PPAR Gamma Receptor: A Novel Target to Improve Morbidity in Preterm Babies.

Worldwide, three-quarters of a million babies are born extremely preterm (<28 weeks gestation) with devastating outcomes: 20% die in the newborn period, a further 35% develop bronchopulmonary dysplasia (BPD), and 10% suffer from cerebral palsy. Pioglitazone, a Peroxisome Proliferator Activated Receptor Gamma (PPARγ) agonist, may reduce the incidence of BPD and improve neurodevelopment in extreme preterm babies. Pioglitazone exerts an anti-inflammatory action mediated through Nuclear Factor-kappa B repression. PPARγ signalling is underactive in preterm babies as adiponectin remains low during the neonatal period. In newborn animal models, pioglitazone has been shown to be protective against BPD, necrotising enterocolitis, and lipopolysaccharide-induced brain injury. Single Nucleotide Polymorphisms of PPARγ are associated with inhibited preterm brain development and impaired neurodevelopment. Pioglitazone was well tolerated by the foetus in reproductive toxicology experiments. Bladder cancer, bone fractures, and macular oedema, seen rarely in adults, may be avoided with a short treatment course. The other effects of pioglitazone, including improved glycaemic control and lipid metabolism, may provide added benefit in the context of prematurity. Currently, there is no formulation of pioglitazone suitable for administration to preterm babies. A liquid formulation of pioglitazone needs to be developed before clinical trials. The potential benefits are likely to outweigh any anticipated safety concerns.

'Moving towards understanding', acceptability of investigations following stillbirth in sub-Saharan Africa: A grounded theory study.

OBJECTIVE: To explore the views of women, partners, families, health workers and community leaders of potential investigations to determine the cause(s) of stillbirth, in Malawi, Tanzania and Zambia. DESIGN: Grounded theory. SETTING: Tertiary facilities and community settings in Blantyre, Malawi, Mwanza, Tanzania and Mansa, Zambia. SAMPLE: Purposive and theoretical sampling was used to recruit 124 participants: 33 women, 18 partners, 19 family members, 29 health workers and 25 community leaders, across three countries. METHODS: Semi-structured interviews were conducted using a topic guide for focus. Analysis was completed using constant comparative analysis. Sampling ceased at data saturation. RESULTS: Women wanted to know the cause of stillbirth, but this was tempered by their fear of the implications of this knowledge; in particular, the potential for them to be blamed for the death of their baby. There were also concerns about the potential consequences of denying tradition and culture. Non-invasive investigations were most likely to be accepted on the basis of causing less 'harm' to the baby. Parents' decision-making was influenced by type of investigation, family and cultural influences and financial cost. CONCLUSIONS: Parents want to understand the cause of death, but face emotional, cultural and economic barriers to this. Offering investigations will require these barriers to be addressed, services to be available and a no-blame culture developed to improve outcomes. Community awareness, education and support for parents in making decisions are vital prior to implementing investigations in these settings.

Maternal depressive symptoms, neonatal white matter, and toddler social-emotional development.

Maternal prenatal depression is associated with increased likelihood of neurodevelopmental and psychiatric conditions in offspring. The relationship between maternal depression and offspring outcome may be mediated by in-utero changes in brain development. Recent advances in magnetic resonance imaging (MRI) have enabled in vivo investigations of neonatal brains, minimising the effect of postnatal influences. The aim of this study was to examine associations between maternal prenatal depressive symptoms, infant white matter, and toddler behaviour. 413 mother-infant dyads enrolled in the developing Human Connectome Project. Mothers completed the Edinburgh Postnatal Depression Scale (median = 5, range = 0-28, n = 52 scores ≥ 11). Infants (n = 223 male) (median gestational age at birth = 40 weeks, range 32.14-42.29) underwent MRI (median postmenstrual age at scan = 41.29 weeks, range 36.57-44.71). Fixel-based fibre metrics (mean fibre density, fibre cross-section, and fibre density modulated by cross-section) were calculated from diffusion imaging data in the left and right uncinate fasciculi and cingulum bundle. For n = 311, internalising and externalising behaviour, and social-emotional abilities were reported at a median corrected age of 18 months (range 17-24). Statistical analysis used multiple linear regression and mediation analysis with bootstrapping. Maternal depressive symptoms were positively associated with infant fibre density in the left (B = 0.0005, p = 0.003, q = 0.027) and right (B = 0.0006, p = 0.003, q = 0.027) uncinate fasciculus, with left uncinate fasciculus fibre density, in turn, positively associated with social-emotional abilities in toddlerhood (B = 105.70, p = 0.0007, q = 0.004). In a mediation analysis, higher maternal depressive symptoms predicted toddler social-emotional difficulties (B = 0.342, t(307) = 3.003, p = 0.003), but this relationship was not mediated by fibre density in the left uncinate fasciculus (Sobel test p = 0.143, bootstrapped indirect effect = 0.035, SE = 0.02, 95% CI: [-0.01, 0.08]). There was no evidence of an association between maternal depressive and cingulum fibre properties. These findings suggest that maternal perinatal depressive symptoms are associated with neonatal uncinate fasciculi microstructure, but not fibre bundle size, and toddler behaviour.

The factor structure of the Edinburgh Postnatal Depression Scale among perinatal high-risk and community samples in London.

Timely and accurate detection of perinatal mental health problems is essential for the wellbeing of both mother and child. Growing evidence has suggested that the Edinburgh Postnatal Depression Scale (EPDS) is not a unidimensional measure of perinatal depression, but can be used to screen for anxiety disorders. We aimed to assess the factor structure of the EPDS in 3 different groups of women: n = 266 pregnant women at high-risk of depression ("Perinatal Stress Study"), n = 471 pregnant women from a community sample, and n = 637 early postnatal women from a community sample ("developing Human Connectome Project"). Exploratory factor analysis (40% of each sample) and confirmatory factor analysis (60% of each sample) were performed. The relationship between EPDS scores and history of mental health concerns was investigated. Results suggested that a 3-factor model (depression, anxiety, and anhedonia) is the most appropriate across groups. The anxiety subscale (EPDS-3A) emerged consistently and was related to maternal history of anxiety disorders in the prenatal sample (W = 6861, p < 0.001). EPDS total score was related to history of mental health problems in both the prenatal (W = 12,185, p < 0.001) and postnatal samples (W = 30,044, p < 0.001). In both high-risk and community samples in the perinatal period, the EPDS appears to consist of depression, anxiety, and anhedonia subscales. A better understanding of the multifactorial structure of the EPDS can inform diagnosis and management of women in the prenatal and postnatal period. Further research is required to validate the EPDS-3A as a screening tool for anxiety.

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy.

Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44-53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known: • Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy. • Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New: • Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia. • There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.

Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma 2 may be associated with adverse neurodevelopment in European preterm babies.

INTRODUCTION: Prematurity is the leading cause of death and disability in children under 5 years of age. Understanding the molecular mechanisms of the biological processes involved in preterm brain injury may help develop novel neuroprotective treatment strategies. A growing body of evidence suggest that peroxisome proliferator-activated receptor gamma (PPARγ) signaling is associated with inhibited brain development in preterm babies. The Ala allele of the Pro12Ala polymorphism of PPARγ2 decreases receptor binding affinity and consequently induces a reduction of PPARγ signaling. METHODS: In this study, we carried out a preliminary analysis of existing datasets to test the hypothesis that reduced transactivation capacity of PPARγ in the presence of the Ala variant of PPARγ2 may be associated with adverse neurodevelopment in preterm babies. The association between PPAR-γ2 Pro12Ala polymorphism and neurodevelopment at 18-24 months of age was assessed in two groups of European infants, 155 born before 33 weeks' gestation and 180 born later than 36 weeks' gestation using a linear regression model. The Bayley Scales of Infant and Toddler Development-3rd edition was administered to assess neurodevelopment at 18-24 months of age. RESULTS: We observed the Ala allele of the Pro12Ala polymorphism in 25% preterm infants and 20% term infants. The Ala allele of PPARγ2 was significantly associated with adverse cognitive (p = .019), language (p = .03), and motor development (p = 0.036) at 18-24 months of age after taking into consideration the duration of ventilation, gender, and index of multiple deprivation scores, but without correction for potential shared ancestry. There was no association between the PPAR-γ2 Pro12Ala polymorphism and neurodevelopment in term infants. CONCLUSIONS: These preliminary data suggest that PPARγ signaling in the presence of the Ala variant of PPARγ2 may be associated with adverse neurodevelopment in preterm infants suggesting that further studies are warranted.

Individualized brain development and cognitive outcome in infants with congenital heart disease.

Infants with congenital heart disease are at risk of neurodevelopmental impairments, the origins of which are currently unclear. This study aimed to characterize the relationship between neonatal brain development, cerebral oxygen delivery and neurodevelopmental outcome in infants with congenital heart disease. A cohort of infants with serious or critical congenital heart disease (N = 66; N = 62 born ≥37 weeks) underwent brain MRI before surgery on a 3T scanner situated on the neonatal unit. T2-weighted images were segmented into brain regions using a neonatal-specific algorithm. We generated normative curves of typical volumetric brain development using a data-driven technique applied to 219 healthy infants from the Developing Human Connectome Project (dHCP). Atypicality indices, representing the degree of positive or negative deviation of a regional volume from the normative mean for a given gestational age, sex and postnatal age, were calculated for each infant with congenital heart disease. Phase contrast angiography was acquired in 53 infants with congenital heart disease and cerebral oxygen delivery was calculated. Cognitive and motor abilities were assessed at 22 months (N = 46) using the Bayley scales of Infant and Toddler Development-Third Edition. We assessed the relationship between atypicality indices, cerebral oxygen delivery and cognitive and motor outcome. Additionally, we examined whether cerebral oxygen delivery was associated with neurodevelopmental outcome through the mediating effect of brain volume. Negative atypicality indices in deep grey matter were associated with both reduced neonatal cerebral oxygen delivery and poorer cognitive abilities at 22 months across the whole sample. In infants with congenital heart disease born ≥37 weeks, negative cortical grey matter and total tissue volume atypicality indices, in addition to deep grey matter structures, were associated with poorer cognition. There was a significant indirect relationship between cerebral oxygen delivery and cognition through the mediating effect of negative deep grey matter atypicality indices across the whole sample. In infants born ≥37 weeks, cortical grey matter and total tissue volume atypicality indices were also mediators of this relationship. In summary, lower cognitive abilities in toddlers with congenital heart disease were associated with smaller grey matter volumes before cardiac surgery. The aetiology of poor cognition may encompass poor cerebral oxygen delivery leading to impaired grey matter growth. Interventions to improve cerebral oxygen delivery may promote early brain growth and improve cognitive outcomes in infants with congenital heart disease.

Exploring the relationship between maternal prenatal stress and brain structure in premature neonates.

BACKGROUND: Exposure to maternal stress in utero is associated with a range of adverse outcomes. We previously observed an association between maternal stress and white matter microstructure in a sample of infants born prematurely. In this study, we aimed to investigate the relationship between maternal trait anxiety, stressful life events and brain volumes. METHODS: 221 infants (114 males, 107 females) born prematurely (median gestational age = 30.43 weeks [range 23.57-32.86]) underwent magnetic resonance imaging around term-equivalent age (mean = 42.20 weeks, SD = 1.60). Brain volumes were extracted for the following regions of interest: frontal lobe, temporal lobe, amygdala, hippocampus, thalamus and normalized to total brain volume. Multiple linear regressions were conducted to investigate the relationship between maternal anxiety/stress and brain volumes, controlling for gestational age at birth, postmenstrual age at scan, socioeconomic status, sex, days on total parenteral nutrition. Additional exploratory Tensor Based Morphometry analyses were performed to obtain voxel-wise brain volume changes from Jacobian determinant maps. RESULTS AND CONCLUSION: In this large prospective study, we did not find evidence of a relationship between maternal prenatal stress or trait anxiety and brain volumes. This was the case for both the main analysis using a region-of-interest approach, and for the exploratory analysis using Jacobian determinant maps. We discuss these results in the context of conflicting evidence from previous studies and highlight the need for further research on premature infants, particularly including term-born controls.

Cognitive function in toddlers with congenital heart disease: The impact of a stimulating home environment.

Infants born with congenital heart disease (CHD) are at increased risk of neurodevelopmental difficulties in childhood. The extent to which perioperative factors, cardiac physiology, brain injury severity, socioeconomic status, and home environment influence early neurodevelopment is not clear. Sixty-nine newborns with CHD were recruited from St Thomas' Hospital. Infants underwent presurgical magnetic resonance imaging on a 3-Tesla scanner situated on the neonatal unit. At 22 months, children completed the Bayley Scales of Infant and Toddler Development-3rd edition and parents completed the cognitively stimulating parenting scale to assess cognitive stimulation at home. Level of maternal education and total annual household income were also collected. Hospital records were reviewed to calculate days on the intensive care unit post-surgery, time on bypass during surgery, and days to corrective or definitive palliative surgical intervention. In the final analysis of 56 infants, higher scores on the cognitively stimulating parenting scale were associated with higher cognitive scores at age 22 months, correcting for gestational age at birth, sex, and maternal education. There were no relationships between outcome scores and clinical factors; socioeconomic status; or brain injury severity. Supporting parents to provide a stimulating home environment for children may promote cognitive development in this high-risk population.

Investigating altered brain development in infants with congenital heart disease using tensor-based morphometry.

Magnetic resonance (MR) imaging studies have demonstrated reduced global and regional brain volumes in infants with congenital heart disease (CHD). This study aimed to provide a more detailed evaluation of altered structural brain development in newborn infants with CHD compared to healthy controls using tensor-based morphometry (TBM). We compared brain development in 64 infants with CHD to 192 age- and sex-matched healthy controls. T2-weighted MR images obtained prior to surgery were analysed to compare voxel-wise differences in structure across the whole brain between groups. Cerebral oxygen delivery (CDO2) was measured in infants with CHD (n = 49) using phase contrast MR imaging and the relationship between CDO2 and voxel-wise brain structure was assessed using TBM. After correcting for global scaling differences, clusters of significant volume reduction in infants with CHD were demonstrated bilaterally within the basal ganglia, thalami, corpus callosum, occipital, temporal, parietal and frontal lobes, and right hippocampus (p < 0.025 after family-wise error correction). Clusters of significant volume expansion in infants with CHD were identified in cerebrospinal fluid spaces (p < 0.025). After correcting for global brain size, there was no significant association between voxel-wise brain structure and CDO2. This study localizes abnormal brain development in infants with CHD, identifying areas of particular vulnerability.

Parental age effects on neonatal white matter development.

OBJECTIVE: Advanced paternal age is associated with poor offspring developmental outcome. Though an increase in paternal age-related germline mutations may affect offspring white matter development, outcome differences could also be due to psychosocial factors. Here we investigate possible cerebral changes prior to strong environmental influences using brain MRI in a cohort of healthy term-born neonates. METHODS: We used structural and diffusion MRI images acquired soon after birth from a cohort (n = 275) of healthy term-born neonates. Images were analysed using a customised tract based spatial statistics (TBSS) processing pipeline. Neurodevelopmental assessment using the Bayley-III scales was offered to all participants at age 18 months. For statistical analysis neonates were compared in two groups, representing the upper quartile (paternal age ≥38 years) and lower three quartiles. The same method was used to assess associations with maternal age. RESULTS: In infants with older fathers (≥38 years), fractional anisotropy, a marker of white matter organisation, was significantly reduced in three early maturing anatomical locations (the corticospinal tract, the corpus callosum, and the optic radiation). Fractional anisotropy in these locations correlated positively with Bayley-III cognitive composite score at 18 months in the advanced paternal age group. A small but significant reduction in total brain volume was also observed in in the infants of older fathers. No significant associations were found between advanced maternal age and neonatal imaging. CONCLUSIONS: The epidemiological association between advanced paternal age and offspring outcome is extremely robust. We have for the first time demonstrated a neuroimaging phenotype of advanced paternal age before sustained parental interaction that correlates with later outcome.

Maternal Prenatal Stress Is Associated With Altered Uncinate Fasciculus Microstructure in Premature Neonates.

BACKGROUND: Maternal prenatal stress exposure (PNSE) increases risk for adverse psychiatric and behavioral outcomes in offspring. The biological basis for this elevated risk is poorly understood but may involve alterations to the neurodevelopmental trajectory of white matter tracts within the limbic system, particularly the uncinate fasciculus. Additionally, preterm birth is associated with both impaired white matter development and adverse developmental outcomes. In this study we hypothesized that higher maternal PNSE was associated with altered uncinate fasciculus microstructure in offspring. METHODS: In this study, 251 preterm infants (132 male, 119 female) (median gestational age = 30.29 weeks [range, 23.57-32.86 weeks]) underwent brain magnetic resonance imaging including diffusion-weighted imaging around term-equivalent age (median = 42.43 weeks [range, 37.86-45.71 weeks]). Measures of white matter microstructure were calculated for the uncinate fasciculus and the inferior longitudinal fasciculus, a control tract that we hypothesized was not associated with maternal PNSE. Multiple regressions were used to investigate the relationship among maternal trait anxiety scores, stressful life events, and white matter microstructure indices in the neonatal brain. RESULTS: Adjusting for gestational age at birth, postmenstrual age at scan, maternal age, socioeconomic status, sex, and number of days on parenteral nutrition, higher stressful life events scores were associated with higher axial diffusivity (ß = .177, q = .007), radial diffusivity (ß = .133, q = .026), and mean diffusivity (ß = .149, q = .012) in the left uncinate fasciculus, and higher axial diffusivity (ß = .142, q = .026) in the right uncinate fasciculus. CONCLUSIONS: These findings suggest that PNSE is associated with altered development of specific frontolimbic pathways in preterm neonates as early as term-equivalent age.

Neuroimaging findings in newborns with congenital heart disease prior to surgery: an observational study.

OBJECTIVES: Neurodevelopmental impairment has become the most important comorbidity in infants with congenital heart disease (CHD). We aimed to (1) investigate the burden of brain lesions in infants with CHD prior to surgery and (2) explore clinical factors associated with injury. STUDY DESIGN: Prospective observational study. SETTING: Single centre UK tertiary neonatal intensive care unit. PATIENTS: 70 newborn infants with critical or serious CHD underwent brain MRI prior to surgery. MAIN OUTCOME MEASURES: Prevalence of cerebral injury including arterial ischaemic strokes (AIS), white matter injury (WMI) and intracranial haemorrhage. RESULTS: Brain lesions were observed in 39% of subjects (95% CI 28% to 50%). WMI was identified in 33% (95% CI 23% to 45%), subdural haemorrhage without mass effect in 33% (95% CI 23% to 45%), cerebellar haemorrhage in 9% (95% CI 4% to 18%) and AIS in 4% (95% CI 1.5% to 12%). WMI was distributed widely throughout the brain, particularly involving the frontal white matter, optic radiations and corona radiata. WMI exhibited restricted diffusion in 48% of cases. AIS was only observed in infants with transposition of the great arteries (TGA) who had previously undergone balloon atrial septostomy (BAS). AIS was identified in 23% (95% CI 8% to 50%) of infants with TGA who underwent BAS, compared with 0% (95% CI 0% to 20%) who did not. CONCLUSIONS: Cerebral injury in newborns with CHD prior to surgery is common.

Social Brain Functional Maturation in Newborn Infants With and Without a Family History of Autism Spectrum Disorder.

Importance: What is inherited or acquired in neurodevelopmental conditions such as autism spectrum disorder (ASD) is not a fixed outcome, but instead is a vulnerability to a spectrum of traits, especially social difficulties. Identifying the biological mechanisms associated with vulnerability requires looking as early in life as possible, before the brain is shaped by postnatal mechanisms and/or the experiences of living with these traits. Animal studies suggest that susceptibility to neurodevelopmental disorders arises when genetic and/or environmental risks for these conditions alter patterns of synchronous brain activity in the perinatal period, but this has never been examined in human neonates. Objective: To assess whether alternation of functional maturation of social brain circuits is associated with a family history of ASD in newborns. Design, Setting, and Participants: In this cohort study of 36 neonates with and without a family history of ASD, neonates underwent magnetic resonance imaging at St Thomas Hospital in London, England, using a dedicated neonatal brain imaging system between June 23, 2015, and August 1, 2018. Neonates with a first-degree relative with ASD (R+) and therefore vulnerable to autistic traits and neonates without a family history (R-) were recruited for the study. Synchronous neural activity in brain regions linked to social function was compared. Main Outcomes and Measures: Regions responsible for social function were selected with reference to a published meta-analysis and the level of synchronous activity within each region was used as a measure of local functional connectivity in a regional homogeneity analysis. Group differences, controlling for sex, age at birth, age at scan, and group × age interactions, were examined. Results: The final data set consisted of 18 R+ infants (13 male; median [range] postmenstrual age at scan, 42.93 [40.00-44.86] weeks) and 18 R- infants (13 male; median [range] postmenstrual age at scan, 42.50 [39.29-44.58] weeks). Neonates who were R+ had significantly higher levels of synchronous activity in the right posterior fusiform (t = 2.48; P = .04) and left parietal cortices (t = 3.96; P = .04). In addition, there was a significant group × age interaction within the anterior segment of the left insula (t = 3.03; P = .04) and cingulate cortices (right anterior: t = 3.00; P = .03; left anterior: t = 2.81; P = .03; right posterior: t = 2.77; P = .03; left posterior: t = 2.55; P = .03). In R+ infants, levels of synchronous activity decreased over 39 to 45 weeks' postmenstrual age, whereas synchronous activity levels increased in R- infants over the same period. Conclusions and Relevance: Synchronous activity is required during maturation of functionally connected networks. This study found that in newborn humans, having a first-degree relative with ASD was associated with higher levels of local functional connectivity and dysmaturation of interconnected regions responsible for processing higher-order social information.

Abnormal Microstructural Development of the Cerebral Cortex in Neonates With Congenital Heart Disease Is Associated With Impaired Cerebral Oxygen Delivery.

Background Abnormal macrostructural development of the cerebral cortex has been associated with hypoxia in infants with congenital heart disease ( CHD ). Animal studies have suggested that hypoxia results in cortical dysmaturation at the cellular level. New magnetic resonance imaging techniques offer the potential to investigate the relationship between cerebral oxygen delivery and cortical microstructural development in newborn infants with CHD . Methods and Results We measured cortical macrostructural and microstructural properties in 48 newborn infants with serious or critical CHD and 48 age-matched healthy controls. Cortical volume and gyrification index were calculated from high-resolution structural magnetic resonance imaging. Neurite density and orientation dispersion indices were modeled using high-angular-resolution diffusion magnetic resonance imaging. Cerebral oxygen delivery was estimated in infants with CHD using phase contrast magnetic resonance imaging and preductal pulse oximetry. We used gray matter-based spatial statistics to examine voxel-wise group differences in cortical microstructure. Microstructural development of the cortex was abnormal in 48 infants with CHD , with regions of increased fractional anisotropy and reduced orientation dispersion index compared with 48 healthy controls, correcting for gestational age at birth and scan (family-wise error corrected for multiple comparisons at P<0.05). Regions of reduced cortical orientation dispersion index in infants with CHD were related to impaired cerebral oxygen delivery ( R2=0.637; n=39). Cortical orientation dispersion index was associated with the gyrification index ( R2=0.589; P<0.001; n=48). Conclusions This study suggests that the primary component of cerebral cortex dysmaturation in CHD is impaired dendritic arborization, which may underlie abnormal macrostructural findings reported in this population, and that the degree of impairment is related to reduced cerebral oxygen delivery.

Automated processing pipeline for neonatal diffusion MRI in the developing Human Connectome Project.

The developing Human Connectome Project is set to create and make available to the scientific community a 4-dimensional map of functional and structural cerebral connectivity from 20 to 44 weeks post-menstrual age, to allow exploration of the genetic and environmental influences on brain development, and the relation between connectivity and neurocognitive function. A large set of multi-modal MRI data from fetuses and newborn infants is currently being acquired, along with genetic, clinical and developmental information. In this overview, we describe the neonatal diffusion MRI (dMRI) image processing pipeline and the structural connectivity aspect of the project. Neonatal dMRI data poses specific challenges, and standard analysis techniques used for adult data are not directly applicable. We have developed a processing pipeline that deals directly with neonatal-specific issues, such as severe motion and motion-related artefacts, small brain sizes, high brain water content and reduced anisotropy. This pipeline allows automated analysis of in-vivo dMRI data, probes tissue microstructure, reconstructs a number of major white matter tracts, and includes an automated quality control framework that identifies processing issues or inconsistencies. We here describe the pipeline and present an exemplar analysis of data from 140 infants imaged at 38-44 weeks post-menstrual age.

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.

Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia.

Therapeutic hypothermia (TH) is now provided as standard care to infants with moderate-severe hypoxic ischemic encephalopathy (HIE). The role of TH in limiting neuronal injury is well recognized, but its effect on hepatic injury which occurs frequently in neonatal HIE is not known. Our objective was to characterize biomarkers of liver injury and function in the setting of neonatal HIE and to describe whether HIE severity and provision of TH influence these hepatic biomarkers. We performed a multicenter retrospective study and compared hepatic biomarkers obtained during the first postnatal week, according to the severity of HIE and whether treated with TH. Of a total of 361 infants with HIE, 223 (62%) received TH and 138 (38%) were managed at normal temperature. Most hepatic biomarkers and C-reactive protein (CRP) were significantly associated with the severity of HIE (p < 0.001). Infants treated with TH had lower peak alanine aminotransferase (ALT) concentrations (p = 0.025) and a delay in reaching peak CRP concentration (p < 0.001). CONCLUSION: We observed a significant association between the clinical grade of HIE and biomarkers of liver metabolism and function. Therapeutic hypothermia was associated with delayed CRP responses and with lower ALT concentrations and so may have the potential to modulate hepatic injury. What is Known: • Ischemic hepatic injury occurs frequently as a part of multiorgan dysfunction in infants with hypoxic ischemic encephalopathy (HIE). • The neuroprotective role of therapeutic hypothermia in management of infants with HIE is well recognized, but the potential hepato-protective effects of hypothermia are unclear. What is New/What this study adds: • Therapeutic hypothermia was associated with lower alanine aminotransferase and albumin concentrations and a delayed C-reactive protein (CRP) response and so may have the potential to modulate hepatic injury. • An elevated CRP concentration during the first postnatal week may be regarded as an expected finding in moderate and severe HIE and, in the overwhelming majority of cases, occurs secondary to hepatic hypoxia-ischemia in the absence of blood culture-positive sepsis.