Perinatal Brain Research Articles

Biomarkers and neuromonitoring for prognosis of development after perinatal brain damage

Das sich entwickelnde Gehirn ist in der Perinatalperiode besonders empfindlich für eine Vielzahl von Insulten, wie z. B. Extremfrühgeburtlichkeit und perinatale Asphyxie. Ihre Komplikationen können zu lebenslangen neurokognitiven, sensorischen und psychosozialen Einschränkungen führen; deren Vorhersage bleibt eine Herausforderung. Eine Schlüsselfunktion kommt der möglichst exakten Identifikation von Hirnläsionen und funktionellen Störungen zu. Die Prädiktion stützt sich auf frühe diagnostische Verfahren und die klinische Erfassung der Meilensteine der Entwicklung. Zur klinischen Diagnostik und zum Neuromonitoring in der Neonatal- und frühen Säuglingsperiode stehen bildgebende Verfahren zur Verfügung. Hierzu zählen zerebrale Sonographie, MRT am errechneten Termin, amplitudenintegriertes (a)EEG und/oder klassisches EEG, Nah-Infrarot-Spektroskopie, General Movements Assessment und die frühe klinische Nachuntersuchung z. B. mithilfe der Hammersmith Neonatal/Infant Neurological Examination. Innovative Biomarker und -muster (Omics) sowie (epi)genetische Prädispositionen sind Gegenstand wissenschaftlicher Untersuchungen. Neben der Erfassung klinischer Risiken kommt psychosozialen Faktoren im Umfeld des Kindes eine entscheidende Rolle zu. Eine möglichst akkurate Prognose ist mit hohem Aufwand verbunden, jedoch zur gezielten Beratung der Familien und der Einleitung von frühen Interventionen, insbesondere vor dem Hintergrund der hohen Plastizität des sich entwickelnden Gehirns, von großer Bedeutung. Diese Übersichtsarbeit fokussiert die Charakterisierung der oben genannten Verfahren und ihrer Kombinationsmöglichkeiten. Zudem wird ein Ausblick gegeben, wie innovative Techniken in Zukunft die Prädiktion der Entwicklung und Nachsorge dieser Kinder vereinfachen können.

The effect of sulforaphane on perinatal hypoxic-ischemic brain injury in rats.

Perinatal hypoxic-ischemic insult (HII) is one of the main devastating causes of morbidity and mortality in newborns. HII induces brain injury which evolves to neurological sequelae later in life. Hypothermia is the only therapeutic approach available capable of diminishing brain impairment after HII. Finding a novel therapeutic method to reduce the severity of brain injury and its consequences is critical in neonatology. The present paper aimed to evaluate the effect of sulforaphane (SFN) pre-treatment on glucose metabolism, neurodegeneration, and functional outcome at the acute, sub-acute, and sub-chronic time intervals in the experimental model of perinatal hypoxic-ischemic insult in rats. To estimate the effect of SFN on brain glucose uptake we have performed 18F-deoxyglucose (FDG) microCT/PET. The activity of FDG was determined in the hippocampus and sensorimotor cortex. Neurodegeneration was assessed by histological analysis of Nissl-stained brain sections. To investigate functional outcomes a battery of behavioral tests was employed. We have shown that although SFN possesses a protective effect on glucose uptake in the ischemic hippocampus 24 h and 1 week after HII, no effect has been observed in the motor cortex. We have further shown that the ischemic hippocampal formation tends to be thinner in HIE and SFN treatment tends to reverse this pattern. We have observed subtle chronic movement deficit after HII detected by ladder rung walking test with no protective effect of SFN. SFN should be thus considered as a potent neuroprotective drug with the capability to interfere with pathophysiological processes triggered by perinatal hypoxic-ischemic insult.

Bioinformatics-based analysis reveals IDR-1018-mediated ceRNA regulation network for protective effect on hypoxia-ischemic brain injury in neonatal mice

Activation of an innate immune response serves as a key, contributing factor in perinatal brain injury. The current study sought to evaluate the clinical significance of innate defense regulatory peptide 1018 (IDR-1018)-derived peptide mediating ceRNA regulation network as a biomarker in neonatal mice with hypoxic-ischemic brain damage (HIBD). Firstly, bioinformatics analyses were performed to screen the HIBD-related candidate genes, miRNAs, and lncRNAs. The StarBase, miRDB, and LncBase databases were retrieved to obtain the lncRNA-miRNA-mRNA network, which revealed the ceRNA regulatory network mediated by IDR-1018. Subsequently, RT-qPCR was adopted to determine the expression patterns of MIAT, miR-7a-5p, and Plp2 in neonatal mice with HIBD after treatment with IDR-1018. Moreover, the relationship among mRNA, miRNA, and lncRNA in primary hippocampal neurons was verified by means of dual-luciferase reporter assay and RIP assay. Initial findings demonstrated that Plp2, mmu-miR-7a-5p, and three lncRNAs (MIAT, XIST, and 1700020I14RIK) were related to HIBD. Moreover, IDR-1018 could relieve HIBD in neonatal mice. Plp2 and MIAT were down-regulated, while mmu-miR-7a-5p was up-regulated in the striatum, hippocampus, and cortical tissues of the neonatal mice with HIBD, whereas treatment with the IDR-1018 could revere these trends. Additionally, MIAT acted as a ceRNA of miR-7a-5p to elevate Plp2 expression. In conclusion, our findings highlighted that IDR-1018 relieved HIBD in neonatal mice via the MIAT/miR-7a-5p/Plp2 axis.

Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury.

Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing evidence that brain injury spreads over time from injured to previously uninjured regions of the brain. At least in part, this spread is related to opening of connexin hemichannels and pannexin channels, both of which are large conductance membrane channels found in many brain cells. Opening of these membrane channels releases adenosine triphosphate (ATP), and other neuroactive molecules, into the extracellular space. ATP has an important role in normal signaling, but pathologically can trigger the assembly of the multi-protein inflammasome complex. The inflammasome complex promotes activation of inflammatory caspases, and release of inflammatory cytokines. Overall, the connexin hemichannel appears to play a primary role in propagation of injury and chronic disease, and connexin hemichannel blockade has been shown to be neuroprotective in multiple animal models. Thus, there is potential for some blockers of connexin or pannexin channels to be developed into targeted interventions that could be used in conjunction with or separate to therapeutic hypothermia.

Interleukin-1: an important target for perinatal neuroprotection?

Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy. Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth. Multiple pathways are involved in the pathogenesis of perinatal inflammation. However, studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1. In this review, we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury. We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage, and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist, anakinra, as a safe and effective therapeutic intervention. We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment, and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.

Activation of TRESK background potassium channels by cloxyquin exerts protective effects against excitotoxic-induced brain injury and neuroinflammation in neonatal rats

We investigated effects of activation of TRESK channels by selective activator cloxyquin on excitotoxic-induced brain injury and neuroinflammation involving brain mast cells and inflammatory cytokines in neonatal rats. Three different doses of cloxyquin (0.2, 1 and 5 mg/kg) were studied in ibotenate-induced perinatal brain injury (PBI) in P5 rat-pups. Cerebral lesions and mast cells in coronal brain sections were evaluated. Concentrations of activin A, IL-1β, IL-6 and IL-10 in brain homogenates were measured using ELISA. Cloxyquin dose-dependently exerted protective effects against excitotoxic-induced neonatal brain injury and neuroinflammation. TRESK channels may be a promising new target for the treatment of PBIs.

Predicting age and clinical risk from the neonatal connectome

The development of perinatal brain connectivity underpins motor, cognitive and behavioural abilities in later life. Diffusion MRI allows the characterisation of subtle inter-individual differences in structural brain connectivity. Individual brain connectivity maps (connectomes) are by nature high in dimensionality and complex to interpret. Machine learning methods are a powerful tool to uncover properties of the connectome which are not readily visible and can give us clues as to how and why individual developmental trajectories differ.In this manuscript we used Deep Neural Networks and Random Forests to predict demographic and neurodevelopmental characteristics from neonatal structural connectomes in a large sample of babies (n = 524) from the developing Human Connectome Project. We achieved an accurate prediction of post menstrual age (PMA) at scan in term-born infants (mean absolute error (MAE) = 0.72 weeks, r = 0.83 and p < 0.001). We also achieved good accuracy when predicting gestational age at birth in a cohort of term and preterm babies scanned at term equivalent age (MAE = 2.21 weeks, r = 0.82, p < 0.001). We subsequently used sensitivity analysis to obtain feature relevance from our prediction models, with the most important connections for prediction of PMA and GA found to predominantly involve frontal and temporal regions, thalami, and basal ganglia. From our models of PMA at scan for infants born at term, we computed a brain maturation index (predicted age minus actual age) of individual preterm neonates and found a significant correlation between this index and motor outcome at 18 months corrected age. Our results demonstrate the applicability of machine learning techniques in analyses of the neonatal connectome and suggest that a neural substrate of brain maturation with implications for future neurodevelopment is detectable at term equivalent age from the neonatal connectome.

Effectiveness of nutritional interventions to prevent nonprogressive congenital and perinatal brain injuries: a systematic review and meta-analysis of randomized trials.

Nutritional interventions for newborns with brain injury are scarce, and there are gaps in the knowledge of their mechanisms of action in preventing the occurrence of cerebral palsy (CP) or the incidence of other developmental disabilities. The objective of this review was to assess the effect of nutritional interventions in preventing nonprogressive congenital or perinatal brain injuries, or in improving outcomes related to neurological development. Randomized trials on any nutritional intervention for pregnant women at risk of preterm delivery, or for children with low birth weight, preterm, or with confirmed or suspected microcephaly, CP, or fetal alcohol syndrome disorders (FASDs) were retrieved from MEDLINE, Embase, Scopus, Web of Science, LILACS, and CENTRAL databases from inception to September 17, 2020. Data extraction, risk of bias (Cochrane Risk of Bias tool 2), and quality of evidence (GRADE approach) were assessed by 2 authors. Pooled risk ratios (RRs) with 95% confidence intervals were calculated using a random-effects meta-analysis. Seventeen studies were included on intravenous interventions (magnesium sulfate [n = 5], amino acids [n = 4], vitamin A [n = 1], and N-acetylcysteine [n = 1]); enteral interventions (vitamin D [n = 1], prebiotic [n = 1], nutrient-enriched formula [n = 1], and speed of increasing milk feeds [n = 1]); and oral interventions (choline [n = 1] and docosahexaenoic acid, choline, and uridine monophosphate [n = 1]). All studies assessed CP, except 1 on FASDs. Eight studies were judged as having high risk of bias. Five studies (7413 babies) with high-quality evidence demonstrated decreased risk of childhood CP (RR = 0.68, 95% CI: 0.52-0.88) with magnesium sulfate. Interventions with amino acids had no effect on CP prevention or other outcomes. Except for 1 study, no other intervention decreased the risk of CP or FASDs. Although different types of nutritional interventions were found, only those with antenatal magnesium sulfate were effective in decreasing CP risk in preterm infants. Well-designed, adequately powered randomized clinical trials are required.

A Role for Insulin-like Growth Factor 1 in the Generation of Epileptic Spasms in a murine model.

Infantile spasms are associated with a wide variety of clinical conditions, including perinatal brain injuries. We have created a model in which prolonged infusion of tetrodotoxin (TTX) into the neocortex, beginning in infancy, produces a localized lesion and reproduces the behavioral spasms, electroencephalogram (EEG) abnormalities, and drug responsiveness seen clinically. Here, we undertook experiments to explore the possibility that the growth factor IGF-1 plays a role in generating epileptic spasms. We combined long-term video EEG recordings with quantitative immunohistochemical and biochemical analyses to unravel IGF-1's role in spasm generation. Immunohistochemistry was undertaken in surgically resected tissue from infantile spasms patients. We used viral injections in neonatal conditional IGF-1R knock-out mice to show that an IGF-1-derived tripeptide (1-3)IGF-1, acts through the IGF-1 receptor to abolish spasms. Immunohistochemical methods revealed widespread loss of IGF-1 from cortical neurons, but an increase in IGF-1 in the reactive astrocytes in the TTX-induced lesion. Very similar changes were observed in the neocortex from patients with spasms. In animals, we observed reduced signaling through the IGF-1 growth pathways in areas remote from the lesion. To show the reduction in IGF-1 expression plays a role in spasm generation, epileptic rats were treated with (1-3)IGF-1. We provide 3 lines of evidence that (1-3)IGF-1 activates the IGF-1 signaling pathway by acting through the receptor for IGF-1. Treatment with (1-3)IGF-1 abolished spasms and hypsarrhythmia-like activity in the majority of animals. Results implicate IGF-1 in the pathogenesis of infantile spasms and IGF-1 analogues as potential novel therapies for this neurodevelopmental disorder. ANN NEUROL 2022;92:45-60.

Dysmature patterns of newborn EEG recordings: Biological markers of transitory brain dysfunction or brain injury

To investigate the prognostic value of dysmature EEG patterns in term or near-term newborns. Neonates with dysmature patterns in their first neonatal EEG, assessed during a 6-year period from January 2010 to December 2015, were included in the study. Their outcomes at their follow-ups in June 2019 (at the age of 3 years or more) were assessed, and the presence of neurological deficits and/or epilepsy was noted. We identified 347 neonates with video-EEG recordings during the observed period, in which 10 neonates had dysmature patterns in their first EEG. Eight were born at term and two were born late preterms, born at the 35 and 36-week gestational age. The reasons for admission were HIE grade I in 2 patients, grade II in 6 neonates, and heart problems in 2 patients. The second EEG was recorded at different time intervals, in 7 infants between 1 and 6 weeks; three infants had second EEG much later and were excluded from the study. Six of seven infants showed normal background activity (BA), and five had sharp waves over different regions, all six had normal developmental outcomes. One child with dysrhythmic pattern in the second EEG was diagnosed with genetic encephalopathy, developed spastic cerebral palsy and died due to severe pneumonia at the age of 6 years. Dysmature patterns may reflect transitory brain dysfunctions. Neonatal EEG tests remain reliable and important diagnostic tool in the very first weeks of life, particularly due to the availability of sequential EEG recordings and interpretations.

P20: P2X7 receptor blockade prevents perinatal brain injury in a mouse model of congenital cytomegalovirus (cCMV) infection

P20: P2X7 receptor blockade prevents perinatal brain injury in a mouse model of congenital cytomegalovirus (cCMV) infection

The Role of Music Therapy with Infants with Perinatal Brain Injury.

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.

Season of birth and vulnerability to the pathology of Alzheimer's disease: an in vivo positron emission tomography study.

This study used positron emission tomography to examine whether the seasonal birth effect as an exogenic indicator of early life environmental factors influenced vulnerability to Alzheimer's disease (AD) pathology in the elderly. We analysed datasets from the Alzheimer's Disease Neuroimaging Initiative, which included the data for 234 cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) (n=114) and AD dementia (n=38). As an index of amyloid β (Aβ)/tau accumulation, the 18 F-AV-45- and 18 F-AV-1451-standardized uptake value ratios (SUVRs) were compared between groups of spring-to-summer births and fall-to-winter births by analysis of covariance. In addition, a multiple linear regression analysis was performed to determine whether the season of birth was a predictor of 18 F-AV-45 and/or 18 F-AV-1451 SUVRs, for which a difference was observed. Seasonal birth difference was a good predictor of 18 F-AV-1451 SUVR. We found that participants with a fall-to-winter birth showed lower 18 F-AV-1451 SUVRs than those with a spring-to-summer birth in both the CN and MCI/AD groups, after correcting for the effect of age, sex, years of education, and Alzheimer's Disease Assessment Scale cognitive subscale score, that could possibly affect tau accumulation. Participants with a fall-to-winter birth showed less tau accumulation than those with a spring-to-summer birth after accounting for the factors that could affect tau accumulation. Our findings showed a vulnerability to tau pathology in participants with a fall-to-winter birth, which may be caused by perinatal or postnatal brain damage due to the risk factors associated with the cold season.

Brain volumes and white matter microstructure in 8- to 10-year-old children born with fetal growth restriction

BackgroundFetal growth restriction caused by placental insufficiency is associated with increased risk of poor neurodevelopment, even in the absence of specific perinatal brain injury. Placental insufficiency leads to chronic hypoxaemia that may alter cerebral tissue organisation and maturation.ObjectiveThe aim of this study was to assess the effects fetal growth restriction and fetal haemodynamic abnormalities have on brain volumes and white matter microstructure at early school age.Materials and methodsThis study examined 32 children born with fetal growth restriction at 24 to 40 gestational weeks, and 27 gestational age-matched children, who were appropriate for gestational age. All children underwent magnetic resonance imaging (MRI) at the age of 8–10 years. Cerebral volumes were analysed, and tract-based spatial statistics and atlas-based analysis of white matter were performed on 17 children born with fetal growth restriction and 14 children with birth weight appropriate for gestational age.ResultsChildren born with fetal growth restriction demonstrated smaller total intracranial volumes compared to children with normal fetal growth, whereas no significant differences in grey or white matter volumes were detected. On atlas-based analysis of white matter, children born with fetal growth restriction demonstrated higher mean and radial diffusivity values in large white matter tracts when compared to children with normal fetal growth.ConclusionChildren ages 8–10 years old born with fetal growth restriction demonstrated significant changes in white matter microstructure compared to children who were appropriate for gestational age, even though no differences in grey and white matter volumes were detected. Poor fetal growth may impact white matter maturation and lead to neurodevelopmental impairment later in life.

Asymmetry in sleep spindles and motor outcome in infants with unilateral brain injury.

To determine whether interhemispheric difference in sleep spindles in infants with perinatal unilateral brain injury could link to a pathological network reorganization that underpins the development of unilateral cerebral palsy (CP). This was a multicentre retrospective study of 40 infants (19 females, 21 males) with unilateral brain injury. Sleep spindles were detected and quantified with an automated algorithm from electroencephalograph records performed at 2 months to 5 months of age. The clinical outcomes after 18 months were compared to spindle power asymmetry (SPA) between hemispheres in different brain regions. We found a significantly increased SPA in infants who later developed unilateral CP (n=13, with the most robust interhemispheric difference seen in the central spindles. The best individual-level prediction of unilateral CP was seen in the centro-occipital spindles with an overall accuracy of 93%. An empiric cut-off level for SPA at 0.65 gave a positive predictive value of 100% and a negative predictive value of 93% for later development of unilateral CP. Our data suggest that automated analysis of interhemispheric SPA provides a potential biomarker of unilateral CP at a very early age. This holds promise for guiding the early diagnostic process in infants with a perinatally identified brain injury. Unilateral perinatal brain injury may affect the development of electroencephalogram (EEG) sleep spindles. Interhemispheric asymmetry in sleep spindles can be quantified with automated EEG analysis. Spindle power asymmetry can be a potential biomarker of unilateral cerebral palsy.

Erythropoietin as a Neuroprotective Drug for Newborn Infants: Ten Years after the First Use.

Protective strategies against perinatal brain injury represent a major challenge for modern neonatology. Erythropoietin (Epo) enhances endogenous mechanisms of repair and angiogenesis. In order to analyse the newest evidence on the role of Epo in prematurity, hypoxic ischemic encephalopathy (HIE) and perinatal stroke, a critical review using 2020 PRISMA statement guidelines was conducted. This review uncovered 26 clinical trials examining the use of Epo for prematurity and brain injury-related outcomes. The effects of Epo on prematurity were analysed in 16 clinical trials. Erythropoietin was provided until 32–35 weeks of corrected postnatal age with a dosage between 500–3000 UI/kg/dose. Eight trials reported the Epo effects on HIE term newborn infants: Erythropoietin was administered in the first weeks of life, at different multiple doses between 250–2500 UI/kg/dose, as either an adjuvant therapy with hypothermia or a substitute for hypothermia. Two trials investigated Epo effects in perinatal stroke. Erythropoietin was administered at a dose of 1000 IU/kg for three days. No beneficial effect in improving morbidity was observed after Epo administration in perinatal stroke. A positive effect on neurodevelopmental outcome seems to occur when Epo is used as an adjuvant therapy with hypothermia in the HIE newborns. Administration of Epo in preterm infants still presents inconsistencies with regard to neurodevelopmental outcome. Clinical trials show significant differences mainly in target population and intervention scheme. The identification of specific markers and their temporal expression at different time of recovery after hypoxia-ischemia in neonates might be implemented to optimize the therapeutic scheme after hypoxic-ischemic injury in the developing brain. Additional studies on tailored regimes, accounting for the risk stratification of brain damage in newborns, are required.

Effect of antenatal magnesium sulphate on MRI biomarkers of white matter development at term equivalent age: The MagNUM Study.

SummaryBackgroundMagnesium sulphate given to women prior to very preterm birth protects the perinatal brain, so fewer babies die or develop cerebral palsy. How magnesium sulphate exerts these beneficial effects remains uncertain. The MagNUM Study aimed to assess the effect of exposure to antenatal magnesium sulphate on MRI measures of brain white matter microstructure at term equivalent age.MethodsNested cohort study within the Magnesium sulphate at 30 to <34 weeks’ Gestational age Neuroprotection Trial (MAGENTA). Australian New Zealand Clinical Trials Registry ACTRN12611000491965. Mothers at risk of preterm birth at 30 to <34 weeks’ gestation were randomised to receive either 4 g of magnesium sulphate heptahydrate [8 mmol magnesium ions], or saline placebo, when preterm birth was planned or expected within 24 h. Participating babies underwent diffusion tensor MRI at term equivalent age. The main outcomes were fractional anisotropy across the white matter tract skeleton compared using Tract-based Spatial Statistics (TBSS), with adjustment for postmenstrual age at birth and at MRI, and MRI site. Researchers and families were blind to treatment group allocation during data collection and analyses.FindingsOf the 109 babies the demographics of the 49 babies exposed to magnesium sulphate were similar to the 60 babies exposed to placebo. In babies whose mothers were allocated to magnesium sulphate, fractional anisotropy was lower within the corticospinal tracts and corona radiata, the superior and inferior longitudinal fasciculi, and the inferior fronto-occipital fasciculi compared to babies whose mothers were allocated placebo (P < 0·05).InterpretationIn babies born preterm after 30 weeks’ gestation, antenatal magnesium sulphate exposure did not promote development of white matter microstructure in pathways affecting motor or cognitive function. This suggests that if the neuroprotective effect of magnesium sulphate treatment prior to preterm birth is confirmed at this gestation, the mechanisms are not related to accelerated white matter maturation inferred from fractional anisotropy.FundingThis study was funded by a project grant from the Health Research Council of New Zealand (HRC 14/153).

Study Protocol: Multimodal Longitudinal Assessment of Infant Brain Organization and Recovery in Perinatal Brain Injury.

Perinatal brain injury is a primary cause of cerebral palsy, a condition resulting in lifelong motor impairment. Infancy is an important period of motor system development, including development of the corticospinal tract (CST), the primary pathway for cortical movement control. The interaction between perinatal stroke recovery, CST organization, and resultant motor outcome in infants is not well understood. Here, we present a protocol for multimodal longitudinal assessment of brain development and motor function following perinatal brain injury using transcranial magnetic stimulation and magnetic resonance imaging to noninvasively measure CST functional and structural integrity across multiple time points in infants 3 to 24 months of age. We will further assess the association between cortical excitability, integrity, and motor function. This protocol will identify bioindicators of motor outcome and neuroplasticity and subsequently inform early detection, diagnosis, and intervention strategies for infants with perinatal stroke, brain bleeds, and related diagnoses.

Protocol for the Birth Asphyxia in African Newborns (Baby BRAiN) Study: a Neonatal Encephalopathy Feasibility Cohort Study

BACKGROUND: Neonatal encephalopathy (NE) is a leading cause of child mortality worldwide and contributes substantially to stillbirths and long-term disability. Ninety-nine percent of deaths from NE occur in low-and-middle-income countries (LMICs). Whilst therapeutic hypothermia significantly improves outcomes in high-income countries, its safety and effectiveness in diverse LMIC contexts remains debated. Important differences in the aetiology, nature and timing of neonatal brain injury likely influence the effectiveness of postnatal interventions, including therapeutic hypothermia. METHODS: This is a prospective pilot feasibility cohort study of neonates with NE conducted at Kawempe National Referral Hospital, Kampala, Uganda. Neurological investigations include continuous video electroencephalography (EEG) (days 1-4), serial cranial ultrasound imaging, and neonatal brain Magnetic Resonance Imaging and Spectroscopy (MRI/ MRS) (day 10-14). Neurodevelopmental follow-up will be continued to 18-24 months of age including Prechtl’s Assessment of General Movements, Bayley Scales of Infant Development, and a formal scored neurological examination. The primary outcome will be death and moderate-severe neurodevelopmental impairment at 18-24 months. Findings will be used to inform explorative science and larger trials, aiming to develop urgently needed neuroprotective and neurorestorative interventions for NE applicable for use in diverse settings. DISCUSSION: The primary aims of the study are to assess the feasibility of establishing a facility-based cohort of children with NE in Uganda, to enhance our understanding of NE in a low-resource sub-Saharan African setting and provide infrastructure to conduct high-quality research on neuroprotective/ neurorestorative strategies to reduce death and disability from NE. Specific objectives are to establish a NE cohort, in order to 1) investigate the clinical course, aetiology, nature and timing of perinatal brain injury; 2) describe electrographic activity and quantify seizure burden and the relationship with adverse outcomes, and; 3) develop capacity for neonatal brain MRI/S and examine associations with early neurodevelopmental outcomes.

Protocol for the Birth Asphyxia in African Newborns (Baby BRAiN) Study: a Neonatal Encephalopathy Feasibility Cohort Study.

BACKGROUND: Neonatal encephalopathy (NE) is a leading cause of child mortality worldwide and contributes substantially to stillbirths and long-term disability. Ninety-nine percent of deaths from NE occur in low-and-middle-income countries (LMICs). Whilst therapeutic hypothermia significantly improves outcomes in high-income countries, its safety and effectiveness in diverse LMIC contexts remains debated. Important differences in the aetiology, nature and timing of neonatal brain injury likely influence the effectiveness of postnatal interventions, including therapeutic hypothermia. METHODS: This is a prospective pilot feasibility cohort study of neonates with NE conducted at Kawempe National Referral Hospital, Kampala, Uganda. Neurological investigations include continuous video electroencephalography (EEG) (days 1-4), serial cranial ultrasound imaging, and neonatal brain Magnetic Resonance Imaging and Spectroscopy (MRI/ MRS) (day 10-14). Neurodevelopmental follow-up will be continued to 18-24 months of age including Prechtl's Assessment of General Movements, Bayley Scales of Infant Development, and a formal scored neurological examination. The primary outcome will be death and moderate-severe neurodevelopmental impairment at 18-24 months. Findings will be used to inform explorative science and larger trials, aiming to develop urgently needed neuroprotective and neurorestorative interventions for NE applicable for use in diverse settings. DISCUSSION: The primary aims of the study are to assess the feasibility of establishing a facility-based cohort of children with NE in Uganda, to enhance our understanding of NE in a low-resource sub-Saharan African setting and provide infrastructure to conduct high-quality research on neuroprotective/ neurorestorative strategies to reduce death and disability from NE. Specific objectives are to establish a NE cohort, in order to 1) investigate the clinical course, aetiology, nature and timing of perinatal brain injury; 2) describe electrographic activity and quantify seizure burden and the relationship with adverse outcomes, and; 3) develop capacity for neonatal brain MRI/S and examine associations with early neurodevelopmental outcomes.