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    ABSTRACT: PURPOSE: The use of tailored RF excitation pulses for prospective correction of non-linear motion-induced phase patterns is shown to enable diffusion-weighted (DW) fast spin echo (FSE) imaging in vivo. Echo-planar imaging (EPI) remains the most used sequence for DW imaging. Despite being highly sensitive to field inhomogeneities, EPI is robust to motion-induced phase shifts. FSE sequences are much less sensitive to field inhomogeneities, but require precise control of the transverse magnetization phase, which is hard to achieve with DW. Real time measurements and correction of phase ramps due to rigid-body motion had been proposed, but performance remained unsatisfactory because of non-linear phase patterns related to pulsatile motion. METHODS: Reproducible non-linear phase components are calibrated using 2D-EPI navigators and tailored RF excitation pulses designed. Real time correction of rigid-body motion was not yet implemented. RESULTS: Phase correction was confirmed with full signal DW-FSE images obtained on co-operative subjects. Full diffusion tensor acquisitions were obtained and color-coded maps displaying principal fiber directionality calculated. Results were consistent with corresponding EPI acquisitions except for absence of spatial distortions. CONCLUSION: Combining the proposed method with real time compensation of rigid-body motion has the potential to allow high quality, distortion free diffusion imaging throughout the brain. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 02/2014; 71(2). DOI:10.1002/mrm.24711
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    ABSTRACT: Patent ductus arteriosus (PDA) remains common in preterm newborns, but uncertainty over optimal management is perpetuated by clinicians' inability to quantify its true haemodynamic impact. Our aim was to develop a technique to quantify ductal shunt volume and the effect of PDA on systemic blood flow volume in neonates. Phase contrast MRI sequences were optimized to quantify left ventricular output (LVO) and blood flow in the distal superior vena cava (SVC) (below the azygos vein insertion), descending aorta (DAo) and azygos vein. Total systemic flow was measured as SVC + DAo - azygos flow. Echo measures were included and correlated to shunt volumes. 75 infants with median (range) corrected gestation 33(+6) (26(+4) -38(+6) ) weeks were assessed. PDA was present in 15. In 60 infants without PDA, LVO matched total systemic flow (mean difference 2.06 ml/kg/min, repeatability index 13.2%). In PDA infants, ductal shunt volume was 7.9-74.2% of LVO. Multiple linear regression analysis correcting for gestational age showed that there was a significant association between ductal shunt volume and decreased upper and lower body flow (p = 0.01 and p < 0.001). However, upper body blood flow volumes were within the control group 95% confidence limits in all 15 infants with PDA, and lower body flow volumes within the control group limits in 12 infants with PDA. Echocardiographic assessment of reversed diastolic flow in the descending aorta had the strongest correlation with ductal shunt volume. We have demonstrated that quantification of shunt volume is feasible in neonates. In the presence of high volume ductal shunting the upper and lower body flow volume are somewhat reduced, but levels remain within or close to the normal range for preterm infants. Copyright © 2013 John Wiley & Sons, Ltd.
    NMR in Biomedicine 09/2013; 26(9). DOI:10.1002/nbm.2927
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    ABSTRACT: White matter injury and abnormal maturation are thought to be major contributors to the neurodevelopmental disabilities observed in children and adolescents who were born preterm. Early detection of abnormal white matter maturation is important in the design of preventive, protective, and rehabilitative strategies for the management of the preterm infant. Diffusion-weighted magnetic resonance imaging (d-MRI) has become a valuable tool in assessing white matter maturation and injury in survivors of preterm birth. In this review, we aim to (1) describe the basic concepts of d-MRI; (2) evaluate the methods that are currently used to analyse d-MRI; (3) discuss neuroimaging correlates of preterm brain injury observed at term corrected age; during infancy, adolescence and in early adulthood; and (4) explore the relationship between d-MRI measures and subsequent neurodevelopmental performance. References for this review were identified through searches of PubMed and Google Scholar before March 2013. The impact of premature birth on cerebral white matter can be observed from term-equivalent age through to adulthood. Disruptions to white matter development, identified by d-MRI, are related to diminished performance in functional domains including motor performance, cognition and behaviour in early childhood and in later life. d-MRI is an effective tool for investigating preterm white matter injury. With advances in image acquisition and analysis approaches, d-MRI has the potential to be a biomarker of subsequent outcome and to evaluate efficacy of clinical interventions in this population.
    Neuroradiology 08/2013; DOI:10.1007/s00234-013-1242-x
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    ABSTRACT: We propose a method for registration of 3D fetal brain ultrasound with a reconstructed magnetic resonance fetal brain volume. This method, for the first time, allows the alignment of models of the fetal brain built from magnetic resonance images with 3D fetal brain ultrasound, opening possibilities to develop new, prior information based image analysis methods for 3D fetal neurosonography. The reconstructed magnetic resonance volume is first segmented using a probabilistic atlas and a pseudo ultrasound image volume is simulated from the segmentation. This pseudo ultrasound image is then affinely aligned with clinical ultrasound fetal brain volumes using a robust block-matching approach that can deal with intensity artefacts and missing features in the ultrasound images. A qualitative and quantitative evaluation demonstrates good performance of the method for our application, in comparison with other tested approaches. The intensity average of 27 ultrasound images co-aligned with the pseudo ultrasound template shows good correlation with anatomy of the fetal brain as seen in the reconstructed magnetic resonance image.
    Medical image analysis 07/2013; 17(8):1137-1150. DOI:10.1016/j.media.2013.07.004
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    ABSTRACT: Early neuroimaging may provide a surrogate marker for brain development and outcome after preterm birth. Tract-Based Spatial Statistics (TBSS) is an advanced Diffusion Tensor Image (DTI) analysis technique that is sensitive to the effects of prematurity and may provide a quantitative marker for neuroprotection following perinatal brain injury or preterm birth. Here, we test the sensitivity of TBSS to detect diffuse microstructural differences in the developing white matter of preterm infants at term-equivalent age by modelling a 'treatment' effect as a global increase in fractional anisotropy (FA). As proof of concept we compare these simulations to a real effect of increasing age at scan. 3-Tesla, 15-direction diffusion tensor imaging (DTI) was acquired from 90 preterm infants at term-equivalent age. Datasets were randomly assigned to 'treated' or 'untreated' groups of increasing size and voxel-wise increases in FA were used to simulate global treatment effects of increasing magnitude in all 'treated' maps. 'Treated' and 'untreated' FA maps were compared using TBSS. Predictions from simulated data were then compared to exemplar TBSS group comparisons based on increasing postmenstrual age at scan. TBSS proved sensitive to global differences in FA within a clinically relevant range, even in relatively small group sizes, and simulated data were shown to predict well a true biological effect of increasing age on white matter development. These data confirm that TBSS is a sensitive tool for detecting global group-wise differences in FA in this population.
    PLoS ONE 07/2013; 8(7):e67706. DOI:10.1371/journal.pone.0067706
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    ABSTRACT: Cortical maturation was studied in 65 infants between 27 and 46 wk postconception using structural and diffusion magnetic resonance imaging. Alterations in neural structure and complexity were inferred from changes in mean diffusivity and fractional anisotropy, analyzed by sampling regions of interest and also by a unique whole-cortex mapping approach. Mean diffusivity was higher in gyri than sulci and in frontal compared with occipital lobes, decreasing consistently throughout the study period. Fractional anisotropy declined until 38 wk, with initial values and rates of change higher in gyri, frontal and temporal poles, and parietal cortex; and lower in sulcal, perirolandic, and medial occipital cortex. Neuroanatomical studies and experimental diffusion-anatomic correlations strongly suggested the interpretation that cellular and synaptic complexity and density increased steadily throughout the period, whereas elongation and branching of dendrites orthogonal to cortical columns was later and faster in higher-order association cortex, proceeding rapidly before becoming undetectable after 38 wk. The rate of microstructural maturation correlated locally with cortical growth, and predicted higher neurodevelopmental test scores at 2 y of age. Cortical microstructural development was reduced in a dose-dependent fashion by longer premature exposure to the extrauterine environment, and preterm infants at term-corrected age possessed less mature cortex than term-born infants. The results are compatible with predictions of the tension theory of cortical growth and show that rapidly developing cortical microstructure is vulnerable to the effects of premature birth, suggesting a mechanism for the adverse effects of preterm delivery on cognitive function. Link https://kclpure.kcl.ac.uk/portal/files/7917360/PNAS_2013_Ball_1301652110_earlyEdition.pdf
    Proceedings of the National Academy of Sciences 05/2013; DOI:10.1073/pnas.1301652110
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    ABSTRACT: Xenon, a monoatomic gas with very high tissue solubility, is a non-competitive inhibitor of N-methyl-D-aspartate (NMDA) glutamate receptor, has antiapoptotic effects and is neuroprotective following hypoxic ischaemic injury in animals. Xenon may be expected to have anticonvulsant effects through glutamate receptor blockade, but this has not previously been demonstrated clinically. We examined seizure activity on the real time and amplitude integrated EEG records of 14 full-term infants with perinatal asphyxial encephalopathy treated within 12 h of birth with 30% inhaled xenon for 24 h combined with 72 h of moderate systemic hypothermia. Seizures were identified on 5 of 14 infants. Seizures stopped during xenon therapy but recurred within a few minutes of withdrawing xenon and stopped again after xenon was restarted. Our data show that subanaesthetic levels of xenon may have an anticonvulsant effect. Inhaled xenon may be a valuable new therapy in this hard-to-treat population.
    Archives of Disease in Childhood - Fetal and Neonatal Edition 04/2013; 98(5). DOI:10.1136/archdischild-2013-303786
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    ABSTRACT: Cerebral white-matter injury is common in preterm-born infants and is associated with neurocognitive impairments. Identifying the pattern of connectivity changes in the brain following premature birth may provide a more comprehensive understanding of the neurobiology underlying these impairments. Here, we characterize whole-brain, macrostructural connectivity following preterm delivery and explore the influence of age and prematurity using a data-driven, nonsubjective analysis of diffusion magnetic resonance imaging data. T1- and T2-weighted and -diffusion MRI were obtained between 11 and 31 months postconceptional age in 49 infants, born between 25 and 35 weeks postconception. An optimized processing pipeline, combining anatomical, and tissue segmentations with probabilistic diffusion tractography, was used to map mean tract anisotropy. White-matter tracts where connection strength was related to age of delivery or imaging were identified using sparse-penalized regression and stability selection. Older children had stronger connections in tracts predominantly involving frontal lobe structures. Increasing prematurity at birth was related to widespread reductions in connection strength in tracts involving all cortical lobes and several subcortical structures. This nonsubjective approach to mapping whole-brain connectivity detected hypothesized changes in the strength of intracerebral connections during development and widespread reductions in connectivity strength associated with premature birth.
    Cerebral Cortex 03/2013; DOI:10.1093/cercor/bht086
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    ABSTRACT: Mild cerebral ventricular enlargement is associated with schizophrenia, autism, epilepsy, and attention-deficit/hyperactivity disorder. Fetal ventriculomegaly is the most common central nervous system (CNS) abnormality affecting 1% of fetuses and is associated with cognitive, language, and behavioral impairments in childhood. Neurodevelopmental outcome is partially predictable by the 2-dimensional size of the ventricles in the absence of other abnormalities. We hypothesized that isolated fetal ventriculomegaly is a marker of altered brain development characterized by relative overgrowth and aimed to quantify brain growth using volumetric magnetic resonance imaging (MRI) in fetuses with isolated ventriculomegaly. Fetal brain MRI (1.5 T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly, across a gestational age range of 22-38 weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3-dimensional reconstructed datasets. Fetuses with isolated ventriculomegaly had increased brain parenchyma volumes when compared with the control cohort (9.6%, P < 0.0001) with enlargement restricted to the cortical gray matter (17.2%, P = 0.002). The extracerebral cerebrospinal fluid and third and fourth ventricles were also enlarged. White matter, basal ganglia, and thalamic volumes were not significantly different between cohorts. The presence of relative cortical overgrowth in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language, and behavioral deficits in these children.
    Cerebral Cortex 03/2013; DOI:10.1093/cercor/bht062
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    ABSTRACT: AimsPreterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. Methods Melatonin was administered to 18 preterm infants in doses ranging from 0.04-0.6gkg(-1) over 0.5-6h. Pharmacokinetic profiles were analyzed individually and by population methods. ResultsBaseline melatonin was largely undetectable. Infants receiving melatonin at 0.1gkg(-1)h(-1) for 2h showed a median half-life of 15.82h and median maximum plasma concentration of 203.3pgml(-1). On population pharmacokinetics, clearance was 0.045lh(-1), volume of distribution 1.098l and elimination half-life 16.91h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. ConclusionsA 2h infusion of 0.1gkg(-1)h(-1) increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants.
    British Journal of Clinical Pharmacology 02/2013; 76(5). DOI:10.1111/bcp.12092
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