Acute post-asphyxial encephalopathy occurring around the time of birth remains a major cause of death and disability. The recent seminal insight that allows active neuroprotective treatment is that even after profound asphyxia (the “primary” phase), many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting approximately 6 h, only to die hours to days later after a “secondary” deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Although many of these secondary processes are potentially injurious, they appear to be primarily epiphenomena of the ‘execution’ phase of cell death. Animal and human studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible but before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, has been associated with potent, long-lasting neuroprotection. Recent clinical trials show that while therapeutic hypothermia significantly reduces morbidity and mortality, many babies still die or survive with disabilities. The challenge for the future is to find ways of improving the effectiveness of treatment. In this review, we will dissect the known mechanisms of hypoxic-ischemic brain injury in relation to the known effects of hypothermic neuroprotection.

With a worldwide incidence of 15 million cases, preterm birth is a major contributor to neonatal mortality and morbidity, and concomitant social and economic burden Preterm infants are predisposed to life-long neurological disorders due to the immaturity of the brain. The risks are inversely proportional to maturity at birth. In the majority of extremely preterm infants (<28 weeks’ gestation), perinatal brain injury is associated with exposure to multiple inflammatory perinatal triggers that include antenatal infection (i.e., chorioamnionitis), hypoxia-ischemia, and various postnatal injurious triggers (i.e., oxidative stress, sepsis, mechanical ventilation, hemodynamic instability). These perinatal insults cause a self-perpetuating cascade of peripheral and cerebral inflammation that plays a critical role in the etiology of diffuse white and grey matter injuries that underlies a spectrum of connectivity deficits in survivors from extremely preterm birth. This review focuses on chorioamnionitis and hypoxia-ischemia, which are two important antenatal risk factors for preterm brain injury, and highlights the latest insights on its pathophysiology, potential treatment, and future perspectives to narrow the translational gap between preclinical research and clinical applications.

Progressive fetal infection/inflammation is strongly associated with neural injury after preterm birth. We aimed to test the hypotheses that progressively developing fetal inflammation leads to neuroinflammation and impaired white matter development and that the histopathological changes can be detected using high-field diffusion tensor magnetic resonance imaging (MRI). Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive intravenous saline (control; n = 6) or a progressive infusion of lipopolysaccharide (LPS, 200 ng intravenous over 24 h then doubled every 24 h for 5 days to induce fetal inflammation, n = 7). Sheep were killed 10 days after starting the infusions, for histology and high-field diffusion tensor MRI. Progressive LPS infusion was associated with increased circulating interleukin (IL)-6 concentrations and moderate increases in carotid artery perfusion and the frequency of electroencephalogram (EEG) activity (p < 0.05 vs. control). In the periventricular white matter, fractional anisotropy (FA) was increased, and orientation dispersion index (ODI) was reduced (p < 0.05 vs. control for both). Histologically, in the same brain region, LPS infusion increased microglial activation and astrocyte numbers and reduced the total number of oligodendrocytes with no change in myelination or numbers of immature/mature oligodendrocytes. Numbers of astrocytes in the periventricular white matter were correlated with increased FA and reduced ODI signal intensities. Astrocyte coherence was associated with increased FA. Moderate astrogliosis, but not loss of total oligodendrocytes, after progressive fetal inflammation can be detected with high-field diffusion tensor MRI.

Perinatal hypoxia-ischemia is associated with disruption of cortical gamma-aminobutyric acid (GABA)ergic interneurons and their surrounding perineuronal nets, which may contribute to persisting neurological deficits. Blockade of connexin43 hemichannels using a mimetic peptide can alleviate seizures and injury after hypoxia-ischemia. In this study, we tested the hypothesis that connexin43 hemichannel blockade improves the integrity of cortical interneurons and perineuronal nets. Term-equivalent fetal sheep received 30 min of bilateral carotid artery occlusion, recovery for 90 min, followed by a 25-h intracerebroventricular infusion of vehicle or a mimetic peptide that blocks connexin hemichannels or by a sham ischemia + vehicle infusion. Brain tissues were stained for interneuronal markers or perineuronal nets. Cerebral ischemia was associated with loss of cortical interneurons and perineuronal nets. The mimetic peptide infusion reduced loss of glutamic acid decarboxylase-, calretinin-, and parvalbumin-expressing interneurons and perineuronal nets. The interneuron and perineuronal net densities were negatively correlated with total seizure burden after ischemia. These data suggest that the opening of connexin43 hemichannels after perinatal hypoxia-ischemia causes loss of cortical interneurons and perineuronal nets and that this exacerbates seizures. Connexin43 hemichannel blockade may be an effective strategy to attenuate seizures and may improve long-term neurological outcomes after perinatal hypoxia-ischemia.

This study introduces transformer-based deep learning models as superior alternatives to convolutional neural network (CNN) architectures for seizure detection after hypoxia–ischemia (HI) in electroencephalography (EEG) recordings in the developing brain. We further demonstrate that these models excel in classifying of varied and subtle morphologies of electrographic seizures observed in the EEG of fetal sheep after HI. The study explores model training combinations from four cohorts of Romney/Suffolk fetal sheep (HI-normothermia-term (n = 7), HI-hypothermia-term (n = 14), sham-normothermia-term (n = 5), and HI-normothermia-preterm (n = 14)), totalling 31,015 EEG segments from 17,300 h of recordings. We evaluated multiple Transformer architectures using both 2D wavelet-scalograms (WS) and 1D raw EEG signals through leave-one-out and k-fold cross-validation, comparing models’ performance with or without sham-normothermia-term data and contrasting them with CNN-based results from our previous work. The Data-Efficient image Transformer (DeiT) emerged as the top-performing model, achieving 99.60 % accuracy (AUC = 0.992) when fed with WS, surpassing the 2D WS CNN result (98.94 % accuracy, AUC = 0.967) from our prior study. Notably, the Wav2Vec2 transformer model, fed with raw 1D EEG segments, demonstrated comparable performance with 99.60 % accuracy (AUC = 0.992), outperforming the 1D CNN result (98.43 % accuracy, AUC = 0.961) from the previous study. More importantly, the transformers can adeptly distinguish between seizures in both the preterm and term brain, and under the influence of treatment with 99.92 % accuracy (AUC = 0.997). Our findings highlight the superior ability of transformer models to capture long-range dependencies within EEG data, enhancing seizure detection without the added complexity of generating 2D WS images. Transformer models show promise for generalized automated seizure detection, irrespective of the perinatal brain maturation stage and the influence of hypothermia, offering potential improvements for seizure detection after HI in newborns.

Improvements in the detection of fetal and neonatal brain injuries, advances in our understanding of the pathophysiology, cellular and molecular bases of encephalopathy, and new treatment options have all combined to produce significant changes in the management of neonatal brain disorders in the past few years. This new edition of Fetal and Neonatal Brain Injury brings the reader fully up to date with all advances in clinical management and outcome assessment. Updated material includes inflammation focusing in particular on chorioamnionitis and fetal brain injury; genetic brain injury; and expanded sections on cholestasis, diabetes, and thyroid disease. An updated, highly illustrated chapter on structural and functional imaging of the fetal and neonatal brain is also included. An outstanding international team of highly experienced neonatologists and maternal-fetal medicine clinicians have produced a practical, authoritative clinical text that gives clear management advice to all clinicians involved in the treatment of these patients.