A radiomics-based study of deep medullary veins in infants: Evaluation of neonatal brain injury with hypoxic-ischemic encephalopathy via susceptibility-weighted imaging

ObjectiveThe deep medullary veins (DMVs) can be evaluated using susceptibility-weighted imaging (SWI). This study aimed to apply radiomic analysis of the DMVs to evaluate brain injury in neonatal patients with hypoxic-ischemic encephalopathy (HIE) using SWI.MethodsThis study included brain magnetic resonance imaging of 190 infants with HIE and 89 controls. All neonates were born at full-term (37+ weeks gestation). To include the DMVs in the regions of interest, manual drawings were performed. A Rad-score was constructed using least absolute shrinkage and selection operator (LASSO) regression to identify the optimal radiomic features. Nomograms were constructed by combining the Rad-score with a clinically independent factor. Receiver operating characteristic curve analysis was applied to evaluate the performance of the different models. Clinical utility was evaluated using a decision curve analysis.ResultsThe combined nomogram model incorporating the Rad-score and clinical independent predictors, was better in predicting HIE (in the training cohort, the area under the curve was 0.97, and in the validation cohort, it was 0.95) and the neurologic outcomes after hypoxic-ischemic (in the training cohort, the area under the curve was 0.91, and in the validation cohort, it was 0.88).ConclusionBased on radiomic signatures and clinical indicators, we developed a combined nomogram model for evaluating neonatal brain injury associated with perinatal asphyxia

MRI spectrum of cerebral palsy in correlation with clinical profile

OBJECTIVES: To describe MRI brain spectrum in a group of Cerebral Palsy children and correlate with perinatal history, clinical subgroups. To correlate callosal thinning with topographies and periventricular leukomalacia grades. METHODS: IRB approved observational study (cross sectional study) on CP children in between the period March 2012-October 2013 in Christian Medical College, Vellore. The important MRI features described are periventricular leukomalacia (PVL), deep gray nuclei involvement, cystic encephalomalacia, arterial territory infarcts, corpus callosal thinning, perirolandic cortical gliosis and malformations. These were correlated with the relevant perinatal history and clinical subgroups by cross tabulation and Chi square tests. RESULTS: A set of specific MRI features can be seen in different clinical pictures and a particular clinical picture can have varied MRI findings. Higher grades of PVL are associated with higher degree of neurological deficit and higher grades of thinning of corpus callosum. Deep gray nucleus signal abnormalities are seen significantly with combination of neonatal hyperbilirubinemia and birth asphyxia. Dystonic cerebral palsy is strongly associated with the deep gray nuclei involvement. Callosal thinning may be an isolated finding in CP; hence an important pick up

Improvements in Neonatal Brain Monitoring after Perinatal Asphyxia

Perinatal hypoxic ischemic encephalopathy (HIE) is a major cause of morbidity and mortality world-wide. Common sequelae in survivors include cerebral palsy (CP), epilepsy and sensory as well as cognitive problems. The consequences of HIE impose significant long-term personal and financial burden on the affected families and the society. The most cost-effective approach to reducing neonatal mortality world-wide would be to improve access to antenatal care4. However, even in developed countries, the exact factors triggering perinatal asphyxia as well as the time of onset of brain injury are often difficult to determine, and it remains a major clinical problem. Seizures commonly occur in the neonate with HIE and are often the only sign of serious underlying brain dysfunction6. Animal studies have shown that neonatal seizures in the context of HIE may cause additional brain injury and that their pharmacological suppression may improve outcome9. Monitoring of brain function using the electroencephalogram (EEG), continuously or by serial EEGs is well-suited to give insight into brain function and its dynamic changes in neonatal HIE and helps to guide treatment as well as prognostication. A good understanding of the pathophysiology of HIE is needed not only in the selection of suitable diagnostic tests and treatment methods, but also to develop new therapeutic strategies

Multimodal image analysis of the human brain

Gedurende de laatste decennia heeft de snelle ontwikkeling van multi-modale en niet-invasieve hersenbeeldvorming technologieën een revolutie teweeg gebracht in de mogelijkheid om de structuur en functionaliteit van de hersens te bestuderen. Er is grote vooruitgang geboekt in het beoordelen van hersenschade door gebruik te maken van Magnetic Reconance Imaging (MRI), terwijl Elektroencefalografie (EEG) beschouwd wordt als de gouden standaard voor diagnose van neurologische afwijkingen. In deze thesis focussen we op de ontwikkeling van nieuwe technieken voor multi-modale beeldanalyse van het menselijke brein, waaronder MRI segmentatie en EEG bronlokalisatie. Hierdoor voegen we theorie en praktijk samen waarbij we focussen op twee medische applicaties: (1) automatische 3D MRI segmentatie van de volwassen hersens en (2) multi-modale EEG-MRI data analyse van de hersens van een pasgeborene met perinatale hersenschade. We besteden veel aandacht aan de verbetering en ontwikkeling van nieuwe methoden voor accurate en ruisrobuuste beeldsegmentatie, dewelke daarna succesvol gebruikt worden voor de segmentatie van hersens in MRI van zowel volwassen als pasgeborenen. Daarenboven ontwikkelden we een geïntegreerd multi-modaal methode voor de EEG bronlokalisatie in de hersenen van een pasgeborene. Deze lokalisatie wordt gebruikt voor de vergelijkende studie tussen een EEG aanval bij pasgeborenen en acute perinatale hersenletsels zichtbaar in MRI

Metabolomic approach to physiological circumstances and pathological conditions in neonatology

En la presente Tesis Doctoral, se ha evaluado diferentes situaciones fisiológicas y patológicas relevantes en el campo neonatal. Por un lado, se ha mejorado la predicción de los resultados de la encefalopatía hipóxico-isquémica, lo que es de vital importancia para desarrollar estrategias de trapiento personalizadas y reducir la mortalidad y morbilidad neonatas. Por lo lado, la lactancia materna es el estándar de oro para la nutrición de recién nacidos a término y pretérmino. Para los bebés prematuros cuyas madres no pueden proporcionar su propia leche materna (OMM), la leche humana de donante pasteurizada (DHM) es la alternativa preferida. En esta Tesis, se ha estudiado la huella metabólica de los recién nacidos prematuros para descifrar el efecto de la nutrición sobre su metabolismo. Asimismo, la transposición de las grandes arterias (TGA) es una cardiopatía congénita caracterizada por hipoxemia y circulación anormal, responsable de alteración cerebral y retraso del neurodesarrollo a largo plazo. La septostomía auricular provoca un aumento repentino de la oxigenación de la sangre arterial que conduce a cambios metabólicos complejos. En esta Tesis, se ha evaluado el cambio metabólico en lactantes con TGA después de la septostomía auricular para arrojar luz sobre el efecto de los cambios en la oxigenación cerebral.In this PhD Thesis different physiological and pathological situations that are relevant to the neonatal field have been assessed. Hypoxic-Ischemic encephalopathy (HIE) is a neurologic sequela of perinatal asphyxia. In this Thesis, the aim was to improve prediction of outcomes of HIE, which would be of key importance for developing personalized treatment strategies and reduce neonatal mortality and morbidity. Furthermore, breastfeeding is the gold standard for nutrition of the term and preterm infants. For preterm infants whose mothers are unable to provide of own mothers’ milk (OMM), pasteurized donor human milk (DHM) is the preferred alternative. In this Thesis, metabolic signature of preterm infants has been studied to unscramble the effect of nutrition on their metabolism. Likewise, transposition of the great arteries (TGA) is a congenital heart disease characterized by hypoxemia and abnormal circulation is responsible for brain alteration and long-term neurodevelopmental delay. Atrial septostomy causes a sudden increase in arterial blood oxygenation leading to complex metabolic changes. In this Thesis, the metabolic switch in infants with TGA after atrial septostomy were assessed to shed light on the effect of the changes in the cerebral oxygenation

The role of endotoxin, the TNF family of cytokines and intracellular pH in perinatal hypoxic-ischemic brain injury

To explore the effect of endotoxin as a sensitising agent prior to neonatal hypoxiaischemia differing doses of endotoxin (E. coli lipopolysaccharide, LPS) were given to neonatal mice prior to hypoxia-ischemia, with sensitising effects noted at dosages of 0.3mg/kg of LPS or higher. Varying the time interval between endotoxin administration and hypoxia-ischemia demonstrated that LPS given between 4 and 12 hours before hypoxia-ischemia had a sensitising effect on subsequent hypoxia ischemia. In contrast, LPS given at the time of or 24 hours before hypoxia-ischemia did not. To help understand the mechanism by which this sensitising effect occurs, a dose-response study of LPS alone was undertaken. Here, a dose-dependent activation of microglia was demonstrated throughout the brain, particularly in the thalamus and cortex, by 12 hours following endotoxin administration. There was also evidence of vascular endothelial activation (ICAM1) as early as 4 hours after endotoxin administration. To study the role of the TNF cluster of cytokines (TNF alpha, lymphotoxin alpha and lymphotoxin beta), animals with a deletion of the entire TNF cluster were examined. Deletion of the TNF cluster was shown to abolish both endotoxin-mediated sensitisation of the developing brain to subsequent hypoxia, and to prevent upregulation of macrophage and vascular endothelium by endotoxin alone. This study also examined the effects of hypoxia-ischemia on intracellular pH. Increasing duration of hypoxia-ischemia resulted in a progressive intracellular acidosis within the brain, initially ipsilateral to the carotid ligation, but becoming bilateral with prolonged hypoxia. In the reoxygenation phase, there was a rebound intracellular alkalosis at 6 hours of reoxygenation across the whole forebrain. Previous studies have suggested that this alkalosis is mediated by a Na+/H+ exchanger. Blockade of this transporter with N-methyl isobutyl amiloride prior to hypoxia-ischemia was shown to confer neuroprotection in the developing brain

The Role of MicroRNAs in Neonates with Hypoxic - Ischaemic Encephalopathy.

PhD Theses MedicalWith increasing knowledge on the role of microRNAs in various diseases, we aimed to identify and study the role of a candidate microRNA in neonates with hypoxic ischaemic encephalopathy (HIE). Neonates with varying degrees of encephalopathy and healthy neonates were recruited to this study. After establishing a novel technique to study microRNAs from dried blood spots, we performed discovery microRNA next generation sequencing on 32 dried blood spots from 16 neonates which identified let-7b as a potential microRNA associated with the apoptotic Hippo pathway. Validation studies using RT-qPCR on 45 neonates showed that let-7b-5p expression was increased on day 1 in neonates with moderate to severe HIE with an unfavourable outcome when compared to mild HIE. Mechanistic studies for let-7b-5p and Yes Associated Protein (YAP) in the Hippo pathway were performed on two animal models of perinatal brain injury (hypoxic-ischaemic and intrauterine inflammation models) and glucose-deprived cell cultures using fluorescence in situ hybridisation and immunohistochemistry. There was significantly reduced let-7b-5p expression in the peripheral blood of the intrauterine inflammation model, and in the cortical neurones of both animal models. Additionally, Hippo pathway activation was evident with increased neuronal/nuclear YAP ratio in the cerebral cortex of both animal models with increased apoptotic neuronal cell death, when compared to the control pups. Similar results were noted for let-7b-5p and YAP expression in glucose-deprived cell cultures. In summary, our results show that in hypoxic ischaemic stress, increased neuronal to nuclear YAP ratio with decreased neuronal let-7b-5p is linked to neuronal apoptosis. Therefore, let-7b-5p could be a potential biomarker for the severity of HIE acting through the Hippo-YAP-Let-7b axis. Further validation of this novel association of let- 7b-5p and the Hippo pathway in larger cohorts and identification of downstream targets of let-7b-5p would help to improve our understanding of the role of let-7b-5p in neonatal HIE

Metabolomics, Oxidative, and Nitrosative Stress in the Perinatal Period

Studies focusing on the perinatal period face unique challenges, yet research in this area is extremely important, as this period of life is highly delicate and adverse events might have a long-lasting impact. With the advent of powerful high-resolution and high-throughput analytical methods, researchers have started to successfully develop and implement novel approaches in this area. New insights have great potential to be translated into novel diagnostic tools, as well as alternative preventive and treatment approaches. This book collects a series of timely review and original research articles focusing on metabolomic, oxidative, and nitrosative stress in the perinatal period.We would like to thank all involved authors for their high-quality contributions and their commitment to the publication of this work and hope that this book will be a useful resource for students, scientists, and doctors working in this specific area of application