Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial

Background Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. Methods Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. Findings The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. Interpretation Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia

Exploring the multiple-hit hypothesis of preterm white matter damage using diffusion MRI.

Background: Preterm infants are at high risk of diffuse white matter injury and adverse neurodevelopmental outcome. The multiple hit hypothesis suggests that the risk of white matter injury increases with cumulative exposure to multiple perinatal risk factors. Our aim was to test this hypothesis in a large cohort of preterm infants using diffusion weighted magnetic resonance imaging (dMRI). Methods: We studied 491 infants (52% male) without focal destructive brain lesions born at < 34 weeks, who underwent structural and dMRI at a specialist Neonatal Imaging Centre. The median (range) gestational age (GA) at birth was 30+ 1 (23+ 2-33+ 5) weeks and median postmenstrual age at scan was 42+ 1 (38-45) weeks. dMRI data were analyzed using tract based spatial statistics and the relationship between dMRI measures in white matter and individual perinatal risk factors was assessed. We tested the hypothesis that increased exposure to perinatal risk factors was associated with lower fractional anisotropy (FA), and higher radial, axial and mean diffusivity (RD, AD, MD) in white matter. Neurodevelopmental performance was investigated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III) in a subset of 381 infants at 20 months corrected age. We tested the hypothesis that lower FA and higher RD, AD and MD in white matter were associated with poorer neurodevelopmental performance. Results: Identified risk factors for diffuse white matter injury were lower GA at birth, fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition, necrotizing enterocolitis and male sex. Clinical chorioamnionitis and patent ductus arteriosus were not associated with white matter injury. Multivariate analysis demonstrated that fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition were independently associated with lower FA values. Exposure to cumulative risk factors was associated with reduced white matter FA and FA values at term equivalent age were associated with subsequent neurodevelopmental performance. Conclusion: This study suggests multiple perinatal risk factors have an independent association with diffuse white matter injury at term equivalent age and exposure to multiple perinatal risk factors exacerbates dMRI defined, clinically significant white matter injury. Our findings support the multiple hit hypothesis for preterm white matter injury

Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia

Background: The TOBY-Xe proof of concept randomised trial found no effect of xenon combined with hypothermia after birth asphyxia on the lactate to N-acetyl aspartate ratio (Lac/NAA) in the thalamus and fractional anisotropy (FA) in white matter tracts measured within 15 days of birth. To confirm that these biomarkers are qualified to predict long-term outcome after neural rescue therapy we assessed surviving participants at 2–3 years of age. Methods: Of the 92 infants in TOBY-Xe, one was omitted from the study, 69 survived and we assessed 62 participants, 32 in the hypothermia and xenon and 30 in the hypothermia only groups. We examined the relation between Lac/NAA and FA and the scores of the Bayley Scales of Infant and Toddler Development III and calculated their predictive accuracy for moderate or severe disability or death. Results: Fifteen of 62 participants (24%) developed moderate/severe disability, and 22/92 (24%) died. The Lac/NAA ratio (difference in medians 0.628, 95% CI -0.392 to 4.684) and FA (difference in means −0.055, 95% CI -0.033 to −0.077) differed significantly between participants with or without moderate or severe disability or death and were significantly related with development scores in both groups. Adverse outcomes were correctly identified in 95.65% of cases by Lac/NAA and 78.79% by FA, with adequate mean calibration of the model. Interpretation: The results confirm the qualification of the cerebral magnetic resonance biomarkers employed in the TOBY-Xe study as predictors of outcome after neuroprotective therapy. Fund: The Centre for the Developing Brain, King's College London, UK

A deformable model for the reconstruction of the neonatal cortex

We present a method based on deformable meshes for the reconstruction of the cortical surfaces of the developing human brain at the neonatal period. It employs a brain segmentation for the reconstruction of an initial inner cortical surface mesh. Errors in the segmentation resulting from poor tissue contrast in neonatal MRI and partial volume effects are subsequently accounted for by a local edge-based refinement. We show that the obtained surface models define the cortical boundaries more accurately than the segmentation. The surface meshes are further guaranteed to not intersect and subdivide the brain volume into disjoint regions. The proposed method generates topologically correct surfaces which facilitate both a flattening and spherical mapping of the cortex

The Developing Human Connectome Project: a minimal processing pipeline for neonatal cortical surface reconstruction

The Developing Human Connectome Project (dHCP) seeks to create the first 4-dimensional connectome of early life. Understanding this connectome in detail may provide insights into normal as well as abnormal patterns of brain development. Following established best practices adopted by the WU-MINN Human Connectome Project (HCP), and pioneered by FreeSurfer, the project utilises cortical surface-based processing pipelines. In this paper, we propose a fully automated processing pipeline for the structural Magnetic Resonance Imaging (MRI) of the developing neonatal brain. This proposed pipeline consists of a refined framework for cortical and sub-cortical volume segmentation, cortical surface extraction, and cortical surface inflation, which has been specifically designed to address considerable differences between adult and neonatal brains, as imaged using MRI. Using the proposed pipeline our results demonstrate that images collected from 465 subjects ranging from 28 to 45 weeks post-menstrual age (PMA) can be processed fully automatically; generating cortical surface models that are topologically correct, and correspond well with manual evaluations of tissue boundaries in 85% of cases. Results improve on state-of-the-art neonatal tissue segmentation models and significant errors were found in only 2% of cases, where these corresponded to subjects with high motion. Downstream, these surfaces will enhance comparisons of functional and diffusion MRI datasets, supporting the modelling of emerging patterns of brain connectivity

The Developing Human Connectome Project Neonatal Data Release

The Developing Human Connectome Project has created a large open science resource which provides researchers with data for investigating typical and atypical brain development across the perinatal period. It has collected 1228 multimodal magnetic resonance imaging (MRI) brain datasets from 1173 fetal and/or neonatal participants, together with collateral demographic, clinical, family, neurocognitive and genomic data from 1173 participants, together with collateral demographic, clinical, family, neurocognitive and genomic data. All subjects were studied in utero and/or soon after birth on a single MRI scanner using specially developed scanning sequences which included novel motion-tolerant imaging methods. Imaging data are complemented by rich demographic, clinical, neurodevelopmental, and genomic information. The project is now releasing a large set of neonatal data; fetal data will be described and released separately. This release includes scans from 783 infants of whom: 583 were healthy infants born at term; as well as preterm infants; and infants at high risk of atypical neurocognitive development. Many infants were imaged more than once to provide longitudinal data, and the total number of datasets being released is 887. We now describe the dHCP image acquisition and processing protocols, summarize the available imaging and collateral data, and provide information on how the data can be accessed

Machine-learning to characterise neonatal functional connectivity in the preterm brain

Brain development is adversely affected by preterm birth. Magnetic resonance image analysis has revealed a complex fusion of structural alterations across all tissue compartments that are apparent by term-equivalent age, persistent into adolescence and adulthood, and associated with wide-ranging neurodevelopment disorders. Although functional MRI has revealed the relatively advanced organisational state of the neonatal brain, the full extent and nature of functional disruptions following preterm birth remain unclear. In this study, we apply machine-learning methods to compare whole-brain functional connectivity in preterm infants at term-equivalent age and healthy term-born neonates in order to test the hypothesis that preterm birth results in specific alterations to functional connectivity by term-equivalent age. Functional connectivity networks were estimated in 105 preterm infants and 26 term controls using group-independent component analysis and a graphical lasso model. A random forest-based feature selection method was used to identify discriminative edges within each network and a nonlinear support vector machine was used to classify subjects based on functional connectivity alone. We achieved 80% cross-validated classification accuracy informed by a small set of discriminative edges. These edges connected a number of functional nodes in subcortical and cortical grey matter, and most were stronger in term neonates compared to those born preterm. Half of the discriminative edges connected one or more nodes within the basal ganglia. These results demonstrate that functional connectivity in the preterm brain is significantly altered by term-equivalent age, confirming previous reports of altered connectivity between subcortical structures and higher-level association cortex following preterm birth

The effects of hemorrhagic parenchymal infarction on the establishment of sensori-motor structural and functional connectivity in early infancy

INTRODUCTION: The objective of the study was to characterize alterations of structural and functional connectivity within the developing sensori-motor system in infants with focal perinatal brain injury and at high risk of cerebral palsy. METHODS: Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data were used to study the developing functional and structural connectivity framework in six infants born prematurely at term equivalent age. This was first characterised in three infants without focal pathology, which was then compared to that derived from three infants with unilateral haemorrhagic parenchymal infarction and a subsequent focal periventricular white matter lesion who developed later haemiparesis. RESULTS: Functional responses to passive hand movement were in the contralateral perirolandic cortex, regardless of focal pathology. In infants with unilateral periventricular injury, afferent thalamo-cortical tracts appeared to have developed compensatory trajectories which circumvented areas of damage. In contrast, efferent corticospinal tracts showed marked asymmetry at term equivalent age following focal brain injury. Sensori-motor network analysis suggested that inter-hemispheric functional connectivity is largely preserved despite pathology and that impairment may be associated with adverse neurodevelopmental outcome. CONCLUSION: Following focal perinatal brain injury, altered structural and functional connectivity is already present and can be characterized with MRI at term equivalent age. The results of this small case series suggest that these techniques may provide valuable new information about prognosis and the pathophysiology underlying cerebral palsy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00234-014-1412-5) contains supplementary material, which is available to authorized users