Deep Learning for Generalized EEG Seizure Detection after Hypoxia-Ischemia-Preclinical Validation.

Brain maturity and many clinical treatments such as therapeutic hypothermia (TH) can significantly influence the morphology of neonatal EEG seizures after hypoxia-ischemia (HI), and so there is a need for generalized automatic seizure identification. This study validates efficacy of advanced deep-learning pattern classifiers based on a convolutional neural network (CNN) for seizure detection after HI in fetal sheep and determines the effects of maturation and brain cooling on their accuracy. The cohorts included HI-normothermia term (n = 7), HI-hypothermia term (n = 14), sham-normothermia term (n = 5), and HI-normothermia preterm (n = 14) groups, with a total of >17,300 h of recordings. Algorithms were trained and tested using leave-one-out cross-validation and k-fold cross-validation approaches. The accuracy of the term-trained seizure detectors was consistently excellent for HI-normothermia preterm data (accuracy = 99.5%, area under curve (AUC) = 99.2%). Conversely, when the HI-normothermia preterm data were used in training, the performance on HI-normothermia term and HI-hypothermia term data fell (accuracy = 98.6%, AUC = 96.5% and accuracy = 96.9%, AUC = 89.6%, respectively). Findings suggest that HI-normothermia preterm seizures do not contain all the spectral features seen at term. Nevertheless, an average 5-fold cross-validated accuracy of 99.7% (AUC = 99.4%) was achieved from all seizure detectors. This significant advancement highlights the reliability of the proposed deep-learning algorithms in identifying clinically translatable post-HI stereotypic seizures in 256Hz recordings, regardless of maturity and with minimal impact from hypothermia.

Dysmaturation of sleep state and electroencephalographic activity after hypoxia-ischaemia in preterm fetal sheep.

Antenatal hypoxia-ischaemia (HI) in preterm fetal sheep can trigger delayed evolution of severe, cystic white matter injury (WMI), in a similar timecourse to WMI in preterm infants. We therefore examined how severe hypoxia-ischaemia affects recovery of electroencephalographic (EEG) activity. Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 min of complete umbilical cord occlusion (UCO, n = 9) or sham occlusion (controls, n = 9), and recovered for 21 days. HI was associated with a shift to lower frequency EEG activity for the first 5 days with persisting loss of EEG power in the delta and theta bands, and initial loss of power in the alpha and beta bands in the first 14 days of recovery. In the final 3 days of recovery, there was a marked rhythmic shift towards higher frequency EEG activity after UCO. The UCO group spent less time in high-voltage sleep, and in the early evening (7:02 pm ± 47 min) abruptly stopped cycling between sleep states, with a shift to a high frequency state for 2 h 48 min ± 40 min, with tonic electromyographic activity. These findings demonstrate persisting EEG and sleep state dysmaturation after severe hypoxia-ischaemia. Loss of fetal or neonatal sleep state cycling in the early evening may be a useful biomarker for evolving cystic WMI.

Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series).

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Postischemic Infusion of Apigenin Reduces Seizure Burden in Preterm Fetal Sheep.

Seizures are common in preterm newborns and are associated with poor neurodevelopmental outcomes. Current anticonvulsants have poor efficacy, and many have been associated with upregulation of apoptosis in the developing brain. Apigenin, a natural bioactive flavonoid, is a potent inhibitor of hyaluronidase and reduces seizures in adult animal models. However, its impact on perinatal seizures is unclear. In the present study, we examined the effect of apigenin and S3, a synthetic, selective hyaluronidase inhibitor, on seizures after cerebral ischemia in preterm fetal sheep at 0.7 gestation (98-99 days, term ~147 days). Fetuses received sham ischemia (n = 9) or ischemia induced by bilateral carotid occlusion for 25 min. Immediately after ischemia, fetuses received either a continuous infusion of vehicle (0.036% dimethyl sulfoxide, n = 8) or apigenin (50 µM, n = 6). In a pilot study, we also tested infusion of S3 (2 µM, n = 3). Fetuses were monitored continuously for 72 h after ischemia. Infusion of apigenin or S3 were both associated with reduced numbers of animals with seizures, total seizure time, and mean seizure burden. S3 was also associated with a reduction in the total number of seizures over the 72 h recovery period. In animals that developed seizures, apigenin was associated with earlier cessation of seizures. However, apigenin or S3 treatment did not alter recovery of electroencephalographic power or spectral edge frequency. These data support that targeting brain hyaluronidase activity with apigenin or S3 may be an effective strategy to reduce perinatal seizures following ischemia. Further studies are required to determine their effects on neurohistological outcomes.

A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia.

The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates were birth weight (BWT), gestational age (GA), survival, and acute kidney injury (AKI). A previously published population model of sCr kinetics in neonates served as the base model. This model predicted not only sCr but also the glomerular filtration rate normalized by its value at birth (GFR/GFR0). The model was used to compare the TH neonates with a reference full term non-asphyxiated population of neonates. The estimates of the model parameters had good precision and showed high between subject variability. AKI influenced most of the estimated parameters denoting a strong impact on sCr kinetics and GFR. BWT and GA were not significant covariates. TH transiently increased [Formula: see text] in TH neonates over the first days compared to the reference group. Asphyxia impacted not only GFR, but also the [Formula: see text] synthesis rate. We also observed that AKI neonates exhibit a delayed onset of postnatal GFR increase and have a higher [Formula: see text] synthesis rate compared to no-AKI patients. Our findings show that the use of [Formula: see text] as marker of renal function in asphyxiated neonates treated with TH to guide dose selection for renally cleared drugs is challenging, while we captured the postnatal sCr patterns in this specific population.

An Update of Our Understanding of Fetal Heart Rate Patterns in Health and Disease.

UNDERSTANDING FETAL HEART RATE PATTERNS THAT MAY PREDICT ANTENATAL AND INTRAPARTUM NEURAL INJURY: Christopher A. Lear, Jenny A. Westgate, Austin Ugwumadu, Jan G. Nijhuis, Peter R. Stone, Antoniya Georgieva, Tomoaki Ikeda, Guido Wassink , Laura Bennet , Alistair J. Gunn Seminars in Pediatric Neurology Volume 28, December 2018, Pages 3-16 Electronic fetal heart rate (FHR) monitoring is widely used to assess fetal well-being throughout pregnancy and labor. Both antenatal and intrapartum FHR monitoring are associated with a high negative predictive value and a very poor positive predictive value. This in part reflects the physiological resilience of the healthy fetus and the remarkable effectiveness of fetal adaptations to even severe challenges. In this way, the majority of "abnormal" FHR patterns in fact reflect a fetus' appropriate adaptive responses to adverse in utero conditions. Understanding the physiology of these adaptations, how they are reflected in the FHR trace and in what conditions they can fail is therefore critical to appreciating both the potential uses and limitations of electronic FHR monitoring.

A systematic review of immune-based interventions for perinatal neuroprotection: closing the gap between animal studies and human trials.

BACKGROUND: Perinatal infection/inflammation is associated with a high risk for neurological injury and neurodevelopmental impairment after birth. Despite a growing preclinical evidence base, anti-inflammatory interventions have not been established in clinical practice, partly because of the range of potential targets. We therefore systematically reviewed preclinical studies of immunomodulation to improve neurological outcomes in the perinatal brain and assessed their therapeutic potential. METHODS: We reviewed relevant studies published from January 2012 to July 2023 using PubMed, Medline (OvidSP) and EMBASE databases. Studies were assessed for risk of bias using the SYRCLE risk of bias assessment tool (PROSPERO; registration number CRD42023395690). RESULTS: Forty preclinical publications using 12 models of perinatal neuroinflammation were identified and divided into 59 individual studies. Twenty-seven anti-inflammatory agents in 19 categories were investigated. Forty-five (76%) of 59 studies reported neuroprotection, from all 19 categories of therapeutics. Notably, 10/10 (100%) studies investigating anti-interleukin (IL)-1 therapies reported improved outcome, whereas half of the studies using corticosteroids (5/10; 50%) reported no improvement or worse outcomes with treatment. Most studies (49/59, 83%) did not control core body temperature (a known potential confounder), and 25 of 59 studies (42%) did not report the sex of subjects. Many studies did not clearly state whether they controlled for potential study bias. CONCLUSION: Anti-inflammatory therapies are promising candidates for treatment or even prevention of perinatal brain injury. Our analysis highlights key knowledge gaps and opportunities to improve preclinical study design that must be addressed to support clinical translation.

The neural and cardiovascular effects of exposure of gram-positive bacterial inflammation in preterm fetal sheep.

Perinatal infection or inflammation are associated with adverse neurodevelopmental effects and cardiovascular impairments in preterm infants. Most preclinical studies have examined the effects of gram-negative bacterial inflammation on the developing brain, although gram-positive bacterial infections are a major contributor to adverse outcomes. Killed Su-strain group 3 A streptococcus pyogenes (Picibanil, OK-432) is being used for pleurodesis in fetal hydrothorax/chylothorax. We therefore examined the neural and cardiovascular effects of clinically relevant intra-plural infusions of Picibanil. Chronically instrumented preterm (0.7 gestation) fetal sheep received an intra-pleural injection of low-dose (0.1 mg, n = 8) or high-dose (1 mg, n = 8) Picibanil or saline-vehicle (n = 8). Fetal brains were collected for histology one-week after injection. Picibanil exposure was associated with sustained diffuse white matter inflammation and loss of immature and mature oligodendrocytes and subcortical neurons, and associated loss of EEG power. These neural effects were not dose-dependent. Picibanil was also associated with acute changes in heart rate and attenuation of the maturational increase in mean arterial pressure. Even a single exposure to a low-dose gram-positive bacterial-mediated inflammation during the antenatal period is associated with prolonged changes in vascular and neural function.

Prediction of Fetal Blood Pressure during Labour with Deep Learning Techniques.

Our objective is to develop a model for the prediction of minimum fetal blood pressure (FBP) during fetal heart rate (FHR) decelerations. Experimental data from umbilical occlusions in near-term fetal sheep (2698 occlusions from 57 near-term lambs) were used to train a convolutional neural network. This model was then used to estimate FBP for decelerations extracted from the final 90 min of 53,445 human FHR signals collected using cardiotocography. Minimum sheep FBP was predicted with a mean absolute error of 6.7 mmHg (25th, 50th, 75th percentiles of 2.3, 5.2, 9.7 mmHg), mean absolute percentage errors of 17.3% (5.5%, 12.5%, 23.9%) and a coefficient of determination R2=0.36. While the model was unable to clearly predict severe compromise at birth in humans, there is positive evidence that such a model could predict human FBP with further development. The neural network is capable of predicting FBP for many of the sheep decelerations accurately but performed far from satisfactory at identifying FHR segments that correspond to the highest or lowest minimum FBP. These results indicate that with further work and a larger, more variable training dataset, the model could achieve higher accuracy.

Circadian patterns of heart rate variability in fetal sheep after hypoxia-ischaemia: A biomarker of evolving brain injury.

Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and severe neurodevelopmental disability in survivors, including cerebral palsy, although there are no reliable biomarkers to detect at risk fetuses that may have suffered a transient period of severe HI. We investigated time and frequency domain measures of fetal heart rate variability (FHRV) for 3 weeks after HI in preterm fetal sheep at 0.7 gestation (equivalent to preterm humans) until 0.8 gestation (equivalent to term humans). We have previously shown that this is associated with delayed development of severe white and grey matter injury, including cystic white matter injury (WMI) resembling that observed in human preterm infants. HI was associated with suppression of time and frequency domain measures of FHRV and reduced their circadian rhythmicity during the first 3 days of recovery. By contrast, circadian rhythms of multiple measures of FHRV were exaggerated over the final 2 weeks of recovery, mediated by a greater reduction in FHRV during the morning nadir, but no change in the evening peak. These data suggest that the time of day at which FHRV measurements are taken affects their diagnostic utility. We further propose that circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury. KEY POINTS: Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and probably for disability in survivors, although there are no reliable biomarkers for antenatal brain injury. In preterm fetal sheep, acute HI that is known to lead to delayed development of severe white and grey matter injury over 3 weeks, was associated with early suppression of multiple time and frequency domain measures of fetal heart rate variability (FHRV) and loss of their circadian rhythms during the first 3 days after HI. Over the final 2 weeks of recovery after HI, exaggerated circadian rhythms of frequency domain FHRV measures were observed. The morning nadirs were lower with no change in the evening peak of FHRV. Circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury.

Advances in neonatal cell therapies: Proceedings of the First Neonatal Cell Therapies Symposium (2022).

Despite considerable advances, there is a need to improve the outcomes of newborn infants, especially related to prematurity, encephalopathy and other conditions. In principle, cell therapies have the potential to protect, repair, or sometimes regenerate vital tissues; and improve or sustain organ function. In this review, we present highlights from the First Neonatal Cell Therapies Symposium (2022). Cells tested in preclinical and clinical studies include mesenchymal stromal cells from various sources, umbilical cord blood and cord tissue derived cells, and placental tissue and membrane derived cells. Overall, most preclinical studies suggest potential for benefit, but many of the cells tested were not adequately defined, and the optimal cell type, timing, frequency, cell dose or the most effective protocols for the targeted conditions is not known. There is as yet no clinical evidence for benefit, but several early phase clinical trials are now assessing safety in newborn babies. We discuss parental perspectives on their involvement in these trials, and lessons learnt from previous translational work of promising neonatal therapies. Finally, we make a call to the many research groups around the world working in this exciting yet complex field, to work together to make substantial and timely progress to address the knowledge gaps and move the field forward. IMPACT: Survival of preterm and sick newborn infants is improving, but they continue to be at high risk of many systemic and organ-specific complications. Cell therapies show promising results in preclinical models of various neonatal conditions and early phase clinical trials have been completed or underway. Progress on the potential utility of cell therapies for neonatal conditions, parental perspectives and translational aspects are discussed in this paper.