T cells in the umbilical blood of preterm infants with (shaded bars) or without (clear bars) abnormalities on MR imaging soon after delivery (from Duggan et al, Lancet 2001) [28] |
To examine the role of intrauterine infection in brain injury further, in collaboration with Dr Mark Sullivan (Obstetrics and Gynaecology) and Prof Gordon Dougan (Centre for Molecular Microbiology) we used fluorescent in situ hybridisation with oligonucleotide probes for bacterial 16s ribosomal RNA to detect bacteria on the placenta and fetal membranes of these infants. We found very large numbers of bacteria on the amnion and chorion, yet not all infants seemed to have mounted a strong immune response to the bacteria. Interestingly, bacterial colonisation without an inflammatory response was also found in term controls. This suggested differential pathogenicity in the bacterial species, and/or that the host response is critical in determining the response to bacterial invasion of the uterus.
3. Advanced Imaging and neuroinformatic image analysis
These data suggesting a role for infection in the initiation of brain injury do not completely explain the high rate of abnormalities seen on term scans, as some infants have no definable infective or other insults, have a normal first scan and yet develop abnormalities of a non-focal nature by term. These are poorly defined and understood, and difficult to investigate without quantitative measures. In collaboration with Prof Hajnal we have therefore used a semi-interactive post-processing technique designed within the MR unit to extract quantitative measures of cerebral volume, cortical surface area and the complexity of the cerebral cortex from one image dataset. We now have some 200 of these measurements and have used them to ask questions about brain development in very preterm infants. We have found that preterm infants achieve logarithmic increases in cerebral volume and surface area after birth despite the hostile extrauterine environment. However, cortical development seems to be delayed compared to growth in the normal intrauterine environment , as the levels of cortical complexity achieved by the corrected age of term are significantly less than for term-born infants. This deficit in development is seen in the absence of focal brain lesions.
These quantitative measures have been a significant advance in image interpretation, however they give only global measures reflecting the state of the whole brain. Advances in neuroinformatics are currently suggesting new and fruitful approaches which will allow detailed regional examination (reviewed in Toga, Nat Rev Neurosci, 2002, 3(4), 302-9). In collaboration with Prof Hajnal and Dr Daniel Rueckert, Department of Computing, Imperial College and with 2 grants from the Engineering and Physical Sciences Research Council we are implementing high-dimensional registration and statistical techniques to neonatal brain imaging, and developing a 4-dimensional (3D + time) brain atlas for the preterm infant.
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Fig 3. Definition of areas of reduced brain volume in preterm infants compared to term controls revealed by deformation based morphometry |
Because of the extremely rapid growth of the brain and the emergence of new structures during our period of interest afine transformation based techniques such as voxel based morphometry are likely to have a limited value, and we have therefore begun to use non-linear systems to atlas brains and compare groups and individuals. Preliminary data suggest that the frontal lobes have particular abnormalities in preterm infants (fig 3) This is consistent with a previously unexplained finding from our diffusion weighted imaging studies: that the apparent diffusion coefficient was higher in the frontal that the posterior white matter. These findings may suggest a neural substrate in the frontal lobes for the cognitive problems common in the survivors of extremely preterm birth. We are actively pursuing this.
Allied with these developments the group has been applying advanced imaging approaches to understand events at a tissue and cellular level, for example using Diffusion Tensor Imaging to investigate the pathological processes involved in injury to the developing brain. DTI can be used to provide a map of white matter tracts in the brain (Fig 4)
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Figure 4 Infants born preterm imaged at one year of age (a) The corpus callosum is thin on conventional imaging (arrow) (b) Diffusion tractography showing white matter tracts through the corpus callosum |
4. Fetal imaging
In parallel with these studies of the preterm infant we have been developing a programme of fetal imaging. While this has obvious interest for radiological and diagnostic development, it has particular value in providing normal and control data for imaging studies of preterm infants. We are currently developing image sequences to allow quantification of fetal brain development, both tissue properties such as diffusion coefficients and T1 and T2 values, and quantification of growth and development of different brain structures. Our first substantive project is to examine intrauterine cerebral ventricular dilation, a poorly understood syndrome with useful parallels to preterm brain injury. Fetal imaging gives us the opportunity to examine the normal development of areas of suspected of abnormalities in the preterm, such as the cortical subplate.
Birth asphyxia and brain damage in term infants
The study of perinatal hypoxic-ischaemic injury has been a central activity since the first MR scan of a human infant brain was carried out at the Hammersmith Hospital in the 1980’s. MRI is now established as the primary tool for defining brain injury in the newborn infants, and work proceeding in many centres. We have played a role in developing a role for MRI in neonatal neurology, including the first diffusion-weighted images of brain injury in the newborn in 1994, and the prize-winning first textbook of neonatal MR imaging edited by Rutherford in 2002.
1. Descriptive studies of brain injury in perinatal hypoxia-ischaemia
Descriptive studies to define the MR characteristics of hypoxic-ischaemic damage, and to determine the prognostic value of MR after asphyxia have formed the bedrock not only of clinical practice but our other research studies in this area. We have carried out detailed analysis of the relation between MR images and histopathological findings, and defined intra- and interobserver variability of MR interpretation after perinatal hypoxi-ischaemia. In collaboration with Dr Frances Cowan, Imperial College, a large follow-up study has defined the value of specific MR appearances, and described a new sign with particularly high positive predictive value (Fig 5). We have laid stress on serial imaging and prolonged neurological follow-up of infants studied, some of whom are now approaching their teens, and this unique collection of patients will allow us to define precisely the significance of images, both soon after birth and in childhood, in the diagnosis of birth injury- this has crucial medical and legal importance.
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Fig 5. Loss of signal in the posterior limb of the internal capsule- a highly sensitive and specific sign of neurological impairment after perinatal hypoxia-ischaemia defined by the M.R. (Rutherford et al, Pediatrics 1998) |
An important recent study (Cowan et al, Lancet 2004) has examined the role of antenatal and perinatal factors in the aetiology of brain injury in infants presenting with neonatal encephalopathy. Contrary to the much current belief, there was little evidence that encephalopathic term infants had longstanding brain damage on MR examination. This work has stimulated considerable debate and further study.
2. Treatment of brain injury in perinatal hypoxia-ischaemia
We havealso investigated the mechanisms of hypoxic-ischaemic injury in linked clinical and laboratory studies. Beginning from the original observation that cerebral energy metabolism is normal immediately after perinatal asphyxia but declines 8-12 hours later (Hope et al, Lancet, 2, 366-70,1984), and the well-accepted phenomenon of ischaemic maturation in animal models, we began in the early 1990s with the then novel hypothesis that neural cell death after hypoxia-ischaemia was apoptotic. In collaboration with the Weston Group (Dr Huseyin Mehmet) we were amongst the first to show apoptotic death in animal models of perinatal hypoxia-ischaemia, and the first to demonstrate that apoptotic death was a prominent feature in human asphyxial damage. Subsequent work from many groups has confirmed the importance of apoptosis in the developing brain, even though there is some renewed scepticism as regards adult hypoxic-ischaemic injury.
Acceptance of a role for apoptosis in perinatal brain injury helped to provide a mechanistic infrastructure to the search for neural rescue therapies which could be usefully applied after the insult. Along with other groups we provided convincing evidence in animals that mild cooling ameliorated hypoxic-ischaemic injury, and in collaboration with researchers in New Zealand (Dr Gunn, Prof Gluckman), Bristol (Profs Whitelaw and Thoresen) and University College London (Prof Wyatt) we established an international multicentre trial with has given proof of principal that clinical hypothermia can reduce brain damage in infants suffering neonatal encephalopathy. (Gluckman et al, Lancet 2005). We are now leading a further multicentre randomised clinical trial of moderate applied hypothermia for neural-rescue which has now funded by the MRC and run from the Weston group (Dr Denis Azzopardi).
We have begun to study the genetic predispositions to brain damage in our population, and with Dr Cowan and Professor Irene Roberts (Haematology) we found a link between disorders of the clotting cascade, such as high concentrations of factor VIII and Leiden factor V homogysosity, and severity of cerebral injury. We plan to develop this work using our large cohort of imaged patients.
Other research: lung, abdominal and molecular imaging
MR imaging of the lung has been particularly difficult in adults, due to low proton density and susceptibility effects. X-ray computed tomography provides a satisfactory imaging modality and MR has rarely been attempted. However in the newborn infant, the high tissue water content makes imaging less problematic, and the high radiation doses of CT scanning prevents its use in this patient group except in extreme circumstances. Nevertheless, respiratory dysfunction remains the commonest cause of death in preterm infants, and despite the advent of artificial surfactant therapy chronic lung disease is increasing in prevalence in neonatal intensive care units.
In collaboration with Prof Hajnal we have undertaken the first study of the preterm lung using MR imaging. Having developed techniques for obtaining images, we addressed the question: is the lung water content higher in preterm lung disease, and what is the effect of this increase? We found that lung water is significantly higher both in acute surfactant deficiency disease and in neonatal chronic lung disease. The increased water burden is associated with a gravity-induced collapse and flooding of dependent lung regions (fig 6). We have also found, using conventional gadolinium imaging, that the inflammatory processes in chronic lung disease are inhomogenously distributed within the lung. This has had immediate impact on our own clinical practice for ventilation strategies.
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Fig 6. MR image of the lung of a preterm infant showing a large pneumatocele and an increase in tissue density in the dorsal regions due to gravity dependent collapse. |
Imaging inflammatory change has become a significant goal for the group, as inflammation appears to lie at the root of a significant number of neonatal diseases, from antenatal fetal infection to the often fatal condition of neonatal necrotising enterocolitis, a condition in which we have obtained the first MR images and clearly demonstrated inflammatory change in vivo.
Because inflammation is a central clinical and research problem we have established a collaborative project with Prof Dorian Haskard (National Heart and Lung Institute) and Prof Andrew George (Immunology), funded by the British Heart Foundation, to develop a molecular imaging tool for MR. We have linked MR visible agents to monoclonal antibodies against E-selectin, an endothelial cell marker expressed only in inflamed tissues. E-selectin is an internalising antibody which accumulates ligand inside endothelial cells, and thus will accumulate MR signal within endothelial cells. We have been able to create a labelled antibody fragment that allow visualisation of E-selectin expression in vivo.
MR Imaging has great potential for further research, and in collaboration with other groups we have been examining novel areas such as neonatal fat imaging and cardiac imaging in preterm infants.
Group Leaders
David Edwards, (Professor of Neonatal Medicine, Faculty Theme Leader, Imaging Science.)
Mary Rutherford, Professor in Perinatal Imaging.
Group Members
Dr James Boardman (Clinical Research Fellow )
Dr Latha Srinivasan (Clinical Research Fellow)
Dr Leigh Dyet (Clinical Research Fellow)
Collaborators
ISD Collaborators
Professor JV Hajnal –physics
Dr Jimmy Bell – molecular imaging
Dr Stephan Schmitz- cardiac imaging
Dr Serena Counsell (Research radiographer)
Ms Joanna Allsop (Research radiographer)
Ms Julie Fitzpatrick (Research radiographer)
Dr Louise Thomas- molecular imaging
Dr David Larkman- physics
Dr Christina Malamateniou (Research radiograhper)
Dr Alex Dresner- functional imaging
Weston Group for Neonatal Research
Prof David Edwards (Weston Professor and Group Head)
Dr Huseyin Mehmet (Weston Senior Lecturer in Neurobiology)
Dr Denis Azzopardi (Senior Lecturer)
Dr Susern Tan (Clinical Research Fellow)
Other Collaborators
Dr Frances Cowan
Dr Daniel Rueckert
Professor Jan Atkinson
Professor Oliver Braddick
Professor Janet Eyre
Professor Francesco Muntoni
Professor Eugenio Mercuri
Professor Nick Fisk
Dr Sailesh Kumar
Dr Neena Modi
Dr Mark Sullivan
Prof A George
Prof D Haskard
SELECTED RECENT PUBLICATIONS
Gluckman,P., Wyatt,J.S., Azzopardi,D., Ballard,R., Edwards,A.D., Ferriero,D.M., Polin,R., Robertson,C.M., Thoresen,M., Whitelaw,A., and Gunn,A. (2005). Selective head cooling with mild systemic hypothermia to improve neurodevelopmental outcome following neonatal encephalopathy. Lancet 365, 633-70.
JP Boardman, V Ganesan, MA Rutherford, DE Saunders, E Mercuri, F Cowan Magnetic Resonance Image Correlates of Hemiparesis After Neonatal and Childhood Middle Cerebral Artery Stroke. Pediatrics 2005;115(2):321-6.
O'Donoghue, K, Kennea, N., Sullivan M.H.F., and Edwards, A. D. Maternal origin of inflammatory leukocytes in preterm fetal membranes shown by fluorescence in situ hybridisation. Placenta . 2005. In Press
Steel,J.H., Malatos,S., Edwards,A.D., Miles,L., Duggan,P., Kennea,N.L., Reynolds,P., Feldman,R.G., and Sullivan M.H.F. (2005). Bacteria and inflammatory cells in fetal membranes do not always cause preterm labour. Pediatr Res. 57, 404-411.
Mercuri E, Barnett A, Rutherford M, Guzzetta A, Haataja L, Cioni G, Cowan F,Dubowitz L.Neonatal cerebral infarction and neuromotor outcome at school age. Pediatrics. 2004 Jan; 113(1 Pt 1): 95-100.
Mercuri E, Anker S, Guzzetta A, Barnett AL, Haataja L, Rutherford M, Cowan F, Dubowitz L, Braddick O, Atkinson J. Visual function at school age in children with neonatal encephalopathy and low Apgar scores. Arch Dis Child Fetal Neonatal Ed. 2004 ;89:F258-62.
Adams,E.W., Harrison,M., Counsell,S., Allsop,J., Kennea,N.L., Hajnal,J.V., Thornton,A., Duggan,P., and Edwards,A.D. (2004). Increased lung water and tissue damage in bronchopulmonary dysplasia. J Pediatr 145, 503-507.
Bhatia, K., Hajnal, J. V., Puri, B. K., Edwards, A. D., and Rueckert, D. Consistent groupwise non-rigid registration for atlas construction. IEEE International Symposium on Biomedical Imaging . 2004. In Press
Horan,M., Ichiba,S., Firmin,D.N., Killer,H.M., Edwards,A.D., Azzopardi,D., Hodge,R., Kotecha,S., and Field,D. (2004). A Pilot investigation of mild hypothermia in neonates receiving extracorporeal membrane oxygenation (ECMO). J Pediatr 144, 301-308.
Le Strange,E., Saeed,N., Cowan,F.M., Edwards,A.D., and Rutherford,M.A. (2004). MR imaging quantification of cerebellar growth following hypoxic-ischemic injury to the neonatal brain. AJNR Am J Neuroradiol. 25, 463-468.
Rutherford,M., Counsell,S., Allsop,J., Boardman,J., Kapellou,O., Larkman,D., Hajnal,J., Edwards,A.D., and Cowan,F. (2004). Diffusion-weighted magnetic resonance imaging in term perinatal brain injury: a comparison with site of lesion and time from birth. Pediatrics 114, 1004-1014.
Shen,Y., Larkman,D.J., Counsell,S., Pu,I.M., Edwards,A.D., and Hajnal,J.V. (2004). Correction of high-order eddy current induced geometric distortion in diffusion-weighted echo-planar images. Magn Reson. Med. 52, 1184-1189.
Srinivasan,L., Bokiniek,R., King,C., Weaver,G., and Edwards,A.D. (2004). Increased Osmolality of breast milk with therapeutic additives. Arch. Dis. Child. 89, 514-517.
Sullivan,M.H., Steel,J., Kennea,N., Feldman,R.G., and Edwards,A.D. (2004). The role of intrauterine bacteria in brain injury. Acta Paediatr. Suppl 93, 4-5.
Thomaz,C.E., Boardman,J.P., Hill,D.G.L., Hajnal,J.V., Edwards,A.D., Rutherford,M.A., Gilles,D.F., and Rueckert,D. (2004). Using a maximum uncertainly LDA-based approach to classify and analyse MR brain images. Lecture Notes in Computer Science 3216, 291-300.
Cowan F, Rutherford M, Groenendaal F, Eken P, Mercuri E, Bydder G, Meiners L, Dubowitz L, De Vries L. Term neonatal encephalopathy and/or seizures - lack of evidence for lesions of antenatal origin. Lancet. 2003 1;361(9359):736-42
Boardman,J.P., Bhatia,K., Counsell,S., Allsop,J., Kapellou,O., Rutherford,M., Edwards,A.D., Hajnal,J.V., and Rueckert,D. (2003). An evaluation of deformation-based morphometry applied to the developing human brain and detection of volumetric changes associated with preterm birth. Lecture Notes in Computer Science 2878, 679-704.
Counsell, S., Kennea, N. L., Herlihy, A. H., Allsop, J., Harrison, M., Cowan, F., Hajnal, J. V., Edwards, B, Edwards, A. D., and Rutherford, M. T2 relaxation values in the developing preterm brain. AJNR Am.J Neuroradiol. 2003. Ref Type: In Press
Counsell,S., Allsop,J., Harrison,M., Larkman,D., Kennea,N.L., Kapellou,O., Cowan,F.M., Hajnal,J.V., Edwards,A.D., and Rutherford,M. (2003). Diffusion weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality. Pediatrics 112, 1-7.
Counsell,S.J., Rutherford,M.A., Cowan,F.M., and Edwards,A.D. (2003). Magnetic resonance imaging of preterm brain injury. Arch. Dis. Child Fetal Neonatal Ed 88, F269-F274.
Ichiba,S., Killer,H.M., Firmin,R.K., Kotecha,S., Edwards,A.D., and Field,D. (2003). Pilot investigation of hypothermia in neonates receiving extracorporeal membrane oxygenation. Arch. Dis. Child Fetal Neonatal Ed 88, F128-F133.
Adams,E., Counsell,S., Hajnal,J.V., Cox,P., Kennea,N.L., Thornton.A.S., Bryan,A.C., and Edwards,A.D. (2002). Magnetic resonance imaging of lung water content and distribution in preterm infants. Am. J. Respir. Crit. Care Med. 166, 397-402.
Counsell,S., Maalouf,E., Fletcher,A.M., Duggan,P.J., Battin,M., Lewis,H.J., Herlihy,A.H., Edwards,A.D., Bydder,G.M., and Rutherford,M. (2002). MRI assessment of myelination in the very preterm brain. AJNR 23, 872-881.
Counsell,S.J., Maalouf,E.F., Fletcher,A.M., Duggan,P., Battin,M., Lewis,H.J., Herlihy,A.H., Edwards,A.D., Bydder,G.M., and Rutherford,M.A. (2002). MR imaging assessment of myelination in the very preterm brain. AJNR Am. J. Neuroradiol. 23, 872-881.
Edwards,A.D. (2002). New approaches to brain injury in preterm infants. Dev Neurosci.
Ichiba,S., Killer,H.M., Firmin,R.K., Kotecha,S., Edwards,A.D., and Field,D.R. (2002). Pilot investigation of hypothermia in neonates receiving extracorporeal membrane oxygenation. Arch. Dis. Child Fetal Neonatal Ed 118-123.
Robertson,N.J., Cowan,F.M., Cox,I.J., and Edwards,A.D. (2002). Brain alkaline intracellular pH after neonatal encephalopathy. Ann. Neurol. 52, 732-742.
Taylor,D.L., Mehmet,H., Cady,E.B., and Edwards,A.D. (2002). Improved neuroprotection with hypothermia delayed by 6 hours following cerebral hypoxia-ischemia in the 14-day-old rat. Pediatr Res 51, 13-19.
Modi N, Lewis H, Al-Naqeeb N, Ajayi-Obe M, Doré C and Rutherford M The effects of repeated antenatal glucocorticoid therapy on the developing brain. Pediatr Res 2001; 50:581-5.
Duggan,P.J., Maalouf,E., Watts,T.L., Sullivan M.H.F., Counsell,S., Allsop,J.M., Al-Nakib L., Rutherford,M., Battin,M., Roberts,I., and Edwards,A.D. (2001). Intrauterine T cell activation and increased pro-inflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet 358, 1699-1700.
Hand,J.W., Van Leeuwen,G.M., Mizushina,S., Van de Kamer,J.B., Maruyama,K., Sugiura,T., Azzopardi,D.V., and Edwards,A.D. (2001). Monitoring of deep brain temperature in infants using multi-frequency microwave radiometry and thermal modelling. Phys. Med. Biol. 46, 1885-1903.
Maalouf,E., Duggan,P.J., Counsell,S., Rutherford,M., Cowan,F., Azzopardi,D., and Edwards,A.D. (2001). Comparison of cranial ultrasound and magnetic resonance imaging in preterm infants. Pediatrics 107, 719-727.
Mercuri,E., Cowan,F.M., Gupte,G., Manning,R., Laffan,M., Rutherford,M., Edwards,A.D., Dubowitz,L., and Roberts,I. (2001). Prothrombotic disorders and abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction. Pediatrics 107, 1400-1404.
Ng,W.F., Duggan,P.J., Ponchel,F., Matarese,G., Lombardi,G., Edwards,A.D., Isaacs,J.D., and Lechler,R.I. (2001). Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood 98, 2736-2744.
Robertson,N.J., Lewis,R.H., Cowan,F.M., Allsop,J.M., Counsell,S.J., Edwards,A.D., and Cox,I.J. (2001). Early increases in brain myo-inositol measured by proton magnetic resonance spectroscopy in term infants with neonatal encephalopathy. Pediatr Res 50, 692-700.
Ajayi-Obe,M., Saeed,N., Rutherford,M., Cowan,F.M., and Edwards,A.D. (2000). Reduced development of the cerebral cortex in extremely preterm infants. Lancet 356, 1162-1163.
Azzopardi,D., Robertson,N.J., Cowan,F., Rutherford,M., Rampling,M., and Edwards,A.D. (2000). Pilot study of treatment with whole body hypothermia for neonatal encepalopathy. Pediatrics 106, 684-694.
Felderhoff-Muser,U., Taylor,D.L., Greenwood,K., Joashi,U., Kozma,M., Stibenz,D., Edwards,A.D., and Mehmet,H. (2000). Fas/Apo1/CD95 can function as a death receptor for neuronal cells in vitro and in vivo and is upregulated following cerebral hypoxic-ischaemic injury to the developing rat brain. Brain Pathol 10, 17-29.
Greenwood,K., Cox,P., Mehmet,H., Penrice,J., Amess,P., Cady,E., Wyatt,J.S., and Edwards,A.D. (2000). Magnesium sulphate treatment after transient hypoxia-ischaemia fails to prevent cerebral damage in the newborn piglet. Pediatr Res 48, 346-350.
Jouvet,P., Rustin,P., Felderhoff,U., Pocock,J., Taylor,D.L., Joashi,U., Mazarakis,N.D., Sarraf,C., Greenwood,K., Edwards,A.D., and Mehmet,H. (2000). Branched chain amino acids induce apoptosis in rat neural cells without mitochondrial membrane depolarisation or cytochrome c release: a model for neurological impairment in maple syrup urine disease. Molecular Biology of the Cell 11, 1919-1932.
Maalouf,E., Fagbemi,A.O., Duggan,P.J., Jayanthi,S., Counsell,S., Lewis,H.J., Fletcher,A.M., Edwards,A.D., and Lakhoo,K. (2000). Diagnosis of intestinal necrosis in perterm infants using magnetic resonance imaging. Pediatrics 105, 510-514.
Robertson,N.J., Kuint,J., Counsell,S., Rutherford,M., Coutts,G.A., Cox,I.J., and Edwards,A.D. (2000). Characterisation of cerebral white matter damage in preterm infants using 1H and 31P magnetic resonance spectroscopy. J Cereb. Blood Flow Metab. 20, 1446-1456.
Van Leeuwen,G.M.J., Hand,J.W., Lagendijk,J.J.W., Azzopardi,D., and Edwards,A.D. (2000). Numerical modelling of temperature distributions within the neonatal head. Pediatr Res 48, 351-356.
Al Naqueeb,N., Edwards,A.D., Cowan,F., and Azzopardi,D. (1999). Assessment of neonatal encepalopathy by amplitude integrated electroencephalography. Pediatrics 103, 1263-1271.
Blumberg,R.M., Taylor,D.L., Yue,X., Aguan,K., McKenzie,J.E., Cady,E.B., Weiner,C.P., Mehmet,H., and Edwards,A.D. (1999). Increased nitric oxide synthesis is not involved in delayed cerebral energy failure following focal hypoxic-ischaemic injury in the developing brain. Pediatr Res 46, 224-231.
Felderhoff,U., Rutherford,M., Squier,M.V., Cox,P., Maalouf,E., Counsell,S., Bydder,G., and Edwards,A.D. (1999). Relation between magnetic resonance images and histopathological findings of the brain in extremely preterm infants. AJNR 20, 1349-1357.
Hanrahan,D., Cox,I.J., Azzopardi,D., Cowan,F., Sargentoni,J., Bell,J.D., Bryant,D.J., and Edwards,A.D. (1999). Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at one year of age. Dev. Med. Child. Neurol. 41, 76-82.
Joashi,U., Greenwood,K., Taylor,D.L., Kozma,M., Mazarakis,N.D., Edwards,A.D., and Mehmet,H. (1999). Poly(ADP ribose) polymerase cleavage precedes neuronal death in the hippocampus and cerebellum following injury to the developing rat forebrain. Eur. J. Neurosci. 11, 91-100.
Jouvet,P., Cowan,F., Cox,P., Lazda,E., Rutherford,M., Wigglesworth,J.S., Mehmet,H., and Edwards,A.D. (1999). Reproducibility and accuracy of magnetic resonance imaging studies of the brain after birth asphyxia. AJNR 20, 1343-1348.
Maalouf,E., Duggan,P.J., Rutherford,M.A., Counsell,S., Fletcher,A.M., Battin,M., Cowan,F.M., and Edwards,A.D. (1999). Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr 135, 351-357.
Robertson,N.J., Cox,I.J., Cowan,F.M., Counsell,S., Azzopardi,D., and Edwards,A.D. (1999). Cerebral intracellular lactic alkalosis persisting months after neonatal encepalopathy measured by magnetic resonance spectroscopy. Pediatr Res 46, 287-297.
Baiden-Amissah,K., Joashi,U., Blumberg,R.M., Mehmet,H., Edwards,A.D., and Cox,P. (1998). Expression of amyloid precursor protein (APP) in the neonatal brain following hypoxic ischaemic injury. Neuropathol. Appl. Neurobiol. 24, 346-352.
Battin,M., Maalouf,E., Counsell,S., Herlihy,A.H., Rutherford,M.A., Azzopardi,D., and Edwards,A.D. (1998). Magnetic resonance imaging of the brain in preterm infants: visualisation of the germinal matrix, early myelination and cortical folding. Pediatrics 101, 957-962.
Mehmet,H., Yue,X., Penrice,J., Cady,E.B., Wyatt,J.S., Sarraf,C.E., Squier,M.V., and Edwards,A.D. (1998). Relation of impaired energy metabolism to apoptosis and necrosis following transient cerebral hypoxia-ischaemia. Cell Death Differ 5, 321-329.
Rutherford,M.A., Pennock,J., Counsell,S., Mercuri,E., Cowan,F., Dubowitz,L., and Edwards,A.D. (1998). Abnormal magnetic resonance signal in the internal capsule predicts poor outcome in infants with hypoxic-ischaemic encephalopathy. Pediatrics 102, 323-328.
Book
MR imaging of the Neonatal Brain Rutherford M A (editor) WB Saunders 2002
Current Research Grant Funding
Modelling and understanding of immature brain development using statistical models of shape and appearance. Academy of Medical Sciences/the Health Foundation Senior Research Fellowship to Prof Rutherford. £300,000 (5 years)
The modulation of intrauterine gene expression by Fusobacerium nucleatum infection Dr M Sullivan, Prof AD Edwards, Dr P Langford, Prof JS Kroll Action Medical Research. £124,308 (2 years)
Compuational analysis of brain abnormalities and neurodevelopmental impairment in preterm infants Dr M Rutherford, Prof AD Edward, Prof J Hajnal, Dr F Cowan March of Dimes $187,821 (2 years)
Novel bioinformatic approaches to detection and characterization of bacterial infection of the placenta Prof AD Edwards The Kidani Foundation, £150,000 (3 years)
Developing a chimeric anti-e-selectin single chain antibody for the clinical imaging of vascular endothelial activation in inflammation. Prof D Haskard, Prof AD Edwards, Prof A George, Dr D Larkman Arthritis Research Campaign £180,255 (3 years)
Neuroinformatics Prof AD Edwards Anonymous £400,000
MRC Discipline Bridging Award in Imaging Sciences Prof AD Edwards, Prof D Firming, Dr R Vilar-Compte Medical Research Council £260,000 (3 years)
Information extraction from Images Prof J Hajnal, Dr D Rueckert, Prof D Hawkes, Prof AD Edwards et al Engineering and Physcial Sciences Research Council £1,072,000 (5 years)
Modelling and understanding immature brain development using statistical models of shape and appearance Prof J Hajnal, Dr D Rueckert, Prof AD Edwards Dr M Rutherford Engineering and Physcial Sciences Research Council £257,205 (3 years)
Relation of Abnormal cortical development and myelination to neurocognitive impairment in preterm infants. Prof AD Edwards, Prof J Hajnal, Dr D Rueckert, Dr M Rutherford Dr F Cowan The Health Foundation £249,000 (3 years)
Total Body Hypothermia as treatment for Neonatal Encephalopathy Dr D Azzopardi, Dr P Brockelhurst, Prof AD Edwards and others Medical Research Council Strategic Grant £1.2 million (6 years)
