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Hypoxic‐ischemic encephalopathy (HIE) is a common neurological syndrome in newborns with high mortality and morbidity. Therapeutic hypothermia (TH), which is standard of care for HIE, mitigates brain injury by suppressing anaerobic metabolism. However, more than 40% of HIE neonates have a poor outcome, even after TH. This study aims to provide metabolic biomarkers for predicting the outcomes of hypoxia‐ischemia (HI) after TH using hyperpolarized [1‐13C] pyruvate magnetic resonance spectroscopy. Postnatal day 10 (P10) mice with HI underwent TH at 1 h and were scanned at 6–8 h (P10), 24 h (P11), 7 days (P17), and 21 days (P31) post‐HI on a 14.1‐T NMR spectrometer. The metabolic images were collected, and the conversion rate from pyruvate to lactate and the ratio of lactate to pyruvate in the injured left hemisphere (kPL(L) and Lac/Pyr(L), respectively) were calculated at each timepoint. The outcomes of TH were determined by the assessments of brain injury on T2‐weighted images and behavioral tests at later timepoint. kPL(L) and Lac/Pyr(L) over time between the good‐outcome and poor‐outcome groups and across timepoints within groups were analyzed. We found significant differences in temporal trends of kPL(L) and Lac/Pyr(L) between groups. In the good‐outcome group, kPL(L) increased until P31 with a significantly higher value at P31 compared with that at P10, while the level of Lac/Pyr(L) at P31 was notably higher than those at all other timepoints. In the poor‐outcome group, kPL(L) and Lac/Pyr(L) increased within 24 h. The kPL(L) value at P11 was considerably higher compared with P10. Discrete temporal changes of kPL(L) and Lac/Pyr(L) after TH between the good‐outcome and poor‐outcome groups were seen as early as 24 h after HI, reflecting various TH effects on brain anaerobic metabolism, which may provide insights for early screening for response to TH. [ABSTRACT FROM AUTHOR]

Recent insights into the frequency of occurrence and the genetic and mechanistic basis of nervous system disease have demonstrated that neurologic disorders occur as a spectrum across all ages. To meet future needs of patients with neurologic disease of all ages and prepare for increasing implementaton of precision therapies, greater integration of child and adult neurology residency training is needed. ANN NEUROL 2023;94:1005–1007 [ABSTRACT FROM AUTHOR]

Objective: Although most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology. Methods: We retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video‐EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic–ischemic encephalopathy. Results: Twenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p <.001). Sodium channel‐blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy. Significance: Seizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by sodium channel‐blocking antiseizure medications. [ABSTRACT FROM AUTHOR]

Premature birth globally affects about 11.1% of all newborns and is a risk factor for neurodevelopmental disability in surviving infants. Histology has suggested that hindbrain subdivisions grow differentially, especially in the third trimester. Prematurity-related brain injuries occurring in this period may selectively affect more rapidly developing areas of hindbrain, thus accompanying region-specific impairments in growth and ultimately neurodevelopmental deficits. The current study aimed to quantify regional growth of the cerebellum and the brainstem in preterm neonates ( n = 65 with individually multiple scans). We probed associations of the regional volumes with severity of brain injury. In neonates with no imaging evidence of injury, our analysis using a mixed-effect linear model showed faster growth in the pons and the lateral convexity of anterior/posterior cerebellar lobes. Different patterns of growth impairment were found in relation to early cerebral intraventricular hemorrhage and cerebellar hemorrhage ( P < 0.05), likely explaining different mechanisms through which neurogenesis is disrupted. The pattern of cerebellar growth identified in our study agreed excellently with details of cerebellar morphogenesis in perinatal development, which has only been observed in histological data. Our proposed analytic framework may provide predictive imaging biomarkers for neurodevelopmental outcome, enabling early identification and treatment of high-risk patients. Hum Brain Mapp 37:678-688, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Neonatal brain injury, caused by perinatal hypoxia-ischemia and extreme prematurity, remains a great challenge for prevention and treatment. There is no effective treatment for term hypoxic-ischemic encephalopathy (HIE) except hypothermia which by itself does not afford complete neuroprotection. Erythropoietin (EPO), a pleiotropic cytokine, has neuroprotective effects in a series of neonatal experimental models and recent clinical trials of HIE. However, the mechanisms, dosing, and the toxicity of EPO in these settings are inconsistently reported. This review will focus on the possible mechanisms, recent clinical advances and potential complications of EPO used in research and the clinic. In addition, optimal dose and administrative routes of EPO, and novel EPO mimetics will be discussed. [Copyright &y& Elsevier]

Why do cells in the central nervous system respond differently to different stressors and why is this response so age-dependent? In the immature brain, there are regions of selective vulnerability that are predictable and depend on the age when the insult occurs and the severity of the insult. This damage is both region and cell population specific. Vulnerable cell populations include the subplate neurons and oligodendrocyte precursors early in development and the neurons closer to the end of human gestation. Mechanisms of injury include excitotoxicity, oxidative stress and inflammation as well as accelerated apoptosis. Advanced imaging techniques have shown us particular patterns of injury according to age at insult. These changes seen in the newborn at the time of injury on magnetic resonance imaging correlate well with the neurodevelopmental outcome. New questions about how the injury evolves and how the newborn brain adapts and repairs itself have emerged as we now know that injury in the newborn brain can evolve over days and weeks, rather than hours. The ability to follow these processes has allowed us to investigate the role of repair in attenuating the injury. Neurogenesis and angiogenesis exist in response to ischemic injury and can be enhanced by processes that are known to protect the brain. The injury response in the developing brain is a complex process that evolves over time and is amenable to repair. [ABSTRACT FROM AUTHOR]

Abstract: The blood–brain barrier (BBB) plays an important role in the pathophysiology of central nervous system (CNS) disorders such as stroke and hypoxic–ischemic brain injury. Vascular endothelial growth factor (VEGF) is involved in angiogenesis and vasogenic edema during stroke and hypoxia. However, the role of VEGF in BBB permeability after hypoxia has not been fully elucidated. We therefore investigated VEGF effects in an in vitro BBB model using rbcec4 endothelial cell line with the stimulation of VEGF or hypoxia. In this study, BBB permeability was studied using 14C-sucrose detection. The expression of BBB tight junction protein ZO-1, and the expression and phosphorylation of vasodilator stimulated phosphoprotein (VASP), VEGF and VEGF receptor 2 (VEGFR2) were determined using fluorescent immunocytochemistry and western blot analyses. We found that hypoxia upregulated VEGF expression, and VEGF increased BBB permeability. Hypoxia also increased VASP phosphorylation, which was mediated, in part, through VEGFR2. We also found that VASP at tight junctions was co-localized with ZO-1 in cell–cell contacts. Our findings show that VASP phosphorylation is affected by hypoxia and VEGFR2 inhibition suggesting a role for VASP in BBB permeability. [ABSTRACT FROM AUTHOR]

Aim: To report findings about the Motor Performance Checklist (MPC) for 5-year-olds, a simple 12-item instrument for assessing gross and fine motor skills, in a research study of neurodevelopmental outcomes after neonatal events. Methods: We trained 10 examiners to use the MPC in a study of the outcomes of neonatal jaundice and dehydration in 339 5-year-old children. We compared MPC scores with those on the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), the Beery–Buktenica Developmental Test of Visual-Motor Integration-Fourth Edition (VMI-4), and a standard neurological examination, and compared failure rates on each MPC item across examiners. Parent concerns about their child’s development were addressed using the Parent Evaluation of Developmental Status (PEDS). Results: Children who ‘failed’ the MPC had 7–10 points lower mean scores on the WPPSI-R subscales ( P = 0.001), 9–10 points lower mean scores on the VMI-4 subscales ( P = 0.001), and were almost twice as likely to have a ‘questionable’ neurological examination score (adjusted OR 1.86, 95% CI 1.00–3.53, P = 0.005). On the PEDS, only the concern about the use of arms and hands was significantly associated with MPC failure. We found significant sex differences on four of the 12 MPC items. We also found differences in failure rates by different examiners. Conclusions: MPC scores correlated with other measures of neurodevelopment. Because of different failure rates across examiners, examiner terms need to be included if it is used in research studies. [ABSTRACT FROM AUTHOR]

Objective Mice subjected to traumatic brain injury at postnatal day 21 show emerging cognitive deficits that coincide with hippocampal neuronal loss. Here we consider glutathione peroxidase (GPx) activity as a determinant of recovery in the injured immature brain. Methods Wild-type and transgenic (GPxTg) mice overexpressing GPx were subjected to traumatic brain injury or sham surgery at postnatal day 21. Animals were killed acutely (3 or 24 hours after injury) to assess oxidative stress and cell injury in the hippocampus or 4 months after injury after behavioral assessments. Results In the acutely injured brains, a reduction in oxidative stress markers including nitrotyrosine was seen in the injured GPxTg group relative to wild-type control mice. In contrast, cell injury, with marked vulnerability in the dentate gyrus, was apparent despite no differences between genotypes. Magnetic resonance imaging demonstrated an emerging cortical lesion during brain maturation that was also indistinguishable between injured genotypes. Stereological analyses of cortical volumes likewise confirmed no genotypic differences between injured groups. However, behavioral tests beginning 3 months after injury demonstrated improved spatial memory learning in the GPxTg group. Moreover, stereological analysis within hippocampal subregions demonstrated a significantly greater number of neurons within the dentate of the GPx group. Interpretation Our results implicate GPx in recovery of spatial memory after traumatic brain injury. This recovery may be attributed, in part, to a reduction in early oxidative stress and selective, long-term sparing of neurons in the dentate. Ann Neurol 2009;65:540-549 [ABSTRACT FROM AUTHOR]

Objective: Neonatal stroke is associated with the N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxic brain injury. Src family kinases (SFKs) are considered to be the molecular hub for NMDAR regulation. We determined the relationship between SFKs activation and NMDAR tyrosine phosphorylation after neonatal hypoxia-ischemia (HI) and investigated the neuroprotective potential of a selective SFKs inhibitor, PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3, 4-d] pyramidine), against neonatal brain ischemic injury.Methods: The Rice-Vannucci model was adapted for neonatal HI injury in postnatal day 7 CD1 mice. SFKs activity in the postsynaptic densities was measured by Western blot. NMDAR tyrosine phosphorylation and their association with SFKs were determined by coimmunoprecipitation. Brains from animals treated with PP2 or its inactive analog, PP3, were examined histologically with cresyl violet and iron stain to assess the degree of damage.Results: Neonatal HI resulted in a rapid and transient increase in tyrosine phosphorylation of NMDAR subunits NR2A and NR2B. This upregulation correlated with the enhanced association of Fyn and Src with NR2A and NR2B. SFKs were activated in the postsynaptic densities after HI. Inhibition of SFKs with PP2 attenuated brain injury after neonatal HI, whereas PP3 did not protect the brain from the HI insult.Interpretation: SFKs may play an important role in NMDAR-mediated excitotoxicity and downstream events leading to neuronal death after neonatal HI. Inhibition of SFKs may provide protection against neonatal stroke. Rather than blockade of NMDAR after HI in the developing brain, it may be safer and more beneficial to manipulate components of the NMDAR signaling complex at the postsynaptic density. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress is a critical component of the injury response to hypoxia-ischemia (HI) in the neonatal brain, and this response is unique and at times paradoxical to that seen in the mature brain. Previously, we showed that copper-zinc superoxide-dismutase (SOD1) over-expression is not beneficial to the neonatal mouse brain with HI injury, unlike the adult brain with ischemic injury. However, glutathione peroxidase 1 (GPx1) over-expression is protective to the neonatal mouse brain with HI injury. To further test the hypothesis that an adequate supply of GPx is critical to protection from HI injury, we crossed SOD1 over-expressing mice (hSOD-tg) with GPx1 over-expressing mice (hGPx-tg). Resulting litters contained wild-type (wt), hGPx-tg, hSOD-tg and hybrid hGPx-tg/hSOD-tg pups, which were subjected to HI at P7. Confirming previous results, the hGPx-tg mice had reduced injury compared to both Wt and hSOD-tg littermates. Neonatal mice over-expressing both GPx1 and SOD1 also had less injury compared to wt or hSOD-tg alone. A result of oxidative stress after neonatal HI is a decrease in the concentration of reduced (i.e. antioxidant-active) glutathione (GSH). In this study, we tested the effect of systemic administration of α-lipoic acid on levels of GSH in the cortex after HI. Although GSH levels were restored by 24h after HI, injury was not reduced compared to vehicle-treated mice. We also tested two other pharmacological approaches to reducing oxidative stress in hSOD-tg and wild-type littermates. Both the specific inhibitor of neuronal nitric oxide synthase, 7-nitroindazole (7NI), and the spin-trapping agent alpha-phenyl-tert-butyl-nitrone (PBN) did not reduce HI injury, however. Taken together, these results imply that H2O2 is a critical component of neonatal HI injury, and GPx1 plays an important role in the defense against this H2O2 and is thereby neuroprotective. [Copyright &y& Elsevier]

This supplement deals with the definition and classification of cerebral palsy (CP). The disease was predominantly studied in relation to pathology and aetiology of the impairment. But it was during the 19th century that the discussion on the definition of CP was first recorded in medical literature. A lecture of English orthopaedic surgeon William Little in 1843 has elucidated the seminal work describing CP. In the 1940s and 1950s, Myer Perlstein, an American neurologist, recounted methods for classifying CP children.

Desferrioxamine inhibits cortical necrosis in neonatal rats with experimental pneumococcal meningitis, suggesting that iron-induced oxidative damage might be responsible for neuronal damage. We therefore examined the spatial and temporal profile of changes in cortical iron and iron homeostatic proteins during pneumococcal meningitis. Infection was associated with a steady and global increase of non-haem iron in the cortex, particularly in neuronal cell bodies of layer II and V, and in capillary endothelial cells. The non-haem iron increase was associated with induction of haem oxygenase (HO)-1 in neurones, microglia and capillary endothelial cells, whereas HO-2 levels remained unchanged, suggesting that the non-haem iron increase might be the result of HO-1-mediated haem degradation. Indeed, treatment with the haem oxygenase inhibitor tin protoporphyrin (which completely blocked the accumulation of bilirubin detected in HO-1-positive cells) completely prevented the infection-associated non-haem iron increase. The same cells also displayed markedly increased ferritin staining, the increase of which occurred independently of HO activity. At the same time, no increase in DNA/RNA oxidation was observed in infected animals (as assessed by in situ detection of 8-hydroxy[deoxy]guanosine), strongly suggesting that ferritin up-regulation protected the brain from iron-induced oxidative damage. Thus, although pneumococcal meningitis leads to an increase of cortical non-haem iron, protective mechanisms up-regulated in parallel prevent iron-induced oxidative damage. Cortical damage does not appear to be a direct consequence of increased iron, therefore. [ABSTRACT FROM AUTHOR]

Brain injury evolves over time, often taking days or even weeks to fully develop. It is a dynamic process that involves immediate oxidative stress and excitotoxicity followed by inflammation and preprogrammed cell death. This article presents a brief overview of mechanisms of neuroprotection in the developing brain. Although the focus is on ischemic injury, the conclusions drawn apply to any type of brain insult—epileptic seizures, trauma, or ischemia. Strategies of neuroprotection include salvaging neurons through the use of targeted pharmacotherapies, protecting neurons through preconditioning, and repairing neurons by enhancing neurogenesis. Drug therapies that dampen the impact of immediate and downstream postinjury events are only modestly effective in protecting the brain from ischemic injury. In experimental models, complete or true protection can be achieved only through preconditioning, a process during which an animal develops tolerance to an otherwise lethal stressor. Although of no clinical use, preconditioning models have provided valuable insight into how repair systems work in the brain. Cumulative evidence indicates that the same genes that are upregulated during preconditioning, those mediating true protection, are also upregulated during injury and repair. Specifically, hypoxic preconditioning and hypoxic-ischemic insult have been shown to induce hypoxia inducible factor-1 (HIF-1) and its target survival genes, vascular endothelial growth factor (VEGF), and erythropoietin (Epo) in rodents. Of particular interest is the upregulation of Epo, a growth factor that may have therapeutic potential in the treatment of ischemic stroke. At this time, however, the postinjury enhancement of neurogenesis appears to offer the best hope for long-lasting functional recovery following brain injury. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the feasibility of performing diffusion tensor tractography (DTT) to map and quantify the pyramidal white matter tracts of premature newborns. Materials and Methods Fourteen diffusion tensor MRI (DTI) examinations of nine premature newborns were evaluated. DTT was performed to segment bilateral pyramidal tracts, using a fiber-tracking algorithm originating in the cerebral peduncle (CP) and filtering through the posterior limb of the internal capsule (PLIC) and precentral gyrus (PCG). Voxels containing the resulting tracts were then used for quantitation of DTI parameters along the tract. The DTT-based tract measurements were compared with standard manually placed region-of-interest (ROI) measurements at four locations along the pyramidal tract, and the reproducibility of each technique was evaluated. Results DTT demonstrated improved reproducibility over manual ROI measurement for pyramidal tract quantitation and was less subject to intra-operator variability ( P < 0.0001, Fisher test for equal variance). In general, the anatomic locations and measurements obtained with the two techniques were in good agreement, although some systematic differences were identified in the PLIC and CP. Conclusion Fiber DTT is feasible in premature newborns, provides more reproducible tract measurements than manual ROI methods, and allows quantitation along the entire tract for more detailed DTI assessment of white matter maturation. J. Magn. Reson. Imaging 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the association between cocaine or cigarette smoke exposure in utero and visual outcome. A total of 153 healthy infants (89 males, 64 females; gestational age range 34 to 42 weeks) were prospectively enrolled in a masked, race-matched study. Quantitative analyses of urine and meconium were used to document exposure to cigarette smoke and cocaine. Infants with exposure to other illicit drugs, excepting marijuana, were excluded. At 6 weeks of age, grating acuity and visual system abnormalities (VSA; eyelid oedema, gaze abnormalities, and visual inattention) of 96 infants from the original study sample were assessed with the Teller acuity card procedure and a detailed neurological examination. Neither cocaine nor cigarette smoke exposure was associated with acuity or VSA. However, VSAs were associated with abnormal neurological examination, independent of drug exposure and other risk factors (odds ratio 7.9; 95% confidence interval 2.0 to 31.5;p=0.004). This unexpected finding could prove a helpful clinical marker for the infant at risk for neurological abnormalities. [ABSTRACT FROM AUTHOR]

The interrelationship between inflammation and ischemia is complex and poorly understood in the developing nervous system. In the preterm newborn, maternal infection may predispose to white matter injury and may be associated with cytokine elevation. In the term infant, few studies exist linking elevation of cytokines with encephalopathy and poor neurodevelopmental outcome. This review discusses the interplay among inflammatory cytokines, neonatal encephalopathy, and neuroimaging parameters. MRDD Research Reviews 2002;8:20–24. © 2002 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Giving 500 mg/kg of fructose-1, 6-bisphosphate intraperitoneally decreases hypoxic/ischaemic CNS injury of neonatal rats. Before administering fructose-1, 6-bisphosphate to human neonates, its toxicity must be determined in neonatal animals. Thus, saline or 4,000, 6,000, or 8,000 mg/kg of fructose-1, 6-bisphosphate was given intraperitoneally to normoxic 7 days old rats. One, 2, and 24 hr and 7 days later, blood Ca2+, P043-, blood urea nitrogen, and creatinine concentrations, and aspartate aminotransferase activity were measured. Organ pathology was determined at necropsy. Pups receiving 4,000 mg/kg of fructose-1, 6-bisphosphate survived without evidence of injury or toxicity. All animals receiving 8,000 mg/kg and 27 percent of those receiving 6,000 mg/kg of fructose-1, 6-bisphosphate died. Surviving fructose-1, 6-bisphosphate-treated animals grew at the same rates and had similar weights as saline-treated animals. Nineteen percent of pups given 6,000 or 8,000 mg/kg of fructose-1, 6-bisphosphate had mild perivascular fluid cuffing and/or microscopic pulmonary haemorrhage, but none of the animals given 4,000 mg/kg of the compound had evidence of injury. No other organ pathology was found in any of the animals. Renal and hepatic function were normal in all animals. Fructose-1, 6-bisphosphate administration was associated with a significant increase in the fructose-1, 6-bisphosphate concentration of blood. Administering 4,000 to 8,000 mg/kg of fructose-1, 6-bisphosphate significantly decreased Ca2+ concentrations and increased P043- concentrations 1 and 2 hrs after fructose-1, 6-bisphosphate administration. Similar changes in Ca2+ and P043- concentrations occurred after the administration of 10 mmol/kg of sodium phosphate. The wide margin of safety for fructose-1, 6-bisphosphate (8 times the dose needed to prevent or reduce CNS injury) may render fructose-1, 6-bisphosphate safe for use in neonates. [ABSTRACT FROM AUTHOR]

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