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Motor disability is common in children born preterm. Interventions focusing on environmental enrichment and emotional connection can positively impact outcomes. The NICU-based rehabilitation (NeoRehab) program consists of evidence-based interventions provided by a parent in addition to usual care. The program combines positive sensory experiences (vocal soothing, scent exchange, comforting touch, skin-to-skin care) as well as motor training (massage and physical therapy) in a gestational age (GA) appropriate fashion. To investigate the acceptability, feasibility and fidelity of the NeoRehab program in very low birthweight (VLBW) infants. All interventions were provided by parents in addition to usual care. Infants (≤ 32 weeks' GA and/or ≤ 1500 g birthweight) were enrolled in a randomized controlled trial comparing NeoRehab to usual care (03/2019–10/2020). The a priori dosing goal was for interventions to be performed 5 days/week. The primary outcomes were the acceptability, feasibility and fidelity of the NeoRehab program. 36 participants were randomized to the intervention group and 34 allocated to usual care. The recruitment rate was 71% and retention rate 98%. None of the interventions met the 5 days per week pre-established goal. 97% of participants documented performing a combination of interventions at least 3 times per week. The NeoRehab program was well received and acceptable to parents of VLBW infants. Programs that place a high demand on parents (5 days per week) are not feasible and goals of intervention at least 3 times per week appear to be feasible in the context of the United States. Parent-provided motor interventions were most challenging to parents and alternative strategies should be considered in future studies. Further studies are needed to evaluate the relationship between intervention dosing on long term motor outcomes.

In these last 25 years, the Neonatal Emergency Transport (NET) service has been widely improved in Italy. To date, all National areas are covered by a NET service; 53 NET centers have been activated in all the Italian territory. Herein, the authors present an observational study to evaluate the rate of infantile mortality after introduction of NET in Sicily, and to study the efficiency of this service in reducing these rates of mortality in vulnerable neonates, transported from primary care birth centers to tertiary facilities to undergo to specialized NICU assistance. All neonates who required an emergency transport by NETS were included. No exclusions criteria were applied. Demographic and regional infantile mortality data, expressed as infant mortality rate, were selected by the official government database (ISTAT- National Statistic Institute—http://www.istat.it). All data were respectively divided into three groups: data concerning transport, clinical condition, and mortality of the transported patients. We transported by NET 325 neonates. The analysis of the infant mortality rate (per 1.000 live births) in Catania from 2016 to 2018 was reduced compared to the same rate calculated before NETS activation (4.41 index before 2016 vs 4.17 index after 2016). These data showed an increase in other provinces (Enna, Caltanissetta, and Agrigento). 61% of neonates showed a respiratory disease. During the study period the proportion of neonates with a Mortality Index for Neonatal Transportation—MINT

This study aimed to examine the reliabilities (test–retest reliability and measurement error), construct validity, and the interpretability (minimal clinically important difference) of the Box and Block Test (BBT) to interpret test scores precisely for children with UCP. A total of 100 children with UCP were recruited and 50 children from the whole sample assessed the BBT twice within 2-week interval. The BBT, the Melbourne Assessment 2, the Bruininks–Oseretsky Test of Motor Proficiency, 2nd Edition, and the Pediatric Motor Activity Log Revised were measured before and immediately after a 36-h intensive neurorehabilitation intervention. Measurement properties of the BBT were performed according to the COnsensus-based Standards for the selection of health Measurement INstruments checklist. The test–retest reliability of the BBT was high (intraclass correlation coefficient = 0.98). The measurement error estimated by the MDC95 value was 5.95. Construct validity was considered good that 4 of 4 (100%) hypotheses were confirmed. The interpretability estimated by the MCID ranged from 5.29 to 6.46. The BBT is a reliable and valid tool for children with UCP. For research and clinical applications, an improvement of seven blocks on the BBT is recommended as an indicator of statistically significant and clinically important change.

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

Use of maternal oxygen for intrauterine resuscitation is contentious because of the lack of evidence for its efficacy and the possibility of fetal harm through oxidative stress. Because the developing brain is rich in lipids and low in antioxidants, it remains vulnerable to oxidative stress. Here, we tested this hypothesis in a term pregnant rat model with oxytocin-induced fetal distress followed by treatment with either room air or 100% oxygen for 6 h. Fetal brains from both sexes were subjected to assays for biomarkers of oxidative stress (4-hydroxynonenal, protein carbonyl, or 8-hydroxy-2ʹ-deoxyguanosine), expression of genes mediating oxidative stress, and mitochondrial oxidative phosphorylation. Contrary to our hypothesis, maternal hyperoxia was not associated with increased biomarkers of oxidative stress in the fetal brain. However, there was significant upregulation of the expression of select genes mediating oxidative stress, of which some were male-specific. These observations, however, were not accompanied by changes in the expression of proteins from the mitochondrial electron transport chain. In summary, maternal hyperoxia in the setting of acute uteroplacental ischemia-hypoxia does not appear to cause oxidative damage to the developing brain.

There is a critical need for development of real time physiological biomarkers for birth asphyxia that constitutes a major global public health burden. Our recent study (Scientific Reports, V10:9183, 2020) established a novel non-invasive neurovascular coupling (NVC) assessment in newborns using dynamic wavelet transform coherence (WTC) analysis irrespective of different aEEG algorithms. As an extended study, the current paper examines whether the variability in processed EEG and amplitude-EEG (aEEG) outputs would impact the determination of NVC in newborns with encephalopathy. Concurrent processed EEG tracings and regional near infrared spectroscopy (NIRS)-based cerebral tissue oxygen saturation (SctO2) readings during a period of twenty hours in their first day of life were selected and processed in this study. After bandpass-filtered in 2–15 Hz, rectified, and down-sampled at 0.21 Hz, the processed EEG tracings along with NIRS-SctO2 (0.21 Hz) were used to perform WTC analysis, followed by comparison of WTC-metrics between SctO2-processed EEG coherence and SctO2-aEEG coherence using Bland–Altman statistics. Our results demonstrated high and significant correlation (R2 = 0.96, p

To evaluate the impact of maternal hypertensive disorders of pregnancy (HDP) on mortality and neurological outcomes in extremely and very preterm infants using a nationwide neonatal database in Japan. This population-based retrospective study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, between 22 and 31 weeks’ gestation. A total of 21,659 infants were randomly divided into two groups, HDP (n = 4,584) and non-HDP (n = 4,584), at a ratio of 1:1 after stratification by four factors including maternal age, parity, weeks of gestation, and year of delivery. Short-term (neonatal period) and medium-term (3 years of age) mortality and neurological outcomes were compared between the two groups by logistic regression analyses. In univariate analysis, HDP was associated with an increased risk for in-hospital death (crude odds ratio [OR], 1.31; 95% confidence interval, 1.04–1.63) and a decreased risk for severe intraventricular haemorrhage (0.68; 0.53–0.87) and periventricular leukomalacia (0.60; 0.48–0.77). In multivariate analysis, HDP was significantly associated with a lower risk for in-hospital death (adjusted OR, 0.61; 0.47–0.80), severe intraventricular haemorrhage (0.47; 0.35–0.63), periventricular leukomalacia (0.59; 0.45–0.78), neonatal seizures (0.40; 0.28–0.57) and cerebral palsy (0.70; 0.52–0.95) at 3 years after adjustment for covariates including birth weight. These results were consistent with those of additional analyses, which excluded cases with histological chorioamnionitis and which divided the infants into two subgroups (22–27 gestational weeks and 28–31 gestational weeks). Maternal HDP was associated with an increased risk for in-hospital death without adjusting for covariates, but it was also associated with a lower risk for mortality and adverse neurological outcomes in extremely and very preterm infants if all covariates except HDP were identical.

Gamma-aminobutyric acid (GABA) and glutamate are principal neurotransmitters essential for late gestational brain development and may play an important role in prematurity-related brain injury. In vivo investigation of GABA in the preterm infant with standard proton magnetic resonance spectroscopy (1H-MRS) has been limited due to its low concentrations in the developing brain, and overlap in the spectrum by other dominant metabolites. We describe early postnatal profiles of in vivo GABA and glutamate concentrations in the developing preterm brain measured by using the J-difference editing technique, Mescher-Garwood point resolved spectroscopy. We prospectively enrolled very preterm infants born ≤32 weeks gestational age and non-sedated 1H-MRS (echo time 68 ms, relaxation time 2000 ms, 256 signal averages) was acquired on a 3 Tesla magnetic resonance imaging scanner from a right frontal lobe voxel. Concentrations of GABA + (with macromolecules) was measured from the J-difference spectra; whereas glutamate and composite glutamate + glutamine (Glx) were measured from the unedited (OFF) spectra and reported in institutional units. We acquired 42 reliable spectra from 38 preterm infants without structural brain injury [median gestational age at birth of 28.0 (IQR 26.0, 28.9) weeks; 19 males (50%)] at a median postmenstrual age of 38.4 (range 33.4 to 46.4) weeks. With advancing post-menstrual age, the concentrations of glutamate OFF increased significantly, adjusted for co-variates (generalized estimating equation β = 0.22, p = 0.02). Advancing postnatal weeks of life at the time of imaging positively correlated with GABA + (β = 0.06, p = 0.02), glutamate OFF (β = 0.11, p = 0.02) and Glx OFF (β = 0.12, p = 0.04). Male infants had higher GABA + (1.66 ± 0.07 vs. 1.33 ± 0.11, p = 0.01) concentrations compared with female infants. For the first time, we report the early ex-utero developmental profile of in vivo GABA and glutamate stratified by age and sex in the developing brain of very preterm infants. This data may provide novel insights into the pathophysiology of neurodevelopmental disabilities reported in preterm infants even in the absence of structural brain injury.

Premature babies are subjected to environmental stresses that can affect brain maturation and cause abnormal neurodevelopmental outcome later in life. Better understanding this link is crucial to developing a clinical tool for early outcome estimation. We defined maturational trajectories between the Electroencephalography (EEG)-derived ‘brain-age’ and postmenstrual age (the age since the last menstrual cycle of the mother) from longitudinal recordings during the baby’s stay in the Neonatal Intensive Care Unit. Data consisted of 224 recordings (65 patients) separated for normal and abnormal outcome at 9–24 months follow-up. Trajectory deviations were compared between outcome groups using the root mean squared error (RMSE) and maximum trajectory deviation (δmax). 113 features were extracted (per sleep state) to train a data-driven model that estimates brain-age, with the most prominent features identified as potential maturational and outcome-sensitive biomarkers. RMSE and δmax showed significant differences between outcome groups (cluster-based permutation test, p RMSE had a median (IQR) of 0.75 (0.60–1.35) weeks for normal outcome and 1.35 (1.15–1.55) for abnormal outcome, while δmax had a median of 0.90 (0.70–1.70) and 1.90 (1.20–2.90) weeks, respectively. Abnormal outcome trajectories were associated with clinically defined dysmature and disorganised EEG patterns, cementing the link between early maturational trajectories and neurodevelopmental outcome.

Introduction. Advances in reproductive and perinatal technologies have led not only to an increase in the number of premature babies and an increase in survival rates, but also to an increase in the incidence of complications. Nervous system diseases play a leading role in the structure of pathologies of premature infants. Early onset of extrauterine life contributes to the disruption of physiological processes of brain maturation, increasing the risk of neurological complications.Objective. To establish the frequency and structure of brain damage in premature infants-patients of the intensive care unit. Materials and methods. The mortality and morbidity rates of premature infants-patients of the intensive care unit who were born in 2019-2020 and the first 3 quarters of 2021 were estimated. The frequency of lesions of the nervous system in premature infants, namely the presence of intraventricular hemorrhages of varying severity, hypoxic-ischemic encephalopathy, periventricular leukomalacia, hydrocephalus. Statistical processing of the obtained results was performed using the software system Microsoft Excel 2010 (14.0.6024.1000) SP 1 MSO (14.0.6023.1000).Results. In 2021, the number of premature babies weighing, Вступ. Прогрес репродуктивних і перинатальних технологій призвів не лише до зростання кількості пе- редчасно народжених дітей та збільшення показників виживання, але й до збільшення частоти ускладнень. Захворювання нервової системи займають провідну роль у структурі захворювань передчасно народжених немовлят. Ранній початок позаутробного життя сприяє порушенню фізіологічних процесів дозрівання голов- ного мозку, збільшуючи ризик неврологічних ускладнень.Мета дослідження. Встановити частоту та структуру ураження головного мозку у передчасно наро- джених дітей – пацієнтів відділення інтенсивної терапії. Матеріали і методи дослідження. Оцінено показники летальності та захворюваності передчасно на- роджених дітей – пацієнтів відділення інтенсивної терапії, які народилися у 2019-2020 та перших 3 квар- талах 2021 року. Встановлено частоту уражень нервової системи у передчасно народжених немовлят, а саме наявність внутрішньошлуночкових крововиливів різних ступенів важкості, гіпоксично-ішемічної енце- фалопатії, перивентрикулярної лейкомаляції, гідроцефалії. Статистична обробка отриманих результатів проводилася за допомогою системи програмного забезпечення Microsoft Excel 2010 (14.0.6024.1000) SP 1 MSO (14.0.6023.1000).Результати дослідження. У 2021 році зросла кількість передчасно народжених дітей з масою тіла < 1500 г порівняно з 2019 роком. Виявлено зменшення показників летальності передчасно народжених дітей – пацієнтів відділення інтенсивної терапії. Найбільш поширеними патологіями передчасно народжених дітей залишаються респіраторний дистрес синдром та ураження нервової системи. Аналіз отриманих даних пока- зав, що у структурі неврологічної патології у передчасно народжених дітей домінують гіпоксично-ішемічна енцефалопатія та внутрішньошлуночкові крововиливи. Висновки. На тлі зменшення показників летальності зростають кількість та важкість внутрішньошлу- ночкових крововиливів у передчасно народжених дітей.

Scientific reports 10, 2373 (2020). doi:10.1038/s41598-020-58761-6, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Very preterm (VPT) infants are at high-risk for neurodevelopmental impairments, however there are few validated biomarkers at term-equivalent age that accurately measure abnormal brain development and predict future impairments. Our objectives were to quantify and contrast cortical features between full-term and VPT infants at term and to associate two key antecedent risk factors, bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP), with cortical maturational changes in VPT infants. We prospectively enrolled a population-based cohort of 110 VPT infants (gestational age ≤31 weeks) and 51 healthy full-term infants (gestational age 38–42 weeks). Structural brain MRI was performed at term. 94 VPT infants and 46 full-term infants with high-quality T2-weighted MRI were analyzed. As compared to full-term infants, VPT infants exhibited significant global cortical maturational abnormalities, including reduced surface area (−5.9%) and gyrification (−6.7%) and increased curvature (5.9%). In multivariable regression controlled for important covariates, BPD was significantly negatively correlated with lobar and global cortical surface area and ROP was significantly negatively correlated with lobar and global sulcal depth in VPT infants. Our cohort of VPT infants exhibited widespread cortical maturation abnormalities by term-equivalent age that were in part anteceded by two of the most potent neonatal diseases, BPD and ROP.

Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood., Robert Jacobs, Mostafa Aboouf, et al. examined the effect of erythropoietin (EPO) in hippocampal mitochondrial function and memory in two mouse models: one overexpressing EPO in the brain, and juvenile mice treated during three days with a high dose of intraperitoneal EPO. Their results suggest that erythropoietin in the neonatal brain may impact spatial memory by increasing mitochondrial content.

Neonatal hypoxic–ischaemic brain damage is a leading cause of child mortality and morbidity, including cerebral palsy, epilepsy, and cognitive disabilities. The majority of neonatal hypoxic–ischaemic cases arise as a result of impaired cerebral perfusion to the foetus attributed to uterine, placental, or umbilical cord compromise prior to or during delivery. Bacterial infection is a factor contributing to the damage and is recorded in more than half of preterm births. Exposure to infection exacerbates neuronal hypoxic–ischaemic damage thus leading to a phenomenon called infection-sensitised hypoxic–ischaemic brain injury. Models of neonatal hypoxia–ischaemia (HI) have been developed in different animals. Both human and animal studies show that the developmental stage and the severity of the HI insult affect the selective regional vulnerability of the brain to damage, as well as the subsequent clinical manifestations. Therapeutic hypothermia (TH) is the only clinically approved treatment for neonatal HI. However, the number of HI infants needed to treat with TH for one to be saved from death or disability at age of 18–22 months, is approximately 6–7, which highlights the need for additional or alternative treatments to replace TH or increase its efficiency. In this review we discuss the mechanisms of HI injury to the immature brain and the new experimental treatments studied for neonatal HI and infection-sensitised neonatal HI.

Preterm very low birth weight infants (VLBWi) are known to be at greater risk of adverse neurodevelopmental outcome. Identifying early factors associated with outcome is essential in order to refer patients for early intervention. Few studies have investigated neurodevelopmental outcome in Italian VLBWi. The aim of our longitudinal study is to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year cohort of 502 Italian preterm VLBWi and to identify associations with outcome. At 24 months, Griffiths’ Mental Developmental Scales were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). 75.3% showed a normal outcome, 13.9% minor sequelae and 10.8% major sequelae (3.8% cerebral palsy). Male gender, bronchopulmonary dysplasia, abnormal neonatal neurological assessment and severe brain ultrasound abnormalities were independently associated with poor outcome on multivariate ordered logistic regression. Rates of major sequelae are in line with international studies, as is the prevalence of developmental delay over cerebral palsy. Analysis of perinatal complications and the combination of close cUS monitoring and neurological assessment are still essential for early identification of infants with adverse outcome.

Cerebral hypoxia-ischemia (HI) compromises the proteasome in a clinically relevant neonatal piglet model. Protecting and activating proteasomes could be an adjunct therapy to hypothermia. We investigated whether chymotrypsin-like proteasome activity differs regionally and developmentally in the neonatal brain. We also tested whether neonatal brain proteasomes can be modulated by oleuropein, an experimental pleiotropic neuroprotective drug, or by targeting a proteasome subunit gene using recombinant adeno-associated virus-9 (AAV). During post-HI hypothermia, we treated piglets with oleuropein, used AAV-short hairpin RNA (shRNA) to knock down proteasome activator 28γ (PA28γ), or enforced PA28γ using AAV-PA28γ with green fluorescent protein (GFP). Neonatal neocortex and subcortical white matter had greater proteasome activity than did liver and kidney. Neonatal white matter had higher proteasome activity than did juvenile white matter. Lower arterial pH 1 h after HI correlated with greater subsequent cortical proteasome activity. With increasing brain homogenate protein input into the assay, the initial proteasome activity increased only among shams, whereas HI increased total kinetic proteasome activity. OLE increased the initial neocortical proteasome activity after hypothermia. AAV drove GFP expression, and white matter PA28γ levels correlated with proteasome activity and subunit levels. However, AAV proteasome modulation varied. Thus, neonatal neocortical proteasomes can be pharmacologically activated. HI slows the initial proteasome performance, but then augments ongoing catalytic activity. AAV-mediated genetic manipulation in the piglet brain holds promise, though proteasome gene targeting requires further development.

Ferroptosis is a novel type of programmed cell death, which is different from apoptosis and autophagic cell death. Recently, ferroptosis has been indicated to contribute to the in vitro neurotoxicity induced by isoflurane, which is one of the most common anesthetics in clinic. However, the in vivo position of ferroptosis in isoflurane-induced neurotoxicity as well as learning and memory impairment remains unclear. In this study, we mainly explored the relationship between ferroptosis and isoflurane-induced learning and memory, as well as the therapeutic methods in mouse model. Our results indicated that isoflurane induced the ferroptosis in a dose-dependent and time-dependent manner in hippocampus, the organ related with learning and memory ability. In addition, the activity of cytochrome c oxidase/Complex IV in mitochondrial electron transport chain (ETC) was increased by isoflurane, which might further contributed to cysteine deprivation-induced ferroptosis caused by isoflurane exposure. More importantly, isoflurane-induced ferroptosis could be rescued by both ferroptosis inhibitor (ferrostatin-1) and mitochondria activator (dimethyl fumarate), which also showed effective therapeutic action against isoflurane-induced learning and memory impairment. Taken together, our data indicate the close association among ferroptosis, mitochondria and isoflurane, and provide a novel insight into the therapy mode against isoflurane-induced learning and memory impairment.

The mammillary bodies (MB) and hippocampi are important for memory function and are often affected following neonatal hypoxic ischemic encephalopathy (HIE). The aim of this study was to assess neurodevelopmental outcome in 10-year-old children with HIE with and without therapeutic hypothermia. Additional aims were to assess the associations between MB atrophy, brain volumes (including the hippocampi), white matter microstructure and neurodevelopmental outcome at school-age. Ten-year-old children with HIE were included, who were treated with therapeutic hypothermia (n = 22) or would have qualified but were born before this became standard of care (n = 28). Children completed a neuropsychological and motor assessment and MRI. Mammillary bodies were scored as normal or atrophic at 10 years. Brain volumes were segmented on childhood MRI and DTI scans were analysed using tract-based spatial statistics. Children with HIE suffered from neurocognitive and memory problems at school-age, irrespective of hypothermia. Hippocampal volumes and MB atrophy were associated with total and performance IQ, processing speed and episodic memory in both groups. Normal MB and larger hippocampi were positively associated with global fractional anisotropy. In conclusion, injury to the MB and hippocampi was associated with neurocognition and memory at school-age in HIE and might be an early biomarker for neurocognitive and memory problems.

Animal studies have demonstrated the therapeutic potential of polyphenol-rich pomegranate juice. We recently reported altered white matter microstructure and functional connectivity in the infant brain following in utero pomegranate juice exposure in pregnancies with intrauterine growth restriction (IUGR). This double-blind exploratory randomized controlled trial further investigates the impact of maternal pomegranate juice intake on brain structure and injury in a second cohort of IUGR pregnancies diagnosed at 24–34 weeks’ gestation. Ninety-nine mothers and their eligible fetuses (n = 103) were recruited from Brigham and Women’s Hospital and randomly assigned to 8 oz pomegranate (n = 56) or placebo (n = 47) juice to be consumed daily from enrollment to delivery. A subset of participants underwent fetal echocardiogram after 2 weeks on juice with no evidence of ductal constriction. 57 infants (n = 26 pomegranate, n = 31 placebo) underwent term-equivalent MRI for assessment of brain injury, volumes and white matter diffusion. No significant group differences were found in brain volumes or white matter microstructure; however, infants whose mothers consumed pomegranate juice demonstrated lower risk for brain injury, including any white or cortical grey matter injury compared to placebo. These preliminary findings suggest pomegranate juice may be a safe in utero neuroprotectant in pregnancies with known IUGR warranting continued investigation.Clinical trial registration: NCT04394910, https://clinicaltrials.gov/ct2/show/NCT04394910, Registered May 20, 2020, initial participant enrollment January 16, 2016.

A specialized neurogenic niche along the ventricles accumulates millions of progenitor cells in the developing brain. After mitosis, fate-committed daughter cells delaminate from this germinative zone. Considering the high number of cell divisions and delaminations taking place during embryonic development, brain malformations caused by ectopic proliferation of misplaced progenitor cells are relatively rare. Here, we report that a process we term developmental anoikis distinguishes the pathological detachment of progenitor cells from the normal delamination of daughter neuroblasts in the developing mouse neocortex. We identify the endocannabinoid-metabolizing enzyme abhydrolase domain containing 4 (ABHD4) as an essential mediator for the elimination of pathologically detached cells. Consequently, rapid ABHD4 downregulation is necessary for delaminated daughter neuroblasts to escape from anoikis. Moreover, ABHD4 is required for fetal alcohol-induced apoptosis, but not for the well-established form of developmentally controlled programmed cell death. These results suggest that ABHD4-mediated developmental anoikis specifically protects the embryonic brain from the consequences of sporadic delamination errors and teratogenic insults., During embryonic development, neural progenitor cells undergo numerous cell divisions. Here, the authors show that ABHD4-mediated developmental anoikis distinguishes the physiological delamination and the pathological detachment of progenitor cells with relevance to fetal alcohol-induced apoptosis.

Preterm infants with periventricular–intraventricular hemorrhage (PV–IVH) have a high risk of neurological sequelae, with severity depending on the severity of the PV–IVH. Previous studies on the pathogenesis of PV–IVH have focused mainly on comparisons of perinatal risk factors between patients with and without PV–IVH. Notably, most cases of PV–IVH occur within the first 3 days after birth, and the condition may worsen within 1 week following the initial diagnosis. However, the risk factors that contribute to the deterioration of PV–IVH have not been investigated. In this cohort study, 514 PV–IVH infants with a gestational age (GA)

The cerebellum is connected to numerous regions of the contralateral side of the cerebrum. Motor and cognitive deficits following neonatal cerebellar hemorrhages (CbH) in extremely preterm neonates may be related to remote cortical alterations, following disrupted cerebello-cerebral connectivity as was previously shown within six CbH infants. In this retrospective case series study, we used MRI and advanced surface-based analyses to reconstruct gray matter (GM) changes in cortical thickness and cortical surface area in extremely preterm neonates (median age = 26; range: 24.9–26.7 gestational weeks) with large isolated unilateral CbH (N = 5 patients). Each CbH infant was matched with their own preterm infant cohort (range: 20–36 infants) based on sex and gestational age at birth. On a macro level, our data revealed that the contralateral cerebral hemisphere of CbH neonates did not show less cortical thickness or cortical surface area than their ipsilateral cerebral hemisphere at term. None of the cases differed from their matched cohort groups in average cortical thickness or average cortical surface area in the ipsilateral or contralateral cerebral hemisphere. On a micro (i.e. vertex) level, we established high variability in significant local cortical GM alteration patterns across case-cohort groups, in which the cases showed thicker or bigger volume in some regions, among which the caudal middle frontal gyrus, insula and parahippocampal gyrus, and thinner or less volume in other regions, among which the cuneus, precuneus and supratentorial gyrus. This study highlights that cerebellar injury during postnatal stages may have widespread bilateral influence on the early maturation of cerebral cortical regions, which implicate complex cerebello-cerebral interactions to be present at term birth.

Motor function after hemispheric lesions has been associated with the structural integrity of either the pyramidal tract (PT) or alternate motor fibers (aMF). In this study, we aimed to differentially characterize the roles of PT and aMF in motor compensation by relating diffusion-tensor-imaging-derived parameters of white matter microstructure to measures of proximal and distal motor function in patients after hemispherotomy. Twenty-five patients (13 women; mean age: 21.1 years) after hemispherotomy (at mean age: 12.4 years) underwent Diffusion Tensor Imaging and evaluation of motor function using the Fugl-Meyer Assessment and the index finger tapping test. Regression analyses revealed that fractional anisotropy of the PT explained (p = 0.050) distal motor function including finger tapping rate (p = 0.027), whereas fractional anisotropy of aMF originating in the contralesional cortex and crossing to the ipsilesional hemisphere in the pons explained proximal motor function (p = 0.001). Age at surgery was found to be the only clinical variable to explain motor function (p

Traumatic brain injury (TBI) is the leading cause of pediatric morbidity and mortality worldwide, and half of all fatalities occur in infants aged less than 1 year. We analyzed 129 infants diagnosed with TBI complicated with intracranial hemorrhage confirmed by brain computed tomography. We defined delta hemoglobin (ΔHB) as nadir HB - age specific mean HB, and the ratio of HB (%) as ΔHB/age specific mean HB x 100. Infants with poor neurologic outcomes had a lower admission HB and ΔHB (p +), 8.24; negative likelihood ratio (LR−), 0.34); the AUC was 0.88 in infants aged from 6–12 months and the optimal cutoff was −20.6% (sensitivity, 89%; specificity, 79%; LR+, 4.13; LR−, 0.15).

Neonatal seizures are a common emergency in the neonatal intensive care unit (NICU). There are many questions yet to be answered regarding the temporal/spatial characteristics of seizures from different pathologies, response to medication, effects on neurodevelopment and optimal detection. The dataset presented in this descriptor contains EEG recordings from human neonates, the visual interpretation of the EEG by the human experts, supporting clinical data and codes to assist access. Multi-channel EEG was recorded from 79 term neonates admitted to the NICU at the Helsinki University Hospital. The median recording duration was 74 min (IQR: 64 to 96 min). The presence of seizures in the EEGs was annotated independently by three experts. An average of 460 seizures were annotated per expert in the dataset; 39 neonates had seizures and 22 were seizure free, by consensus. The dataset can be used as a reference set of neonatal seizures, in studies of inter-observer agreement and for the development of automated methods of seizure detection and other EEG analyses. Machine-accessible metadata file describing the reported data (ISA-Tab format)

In children with unilateral cerebral palsy (uCP), the corticospinal tract (CST)-wiring patterns may differ (contralateral, ipsilateral or bilateral), partially determining motor deficits. However, the impact of such CST-wiring on functional connectivity remains unknown. Here, we explored resting-state sensorimotor functional connectivity in 26 uCP with periventricular white matter lesions (mean age (standard deviation): 12.87 m (±4.5), CST wiring: 9 contralateral, 9 ipsilateral, 6 bilateral) compared to 60 healthy controls (mean age (standard deviation): 14.54 (±4.8)), and between CST-wiring patterns. Functional connectivity from each M1 to three bilateral sensorimotor regions of interest (primary sensory cortex, dorsal and ventral premotor cortex) and the supplementary motor area was compared between groups (controls vs. uCP; and controls vs. each CST-wiring group). Seed-to-voxel analyses from bilateral M1 were compared between groups. Additionally, relations with upper limb motor deficits were explored. Aberrant sensorimotor functional connectivity seemed to be CST-dependent rather than specific from all the uCP population: in the dominant hemisphere, the contralateral CST group showed increased connectivity between M1 and premotor cortices, whereas the bilateral CST group showed higher connectivity between M1 and somatosensory association areas. These results suggest that functional connectivity of the sensorimotor network is CST-wiring-dependent, although the impact on upper limb function remains unclear., Scientific Reports, 9 (1), ISSN:2045-2322

Therapeutic hypothermia (HT) is standard care for moderate and severe neonatal hypoxic-ischaemic encephalopathy (HIE), the leading cause of permanent brain injury in term newborns. However, the optimal temperature for HT is still unknown, and few preclinical studies have compared multiple HT treatment temperatures. Additionally, HT may not benefit infants with severe encephalopathy. In a neonatal rat model of unilateral hypoxia-ischaemia (HI), the effect of five different HT temperatures was investigated after either moderate or severe injury. At postnatal-day seven, rat pups underwent moderate or severe HI followed by 5 h at normothermia (37 °C), or one of five HT temperatures: 33.5 °C, 32 °C, 30 °C, 26 °C, and 18 °C. One week after treatment, neuropathological analysis of hemispheric and hippocampal area loss, and CA1 hippocampal pyramidal neuron count, was performed. After moderate injury, a significant reduction in hemispheric and hippocampal loss on the injured side, and preservation of CA1 pyramidal neurons, was seen in the 33.5 °C, 32 °C, and 30 °C groups. Cooling below 33.5 °C did not provide additional neuroprotection. Regardless of treatment temperature, HT was not neuroprotective in the severe HI model. Based on these findings, and previous experience translating preclinical studies into clinical application, we propose that milder cooling should be considered for future clinical trials.

Inflammation is an important factor contributing to developmental brain injury in preterm infants. Although tumor necrosis factor-inducible gene 6 protein (TSG-6) has immunomodulatory effects in several inflammatory conditions of adult animals, nothing is currently known about the role of TSG-6 in the developing brain, its impact on perinatal inflammation and its therapeutic potential. The aim of the current work was 1) to characterize the developmental expression of TSG-6 in the newborn rat brain, 2) to evaluate the impact of LPS exposure on TSG-6 expression and 3) to assess the therapeutic potential of exogenous TSG-6 administration. Brain hemispheres of healthy Wistar rats (postnatal day 1–postnatal day 15 (P1–P15)) were evaluated with regard to the physiological expression of TSG-6. LPS-treated rats (0.25mg/kg LPS i.p. on P3) were analyzed for inflammation-induced changes in TSG-6 and cytokine expression. To evaluate whether exogenous recombinant human (rh)TSG-6 affects inflammation-induced brain injury, newborn Wistar rats, exposed to LPS on P3, were treated with rhTSG-6 i.p. (four repetitive doses of 2.25mg/kg every 12h, first dose 3h before LPS injection). PCR, Western blotting and multiplex ELISA were performed according to standard protocols. TSG-6 is physiologically expressed in the developing brain with a linear increase in expression from P1 to P15 at the mRNA level. At P6, regional differences in TSG-6 expression in the cortex, thalamus and striatum were detected at mRNA and protein level. Furthermore, TSG-6 gene expression was significantly increased by inflammation (induced by LPS treatment). Combined treatment with LPS and TSG-6 vs. LPS exposure alone, resulted in significant down-regulation of cleaved caspase-3, a marker of apoptosis and neuronal plasticity. In addition, several inflammatory serum markers were decreased after TSG-6 treatment. Finally, TSG-6 is physiologically expressed in the developing brain. Changes of TSG-6 expression associated with inflammation suggest a role of TSG-6 in neuroinflammation. Reduction of cleaved caspase-3 by TSG-6 treatment demonstrates the putative neuroprotective potential of exogenous TSG-6 administration in inflammation-induced developmental brain injury.