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To investigate the feasibility of automated sleep staging based on quantitative analysis of dual-channel electroencephalography (EEG) for extremely and very preterm infants during their first postnatal days.We enrolled 17 preterm neonates born between 25 and 30 weeks of gestational age. Three-hour behavioral sleep observations and simultaneous dual-channel EEG monitoring were conducted for each infant within their first 72 hours after birth. Four kinds of representative and complementary quantitative EEG (qEEG) metrics (i.e., bursting, synchrony, spectral power, and complexity) were calculated and compared between active sleep, quiet sleep, and wakefulness. All analyses were performed in offline mode.In separate comparison analyses, significant differences between sleep-wake states were found for bursting, spectral power and complexity features. The automated sleep-wake state classifier based on the combination of all qEEG features achieved a macro-averaged area under the curve of receiver operating characteristic of 74.8%. The complexity features contributed the most to sleep-wake state classification.It is feasible to distinguish between sleep-wake states within the first 72 postnatal hours for extremely and very preterm infants using qEEG metrics.Our findings offer the possibility of starting personalized care dependent on preterm infants' sleep-wake states directly after birth, potentially yielding long-run benefits for their developmental outcomes.

Aim To assess the relationship between neonatal brain development and injury with early motor outcomes in infants with critical congenital heart disease (CCHD). Method Neonatal brain magnetic resonance imaging was performed after open-heart surgery with cardiopulmonary bypass. Cortical grey matter (CGM), unmyelinated white matter, and cerebellar volumes, as well as white matter motor tract fractional anisotropy and mean diffusivity were assessed. White matter injury (WMI) and arterial ischaemic stroke (AIS) with corticospinal tract (CST) involvement were scored. Associations with motor outcomes at 3, 9, and 18 months were corrected for repeated cardiac surgery. Results Fifty-one infants (31 males, 20 females) were included prospectively. Median age at neonatal surgery and postoperative brain magnetic resonance imaging was 7 days (interquartile range [IQR] 5-11d) and 15 days (IQR 12-21d) respectively. Smaller CGM and cerebellar volumes were associated with lower fine motor scores at 9 months (CGM regression coefficient=0.51, 95% confidence interval [CI]=0.15-0.86; cerebellum regression coefficient=3.08, 95% CI=1.07-5.09) and 18 months (cerebellum regression coefficient=2.08, 95% CI=0.47-5.12). The fractional anisotropy and mean diffusivity of white matter motor tracts were not related with motor scores. WMI was related to lower gross motor scores at 9 months (mean difference -0.8SD, 95% CI=-1.5 to -0.2). AIS with CST involvement increased the risk of gross motor problems and muscle tone abnormalities. Cerebral palsy (n=3) was preceded by severe ischaemic brain injury. Interpretation Neonatal brain development and injury are associated with fewer favourable early motor outcomes in infants with CCHD.

Stress following preterm birth can disrupt the emerging foundation of the neonatal brain. The current study examined how structural brain development is affected by a stressful early environment and whether changes in topological architecture at term-equivalent age could explain the increased vulnerability for behavioral symptoms during early childhood. Longitudinal changes in structural brain connectivity were quantified using diffusion-weighted imaging (DWI) and tractography in preterm born infants (gestational age N= 145, 43.5% female). A global index of postnatal stress was determined based on the number of invasive procedures during hospitalization (e.g., heel lance). Higher stress levels impaired structural connectivity growth in a subnetwork of 48 connections (p= 0.003), including the amygdala, insula, hippocampus, and posterior cingulate cortex. Findings were replicated in an independent validation sample (N= 123, 39.8% female,n= 91 with follow-up). Classifying infants into vulnerable and resilient based on having more or less internalizing symptoms at two to five years of age (n= 71) revealed lower connectivity in the hippocampus and amygdala for vulnerable relative to resilient infants (p< 0.001). Our findings suggest that higher stress exposure during hospital admission is associated with slower growth of structural connectivity. The preservation of global connectivity of the amygdala and hippocampus might reflect a stress-buffering or resilience-enhancing factor against a stressful early environment and early-childhood internalizing symptoms.SIGNIFICANCE STATEMENTThe preterm brain is exposed to various external stimuli following birth. The effects of early chronic stress on neonatal brain networks and the remarkable degree of resilience are not well understood. The current study aims to provide an increased understanding of the impact of postnatal stress on third-trimester brain development and describe the topological architecture of a resilient brain. We observed a sparser neonatal brain network in infants exposed to higher postnatal stress. Limbic regulatory regions, including the hippocampus and amygdala, may play a key role as crucial convergence sites of protective factors. Understanding how stress-induced alterations in early brain development might lead to brain (re)organization may provide essential insights into resilient functioning.

Background Infants born preterm are known to be at risk for abnormal brain development and adverse neurobehavioral outcomes. To improve early neurodevelopment, several non-pharmacological interventions have been developed and implemented in the neonatal intensive care unit (NICU). Sensory-based interventions seem to improve short-term neurodevelopmental outcomes in the inherently stressful NICU environment. However, how this type of intervention affects brain development in the preterm population remains unclear. Methods A systematic review of the literature was conducted for published studies in the past 20 years reporting the effects of early, non-pharmacological, sensory-based interventions on the neonatal brain after preterm birth. Results Twelve randomized controlled trials (RCT) reporting short-term effects of auditory, tactile, and multisensory interventions were included after the screening of 1202 articles. Large heterogeneity was identified among studies in relation to both types of intervention and outcomes. Three areas of focus for sensory interventions were identified: auditory-based, tactile-based, and multisensory interventions. Conclusions Diversity in interventions and outcome measures challenges the possibility to perform an integrative synthesis of results and to translate these for evidence-based clinical practice. This review identifies gaps in the literature and methodological challenges for the implementation of RCTs of sensory interventions in the NICU. Impact This paper represents the first systematic review to investigate the effect of non-pharmacological, sensory-based interventions in the NICU on neonatal brain development. Although reviewed RCTs present evidence on the impact of such interventions on the neonatal brain following preterm birth, it is not yet possible to formulate clear guidelines for clinical practice. This review integrates existing literature on the effect of sensory-based interventions on the brain after preterm birth and identifies methodological challenges for the conduction of high-quality RCTs.

Data on microstructural white matter integrity in preterm infants with post-hemorrhagic ventricular dilatation (PHVD) using diffusion tensor imaging (DTI) are limited. Also, to date, no study has focused on the DTI changes in extremely preterm (EP) infants with PHVD. A case–control study of EP infants

BACKGROUND Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for fetal brain growth and development. Our aim was to evaluate the association between serum DHA and AA levels and brain volumes in extremely preterm infants. METHODS Infants born at

BACKGROUND: Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. OBJECTIVES: The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. METHODS: The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. RESULTS: Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). CONCLUSIONS: Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03162653. ispartof: CLINICAL PHARMACOKINETICS vol:60 issue:7 pages:897-906 ispartof: location:Switzerland status: published

Objective Neonatal seizures are often the first symptom of perinatal brain injury. High-frequency oscillations (HFOs) are promising new biomarkers for epileptogenic tissue and can be found in intracranial and surface EEG. To date, we cannot reliably predict which neonates with seizures will develop childhood epilepsy. We questioned whether epileptic HFOs can be generated by the neonatal brain and potentially predict epilepsy. Methods We selected 24 surface EEGs sampled at 2048 Hz with 175 seizures from 16 neonates and visually reviewed them for HFOs. Interictal epochs were also reviewed. Results We found HFOs in thirteen seizures (7%) from four neonates (25%). 5025 ictal ripples (rate 10 to 1311/min; mean frequency 135 Hz; mean duration 66 ms) and 1427 fast ripples (rate 8 to 356/min; mean frequency 298 Hz; mean duration 25 ms) were marked. Two neonates (13%) showed interictal HFOs (285 ripples and 25 fast ripples). Almost all HFOs co-occurred with sharp transients. We could not find a relationship between neonatal HFOs and outcome yet. Conclusions Neonatal HFOs co-occur with ictal and interictal sharp transients. Significance The neonatal brain can generate epileptic ripples and fast ripples, particularly during seizures, though their occurrence is not common and potential clinical value not evident yet.

Background Preterm infants are at risk of neurodevelopmental impairments. At present, proton magnetic resonance spectroscopy (1H-MRS) is used to evaluate brain metabolites in asphyxiated term infants. The aim of this review is to assess associations between cerebral 1H-MRS and neurodevelopment after preterm birth. Methods PubMed and Embase were searched to identify studies using 1H-MRS and preterm birth. Eligible studies for this review included 1H-MRS of the brain, gestational age ≤32 weeks, and neurodevelopment assessed at a corrected age (CA) of at least 12 months up to the age of 18 years. Results Twenty papers evaluated 1H-MRS in preterm infants at an age between near-term and 18 years and neurodevelopment. 1H-MRS was performed in both white (WM) and gray matter (GM) in 12 of 20 studies. The main regions were frontal and parietal lobe for WM and basal ganglia for GM. N-acetylaspartate/choline (NAA/Cho) measured in WM and/or GM is the most common metabolite ratio associated with motor, language, and cognitive outcome at 18-24 months CA. Conclusions NAA/Cho in WM assessed at term-equivalent age was associated with motor, cognitive, and language outcome, and NAA/Cho in deep GM was associated with language outcome at 18-24 months CA. Impact In preterm born infants, brain metabolism assessed using 1H-MRS at term-equivalent age is associated with motor, cognitive, and language outcomes at 18-24 months. 1H-MRS at term-equivalent age in preterm born infants may be used as an early indication of brain development. Specific findings relating to NAA were most predictive of outcome.

The COVID-19 pandemic exposed weaknesses in multiple domains and widened gender-based inequalities across the world. It also stimulated extraordinary scientific achievement, bringing vaccines to the public in under a year. In this article, we discuss the implications of current vaccination guidance for pregnant and lactating women, whether their exclusion from the first wave of vaccine trials was justified, and if a change in the current vaccine development pathway is necessary. Pregnant and lactating women were not included in initial SARS-CoV-2 vaccine trials. Perhaps unsurprisingly therefore, the first vaccine regulatory approvals have been accompanied by inconsistent advice from public health, governmental, and professional authorities around the world. Denying vaccination to women who though pregnant or breastfeeding are fully capable of autonomous decision-making is a throwback to a paternalistic era. Conversely, lack of evidence upon which to make an informed decision generated in a timely manner, shifts responsibility from research sponsors and regulators, and places the burden of decision-making upon a woman and her healthcare advisor. The World Health Organization (WHO), the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC), and others have highlighted the long-standing disadvantage experienced by women in relation to the development of vaccines and medicines. It is uncertain whether there was sufficient justification for excluding pregnant and lactating women from initial SARS-CoV-2 vaccine trials. In future, we recommend regulators mandate plans that describe the development pathway for new vaccines and medicines that address the needs of women who are pregnant or lactating. These should incorporate at the outset, careful consideration of the balance of risks of exclusion or inclusion from initial studies, patient and public perspectives, details of “Developmental and Reproductive Toxicity” studies, and approaches to collect data systematically from participants who are unknowingly pregnant at the time of exposure. This requires careful consideration of any prior knowledge of the mode of action of the vaccine and the likelihood of toxicity or teratogenicity. We also support the view that the default position should be a “presumption of inclusion”, with exclusion of women who are pregnant or lactating only if justified on specific, not generic, grounds. Finally, we recommend closer coordination across countries with the aim of issuing consistent public health advice.

Encephalopathy of prematurity (EoP) is a common cause of long‐term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double‐hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia‐ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC‐treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia‐ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future., Main Points Intranasal MSC therapy potently restores myelination after encephalopathy of prematurity.MSCs modify their secretome in situ to support OL maturation by upregulating valuable, beneficial growth factors and/or anti‐inflammatory cytokines.

Encephalopathy of prematurity (EoP) is a major cause of morbidity in preterm neonates, causing neurodevelopmental adversities that can lead to lifelong impairments. Preterm birth‐related insults, such as cerebral oxygen fluctuations and perinatal inflammation, are believed to negatively impact brain development, leading to a range of brain abnormalities. Diffuse white matter injury is a major hallmark of EoP and characterized by widespread hypomyelination, the result of disturbances in oligodendrocyte lineage development. At present, there are no treatment options available, despite the enormous burden of EoP on patients, their families, and society. Over the years, research in the field of neonatal brain injury and other white matter pathologies has led to the identification of several promising trophic factors and cytokines that contribute to the survival and maturation of oligodendrocytes, and/or dampening neuroinflammation. In this review, we discuss the current literature on selected factors and their therapeutic potential to combat EoP, covering a wide range of in vitro, preclinical and clinical studies. Furthermore, we offer a future perspective on the translatability of these factors into clinical practice., Main points Arrested OL maturation and neuroinflammation underlie WMI in preterm infants.Several trophic factors can aid OL differentiation and dampen neuroinflammation.These factors have great potential as rapidly available therapies for preterm WMI.

Preterm birth disrupts the emerging foundations of the brain’s architecture, and the continuum of early-life stress-provoked alterations reaches from a healthy adaptation with resilience to severe vulnerability and maladjustment with psychopathology. The current study examined how structural brain development is affected by a stressful extra-uterine environment and whether changes in topological architecture at term-equivalent age could explain the increased vulnerability for behavioral symptoms during early childhood. Longitudinal changes in structural brain connectivity were quantified using diffusion-weighted imaging (DWI) and tractography in preterm born infants (gestational age N=145, 43.5% female). A global index of postnatal stress was based on invasive procedures during hospitalization (e.g., heel lance). Infants were classified as vulnerable and resilient based on having more or less internalizing symptoms at 2-5 years of age (n=71). Findings were replicated in an independent validation sample (N=123, 39.8% female, n=91 with follow-up). Higher stress levels impaired structural connectivity growth in the amygdala, insula, hippocampus, and posterior cingulate cortex. The hippocampus, amygdala, and subthalamic nucleus showed lower global connectivity in vulnerable relative to resilient individuals. The distinct characteristics of the resilient brain allowed for a good predictive accuracy of group membership using local network measures (80%, p−5, κ=0.61). These findings emphasize the detrimental impact of postnatal stress and, more importantly, the relative plasticity of the preterm brain. Resilience following postnatal stress appertains to a potential compensatory or innate ability to propagate global information flow.Significance StatementThe underdeveloped preterm brain is exposed to various external stimuli following birth. Although the importance of early adversity has been widely recognized, the essential understanding of the effects of early chronic stress on neonatal brain networks as well as the remarkable degree of resilience is not well understood. We aim to provide an increased understanding of the impact of postnatal stress on brain development between 30 and 40 weeks of gestation and describe the topological architecture of a resilient brain. We observed global alteration in neonatal brain networks following postnatal stress and identified key contributive regions conferring resilience to the development of future internalizing symptoms.

Background Growth factors important for normal brain development are low in preterm infants. This study investigated the link between growth factors and preterm brain volumes at term. Material/methods Infants born Results In total, 49 infants (median [range] GA 25.4 [22.9–27.9] weeks) were included following MRI segmentation quality assessment and AUC calculation. IGF-1 levels were independently positively associated with the total brain (p β = 0.90), white matter (p = 0.007, β = 0.33), cortical gray matter (p = 0.002, β = 0.43), deep gray matter (p = 0.008, β = 0.05), and cerebellar (p = 0.006, β = 0.08) volume adjusted for GA at birth and postmenstrual age at MRI. No associations were seen for other growth factors. Conclusions Endogenous exposure to IGF-1 during the first 4 weeks of life was associated with total and regional brain volumes at term. Optimizing levels of IGF-1 might improve brain growth in extremely preterm infants. Impact High serum levels of insulin-like growth factor (IGF)-1 during the first month of life were independently associated with increased total brain volume, white matter, gray matter, and cerebellar volume at term equivalent age in extremely preterm infants. IGF-1 is a critical regulator of neurodevelopment and postnatal levels are low in preterm infants. The effects of IGF-1 levels on brain development in extremely preterm infants are not fully understood. Optimizing levels of IGF-1 may benefit early brain growth in extremely preterm infants. The effects of systemically administered IGF-1/IGFBP3 in extremely preterm infants are now being investigated in a randomized controlled trial (Clinicaltrials.gov: NCT03253263).

Sleep is paramount for optimal brain development in infants admitted to the neonatal intensive care unit. Besides (minimally) invasive technical approaches to study sleep in infants, there is currently a large variety of behavioral sleep stage classification methods (BSSCs) that can be used to identify sleep stages in preterm infants born37 weeks gestational age. However, they operate different criteria to define sleep stages, which limits the comparability and reproducibility of research on preterm sleep. This scoping review aims to: 1) identify and elaborate on existing neonatal BSSCs used for preterm infants, 2) examine the reliability and validity of these BSSCs, and 3) identify which criteria are most used for different ages, ranging from 23 to 37 weeks postmenstrual age at observation.To map the existing BSSCs, PubMed, EMBASE and Cochrane were searched for studies using a BSSC to identify sleep stages in preterm infants.In total, 36 BSSCs were identified with on average five item categories assessed per BSSC, most frequently: eyes, body movements, facial movements, sounds, and respiratory pattern. Furthermore, validity and reliability of the BSSCs were tested in less than half of the included studies. Finally, BSSCs were used in infants of all ages, regardless the age for which the BSSC was originally developed.Items used for scoring in the different BSSCs were relatively consistent. The age ranges, reliability, and validity of the BSSCs were not consistently reported in most studies. Either validation studies of existing BSSCs or new BSSCs are necessary to improve the comparability and reproducibility of previous and future preterm behavioral sleep studies.

Cardiorespiratory activity is highly associated with infants’ sleep duration and quality. We performed a systematic literature search of PubMed and EMBASE databases to investigate if and how cardiorespiratory parameters can be used for sleep state classification in preterm infants and in what way maturation influences this relation. All retrieved citations were screened against predetermined inclusion and exclusion criteria. Only studies of preterm infants (

Introduction: Prediction of neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy remains an important challenge. Various studies have shown that the predictive ability of different modalities changed after the introduction of therapeutic hypothermia. This paper reviews the diagnostic test accuracy of the different modalities that are being used to predict neurodevelopmental outcomes following therapeutic hypothermia. Methods: A systematic literature search was performed using Embase and PubMed. Two reviewers independently included eligible studies and extracted data. The quality of the studies was assessed using the Quality in Prognosis Studies Tool. Meta-analyses were performed where possible. Results: Forty-seven articles and 3 conference abstracts were included, reporting on 3,072infants of whom 39% died or had an adverse neurodevelopmental outcome. A meta-analysis could be performed using 37 articles on (amplitude-integrated) electroencephalography (EEG), conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and proton magnetic resonance spectroscopy (1H-MRS). Amplitude-integrated EEG (aEEG) at 24 and 72 h showed similar high diagnostic OR, while aEEG at 6 h and EEG performed less, both due to a low specificity. For MRI, most studies reported scoring systems in which early (1H-MRS. Conclusions: In the era of therapeutic hypothermia, the different modalities remain good predictors of neurodevelopmental outcome. However, timing should be taken into account. aEEG may initially be false positive and gets more reliable after 24 h. In contrast, MRI should be used during the first week, as its predictive value decreases afterwards.

Background: Neonates with unilateral perinatal brain injury (UPBI) are at risk for developing unilateral spastic cerebral palsy (USCP). This study compares several predictors for USCP later in life. Methods: Twenty-one preterm and 24 term born infants with UPBI were included, with an MRI scan including diffusion tensor imaging (DTI) performed at term equivalent age or around 3 months after birth, respectively. T2-weighted images and DTI-based tractography were used to measure the surface area, diameter, and fractional anisotropy (FA) of both corticospinal tracts (CSTs). The hand assessment for infants (HAI) was performed before 5, between 5 and 8 and between 8 and 12 months of (corrected) age. Asymmetry indices were derived from all techniques and related to USCP at ≥2 years of age. Results: MRI measures and HAI scores were significantly lower for the affected compared to the unaffected side. Before 5 months of age, FA asymmetry on DTI yielded the highest area under the curve compared to conventional MRI and HAI. Conclusions: Prediction of USCP after UPBI is reliable using asymmetry of the CST on MRI, as well as clinical hand assessment. Before 5 months of age, DTI tractography provides strongest predictive information, while HAI specifically aids to prognosis of USCP at later age points.

Supplemental Digital Content is available in the text., Background and Purpose— In infants with perinatal arterial ischemic stroke (PAIS), early prognosis of neurodevelopmental outcome is important to adequately inform parents and caretakers. Early continuous neuromonitoring after PAIS may improve early prognosis. Our aim was to study early cerebral electrical activity and oxygenation measured by amplitude-integrated electroencephalography (aEEG) and near-infrared spectroscopy in term neonates with PAIS and relate these to the development of cerebral palsy and cognitive deficit. Methods— aEEG patterns and regional cerebral oxygen saturation (rScO2) levels of both hemispheres were studied for 120 hours from the first clinical symptoms of PAIS (ie, seizures) onward. Multivariable analyses were used to investigate the association between aEEG, near-infrared spectroscopy, clinical variables, and neurodevelopmental outcome. Results— In 52 patients with PAIS (gestational age, 40.4±1.4 weeks; birth weight, 3282±479 g), median time to a continuous background pattern was longer in the ipsilesional compared with the contralesional hemisphere (13.5 versus 10.0 hours; P

Background The gut microbiota and the brain are connected through different mechanisms. Bacterial colonisation of the gut plays a substantial role in normal brain development, providing opportunities for nutritional neuroprotective interventions that target the gut microbiome. Preterm infants are at risk for brain injury, especially white matter injury, mediated by inflammation and infection. Probiotics, prebiotics and L-glutamine are nutritional components that have individually already demonstrated beneficial effects in preterm infants, mostly by reducing infections or modulating the inflammatory response. The NutriBrain study aims to evaluate the benefits of a combination of probiotics, prebiotics and L-glutamine on white matter microstructure integrity (i.e., development of white matter tracts) at term equivalent age in very and extremely preterm born infants. Methods This study is a double-blind, randomised, controlled, parallel-group, single-center study. Eighty-eight infants born between 24 + 0 and Bifidobacterium breve M-16V, short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides and L-glutamine and will be given enterally in addition to regular infant feeding from 48 to 72 h after birth until 36 weeks postmenstrual age. The primary study outcome of white matter microstructure integrity will be measured as fractional anisotropy, assessed using magnetic resonance diffusion tensor imaging at term equivalent age and analysed using Tract-Based Spatial Statistics. Secondary outcomes are white matter injury, brain tissue volumes and cortical morphology, serious neonatal infections, serum inflammatory markers and neurodevelopmental outcome. Discussion This study will be the first to evaluate the effect of a combination of probiotics, prebiotics and L-glutamine on brain development in preterm infants. It may give new insights in the development and function of the gut microbiota and immune system in relation to brain development and provide a new, safe treatment possibility to improve brain development in the care for preterm infants. Trial registration ISRCTN, ISRCTN96620855. Date assigned: 10/10/2017.

Background The mammillary bodies (MBs) have repeatedly been shown to be critical for memory, yet little is known about their involvement in numerous neurological conditions linked to memory impairments, including neonatal encephalopathy. Methods We implemented a multicentre retrospective study, assessing magnetic resonance scans of 219 infants with neonatal encephalopathy who had undergone hypothermia treatment in neonatal intensive care units located in the Netherlands and Italy. Results Abnormal MB signal was observed in ~40% of infants scanned; in half of these cases, the brain appeared otherwise normal. MB involvement was not related to the severity of encephalopathy or the pattern/severity of hypoxic–ischaemic brain injury. Follow-up scans were available for 18 cases with abnormal MB signal; in eight of these cases, the MBs appeared severely atrophic. Conclusions This study highlights the importance of assessing the status of the MBs in neonatal encephalopathy; this may require changes to scanning protocols to ensure that the slices are sufficiently thin to capture the MBs. Furthermore, long-term follow-up of infants with abnormal MB signal is needed to determine the effects on cognition, which may enable the use of early intervention strategies. Further research is needed to assess the role of therapeutic hypothermia in MB involvement in neonatal encephalopathy. Impact The MBs are particularly sensitive to hypoxia in neonates. Current hypothermia treatment provides incomplete protection against MB injury. MB involvement is likely overlooked as it can often occur when the rest of the brain appears normal. Given the importance of the MBs for memory, it is necessary that this region is properly assessed in neonatal encephalopathy. This may require improvements in scanning protocols.

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

Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia treatment. Advances toward new neuroprotective interventions have been limited by incomplete knowledge about secondary injurious processes such as cerebral hyperperfusion commonly observed during the first 1–5 days after asphyxia. Cerebral hyperperfusion is correlated with adverse neurodevelopmental outcome and it is a process that remains poorly understood. In order to provide an overview of the existing knowledge on the pathophysiology and highlight the gaps in current understanding of cerebral hyperperfusion in term animals and neonates with HIE, we performed a systematic research. We included papers scoping for study design, population, number of participants, study technique and relevant findings. Methodological quality was assessed using the checklist for cohort studies from The Joanna Briggs Institute. Out of 2,690 results, 34 studies were included in the final review—all prospective cohort studies. There were 14 studies of high, 17 moderate and 3 of low methodological quality. Data from the literature were analyzed in two main subjects: (1) Hemodynamic Changes subdivided into macro- and microscopic hemodynamic changes, and (2) Endogenous Pathways which was subdivided into N-methyl-D-aspartate/Mitogen activated protein kinase (NDMA/MAPK), Nitric Oxide (NO), prostanoids and other endogenous studies. Cerebral hyperperfusion in term neonates with HIE was found to be present 10–30 min after the hypoxic-ischemic event and was still present around day 10 and up to 1 month after birth. Cerebral hyperperfusion was also characterized by angiogenesis and cerebral vasodilation. Additionally, cerebral vasodilation was mediated by endogenous pathways such as MAPK through urokinase Plasminogen Activator (uPA), by neuronal NO synthase following NMDA and by prostanoid synthesis. Future research should elucidate the precise role of NMDA, MAPK and prostanoids in cerebral hyperperfusion. Moreover, research should focus on possible interventions and the effect of hypothermia on hyperperfusion. These findings should be taken into account simultaneously with brain imagining techniques, becoming a valuable asset in assessing the impact in neurodevelopmental outcome.

In term and near-term neonates with neonatal encephalopathy, therapeutic hypothermia protocols are well established. The current focus is on how to improve outcomes further and the challenge is to find safe and complementary therapies that confer additional protection, regeneration or repair in addition to cooling. Following hypoxia-ischemia, brain injury evolves over three main phases (latent, secondary and tertiary), each with a different brain energy, perfusion, neurochemical and inflammatory milieu. While therapeutic hypothermia has targeted the latent and secondary phase, we now need therapies that cover the continuum of brain injury that spans hours, days, weeks and months after the initial event. Most agents have several therapeutic actions but can be broadly classified under a predominant action (e.g., free radical scavenging, anti-apoptotic, anti-inflammatory, neuroregeneration, and vascular effects). Promising early/secondary phase therapies include Allopurinol, Azithromycin, Exendin-4, Magnesium, Melatonin, Noble gases and Sildenafil. Tertiary phase agents include Erythropoietin, Stem cells and others. We review a selection of promising therapeutic agents on the translational pipeline and suggest a framework for neuroprotection and neurorestoration that targets the evolving injury.

Despite advances in neonatal care to prevent neonatal brain injury and neurodevelopmental impairment, predicting long-term outcome in neonates at risk for brain injury remains difficult. Early prognosis is currently based on cranial ultrasound (CUS), MRI, EEG, NIRS, and/or general movements assessed at specific ages, and predicting outcome in an individual (precision medicine) is not yet possible. New algorithms based on large databases and machine learning applied to clinical, neuromonitoring, and neuroimaging data and genetic analysis and assays measuring multiple biomarkers (omics) can fulfill the needs of modern neonatology. A synergy of all these techniques and the use of automatic quantitative analysis might give clinicians the possibility to provide patient-targeted decision-making for individualized diagnosis, therapy, and outcome prediction. This review will first focus on common neonatal neurological diseases, associated risk factors, and most common treatments. After that, we will discuss how precision medicine and machine learning (ML) approaches could change the future of prediction and prognosis in this field.

Background and Aim: Preterm white matter is vulnerable to lipid peroxidation-mediated injury. F2-isoprostanes (IPs), are a useful biomarker for lipid peroxidation. Aim was to assess the association between early peri-postnatal IPs, white matter injury (WMI) at term equivalent age (TEA), and neurodevelopmental outcome in preterm infants.Methods: Infants with a gestational age (GA) below 28 weeks who had an MRI at TEA were included. IPs were measured in cord blood (cb) at birth and on plasma (pl) between 24 and 48 h after birth. WMI was assessed using Woodward MRI scoring system. Multiple regression analyses were performed to assess the association between IPs with WMI and then with BSITD-III scores at 24 months corrected age (CA). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of pl-IPs for the development of WMI.Results: Forty-four patients were included. cb-IPs were not correlated with WMI score at TEA, whereas higher pl-IPs and lower GA predicted higher WMI score (p = 0.037 and 0.006, respectively) after controlling for GA, FiO2 at sampling and severity of IVH. The area under the curve was 0.72 (CI 95% = 0.51–0.92). The pl-IPs levels plotted curve indicated that 31.8 pg/ml had the best predictive threshold with a sensitivity of 86% and a specificity of 60%, to discriminate newborns with any WMI from newborns without WMI. IPs were not associated with outcome at 24 months.Conclusion: Early measurement of pl-IPs may help discriminate patients showing abnormal WMI score at TEA, thus representing an early biomarker to identify newborns at risk for brain injury.

Background Postmortem examinations frequently show cerebellar injury in infants with severe hypoxic-ischemic encephalopathy (HIE), while it is less well visible on MRI. The primary aim was to investigate the correlation between cerebellar apparent diffusion coefficient (ADC) values and histopathology in infants with HIE. The secondary aim was to compare ADC values in the cerebellum of infants with HIE and infants without brain injury. Methods ADC values in the cerebellar vermis, hemispheres and dentate nucleus (DN) of (near-)term infants with HIE (n = 33) within the first week after birth were compared with neonates with congenital non-cardiac anomalies, normal postoperative MRIs and normal outcome (n = 22). Microglia/macrophage activation was assessed using CD68 and/or HLA-DR staining and Purkinje cell (PC) injury using HE otherwise ADC values and histology were not correlated. Conclusion Histopathological injury in the cerebellum is common in infants with HIE. ADC values underestimate histopathological injury. Impact ADC values might underestimate cerebellar injury in neonates with HIE. ADC values in the vermis and dentate nucleus of infants with HIE are lower compared to controls, but not in the cerebellar hemispheres. Abnormal ADC values are only found when cytotoxic edema is very severe. ADC values in the vermis are correlated with Purkinje cell injury in the vermis; furthermore, there were no correlations between ADC values and histopathological measures.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequently reported adverse effects of cancer treatment. CIPN often persists long after treatment completion and has detrimental effects on patient’s quality of life. There are no efficacious FDA-approved drugs for CIPN. We recently demonstrated that nasal administration of mesenchymal stem cells (MSC) reverses the cognitive deficits induced by cisplatin in mice. Here we show that nasal administration of MSC after cisplatin- or paclitaxel treatment- completely reverses signs of established CIPN, including mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. Nasally administered MSC enter rapidly the meninges of the brain, spinal cord and peripheral lymph nodes to promote IL-10 production by macrophages. MSC-mediated resolution of mechanical allodynia, recovery of IENFs and restoration of DRG mitochondrial function critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, WT MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons. In conclusion, only two nasal administrations of MSC fully reverse CIPN and the associated mitochondrial abnormalities via an IL-10 dependent pathway. Since MSC are already applied clinically, we propose that nasal MSC treatment could become a powerful treatment for the large group of patients suffering from neurotoxicities of cancer treatment.

Premature birth (before 37 weeks of gestation) has been linked to a variety of adverse neurological outcomes. Sleep problems are associated with decreased neurocognitive functioning, which is especially common in children born preterm. The exact relationship between prematurity and sleep at school age is unknown. A systematic review is performed with the aim to assess the relationship between prematurity and sleep at school age (5th to 18th year of life), in comparison to sleep of their peers born full-term. Of 347 possibly eligible studies, nine were included. The overall conclusion is that prematurity is associated with earlier bedtimes and a lower sleep quality, in particular more nocturnal awakenings and more non-rapid eye movement stage 2 sleep. Interpretations and limitations of the review are discussed. Moreover, suggestions for future research are brought forward, including the need for a systematic approach with consistent outcome measures in this field of research. A better understanding of the mechanisms that influence sleep in the vulnerable group of children born preterm could help optimize these children's behavioral and intellectual development. (C) 2021 The Author(s). Published by Elsevier Ltd.

Background Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality in neonates. When the gold standard MRI is not feasible, cerebral ultrasound (CUS) might offer an alternative. In this study, the association between a novel CUS scoring system and neurodevelopmental outcome in neonates with HIE was assessed. Methods (Near-)term infants with HIE and therapeutic hypothermia, a CUS on day 1 and day 3–7 after birth and available outcome data were retrospectively included in cohort I. CUS findings on day 1 and day 3–7 were related to adverse outcome in univariate and the CUS of day 3–7 also in multivariable logistic regression analyses. The resistance index, the sum of deep grey matter and of white matter involvement were included in multivariable logistic regression analyses. A comparable cohort from another hospital was used for validation (cohort II). Results Eighty-three infants were included in cohort I and 35 in cohort II. The final CUS scoring system contained the sum of white matter (OR = 2.6, 95% CI 1.5–4.7) and deep grey matter involvement (OR = 2.7, 95% CI 1.7–4.4). The CUS scoring system performed well in cohort I (AUC = 0.90) and II (AUC = 0.89). Conclusion This validated CUS scoring system is associated with neurodevelopmental outcome in neonates with HIE.

Large-scale functional connectome formation and reorganization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated before birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules, and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function.SIGNIFICANCE STATEMENTThe fetal to neonatal period is well known as a critical stage in brain development. Rapid neurodevelopmental processes establish key functional neural circuits of the human brain. Prenatal risk factors may interfere with early trajectories of connectome formation and thereby shape future health outcomes. Recent advances in MRI have made it possible to examine fetal brain functional connectivity. In this study, we evaluate the network topography of normative functional network development during connectome genesisin utero. Understanding the developmental trajectory of brain connectivity provides a basis for understanding how the prenatal period shapes future brain function and disease dysfunction.

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

ObjectiveTo test the hypothesis that a strategy of prolonged arterial line (AL) and central venous line (CVL) use is associated with reduced neonatal invasive procedures and improved growth of the thalamus in extremely preterm neonates (MethodsTwo international cohorts of very preterm neonates (n = 143) with prolonged (≥14 days) or restricted (ResultsProlonged AL/CVL use in neonates (n = 86) was associated with fewer skin breaks (median 34) during the hospital stay compared to restricted AL/CVL use (n = 57, median 91, 95% confidence interval [CI] 60.35–84.89). Neonates with prolonged AL/CVL use with fewer skin breaks had significantly larger thalamic volumes early in life compared to neonates with restricted line use (B = 121.8, p = 0.001, 95% CI 48.48–195.11). Neonatal thalamic growth predicted preschool-age cognitive (B = 0.001, 95% CI 0.0003–0.001, p = 0.002) and motor scores (B = 0.01, 95% CI 0.001–0.10, p = 0.02). Prolonged AL/CVL use was not associated with greater incidence of sepsis or multiple infections.ConclusionsProlonged AL/CVL use in preterm neonates may provide an unprecedented opportunity to reduce invasive procedures in preterm neonates. Pain reduction in very preterm neonates is associated with optimal thalamic growth and neurodevelopment.

Objectives Neonates with congenital heart disease may have an increased risk of cerebral sinovenous thrombosis, but incidence rates are lacking. This study describes the clinical and neuroimaging characteristics of cerebral sinovenous thrombosis in neonates undergoing cardiac surgery. Methods Forty neonates (78% male) requiring neonatal univentricular or biventricular cardiac repair using cardiopulmonary bypass were included. All underwent preoperative (median postnatal day 7) and postoperative (median postoperative day 7) magnetic resonance imaging of the brain, including venography, to detect cerebral sinovenous thrombosis. Clinical characteristics were compared between cerebral sinovenous thrombosis positive and cerebral sinovenous thrombosis negative neonates. Results Postoperatively, cerebral sinovenous thrombosis was diagnosed in 11 neonates (28%), with the transverse sinus affected in all, and involvement of multiple sinuses in 10 (91%). Preoperatively, signs of thrombosis were seen in 3 cases (8%). Focal infarction of the basal ganglia was significantly more common in cerebral sinovenous thrombosis positive than cerebral sinovenous thrombosis negative neonates ( P = .025). Cerebral sinovenous thrombosis positive neonates spent more time in the intensive care unit preoperatively ( P = .001), had lower weight ( P = .024) and lower postmenstrual age ( P = .030) at surgery, and had prolonged use of a central venous catheter ( P = .023) and a catheter placed in the internal jugular vein more often ( P = .039). Surgical and postoperative factors were not different between new postoperative cerebral sinovenous thrombosis positive and cerebral sinovenous thrombosis negative neonates. Conclusions Cerebral sinovenous thrombosis might be more common than previously understood in neonates undergoing cardiac surgery. In our study, cerebral sinovenous thrombosis was associated with a higher risk of additional intra-parenchymal brain injury.

Objective To assess the predictive value of a novel magnetic resonance imaging (MRI) score, which includes diffusion-weighted imaging as well as assessment of the deep grey matter, white matter, and cerebellum, for neurodevelopmental outcome at 2 years and school age among term infants with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia. Study design This retrospective cohort study (cohort 1, The Netherlands 2008-2014; cohort 2, Sweden 2007-2012) including infants born at >36 weeks of gestational age treated with therapeutic hypothermia who had an MRI in the first weeks of life. The MRI score consisted of 3 subscores: deep grey matter, white matter/cortex, and cerebellum. Primary adverse outcome was defined as death, cerebral palsy, Bayley Scales of Infant and Toddler Development, third edition, motor or cognitive composite scores at 2 years of 0.83 in both cohorts, whereas the specificity was >0.91 with variable sensitivity. Conclusion A novel MRI score, which includes diffusion-weighted imaging and assesses all brain areas of importance in infants with therapeutic hypothermia after perinatal asphyxia, has predictive value for outcome at 2 years of age and at school age, for which the grey matter subscore can be used independently.

There is increasing evidence that sleep plays a major role in the development of neural pathways in the neonatal brain. Several studies have suggested evidence-based approaches to improve sleep for infants admitted to the neonatal intensive care unit (NICU); however, in many neonatal centers very few of these strategies seem to be implemented in routine care. Objective To systematically review the literature to determine interventions promoting neonatal sleep on the NICU, in order to develop key guidelines to improve neonatal sleep. Methods A systematic search was conducted according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for conducting and reporting systematic reviews. The search was performed in Pubmed, CINAHL and the Cochrane Library on 19 September 2016 and again on 28 January 2017. Results In total, fourteen studies were included (10 RCT's and three quasi-experimental study designs): four studies were of high quality, eight of moderate quality and two of low quality. Two studies investigating kangaroo care reported significant effect on infant sleep behavior, two studies comparing Yakson and Gentle Human Touch (GHT) found significant effect on behavioral states and one study reported an increase in sleep behavior using different sleep surfaces. One study showed a significant effect on sleep patterns using music as an intervention and one study showed no significant effect using music. Two studies showed no significant effect on infant sleep using cycled light and different types of LED-light and one study showed significant effect of cycled lightning. There were no effects of Neonatal Individualized Developmental Care Program (NIDCAP) or massage therapy. Conclusion Although many different interventions have been reported to promote sleep in infants who require intensive care, there is great heterogeneity across studies: the methods of sleep assessment, the targeted sleep behaviors, and the study populations vary significantly across published reports. Based on the results there seems to be insufficient evidence to recommend any new intervention to promote neonatal sleep on the NICU. However because of the importance of sleep for the development of the neonatal brain we do suggest some key guidelines based on moderate evidence, expert opinion and parental values to improve sleep on the NICU and to direct future neonatal sleep studies.

Objective: To compare the effect of intervention at low vs high threshold of ventriculomegaly in preterm infants with posthemorrhagic ventricular dilatation on death or severe neurodevelopmental disability. Study design: This multicenter randomized controlled trial reviewed lumbar punctures initiated after either a low threshold (ventricular index of >p97 and anterior horn width of >6 mm) or high threshold (ventricular index of >p97 + 4 mm and anterior horn width of >10 mm). The composite adverse outcome was defined as death or cerebral palsy or Bayley composite cognitive/motor scores

Highlights • The majority of patients with perinatal thalamic injury, will develop epilepsy with ESES after the age of two years. • ESES is associated with neurodevelopmental deficits. • Larger residual thalamic volume at the three months MRI correlates to higher total IQ/DQ during follow-up. • MRI at three months appears to be useful to predict neurodevelopmental outcome in this population., Objective Perinatal thalamic injury is associated with epilepsy with electrical status epilepticus in sleep (ESES). The aim of this study was to prospectively quantify the risk of ESES and to assess neuroimaging predictors of neurodevelopment. Methods We included patients with perinatal thalamic injury. MRI scans were obtained in the neonatal period, around three months of age and during childhood. Thalamic and total brain volumes were obtained from the three months MRI. Diffusion characteristics were assessed. Sleep EEGs distinguished patients into ESES (spike-wave index (SWI) >85%), ESES-spectrum (SWI 50–85%) or no ESES (SWI

Objectives: To determine prevalence and risk factors for brain injury in infants with critical congenital heart disease (CHD) from 2 sites with different practice approaches who were scanned clinically. Study design: Prospective, longitudinal cohort study (2016-2017) performed at Hospital for Sick Children Toronto (HSC) and Wilhelmina Children's Hospital Utrecht (WKZ), including 124 infants with cardiac surgery ≤60 days (HSC = 77; WKZ = 47). Magnetic resonance imaging was performed per clinical protocol, preoperatively (n = 100) and postoperatively (n = 120). Images were reviewed for multifocal (watershed, white matter injury) and focal ischemic injury (stroke, single white matter lesion). Results: The prevalence of ischemic injury was 69% at HSC and 60% at WKZ (P =.20). Preoperative multifocal injury was associated with low cardiac output syndrome (OR, 4.6), which was equally present at HSC and WKZ (20% vs 28%; P =.38). Compared with WKZ, HSC had a higher prevalence of balloon-atrioseptostomy in transposition of the great arteries (83% vs 53%; P =.01) and more frequent preoperative focal injury (27% vs 6%; P =.06). Postoperatively, 30% of new multifocal injury could be attributed to postoperative low cardiac output syndrome, which was equally present at HSC and WKZ (38% vs 28%; P =.33). Postoperative focal injury was associated with intraoperative selective cerebral perfusion in CHD with arch obstruction at both sites (OR, 2.7). Compared with HSC, WKZ had more arch obstructions (62% vs 35%; P

To assess the effect of early life nutrition on structural brain development in 2 cohorts of extremely preterm infants, before and after the implementation of a nutrition regimen containing more protein and lipid.We included 178 infants retrospectively (median gestational age, 26.6 weeks; IQR, 25.9-27.3), of whom 99 received the old nutrition regimen (cohort A, 2011-2013) and 79 the new nutrition regimen (cohort B, 2013-2015). Intake of protein, lipids, and calories was calculated for the first 28 postnatal days. Brain magnetic resonance imaging (MRI) was performed at 30 weeks postmenstrual age (IQR, 30.3-31.4) and term-equivalent age (IQR, 40.9-41.4). Volumes of 42 (left + right) brain structures were calculated.Mean protein and caloric intake in cohort B (3.4 g/kg per day [P .001] and 109 kcal/kg per day [P = .038]) was higher than in cohort A (2.7 g/kg per day; 104 kcal/kg per day). At 30 weeks, 22 regions were significantly larger in cohort B compared with cohort A, whereas at term-equivalent age, only the caudate nucleus was significantly larger in cohort B compared with cohort A.An optimized nutrition protocol in the first 28 days of life is associated with temporarily improved early life brain volumes.

Background Elongation and repair of long gap esophageal atresia (LGEA) can be performed thoracoscopically, even directly after birth. The effect of thoracoscopic CO2-insufflation on cerebral oxygenation (rScO2) during the consecutive thoracoscopic procedures in repair of LGEA was evaluated. Methods Prospective case series of five infants, with in total 16 repetitive thoracoscopic procedures. A CO2-pneumothorax was installed with a pressure of maximum 5 mmHg and flow of 1 L/min. Parameters influencing rScO2 were monitored. For analysis 10 time periods of 10’ during surgery and in the perioperative period were selected. Results Median gestational age was 35+3 [range 33+4 to 39+6] weeks; postnatal age at time of first procedure 4 [2–53] days and time of insufflation 127[22–425] min. Median rScO2 varied between 55 and 90%. Transient outliers in cerebral oxygenation were observed in three patients. In Patient 2 oxygenation values below 55% occurred during a low MABP and Hb 85% during the first procedure with a concomitant high FiO2 > 45%. All parameters recovered during the surgical course. Conclusions This prospective case series of NIRS during consecutive thoracoscopic repair of LGEA showed that cerebral oxygenation remained stable. Transient outliers in rScO2 occurred during changes in hemodynamic or respiratory parameters and normalized after interventions of the anesthesiologist. This study underlines the importance of perioperative neuromonitoring and the close collaboration between pediatric surgeon, anesthesiologist and neonatologist. Electronic supplementary material The online version of this article (doi:10.1007/s00268-016-3853-y) contains supplementary material, which is available to authorized users.

Encephalopathy of Prematurity (EoP) is a major cause of morbidity in (extreme) preterm neonates. Though the majority of EoP research has focused on failure of oligodendrocyte maturation as an underlying pathophysiological mechanism, recent pioneer work has identified developmental disturbances in inhibitory interneurons to contribute to EoP. Here we investigated interneuron abnormalities in two experimental models of EoP and explored the potential of two promising treatment strategies, namely intranasal mesenchymal stem cells (MSCs) or insulin-like growth factor I (IGF1), to restore interneuron development. In rats, fetal inflammation and postnatal hypoxia led to a transient increase in total cortical interneuron numbers, with a layer-specific deficit in parvalbumin (PV)+ interneurons. Additionally, a transient excess of total cortical cell density was observed, including excitatory neuron numbers. In the hippocampal cornu ammonis (CA) 1 region, long-term deficits in total interneuron numbers and PV+ subtype were observed. In mice subjected to postnatal hypoxia/ischemia and systemic inflammation, total numbers of cortical interneurons remained unaffected, however, subtype analysis revealed a global, transient reduction in PV+ cells and a long-lasting layer-specific increase in vasoactive intestinal polypeptide (VIP)+ cells. In the dentate gyrus, a long-lasting deficit of somatostatin (SST)+ cells was observed. Both intranasal MSC and IGF1 therapy restored the majority of interneuron abnormalities in EoP mice. In line with the histological findings, EoP mice displayed impaired social behavior, which was partly restored by the therapies. In conclusion, induction of experimental EoP is associated with model-specific disturbances in interneuron development. In addition, intranasal MSCs and IGF1 are promising therapeutic strategies to aid interneuron development after EoP.

Cortical folding in humans is different for every individual, and is associated with functional specificities. It forms mainly during the last trimester of pregnancy, hence its development lacks description, especially in a longitudinal way. To cope with this issue, this study focused on the evolution of the central sulcus’ variability of 71 preterm infants studied longitudinally with MRI at 30 and 40 weeks (w) postmenstrual age (PMA). Our aim was to investigate the main shape characteristics and whether they are encoded early on or appear closer to term birth. We captured shape dissimilarity between the sulci using a distance matrix after pairwise co-registration using an Iterative Closest Point algorithm. We applied non-linear dimensionality reduction to this matrix using the Isomap algorithm in order to capture the most discriminative shape features among the central sulci. We characterized the three most discriminative features over the group, and found that the sulci evolved consistently from a given feature at 30w PMA to the 40w PMA equivalent feature. We incidentally captured a feature that could coincide with the most discriminative adult feature, both visually and by its asymmetry in left and right sulcal distribution. These results captured the main shape features of the central sulcus in preterm infants and suggest that they are already encoded at 30w PMA.

Objective: The aim of this study was to evaluate whether a new MRI scoring system for preterm non-haemorrhagic white matter injury (WMI), derived from the analysis of the natural evolution of WMI throughout the neonatal period until term-equivalent age, can be used for outcome prediction. Methods: Eighty-two infants Results: In 74 surviving children WMI severity was strongly associated with the presence and severity of cerebral palsy (CP) and other neurodevelopmental impairments (Spearman’s rank correlation 0.88, p < 0.001). Only 3 children with grade I WMI (9%) developed CP (all ambulant) and their developmental scores were not different to those from the controls, although they started walking significantly later (p = 0.036). Of the 6 children with grade II, 83% developed CP (mild in most), whereas 91% of the 34 children with grade III had CP (moderate-severe in 76%) and all had some degree of neurodevelopmental impairment. Three children with grade III WMI did not develop CP; their imaging showed, in contrast to children who developed CP, that the cysts did not affect the corticospinal tracts; also, myelin in the posterior limb of the internal capsule appeared normal in 2 children and suboptimal in 1. Conclusions: This MRI scoring system for preterm WMI can be used to predict neurodevelopmental outcomes. Individualized assessment of the site of lesions and the progression of myelination improves prognostic accuracy.

Background Brain microstructural maturation progresses rapidly in the third trimester of gestation and first weeks of life, but typical microstructural development may be influenced by the presence of critical congenital heart disease (CHD). Objective The aim of this study was to investigate the pattern of white matter (WM) microstructural development in neonates with different types of critical CHD. The secondary aim was to examine whether there is an association between WM microstructural maturity and neonatal ischemic brain injury. Methods For this prospective, longitudinal cohort study, 74 term born neonates underwent diffusion tensor imaging (DTI) before (N = 56) and after (N = 71) cardiac surgery performed, Highlights • Preoperative white matter integrity related to critical CHD type. • Largest difference across CHD types in most mature white matter structures. • Pattern of white matter development not related to critical CHD type. • White matter maturity not related to higher risk neonatal ischemic brain injury.

Background: Hypoxic–ischemic encephalopathy (HIE) in term-born infants can lead to memory problems. The hippocampus is important for long-term episodic memory. The primary aim was to investigate the effect of HIE on hippocampal volumes in 9- to 10-year-old children. The secondary aim was to investigate the association between hippocampal volumes and previously found impaired memory and cognitive functions in the current cohort. Methods: In total 26 children with mild HIE, 26 with moderate HIE, and 37 controls were included. The intelligence quotient (IQ) and memory were tested. A 3D-volumetric MRI was obtained. Brain segmentation was performed for hippocampal volumes and intracranial volume. The differences in hippocampal volumes, memory, and IQ between the groups were determined. Multivariable linear regression analyses were performed, including hippocampal volume as a percentage of intracranial volume as a dependent variable. Results: Smaller hippocampal volumes were found in moderate HIE (p < 0.001), with a trend toward smaller volumes in mild HIE, compared to controls. In multivariable linear regression analysis, hippocampal volume as a percentage of intracranial volume was significantly associated with long-term visuospatial memory. Conclusion: Children with moderate HIE had smaller hippocampal volumes than controls, with a trend toward smaller volumes following mild HIE. Reduced hippocampal volumes were associated with poorer long-term visuospatial memory.

Aim: To assess the impact of perioperative neonatal brain injury and brain volumes on neurodevelopment throughout school-age children with critical congenital heart disease (CHD). Method: Thirty-four survivors of neonatal cardiac surgery (seven females, 27 males) were included. Neonatal preoperative and postoperative cerebral magnetic resonance imaging was performed and neurodevelopment was assessed at 24 months (SD 0.7, n=32, using Bayley Score of Infant and Toddler Development, Child Behavior Checklist) and 6 years (mean age 5y 11mo; SD 0.3, n=30, using Movement Assessment Battery for Children, Wechsler Preschool and Primary Scale of Intelligence, Child Behavior Checklist, Teacher Report Form). Brain injury, brain volumes, and cortical measures were related to outcome with adjustment for maternal educational level. Results: Two-year cognitive score and 6-year Full-scale IQ were poorer in children with neonatal white matter injury (n=21, all p

CONTEXT: The effect of neonatal cerebellar hemorrhage on neurodevelopmental outcome (NDO) in the absence of supratentorial injury is still largely unknown. OBJECTIVE: To evaluate the influence of isolated neonatal cerebellar hemorrhage on cognitive, motor, language, and behavioral NDOs and assess the effect of location and size on outcome. DATA SOURCES: Embase, Medline, and Scopus were searched from inception to September 30, 2017. STUDY SELECTION: Studies in which a diagnosis of isolated cerebellar hemorrhage was reported in preterm infants ( DATA EXTRACTION: Patient characteristics, location, and size of bleeding and NDO (defined as severe [yes or no] on the basis of given cutoff points) in 4 domains were extracted. RESULTS: Of the 1519 studies identified, 8 were included in final analyses. Of infants with isolated cerebellar hemorrhage, 128 were described (cumulative incidence: 2.3%). The incidence of severe delay in cognition, motor, language, and behavioral development was 38%, 39%, 41%, and 38%, respectively. The overall incidence of severe neurodevelopmental delay in ≥1 domain ranged from 43% to 75% and was most seen in infants with vermis involvement (87%–93%) and with large bleeds (46%–82%). LIMITATIONS: Different neurodevelopmental scales lead to data heterogeneity, and reporting of data on a group level limited possibilities for an outcome description on an individual level. CONCLUSIONS: Of infants with isolated cerebellar hemorrhage, 43% to 75% were severely delayed in cognition, motor, language, and/or behavioral development, with the highest incidence with vermis involvement and with large bleeds.