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Introduction: Our laboratory has been exploring the MRI detection of fetal brain injury, which previously provided a prognostic biomarker for newborn hypertonia in an animal model of cerebral palsy (CP). The biomarker relies on distinct patterns of diffusion-weighted imaging-defined apparent diffusion coefficient (ADC) in fetal brains during uterine hypoxia-ischemia (H-I). Despite the challenges posed by small brains and tissue acquisition, our objective was to differentiate between left and right brain ADC changes. Methods: A novel aspect involved utilizing three-dimensional rendering techniques to refine ADC measurements within spheroids encompassing fetal brain tissue. 25-day gestation age of rabbit fetuses underwent global hypoxia due to maternal uterine ischemia. Results: Successful differentiation of left and right brain regions was achieved in 28% of the fetal brains. Ordinal analysis revealed predominantly higher ADC on the left side compared to the right at baseline and across the entire time series. During H-I and reperfusion-reoxygenation, the right side exhibited a favored percentage change. Among these fetal brains, 73% exhibited the ADC pattern predictive of hypertonia. No significant differences between left and right sides were observed in patterns predicting hypertonia, except for one timepoint during H-I. This study also highlights a balance between left-sided and right-sided alterations within the population. Conclusion: This study emphasizes the importance of investigating laterality and asymmetric hemispheric lesions for early diagnosis of brain injury, leading to CP. The technological limitations in obtaining a clear picture of the entire fetal brain for every fetus mirror the challenges encountered in human studies. Introduction: Our laboratory has been exploring the MRI detection of fetal brain injury, which previously provided a prognostic biomarker for newborn hypertonia in an animal model of cerebral palsy (CP). The biomarker relies on distinct patterns of diffusion-weighted imaging-defined apparent diffusion coefficient (ADC) in fetal brains during uterine hypoxia-ischemia (H-I). Despite the challenges posed by small brains and tissue acquisition, our objective was to differentiate between left and right brain ADC changes. Methods: A novel aspect involved utilizing three-dimensional rendering techniques to refine ADC measurements within spheroids encompassing fetal brain tissue. 25-day gestation age of rabbit fetuses underwent global hypoxia due to maternal uterine ischemia. Results: Successful differentiation of left and right brain regions was achieved in 28% of the fetal brains. Ordinal analysis revealed predominantly higher ADC on the left side compared to the right at baseline and across the entire time series. During H-I and reperfusion-reoxygenation, the right side exhibited a favored percentage change. Among these fetal brains, 73% exhibited the ADC pattern predictive of hypertonia. No significant differences between left and right sides were observed in patterns predicting hypertonia, except for one timepoint during H-I. This study also highlights a balance between left-sided and right-sided alterations within the population. Conclusion: This study emphasizes the importance of investigating laterality and asymmetric hemispheric lesions for early diagnosis of brain injury, leading to CP. The technological limitations in obtaining a clear picture of the entire fetal brain for every fetus mirror the challenges encountered in human studies. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion To investigate the association between retinopathy of prematurity and autism spectrum disorder in extremely preterm children.Data in children born extremely preterm at <28 weeks’ gestational age in the Region Västra Götaland, 2013–2017, were analysed for association between retinopathy of prematurity and neurodevelopmental disorders. We focussed on autism spectrum disorder and excluded children with perinatal brain injuries or genetic disorders.Of 266 children with neurodevelopmental evaluation, 143 had no documented brain injury or genetic disorders. Of these 143, autism spectrum disorder was diagnosed in 18%, attention deficit hyperactivity disorder in 15% and intellectual disability in 7%. Of the 72/143 children with a history of no or mild retinopathy of prematurity (stage <1), 10% were diagnosed with autism spectrum disorder compared to 27% of 71/143 with prior moderate‐to‐severe retinopathy of prematurity (stages ≥2), (p = 0.008). A history of retinopathy of prematurity stages ≥2 was associated with a threefold increased likelihood of later autism spectrum disorder even when adjusting for gestational age and sex (p = 0.011).Moderate‐to‐severe retinopathy of prematurity associated with a higher likelihood of later autism spectrum disorder diagnosis in extremely preterm children without documented brain injuries or genetic disorders. [ABSTRACT FROM AUTHOR]

• VGB effectiveness for IESS was evaluated based on etiology excluding TSC. • Overall effectiveness of VGB for IESS with variable etiologies was 39.0 % (16/41 cases). • VGB effectiveness for congenital structural diseases was 9.1 % (1/11 cases). • Alternative treatments should be considered for congenital structural diseases. We aimed to assess the effectiveness of vigabatrin (VGB) in patients diagnosed with infantile epileptic spasm syndrome (IESS) and categorize these patients based on their etiologies. This retrospective study included patients diagnosed with IESS who exhibited epileptic spasms before the age of 2 years between January 1, 2015, and October 31, 2023 at Saitama Children's Medical Center. Patients with tuberous sclerosis as the identified etiology were excluded. The effectiveness of VGB was assessed based on the resolution of ES for three months with the absence of hypsarrhythmia on interictal electroencephalogram. This study analyzed 41 patients (26 boys). The etiologies included genetic, congenital structural, acquired structural, and unknown in 12, 11, 10, and 8 patients, respectively. Patient characteristics did not significantly differ among the four groups. The overall effectiveness of VGB for IESS was 39.0 % (16/41). Categorized based on etiology, VGB was effective in 41.7 % (5/12), 9.1 % (1/11), 50 % (5/10), and 75 % (6/8) in the genetic, congenital structural, acquired structural, and unknown groups, respectively. Statistical analysis revealed a significant difference in effectiveness among the four groups (p = 0.03). Categorized based on diseases, VGB was effective in 28.6 % (2/7) and 50 % (4/8) in trisomy 21 and perinatal brain injury, respectively. The effectiveness of VGB in patients with IESS varied with etiology. Further investigations into the effectiveness of VGB in etiological subtypes of IESS could facilitate the development of tailored treatment algorithms for each etiology, representing valuable guidelines for future medical practice. [ABSTRACT FROM AUTHOR]

ABSTRACTPremature infants lack a normal intestinal microbial community and also at risk of perinatal hypoxic-ischemic (HI) brain injury, which is considered to be one of the major factors for motor, sensory, and cognitive deficits. We hypothesized that neonatal gut microbiota composition modulated the immune reaction and severity of neonatal H-I brain injury. Neonatal C57BL/6J mouse pups were exposed to H-I protocol consisting of permanent left carotid artery ligation, followed by 8% hypoxia for 60 min. Microbial manipulation groups included 1) antibiotic treatment, E18 (maternal) to P5; 2) antibiotic treatment E18 to P5 + E. coli gavage; 3) antibiotic treatment E18 to P5 + B. infantis gavage; and 4) saline to pups with dams getting fresh water. The extent of brain injury and recovery was measured on MRI. Edematous injury volume was significantly higher in E. coli group than that in B. infantis group and in fresh water group. Gene expression in brains of pro-inflammatory cytokines (IL1β, IL6, IL2, TNF-α and toll-like receptors 2–6) were elevated to a greater extent in the E. coli group at P10, no injury, and at P13, 72 hours after H-I relative to sham control and B. infantis groups. Significant effects of microbiome and brain injury and interaction of these factors were found in abundance of major phyla. The neuroinflammatory response and brain injury after neonatal hypoxia-ischemia are affected by intestinal microbiota, providing opportunities for therapeutic intervention through targeting the early colonization and development of the gut microbiota.

The management of status epilepticus (SE) has mainly focused on the termination of ongoing SE episodes. However, long-term therapeutic strategies for the prevention of SE are lacking. This study aimed to investigate the effectiveness of prophylactic antiseizure medications (ASMs) for SEs in nonsyndromic childhood epilepsy. This retrospective study was conducted at Jikei University Hospital. Patients <18 years of age, diagnosed with epilepsy, and experiencing three or more SE episodes within 1 year between April 1, 2017, and October 1, 2021, were included. ASMs introduced for seizure types that developed into SE were evaluated. The effectiveness of ASMs was determined by using the "Rule of Three": An ASM was determined effective if patients were free of SE for a duration at least three times that of their longest SE interval in 12 months prior to intervention. The investigation included a total of 32 ASMs administered to 13 patients. The longest interval between SE episodes before ASM administration was 28–257 d. The first SE interval after ASM administration was 12–797 d. Levetiracetam (LEV) and clobazam (CLB) showed effectiveness in 2/10 and 5/6 patients, respectively. Other ASMs were ineffective. The leading etiology of epilepsy was perinatal brain injury, identified in four patients, and CLB was effective in all of them. The present study suggests that CLB and LEV may prolong the SE interval in some cases of nonsyndromic childhood epilepsy. CLB may be beneficial, particularly in patients with perinatal brain injury. [ABSTRACT FROM AUTHOR]

Single-pulse transcranial magnetic stimulation (TMS) has many applications for pediatric clinical populations, including infants with perinatal brain injury. As a noninvasive neuromodulation tool, single-pulse TMS has been used safely in infants and children to assess corticospinal integrity and circuitry patterns. TMS may have important applications in early detection of atypical motor development or cerebral palsy. The authors identified and summarized relevant studies incorporating TMS in infants, including findings related to corticospinal development and circuitry, motor cortex localization and mapping, and safety. This special report also describes methodologies and safety considerations related to TMS assessment in infants, and discusses potential applications related to diagnosis of cerebral palsy and early intervention. Single-pulse TMS has demonstrated safety and feasibility in infants with perinatal brain injury and may provide insight into neuromotor development and potential cerebral palsy diagnosis. Additional research in larger sample sizes will more fully evaluate the utility of TMS biomarkers in early diagnosis and intervention. Methodological challenges to performing TMS in infants and technical/equipment limitations require additional consideration and innovation toward clinical implementation. Future research may explore use of noninvasive neuromodulation techniques as an intervention in younger children with perinatal brain injury to improve motor outcomes. Single pulse transcranial magnetic stimulation (TMS) is a safe and noninvasive way to study brain activity in infants and children who have experienced brain injuries around the time of birth. Infants who have had an early brain injury may develop cerebral palsy, a developmental disability that affects movement. TMS uses a device that gives single pulses of energy to activate specific areas of the brain. This can be used to study how the brain connects to the muscles in the body through paths or 'tracts.' TMS helps researchers understand the development of the tracts and the potential need for therapy. This article reviews research studies that used TMS in infants and explains how TMS can be used to assess brain development. It also reviews safety considerations and challenges related to using TMS in infants. TMS could be a valuable tool for early diagnosis of cerebral palsy and could also help guide treatments for infants with brain injuries. However, more research is needed, using larger groups of infants, to potentially expand the use of TMS in clinical practice. Future directions include developing infant-specific research tools and using noninvasive brain stimulation to improve recovery for infants with brain injuries. [ABSTRACT FROM AUTHOR]

Purpose: Congenital diaphragmatic hernia (CDH) survivors may experience neurodevelopmental impairment, whose etiology remains elusive. Preclinical evidence indicates that amniotic fluid stem cell extracellular vesicle (AFSC-EV) administration promotes lung development but their effects on other organs are unknown. Herein, we investigated the brain of rat fetuses with CDH for signs of inflammation and response to AFSC-EVs. Methods: CDH was induced by maternal nitrofen administration at E9.5. At E18.5, fetuses were injected intra-amniotically with saline or AFSC-EVs (isolated by ultracentrifugation, characterized as per MISEV guidelines). Fetuses from vehicle-gavaged dams served as controls. Groups were compared for: lung hypoplasia, TNFa and IL-1B brain expression, and activated microglia (Iba1) density in the subgranular zone (SGZ). Results: CDH lungs had fewer airspaces compared to controls, whereas AFSC-EV-treated lungs had rescued branching morphogenesis. Fluorescently labeled AFSC-EVs injected intra-amniotically into CDH fetuses had fluorescent signal in the brain. Compared to controls, the brain of CDH fetuses had higher TNFa and IL-1B levels, and increased activated microglia density. Conversely, the brain of AFSC-EV treated fetuses had inflammatory marker expression levels and microglia density similar to controls. Conclusion: This study shows that the brain of rat fetuses with CDH has signs of inflammation that are abated by the intra-amniotic administration of AFSC-EVs. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic encephalopathy (HIE) is a common disease among newborns, which is a leading cause of neonatal death and permanent neurological sequelae. Therapeutic hypothermia (TH) is the only method for the treatment of HIE that has been recognized effective clinically at home and abroad, but the efficacy is limited. Recent research suggests that the cord blood-derived mononuclear cells (CB-MNCs), which the refer to blood cells containing one nucleus in the cord blood, exert anti-oxidative, anti-inflammatory, anti-apoptotic effects and play a neuroprotective role in HIE. This review focuses on safety and efficacy, the route of administration, dose, timing and combination treatment of CB-MNCs in HIE. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to evaluate the impact of birth weight (BW), gestational age (GA), retinopathy of prematurity (ROP), and perinatal brain injury (PBI) on optic nerve head (ONH) parameters and nerve fiber layer thickness (RNFLT) in preterm children. Methods: ONH parameters and RNFLT were examined prospectively in 5–15-year-old preterm and full-term children with RTVue-100 OCT (Optovue, USA). The parameters of the two groups were compared and possible influences of BW, GA, ROP, and PBI analyzed in preterm children. Results: In total, 51 full-term and 55 preterm children were included. The mean age was 9.98 ± 3.4 years in full-term and 10.0 ± 2.5 years in preterm children. The mean GA in preterm children was 29.6 ± 3.8 weeks with a BW of 1523 ± 732 g. RNFLT was significantly lower in preterm than in full-term children in all but temporal quadrants. Cup area, volume, cup/disc area ratio, and horizontal cup/disc ratio (CDR) were significantly larger and rim area significantly thinner in preterm children. GA was positively correlated with superior, nasal, and overall RNFLT and negatively correlated with cup area, volume, and horizontal CDR. ROP stage correlated negatively with superior and nasal RNFLT. PBI was the only significant predicting factor for RNFL thinning in all but temporal quadrant in multiple regression analysis. Preterm children with PBI had a significantly larger optic cup (CDR 0.70 ± 0.33 vs. 0.37 ± 0.27) and thinner optic rim. Conclusion: PBI correlated strongest with RNFL thinning, a thinner optic rim, and a larger optic cup in preterm children and should be evaluated in each patient to prevent incorrect diagnosis like glaucoma. [ABSTRACT FROM AUTHOR]

Introduction: Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer from a singular etiology. Most experience cumulative insults from prenatal inflammation, genetic and epigenetic vulnerability, toxins (opioids, other drug exposures, environmental exposure), hypoxia-ischemia, and postnatal stressors such as sepsis and seizures. Accordingly, tailoring of emerging therapeutic regimens with endogenous repair or neuro-immunomodulatory agents for individuals requires a more precise understanding of ligand, receptor-, and non-receptor-mediated regulation of essential developmental hormones. Given the recent clinical focus on neurorepair for PBI, we hypothesized that there would be injury induced changes in erythropoietin (EPO), erythropoietin receptor (EPOR), melatonin receptor (MLTR), NAD-dependent deacetylase sirtuin-1 (SIRT1) signaling, and hypoxia inducible factors (HIF1α, HIF2α). Specifically, we predicted that EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α alterations after chorioamnionitis (CHORIO) would reflect relative changes observed in human preterm infants. Similarly, we expected unique developmental regulation after injury that would reveal potential clues to mechanisms and timing of inflammatory and oxidative injury after CHORIO that could inform future therapeutic development to treat PBI. Methods: To induce CHORIO, a laparotomy was performed on embryonic day 18 (E18) in rats with transient uterine artery occlusion plus intra-amniotic injection of lipopolysaccharide (LPS). Placentae and fetal brains were collected at 24 h. Brains were also collected on postnatal day 2 (P2), P7, and P21. EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α levels were quantified using a clinical electrochemiluminescent biomarker platform, qPCR, and/or RNAscope. MLT levels were quantified with liquid chromatography mass spectrometry Results: Examination of EPO, EPOR, and MLTR1 at 24 h showed that while placental levels of EPO and MLTR1 mRNA were decreased acutely after CHORIO, cerebral levels of EPO, EPOR and MLTR1 mRNA were increased compared to control. Notably, CHORIO brains at P2 were SIRT1 mRNA deficient with increased HIF1α and HIF2α despite normalized levels of EPO, EPOR and MLTR1, and in the presence of elevated serum EPO levels. Uniquely, brain levels of EPO, EPOR and MLTR1 shifted at P7 and P21, with prominent CHORIO-induced changes in mRNA expression. Reductions at P21 were concomitant with increased serum EPO levels in CHORIO rats compared to controls and variable MLT levels. Discussion: These data reveal that commensurate with robust inflammation through the maternal placental-fetal axis, CHORIO impacts EPO, MLT, SIRT1, and HIF signal transduction defined by dynamic changes in EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α mRNA, and EPO protein. Notably, ligand-receptor mismatch, tissue compartment differential regulation, and non-receptormediated signaling highlight the importance, complexity and nuance of neural and immune cell development and provide essential clues to mechanisms of injury in PBI. As the placenta, immune cells, and neural cells share many common, developmentally regulated signal transduction pathways, further studies are needed to clarify the perinatal dynamics of EPO and MLT signaling and to capitalize on therapies that target endogenous neurorepair mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Perinatal brain injury is a leading cause of death and disability in children. Hypoxic-ischemic encephalopathy in full term infants, and white matter injury in premature infants are most known brain injury in perinatal period. Human umbilical cord blood mononuclear cells contain hematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells, lymphocytes, monocytes, and so on. Human umbilical cord blood mononuclear cells have many biological functions, such as nerve and vascular regeneration, anti-apoptosis, anti-inflammation, and immune regulation. Human umbilical cord blood mononuclear cells transplantation has achieved significant efficacy and safety in animal and clinical trials for the treatment of perinatal brain injury. We will review human umbilical cord blood mononuclear cells transplantation for perinatal brain injury in this review.

Background: Creatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in nearterm sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study investigated the effects of acute hypoxia with or without fetal creatine supplementation on neuropathology in multiple brain regions. Methods: Near-term fetal sheep were administered continuous intravenous infusion of either creatine (6 mg kg-1 h-1) or isovolumetric saline from 122 to 134 days gestational age (dGA; term is approx. 145 dGA). At 131 dGA, global hypoxia was induced by a 10 min umbilical cord occlusion (UCO). Fetuses were then recovered for 72 h at which time (134 dGA) cerebral tissue was collected for either RT-qPCR or immunohistochemistry analyses. Results: UCO resulted in mild injury to the cortical gray matter, thalamus and hippocampus, with increased cell death and astrogliosis and downregulation of genes involved in regulating injury responses, vasculature development and mitochondrial integrity. Creatine supplementation reduced astrogliosis within the corpus callosum but did not ameliorate any other gene expression or histopathological changes induced by hypoxia. Of importance, effects of creatine supplementation on gene expression irrespective of hypoxia, including increased expression of anti-apoptotic (BCL-2) and pro-inflammatory (e.g., MPO, TNFa, IL-6, IL-1b) genes, particularly in the gray matter, hippocampus, and striatum were identified. Creatine treatment also effected oligodendrocyte maturation and myelination in white matter regions. Conclusion: While supplementation did not rescue mild neuropathology caused by UCO, creatine did result in gene expression changes that may influence in utero cerebral development. [ABSTRACT FROM AUTHOR]

Hypoxic-ischaemic encephalopathy (HIE) in the newborn baby is a major contributor to neonatal mortality and morbidity across the world. Therapeutic hypothermia (TH) is the current standard treatment for moderate to severe HIE, but not all babies benefit. Potential neuroprotective actions of progesterone (PROG) include anti-apoptotic, anti-inflammatory, and anti-oxidative effects and reduction of energy depletion, tissue/cellular oedema, and excitotoxicity. In pre-clinical studies of neonatal HIE, PROG has neuroprotective properties but has not been the subject of systematic review. Here, our objective was to evaluate the evidence base for PROG as a potential therapeutic agent in HIE. The PICO framework was used to define the following inclusion criteria. Population: human neonates with HIE/animal models of HIE; intervention: PROG +/− other agents; comparison: V.S. control; outcome: pathological, neurobehavioural, and mechanistic outcome measures. Medline, EMBASE, and CINHAL were then searched between August to October 2018 using pre-defined medical subject heading and keywords. Study inclusion, data extraction, and risk of bias (ROB) analysis using the SYRCLE ROB tool were carried out by two authors. 14 studies were included in the review. They typically displayed a high ROB. This systematic review suggests that PROG reduced neuropathology and reduced neurobehavioural deficits post-hypoxic-ischaemic (HI) insult in 8 and 3 studies, respectively. However, there was sex dimorphism in the effects of PROG. In addition, there are limitations and biases in these studies, and there remains a need for well-designed large pre-clinical studies with greater methodological quality to further inform the efficacy, safety, dose, timing, and frequency of PROG administration. With such data, large animal studies could be planned combining PROG administration with and without TH. [ABSTRACT FROM AUTHOR]

BackgroundCreatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in near-term sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study investigated the effects of acute hypoxia with or without fetal creatine supplementation on neuropathology in multiple brain regions.MethodsNear-term fetal sheep were administered continuous intravenous infusion of either creatine (6 mg kg–1 h–1) or isovolumetric saline from 122 to 134 days gestational age (dGA; term is approx. 145 dGA). At 131 dGA, global hypoxia was induced by a 10 min umbilical cord occlusion (UCO). Fetuses were then recovered for 72 h at which time (134 dGA) cerebral tissue was collected for either RT-qPCR or immunohistochemistry analyses.ResultsUCO resulted in mild injury to the cortical gray matter, thalamus and hippocampus, with increased cell death and astrogliosis and downregulation of genes involved in regulating injury responses, vasculature development and mitochondrial integrity. Creatine supplementation reduced astrogliosis within the corpus callosum but did not ameliorate any other gene expression or histopathological changes induced by hypoxia. Of importance, effects of creatine supplementation on gene expression irrespective of hypoxia, including increased expression of anti-apoptotic (BCL-2) and pro-inflammatory (e.g., MPO, TNFa, IL-6, IL-1β) genes, particularly in the gray matter, hippocampus, and striatum were identified. Creatine treatment also effected oligodendrocyte maturation and myelination in white matter regions.ConclusionWhile supplementation did not rescue mild neuropathology caused by UCO, creatine did result in gene expression changes that may influence in utero cerebral development.

Necrotizing enterocolitis (NEC) is a devastating condition of multi-factorial origin that affects the intestine of premature infants and results in high morbidity and mortality. Infants that survive contend with several long-term sequelae including neurodevelopmental impairment (NDI)—which encompasses cognitive and psychosocial deficits as well as motor, vision, and hearing impairment. Alterations in the gut-brain axis (GBA) homeostasis have been implicated in the pathogenesis of NEC and the development of NDI. The crosstalk along the GBA suggests that microbial dysbiosis and subsequent bowel injury can initiate systemic inflammation which is followed by pathogenic signaling cascades with multiple pathways that ultimately lead to the brain. These signals reach the brain and activate an inflammatory cascade in the brain resulting in white matter injury, impaired myelination, delayed head growth, and eventual downstream NDI. The purpose of this review is to summarize the NDI seen in NEC, discuss what is known about the GBA, explore the relationship between the GBA and perinatal brain injury in the setting of NEC, and finally, highlight the existing research into possible therapies to help prevent these deleterious outcomes.

Background: Infantile epileptic spasm syndrome (IESS) is an age-dependent epileptic encephalopathy with a significant risk of developmental regression. This study investigates the association between heart rate variability (HRV) in infants at risk of IESS and the clinical onset of IESS. Methods: Sixty neonates at risk of IESS were prospectively followed from birth to 12 months with simultaneous electroencephalogram (EEG) and electrocardiogram recordings for 60min at every 2-month interval. HRV metrics were calculated from 5min time-epoch during sleep including frequency domain measures, Poincare analysis including cardiac vagal index (CVI) and cardiac sympathetic index (CSI), and detrended fluctuation analysis (DFA a1, DFA a2). To assess the effect of each HRV metric at the 2-month baseline on the time until the first occurrence of either hypsarrhythmia on EEG and/or clinical spasm, univariate cox-proportional hazard models were fitted for each HRV metric. Results: Infantile epileptic spasm syndrome was diagnosed in 20/60 (33%) of the cohort in a 12-month follow-up and 3 (5%) were lost to follow-up. The median age of developing hypsarrhythmia was 25 (7-53) weeks and clinical spasms at 24 (8-40) weeks. Three (5%) patients had clinical spasms without hypsarrhythmia, and 5 (8%) patients had hypsarrhythmia before clinical spasms at the initial presentation. The infants with high CSI (hazard ratio 2.5, 95% CI 1.2-5.2, P = 0.01) and high DFA α1 (hazard ratio 16, 95% CI 1.1-240, P = 0.04) at 2 months were more likely to develop hypsarrhythmia by the first year of age. There was a trend toward decreasing CSI and DFA a1 and increasing CVI in the first 8 months of age. Conclusion: Our data suggest that relative sympathetic predominance at an early age of 2monthsmay be a potential predictor for developing IESS. Hence, early HRV patterns may provide valuable prognostic information in children at risk of IESS allowing early detection and optimization of cognitive outcomes. Whether early intervention to restore sympathovagal balance per se would provide clinical benefit must be addressed by future studies. [ABSTRACT FROM AUTHOR]

The selection of an appropriate animal model is key to the production of results with optimal relevance to human disease. Particularly in the case of perinatal brain injury, a dearth of affected human neonatal tissue available for research purposes increases the reliance on animal models for insight into disease mechanisms. Improvements in obstetric and neonatal care in the past 20 years have caused the pathologic hallmarks of perinatal white matter injury (WMI) to evolve away from cystic necrotic lesions and toward diffuse regions of reactive gliosis and persistent myelin disruption. Therefore, updated animal models are needed that recapitulate the key features of contemporary disease. Here, we report a murine model of acute diffuse perinatal WMI induced through a two-hit inflammatory–hypoxic injury paradigm. Consistent with diffuse human perinatal white matter injury (dWMI), our model did not show the formation of cystic lesions. Corresponding to cellular outcomes of dWMI, our injury protocol produced reactive microgliosis and astrogliosis, disrupted oligodendrocyte maturation, and disrupted myelination.. Functionally, we observed sensorimotor and cognitive deficits in affected mice. In conclusion, we report a novel murine model of dWMI that induces a pattern of brain injury mirroring multiple key aspects of the contemporary human clinical disease scenario. [ABSTRACT FROM AUTHOR]

BackgroundInfantile epileptic spasm syndrome (IESS) is an age-dependent epileptic encephalopathy with a significant risk of developmental regression. This study investigates the association between heart rate variability (HRV) in infants at risk of IESS and the clinical onset of IESS.MethodsSixty neonates at risk of IESS were prospectively followed from birth to 12 months with simultaneous electroencephalogram (EEG) and electrocardiogram recordings for 60 min at every 2-month interval. HRV metrics were calculated from 5 min time-epoch during sleep including frequency domain measures, Poincare analysis including cardiac vagal index (CVI) and cardiac sympathetic index (CSI), and detrended fluctuation analysis (DFA α1, DFA α2). To assess the effect of each HRV metric at the 2-month baseline on the time until the first occurrence of either hypsarrhythmia on EEG and/or clinical spasm, univariate cox-proportional hazard models were fitted for each HRV metric.ResultsInfantile epileptic spasm syndrome was diagnosed in 20/60 (33%) of the cohort in a 12-month follow-up and 3 (5%) were lost to follow-up. The median age of developing hypsarrhythmia was 25 (7–53) weeks and clinical spasms at 24 (8–40) weeks. Three (5%) patients had clinical spasms without hypsarrhythmia, and 5 (8%) patients had hypsarrhythmia before clinical spasms at the initial presentation. The infants with high CSI (hazard ratio 2.5, 95% CI 1.2–5.2, P = 0.01) and high DFA α1 (hazard ratio 16, 95% CI 1.1–240, P = 0.04) at 2 months were more likely to develop hypsarrhythmia by the first year of age. There was a trend toward decreasing CSI and DFA α1 and increasing CVI in the first 8 months of age.ConclusionOur data suggest that relative sympathetic predominance at an early age of 2 months may be a potential predictor for developing IESS. Hence, early HRV patterns may provide valuable prognostic information in children at risk of IESS allowing early detection and optimization of cognitive outcomes. Whether early intervention to restore sympathovagal balance per se would provide clinical benefit must be addressed by future studies.

Perinatal brain injury is a leading cause of death and disability in children. Hypoxic-ischemic encephalopathy in full term infants, and white matter injury in premature infants are most known brain injury in perinatal period. Human umbilical cord blood mononuclear cells contain hematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells, lymphocytes, monocytes, and so on. Human umbilical cord blood mononuclear cells have many biological functions, such as nerve and vascular regeneration, anti-apoptosis, anti-inflammation, and immune regulation. Human umbilical cord blood mononuclear cells transplantation has achieved significant efficacy and safety in animal and clinical trials for the treatment of perinatal brain injury. We will review human umbilical cord blood mononuclear cells transplantation for perinatal brain injury in this review. [ABSTRACT FROM AUTHOR]

Perinatal brain injury occurs in 5.14/1000 live births in England. A significant proportion of these injuries result from hypoxic ischaemic encephalopathy (HIE) in term infants and intracranial haemorrhage (IVH) or periventricular leukomalacia (PVL) in preterm infants. Standardised care necessitates minimal handling from parents and professionals to reduce the progression of injury. This can potentially increase parental stress through the physical inability to bond with their baby. Recent research highlights the ability of music therapy (MT) to empower parental bonding without handling, through sharing culturally informed personal music with their infant. This review therefore aimed to systematically evaluate the use of MT with infants diagnosed with perinatal brain injury in a neonatal intensive care unit (NICU). Search terms were combined into three categories (audio stimulation (MT), population (neonates) and condition (brain injury), and eight electronic databases were used to identify relevant studies following PRISMA guidelines. Eleven studies using music or vocal stimulation with infants diagnosed with perinatal brain injury were identified and quality assessed using Cochrane ROB2, the ROBINSI Tool and the Newcastle Ottawa Scale. Studies used either voice as live (n = 6) or pre-recorded (n = 3) interventions or pre-recorded instrumental music (n = 2). Studies had two primary areas of focus: developmental outcomes and physiological effects. Results suggested the use of music interventions led to a reduction of infants' pain scores during procedures and cardiorespiratory events, improved feeding ability (increase oral feeding rate, volume intake and feeds per day) and resulted in larger amygdala volumes than control groups. Additionally, MT intervention on the unit supported long-term hospitalised infants in the acquisition of developmental milestones. Vocal soothing was perceived to be an accessible intervention for parents. However, infants with PVL showed signs of stress in complex interventions, which also potentially resulted in an increase in maternal anxiety in one study. MT with infants diagnosed with perinatal brain injury can have positive effects on infants' behavioural and neurological parameters and support parental involvement in their infants' developmental care. Further feasibility studies are required using MT to determine appropriate outcome measures for infants and the support required for parents to allow future comparison in large-scale randomised control trials. [ABSTRACT FROM AUTHOR]

The observation reveals the diagnostic capabilities of computed tomography to address issues arising in the implementation of forensic medical examinations. It considers a case of computed tomography used to determine the nature of brain injury in a 1-month-old baby. Cranial injuries detected by computed tomography had characteristic signs indicating the compression mechanism of causing brain injury. An interdisciplinary approach made it possible to exclude causes for a child's head injuries resulting from a fall.

Perinatal pathologies and foremost perinatal central nervous system injury are attended with delayed neurosomatic disorders frequently leading to disability. The success of realisation of individual compensation potential of every child depends on dynamics analysis of patient's condition on every survey stage, personalized choice of necessary and sufficient methods of polysystemic diseases correction. The contemporary view on ethiology and pathogenesis of main perinatal pathologies are presented in this review, main mechanisms of its development are also revealed. Recent non-invasive diagnostic technique allow to perform correction of vital signs and prevent cascade reactions of neuronal apoptosis. The sanogenetic importance of some therapeutic interventions (therapeutic hypothermia, erythropoietin, caffeine) is established in early neonatal period. The role of implementation of external factors causing epigenetic effects is clear: optimal nutrition, correction of intestinal microbiota, sensory and motional stimulation. The abilitation success depends largely on successive team activity of specialists and their collaboration with the family. Methods of multifactorial statistical analysis allow not only to prognosticate the outcomes of perinatal affection, but also to create effective mathematical models for personalized choice of facilitation measures.

The selection of an appropriate animal model is key to the production of results with optimal relevance to human disease. Particularly in the case of perinatal brain injury, a dearth of affected human neonatal tissue available for research purposes increases the reliance on animal models for insight into disease mechanisms. Improvements in obstetric and neonatal care in the past 20 years have caused the pathologic hallmarks of perinatal white matter injury (WMI) to evolve away from cystic necrotic lesions and toward diffuse regions of reactive gliosis and persistent myelin disruption. Therefore, updated animal models are needed that recapitulate the key features of contemporary disease. Here, we report a murine model of acute diffuse perinatal WMI induced through a two-hit inflammatory–hypoxic injury paradigm. Consistent with diffuse human perinatal white matter injury (dWMI), our model did not show the formation of cystic lesions. Corresponding to cellular outcomes of dWMI, our injury protocol produced reactive microgliosis and astrogliosis, disrupted oligodendrocyte maturation, and disrupted myelination.. Functionally, we observed sensorimotor and cognitive deficits in affected mice. In conclusion, we report a novel murine model of dWMI that induces a pattern of brain injury mirroring multiple key aspects of the contemporary human clinical disease scenario.

This comprehensive review focuses on our current understanding of the proposed physiological and pathological functions of extracellular vesicles (EVs) in the developing brain. Furthermore, since EVs have attracted great interest as potential novel cell-free therapeutics, we discuss advances in the knowledge of stem cell- and astrocyte-derived EVs in relation to their potential for protection and repair following perinatal brain injury. This review identified 13 peer-reviewed studies evaluating the efficacy of EVs in animal models of perinatal brain injury; 12/13 utilized mesenchymal stem cell-derived EVs (MSC-EVs) and 1/13 utilized astrocyte-derived EVs. Animal model, method of EV isolation and size, route, timing, and dose administered varied between studies. Notwithstanding, EV treatment either improved and/or preserved perinatal brain structures both macroscopically and microscopically. Additionally, EV treatment modulated inflammatory responses and improved brain function. Collectively this suggests EVs can ameliorate, or repair damage associated with perinatal brain injury. These findings warrant further investigation to identify the optimal cell numbers, source, and dosage regimens of EVs, including long-term effects on functional outcomes.

This comprehensive review focuses on our current understanding of the proposed physiological and pathological functions of extracellular vesicles (EVs) in the developing brain. Furthermore, since EVs have attracted great interest as potential novel cell-free therapeutics, we discuss advances in the knowledge of stem cell- and astrocyte-derived EVs in relation to their potential for protection and repair following perinatal brain injury. This review identified 13 peer-reviewed studies evaluating the efficacy of EVs in animal models of perinatal brain injury; 12/13 utilized mesenchymal stem cell-derived EVs (MSC-EVs) and 1/13 utilized astrocyte-derived EVs. Animal model, method of EV isolation and size, route, timing, and dose administered varied between studies. Notwithstanding, EV treatment either improved and/or preserved perinatal brain structures both macroscopically and microscopically. Additionally, EV treatment modulated inflammatory responses and improved brain function. Collectively this suggests EVs can ameliorate, or repair damage associated with perinatal brain injury. These findings warrant further investigation to identify the optimal cell numbers, source, and dosage regimens of EVs, including long-term effects on functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Institutional physiotherapy as a standard of care for management of cerebral palsy (CP) has certain shortcomings, especially in resource-constrained settings. This is a proof-of-concept trial to evaluate the efficacy of individualized home-centered activity-based therapy in children with spastic diplegic CP. Design: Randomized controlled trial (open-label). Settings: Tertiary-care hospital with pediatric neurology services (July, 2014 to July, 2016). Participants: Consecutive sample of 59 children (5–12 y) with spastic diplegic CP (Gross Motor Function Classification System scores II–III) without fixed lower-limb contractures, illnesses impeding physiotherapy or history of recent botulinum toxin injection/surgery were recruited. Procedure: Children were randomized to Intervention or Control arms. Their 6-minute-walk Test (6MWT) scoring and clinical examination were performed at baseline, 3 and 6 months. Children in Intervention arm (n=30) were prescribed parent-supervised home-centered activity-based therapy (walking, standing, squatting, climbing upstairs/downstairs, kicking a ball, dancing, riding a tricycle/bicycle) in addition to their institutional physiotherapy. Children in Control arm (n=29) were prescribed ongoing institutional physiotherapy alone. Logbooks, home videos and telephonic follow-ups were used to ensure compliance. Main outcome measures: Comparison of the mean change in 6MWT scores at 6 months (from baseline) between the two groups. Results: Median (IQR) change in 6MWT scores at 6 months (from baseline) in the Intervention and Control arms were 3.5 (−5.3, 9) m and 3 (−7.8, 6.3) m Conclusions: Adjunct home-centered activity-based therapy was safe and feasible, but did not result in appreciable gains over 6 months. [ABSTRACT FROM AUTHOR]

Perinatal brain injury is a significant cause of adverse neurodevelopmental outcomes. The objective of this systematic review was to identify patterns of altered brain function, quantified using functional connectivity (FC) changes in resting-state fMRI (rs-fMRI) data, that were associated with motor and language outcomes in individuals with a history of perinatal brain injury. A systematic search using electronic databases was conducted to identify relevant studies. A total of 10 studies were included in the systematic review, representing 260 individuals with a history of perinatal brain injury. Motor and language outcomes were measured at time points ranging from 4 months to 29 years 1 month. Relations between FC and motor measures revealed increased intra-hemispheric FC, reduced inter-hemispheric FC and impaired lateralization of motor-related brain regions associated with motor outcomes. Altered FC within sensorimotor, visual, cerebellum and frontoparietal networks, and between sensorimotor, visual, auditory and higher-order networks, including cerebellum, frontoparietal, default-mode, salience, self-referential and attentional networks were also associated with motor outcomes. In studies assessing the relationship between rs-fMRI and language outcome, reduced intra-hemispheric FC, increased inter-hemispheric FC and right-hemisphere lateralization of language-related brain regions correlated with language outcomes. Evidence from this systematic review suggests a possible association between diaschisis and motor and language impairments in individuals after perinatal brain lesions. These findings support the need to explore the contributions of additional brain regions functionally connected but remote from the primary lesioned brain area for targeted treatments and appropriate intervention, though more studies with increased standardization across neuroimaging and neurodevelopmental assessments are needed. • Impaired functional connectivity of motor and language brain regions was associated with motor and language outcomes. • Altered functional connectivity of primary and higher-order resting-state networks were associated with motor outcomes. • A possible association between diaschisis and motor and language impairments emerged. • This review supports the need to explore brain regions functionally connected but remote from the primary lesioned area. [ABSTRACT FROM AUTHOR]

The perinatal period represents a time of great vulnerability for the developing brain. A variety of injuries can result in death or devastating injury causing profound neurocognitive deficits. Hypoxic-ischemic neonatal encephalopathy (HIE) remains the leading cause of brain injury in term infants during the perinatal period with limited options available to aid in recovery. It can result in long-term devastating consequences with neurologic complications varying from mild behavioral deficits to severe seizure, intellectual disability, and/or cerebral palsy in the newborn. Despite medical advances, the only viable option is therapeutic hypothermia which is classified as the gold standard but is not used, or may not be as effective in preterm cases, infection-associated cases or low resource settings. Therefore, alternatives or adjunct therapies are urgently needed. Ongoing research continues to advance our understanding of the mechanisms contributing to perinatal brain injury and identify new targets and treatments. Drugs used for the treatment of patients with type 2 diabetes mellitus (T2DM) have demonstrated neuroprotective properties and therapeutic efficacy from neurological sequelae following HIE insults in preclinical models, both alone, or in combination with induced hypothermia. In this short review, we have focused on recent findings on the use of diabetes drugs that provide a neuroprotective effect using in vitro and in vivo models of HIE that could be considered for clinical translation as a promising treatment.

The objective of this study was to determine if mouse bone marrow-derived mesenchymal stem cells (BMMSCs) ameliorate preterm birth and perinatal brain injury induced by intrauterine inflammation (IUI). A mouse model of IUI-induced perinatal brain injury at embryonic (E) day 17 was utilized. BMMSCs were derived from GFP-transgenic mice and phenotypically confirmed to be CD44+, Sca-1+, CD45−, CD34−, CD11b−, and CD11c− by flow cytometry and sorted by fluorescence-activated cell sorting (FACS). Dams were assigned to four groups: phosphate-buffered saline (PBS) + PBS, PBS + BMMSCs, lipopolysaccharide (LPS) + PBS, and LPS + BMMSCs. Following maternal IUI, there was a significant increase in CD8+ T cells in the placentas. Maternally administered BMMSCs trafficked to the fetal side of the placenta and resulted in significantly decreased placental CD8+ T cells. Furthermore, fetal trafficking of maternally administered BMMSCs correlated with an improved performance on offspring neurobehavioral testing in LPS + BMMSC group compared with LPS + PBS group. Our data support that maternal administration of BMMSCs can alleviate perinatal inflammation-induced brain injury and improve neurobehavioral outcomes in the offspring via CD8+ T cell immunomodulation at the feto-placental interface. [ABSTRACT FROM AUTHOR]

Problem: Systemic maternal inflammation is associated with adverse neonatal sequelae. We tested the hypothesis that IL‐1β is a key inflammatory regulator of adverse pregnancy outcomes. Method of study: Pregnant mice were treated with intraperitoneal injections of IL‐1β (0, 0.1, 0.5, or 1 μg) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL‐1β signaling markers. Results: As compared with non‐treated dams, maternal injections with IL‐1β resulted in increased p‐NF‐κB and caspase‐1 in placentas and fetal brains, but not consistently in spleens, suggesting induction of intrinsic IL‐1β production. These findings were confirmed by increased levels of IL‐1β in the placentas of the IL‐1β‐treated dams. Systemic treatment of dams with IL‐1β suppressed Stat1 signaling. Maternal inflammation caused by IL‐1β treatment reduced fetal viability to 80.6% and 58.9%, in dams treated with either 0.5 or 1 μg of IL‐1β, respectively. In the placentas, there was an IL‐1β dose‐dependent distortion of the labyrinth structure, decreased numbers of mononuclear trophoblast giant cells, and reduced proportions of endothelial cells as compared to placentas from control dams. In fetal brains collected at E17, there was an IL‐1β dose‐dependent reduction in cortical neuronal morphology. Conclusion: This work demonstrates that systemic IL‐1β injection causes dose‐dependent structural and functional changes in the placenta and fetal brain. [ABSTRACT FROM AUTHOR]

The perinatal period represents a time of great vulnerability for the developing brain. A variety of injuries can result in death or devastating injury causing profound neurocognitive deficits. Hypoxic-ischemic neonatal encephalopathy (HIE) remains the leading cause of brain injury in term infants during the perinatal period with limited options available to aid in recovery. It can result in long-term devastating consequences with neurologic complications varying from mild behavioral deficits to severe seizure, intellectual disability, and/or cerebral palsy in the newborn. Despite medical advances, the only viable option is therapeutic hypothermia which is classified as the gold standard but is not used, or may not be as effective in preterm cases, infection-associated cases or low resource settings. Therefore, alternatives or adjunct therapies are urgently needed. Ongoing research continues to advance our understanding of the mechanisms contributing to perinatal brain injury and identify new targets and treatments. Drugs used for the treatment of patients with type 2 diabetes mellitus (T2DM) have demonstrated neuroprotective properties and therapeutic efficacy from neurological sequelae following HIE insults in preclinical models, both alone, or in combination with induced hypothermia. In this short review, we have focused on recent findings on the use of diabetes drugs that provide a neuroprotective effect using in vitro and in vivo models of HIE that could be considered for clinical translation as a promising treatment. [ABSTRACT FROM AUTHOR]

Abstract Background It is well understood that hypoxic-ischemic (HI) brain injury during the highly vulnerable perinatal period can lead to cerebral palsy, the most prevalent cause of chronic disability in children. Recently, human clinical trials have reported safety and some efficacy following treatment of cerebral palsy using umbilical cord blood (UCB) cells. UCB is made up of many different cell types, including endothelial progenitor cells (EPCs), T regulatory cells (Tregs), and monocyte-derived suppressor cells (MDSCs). How each cell type contributes individually towards reducing neuroinflammation and/or repairing brain injury is not known. In this study, we examined whether human (h) UCB, or specific UCB cell types, could reduce peripheral and cerebral inflammation, and promote brain repair, when given early after perinatal HI brain injury. Methods HI brain injury was induced in postnatal day (PND) 7 rat pups and cells were administered intraperitoneally on PND 8. Behavioral testing was performed 7 days post injury, and then, brains and spleens were collected for analysis. Results We found in vitro that all UCB cell types, except for EPCs, were immunomodulatory. Perinatal HI brain injury induced significant infiltration of CD4+ T cells into the injured cerebral hemisphere, and this was significantly reduced by all hUCB cell types tested. Compared to HI, UCB, Tregs, and EPCs were able to reduce motor deficits, reduce CD4+ T cell infiltration into the brain, and reduce microglial activation. In addition to the beneficial effects of UCB, EPCs also significantly reduced cortical cell death, returned CD4+ T cell infiltration to sham levels, and reduced the peripheral Th1-mediated pro-inflammatory shift. Conclusion This study highlights that cells found in UCB is able to mediate neuroinflammation and is an effective neuroprotective therapy. Our study also shows that particular cells found in UCB, namely EPCs, may have an added advantage over using UCB alone. This work has the potential to progress towards tailored UCB therapies for the treatment of perinatal brain injury.

Brain injury resulting from birth asphyxia-related hypoxia-ischemia (HI) is associated with the development of cerebral palsy and cognitive deficits in those who survive such injuries (Zhang et al., [16]). Perinatal brain injury causes developmental impairment and permanent neurological deficits such as cerebral palsy, autism, and intellectual disability in children, and these are major burdens to those afflicted, their families, and society as a whole. Perinatal brain injury, white matter injury, neuroprotection, cerebral palsy, autism, intellectual disability, cell death, preterm birth Keywords: perinatal brain injury; white matter injury; neuroprotection; cerebral palsy; autism; intellectual disability; cell death; preterm birth EN perinatal brain injury white matter injury neuroprotection cerebral palsy autism intellectual disability cell death preterm birth 1 3 3 10/14/21 20211011 NES 211011 Brain injuries during the perinatal period - resulting from encephalopathy-related asphyxia, prematurity, fetal growth restriction, antenatal toxicity exposure, neonatal stroke, systemic infections, and metabolic abnormalities - are a significant cause of adverse neurodevelopmental outcomes, and such injuries occur at different times during the perinatal period and in different clinical settings (Leaw et al., [4]). [Extracted from the article]

Pediatric traumatic brain injury (TBI) remains a leading cause of childhood morbidity and mortality worldwide. Most efforts to reduce the chronic impact of pediatric TBI involve prevention and minimization of secondary injury. Currently, no treatments are used in routine clinical care during the acute and subacute phases to actively repair injury to the developing brain. The endogenous pluripotent cytokine erythropoietin (EPO) holds promise as an emerging neuroreparative agent in perinatal brain injury (PBI). EPO signaling in the central nervous system (CNS) is essential for multiple stages of neurodevelopment, including the genesis, survival and differentiation of multiple lineages of neural cells. Postnatally, EPO signaling decreases markedly as the CNS matures. Importantly, high-dose, extended EPO regimens have shown efficacy in preclinical controlled cortical impact (CCI) models of infant TBI at two different, early ages by independent research groups. Specifically, extended high-dose EPO treatment after infantile CCI prevents long-term cognitive deficits in adult rats. Because of the striking differences in the molecular and cellular responses to both injury and recovery in the developing and mature CNS, and the excellent safety profile of EPO in infants and children, extended courses of EPO are currently in Phase III trials for neonates with PBI. Extended, high-dose EPO may also warrant testing for infants and young children with TBI. [ABSTRACT FROM AUTHOR]

We have studied peculiarities of P-glycoprotein (Pgp) expressionon neuronal, astroglial and endothelial cells in newborn rats (P10)underwent perinatal hypoxic-ischemic brain damage. Expressionof Pgp was markedly elevated in all the cells tested reaching thehighest levels in astrocytes (4 hrs after injury) followed by increasedlevels in neuronal and endothelial cells (12 hrs after injury). Thepossible role of Pgp in pathogenesis of perinatal brain injury is discussed.

Perinatal brain injury or neonatal encephalopathy (NE) is a state of disturbed neurological function in neonates, caused by a number of different aetiologies. The most prominent cause of NE is hypoxic ischaemic encephalopathy, which can often induce seizures. NE and neonatal seizures are both associated with poor neurological outcomes, resulting in conditions such as cerebral palsy, epilepsy, autism, schizophrenia and intellectual disability. The current treatment strategies for NE and neonatal seizures have suboptimal success in effectively treating neonates. Therapeutic hypothermia is currently used to treat NE and has been shown to reduce morbidity and has neuroprotective effects. However, its success varies between developed and developing countries, most likely as a result of lack of sufficient resources. The first-line pharmacological treatment for NE is phenobarbital, followed by phenytoin, fosphenytoin and lidocaine as second-line treatments. While these drugs are mostly effective at halting seizure activity, they are associated with long-lasting adverse neurological effects on development. Over the last years, inflammation has been recognized as a trigger of NE and seizures, and evidence has indicated that this inflammation plays a role in the long-term neuronal damage experienced by survivors. Researchers are therefore investigating the possible neuroprotective effects that could be achieved by using anti-inflammatory drugs in the treatment of NE. In this review we will highlight the current knowledge of the inflammatory response after perinatal brain injury and what we can learn from animal models.

Rabbit kits after global antenatal hypoxic-ischemic injury exhibit motor deficits similar to humans with cerebral palsy. We tested several mechanisms previously implicated in spinal hyper-excitability after perinatal brain injury that may explain muscle hypertonia in newborns. Stiffness of hind limb muscles during passive stretch, electromyogram, and spinal excitability by Hoffman reflex, were assessed in rabbit kits with muscle hypertonia after global hypoxic-ischemic brain injury and naïve controls. Affected muscle architecture, motoneuron morphology, primary afferents density, gliosis, and KCC2 expression transporter in the spinal cord were also examined. Decrease knee stiffness after anesthetic administration was larger, but residual stiffness was higher in hypertonic kits compared to controls. Hypertonic kits exhibited muscle shortening and atrophy, in both agonists and antagonists. Sarcomere length was longer in tibialis anterior in hypertonic kits than in controls. Hypertonic kits had decreased rate dependent depression and increased Hmax/Mmax in H-reflex. Motor neuron soma sizes, primary afferent density were not different between controls and hypertonic kits. Length of dendritic tree and ramification index were lower in hypertonic group. Gene expression of KCC2 was lower in hypertonic kits, but protein content was not different between the groups. In conclusion, while we found evidence of decreased supraspinal inhibitory control and increased excitability by H-reflex that may contribute to neuronal component in hypertonia, increased joint resistance to stretch was explained predominantly by changes in passive properties of muscles and joints. We did not find structural evidence of increased sensory afferent input or morphological changes in motoneurons that might explain increased excitability. Gliosis, observed in spinal gray matter, may contribute to muscle hypertonia.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia–ischemia (HI). We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To assess the role of TWEAK signaling after HI, the size of the injury was measured in neonatal mice genetically deficient in Fn14 and compared with their wild-type and heterozygote littermates. A significant sex difference in the Fn14 knockout (KO) animals was observed. Fn14 gene KO was beneficial in females; conversely, reducing Fn14 expression exacerbated the brain injury in male mice. Our findings indicate that the TWEAK/Fn14 pathway is critical for development of hypoxic–ischemic brain injury in immature animals. However, as the responses are different in males and females, clinical implementation depends on development of sex-specific therapies.

Rabbit kits after global antenatal hypoxic-ischemic injury exhibit motor deficits similar to humans with cerebral palsy. We tested several mechanisms previously implicated in spinal hyper-excitability after perinatal brain injury that may explain muscle hypertonia in newborns. Stiffness of hind limb muscles during passive stretch, electromyogram, and spinal excitability by Hoffman reflex, were assessed in rabbit kits with muscle hypertonia after global hypoxic-ischemic brain injury and naïve controls. Affected muscle architecture, motoneuron morphology, primary afferents density, gliosis, and KCC2 expression transporter in the spinal cord were also examined. Decrease knee stiffness after anesthetic administration was larger, but residual stiffness was higher in hypertonic kits compared to controls. Hypertonic kits exhibited muscle shortening and atrophy, in both agonists and antagonists. Sarcomere length was longer in tibialis anterior in hypertonic kits than in controls. Hypertonic kits had decreased rate dependent depression and increased Hmax/Mmax in H-reflex. Motor neuron soma sizes, primary afferent density were not different between controls and hypertonic kits. Length of dendritic tree and ramification index were lower in hypertonic group. Gene expression of KCC2 was lower in hypertonic kits, but protein content was not different between the groups. In conclusion, while we found evidence of decreased supraspinal inhibitory control and increased excitability by H-reflex that may contribute to neuronal component in hypertonia, increased joint resistance to stretch was explained predominantly by changes in passive properties of muscles and joints. We did not find structural evidence of increased sensory afferent input or morphological changes in motoneurons that might explain increased excitability. Gliosis, observed in spinal gray matter, may contribute to muscle hypertonia. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The majority of brain injuries that lead to cerebral palsy, developmental disability, and mental health disorders have their onset in utero. These lifelong conditions come with great economic and emotional burden as they impact function in nearly all domains of affected individuals' lives. Unfortunately, current therapeutic options are limited. There remains a focus on rescue, rehabilitation, and regeneration after the injury has occurred, rather than aiming to prevent the initial injury. Prevention would imply treating the mother during pregnancy to alter the fetal environment and in turn, treat the fetus. Fear of harming the developing fetus remains as a result of errors of the past such as the release of thalidomide. In this review, we outline evidence from animal studies and clinical trials that have explored maternal dietary supplementation with natural health products (including nutraceuticals and functional foods) for perinatal brain injury prevention. Namely, we discuss magnesium sulphate, creatine, choline, melatonin, resveratrol and broccoli sprouts/sulforaphane. Although clinical trials have only been completed in this realm for magnesium sulphate, results in animal models have been promising, suggesting that this is a productive avenue for further research. Natural health products may provide safe, effective, affordable, and easily accessible prevention of fetal brain injury and resulting lifelong disabilities. [ABSTRACT FROM AUTHOR]

Highlights • Sub-chronic maternal IL-1β administration is presented as a novel model of inflammation. • Sub-chronic maternal inflammation adversely affects offspring neurobehavior. • Inflammation-induced changes in placental T cell trafficking implicated in offspring outcomes. Abstract Interleukin-1 beta (IL-1β) is a cytokine mediator of perinatal brain injury. The effect of sub-chronic systemic IL-1β exposure in perinatal and offspring outcomes is unclear. The aim of this study was to examine the effects of maternal IL-1β exposure on pregnancy and offspring outcomes. At E15, CD1 dams were allocated to receive intraperitoneal injection of phosphate buffered saline or mouse recombinant IL-1β (1 mcg) for four consecutive days. We analyzed pup survival and neurobehavioral status. At E18, placental H&E staining and fetal brain Nissl staining was performed. Placental gene expression was analyzed by qPCR and T cell infiltration was analyzed by flow cytometry. Effects of inflammation on feto-placental blood flow were analyzed by Doppler ultrasonography. IL-1β decreased pup survival (P <.0001) and adversely affected offspring performance on neurodevelopmental tests (P <.05). Placentas of exposed dams exhibited significant thinning of maternal and fetal sides, and fetal brain exhibited cortical thinning. Placental qPCR analysis revealed significant upregulation of NFκB2 (P =.0021) and CXCL11 (P =.0401). While maternal IL-1β exposure did not affect feto-placental blood flow, placental flow cytometry showed an increase in placental infiltration of CD4+ T cells at 24 h post-injection (hpi, P <.0001) and CD8+ T cells at 72 hpi (P =.0217). Maternal sub-chronic, systemic inflammation with IL-1β decreased pup survival and played a key role in perinatal brain injury. The mechanisms behind these outcomes may involve immune system activation and alterations in placental T cell trafficking. [ABSTRACT FROM AUTHOR]

The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury. Using a constitutive conditional knockout of all activin receptor signaling in oligodendrocyte lineage cells, we discovered this signaling to be required for myelination via regulation of oligodendrocyte differentiation and myelin compaction. These processes were found to be dependent on the activin receptor subtype Acvr2a, which is expressed during oligodendrocyte differentiation and axonal ensheathment in development and following myelin injury. During efficient myelin regeneration, Acvr2a upregulation was seen to coincide with downregulation of Acvr2b, a receptor subtype with relatively higher ligand affinity; Acvr2b was shown to be dispensable for activin receptor-driven oligodendrocyte differentiation and its overexpression was sufficient to impair the abovementioned ligand-driven responses. In actively myelinating or remyelinating areas of human perinatal brain injury and multiple sclerosis tissue, respectively, oligodendrocyte lineage cells expressing Acvr2a outnumbered those expressing Acvr2b, whereas in non-repairing lesions Acvr2b+ cells were increased. Thus, we propose that following human white matter injury, this increase in Acvr2b expression would sequester ligand and consequently impair Acvr2a-driven oligodendrocyte differentiation and myelin formation. Our results demonstrate dysregulated activin receptor signaling in common myelin disorders and reveal Acvr2a as a novel therapeutic target for myelin generation following injury across the lifespan. [ABSTRACT FROM AUTHOR]