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The evolution of non-hemorrhagic white matter injury (WMI) based on sequential magnetic resonance imaging (MRI) has not been well studied. Our aim was to describe sequential MRI findings in preterm infants with non-hemorrhagic WMI and to develop an MRI classification system for preterm WMI based on these findings. Eighty-two preterm infants (gestation ≤35 weeks) were retrospectively included. WMI was diagnosed and classified based on sequential cranial ultrasound (cUS) and confirmed on MRI. 138 MRIs were obtained at three time-points: early (<2 weeks; n = 32), mid (2-6 weeks; n = 30) and term equivalent age (TEA; n = 76). 63 infants (77%) had 2 MRIs during the neonatal period. WMI was non-cystic in 35 and cystic in 47 infants. In infants with cystic-WMI early MRI showed extensive restricted diffusion abnormalities, cysts were already present in 3 infants; mid MRI showed focal or extensive cysts, without acute diffusion changes. A significant reduction in the size and/or extent of the cysts was observed in 32% of the infants between early/mid and TEA MRI. In 4/9 infants previously seen focal cysts were no longer identified at TEA. All infants with cystic WMI showed ≥2 additional findings at TEA: significant reduction in WM volume, mild-moderate irregular ventriculomegaly, several areas of increased signal intensity on T1-weighted-images, abnormal myelination of the PLIC, small thalami. In infants with extensive WM cysts at 2-6 weeks, cysts may be reduced in number or may even no longer be seen at TEA. A single MRI at TEA, without taking sequential cUS data and pre-TEA MRI findings into account, may underestimate the extent of WMI; based on these results we propose a new MRI classification for preterm non-hemorrhagic WMI.

To evaluate the contribution of sequential cranial ultrasound (cUS) and term-equivalent age magnetic resonance imaging (TEA-MRI) including diffusion weighted imaging (DWI) to the early prognosis of neurodevelopmental outcome in a cohort of very preterm infants (gestational age [GA] <31 weeks). In total, 93 preterm infants (median [range] GA in weeks: 28.3 [25.0-30.9]) were enrolled in this prospective cohort study and underwent early and term cUS as well as TEA-MRI including DWI. Early cUS abnormalities were classified as normal, mild, moderate or severe. Term cUS was evaluated for ex-vacuo ventriculomegaly (VM) and enlargement of the extracerebral cerebrospinal fluid (eCSF) space. Abnormalities on T1- and T2-weighted TEA-MRI were scored according to Kidokoro et al. Using DWI at TEA, apparent diffusion coefficients (ADCs) were measured in four white matter regions bilaterally and both cerebellar hemispheres. Neurodevelopmental outcome was assessed at two years' corrected age (CA) using the Bayley Scales of Infant and Toddler Development, third edition. Linear regression analysis was conducted to explore the correlation between the different neuroimaging modalities and outcome. Moderate/severe abnormalities on early cUS, ex-vacuo VM and enlargement of the eCSF space on term cUS and increased cerebellar ADC values on term DWI were independently associated with worse motor outcome (p<.05). Ex-vacuo VM on term cUS was also related to worse cognitive performance at two years' CA (p<.01). These data support the clinical value of sequential cUS and recommend repeating cUS at TEA. In particular, assessment of moderate/severe early cUS abnormalities and ex-vacuo VM on term cUS provides important prognostic information. Cerebellar ADC values may further aid in the prognostication of gross motor function.

Introduction Punctate white matter lesions (PWML) are recognized with magnetic resonance imaging (MRI) as hypersignal on T1-weighted imaging and hyposignal on T2-weighted imaging. Our aim was to assess how often a hemorrhagic component was present in PWML using susceptibility-weighted imaging (SWI). Methods Seventeen preterm (gestational age, 25–34 weeks) and seven full-term infants (age at MRI, 37–42 weeks) with PWML were included. Seven preterm infants had sequential MRIs. PWML were diagnosed with conventional MRI and compared with SWI, where signal loss is suggestive of hemorrhage. The pattern of associated brain lesions was taken into account, and the percentage of lesions with signal loss on SWI was calculated for each infant. Results A significantly higher percentage of signal loss on SWI (median, 93.9%) was found among infants with germinal matrix and intraventricular hemorrhage as the primary diagnosis ( n  = 8) compared to those with a primary diagnosis of white matter injury ( n  = 14; median, 14.2%; p  < 0.01). In the infants with serial MRIs, a reduction in the number of PWML and/or signal loss on SWI was noted at term equivalent age. In the patient who died, cystic lesions, associated with hemorrhage and gliosis, were demonstrated on histology. Conclusions SWI can distinguish hemorrhagic and non-hemorrhagic PWML. Signal loss on SWI was more common when PWML were associated with an intraventricular hemorrhage. Longitudinal imaging showed a decrease in the number of PWML over time, with some PWML no longer showing signal loss on SWI, suggesting early gliosis.

BackgroundThe 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.MethodsWe 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.ResultsAbnormal 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.ConclusionsThis 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.ImpactThe 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 cerebral cortex develops rapidly in the last trimester of pregnancy. In preterm infants, brain development is very vulnerable because of their often complicated extra-uterine conditions. The aim of this study was to quantitatively describe cortical development in a cohort of 85 preterm infants with and without brain injury imaged at 30 and 40 weeks postmenstrual age (PMA). In the acquired T2-weighted MR images, unmyelinated white matter (UWM), cortical grey matter (CoGM), and cerebrospinal fluid in the extracerebral space (CSF) were automatically segmented. Based on these segmentations, cortical descriptors evaluating volume, surface area, thickness, gyrification index, and global mean curvature were computed at both time points, for the whole brain, as well as for the frontal, temporal, parietal, and occipital lobes separately. Additionally, visual scoring of brain abnormality was performed using a conventional scoring system at 40 weeks PMA. The evaluated descriptors showed larger change in the occipital lobes than in the other lobes. Moreover, the cortical descriptors showed an association with the abnormality scores: gyrification index and global mean curvature decreased, whereas, interestingly, median cortical thickness increased with increasing abnormality score. This was more pronounced at 40 weeks PMA than at 30 weeks PMA, suggesting that the period between 30 and 40 weeks PMA might provide a window of opportunity for intervention to prevent delay in cortical development.

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.

Early brain activity, measured using amplitude-integrated EEG (aEEG), is correlated with neurodevelopmental outcome in preterm newborns. F2-isoprostanes (IPs) are early biomarkers predictive for brain damage. We aimed to investigate the relationship between perinatal IPs concentrations and quantitative aEEG measures in preterm newborns. Thirty-nine infants (gestational age (GA) 24–27 ± 6 weeks) who underwent neuromonitoring using aEEG during the first two days after birth were enrolled. The rate of spontaneous activity transients per minute (SAT rate) and inter-SAT interval (ISI) in seconds were computed. Two postnatal time-points were examined: within 12 h (day 1) and between 24 and 48 h (day 2). IPs were measured in plasma from cord blood (cb-IPs) and between 24 and 48 h (pl-IPs). Multivariable regression analyses were performed to assess the correlation between IPs and brain activity. Cb-IPs were not associated with SAT rate and ISI at day 1. Higher pl-IPs were followed by longer ISI (R = 0.68; p = 0.034) and decreased SAT rate (R = 0.58; p = 0.007) at day 2 after adjusting for GA, FiO2 and IVH. Higher pl-IPs levels are associated with decreased functional brain activity. Thus, pl-IPs may represent a useful biomarker of brain vulnerability in high-risk infants.

The stressful extrauterine environment following premature birth likely has far-reaching and persistent adverse consequences. The effects of early “third-trimester” ex utero stress on large-scale brain networks’ covariance patterns may provide a potential avenue to understand how early-life stress following premature birth increases risk or resilience. We evaluated the impact of early-life stress exposure (e.g., quantification of invasive procedures) on maturational covariance networks (MCNs) between 30 and 40 weeks of gestational age in 180 extremely preterm-born infants (<28 weeks of gestation; 43.3% female). We constructed MCNs using covariance of gray matter volumes between key nodes of three large-scale brain networks: the default mode network (DMN), executive control network (ECN), and salience network (SN). Maturational coupling was quantified by summating the number of within- and between-network connections. Infants exposed to high stress showed significantly higher SN but lower DMN maturational coupling, accompanied by DMN-SN decoupling. Within the SN, the insula, amygdala, and subthalamic nucleus all showed higher maturational covariance at the nodal level. In contrast, within the DMN, the hippocampus, parahippocampal gyrus, and fusiform showed lower coupling following stress. The decoupling between DMN-SN was observed between the insula/anterior cingulate cortex and posterior parahippocampal gyrus. Early-life stress showed longitudinal network-specific maturational covariance patterns, leading to a reprioritization of developmental trajectories of the SN at the cost of the DMN. These alterations may enhance the ability to cope with adverse stimuli in the short term but simultaneously render preterm-born individuals at a higher risk for stress-related psychopathology later in life.

Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of intranasally delivered bone marrow-derived allogeneic mesenchymal stromal cells (MSCs) to treat PAIS in neonates. In this open-label intervention study in collaboration with all neonatal intensive care units in the Netherlands, we included neonates born at full term (≥36 weeks of gestation) with MRI-confirmed PAIS in the middle cerebral artery region. All eligible patients were transferred to the neonatal intensive care unit of the Wilhelmina Children's Hospital. Neonates received one dose of 45–50 × 106 bone-marrow derived MSCs intranasally within 7 days of presenting signs of PAIS. The primary endpoints were acute and subacute safety outcomes, including vital signs, blood markers, and the occurrence of toxicity, adverse events, and serious adverse events. The occurrence of unexpected cerebral abnormalities by a repeat MRI at 3 months of age was a secondary endpoint. As part of standard clinical follow-up at Wilhelmina Children's Hospital, we assessed corticospinal tract development on MRI and performed motor assessments at 4 months of age. This study is registered with ClinicalTrials.gov, NCT03356821. Between Feb 11, 2020, and April 29, 2021, ten neonates were enrolled in the study. Intranasal administration of MSCs was well tolerated in all ten neonates. No serious adverse events were observed. One adverse event was seen: a mild transient fever of 38°C without the need for clinical intervention. Blood inflammation markers (C-reactive protein, procalcitonin, and leukocyte count) were not significantly different pre-administration versus post-administration and, although thrombocyte levels increased (p=0·011), all were within the physiological range. Follow-up MRI scans did not show unexpected structural cerebral abnormalities. All ten patients had initial pre-Wallerian changes in the corticospinal tracts, but only four (40%) patients showed asymmetrical corticospinal tracts at follow-up MRI. Abnormal early motor assessment was found in three (30%) infants. This first-in-human study demonstrates that intranasal bone marrow-derived MSC administration in neonates after PAIS is feasible and no serious adverse events were observed in patients followed up until 3 months of age. Future large-scale placebo-controlled studies are needed to determine the therapeutic effect of intranasal MSCs for PAIS. Netherlands Organization for Health Research and Development (ZonMw).

This study investigates the predictive ability of automatic quantitative brain MRI descriptors for the identification of infants with low cognitive and/or motor outcome at 2–3 years chronological age. MR brain images of 173 patients were acquired at 30 weeks postmenstrual age (PMA) (n = 86) and 40 weeks PMA (n = 153) between 2008 and 2013. Eight tissue volumes and measures of cortical morphology were automatically computed. A support vector machine classifier was employed to identify infants who exhibit low cognitive and/or motor outcome (<85) at 2–3 years chronological age as assessed by the Bayley scales. Based on the images acquired at 30 weeks PMA, the automatic identification resulted in an area under the receiver operation characteristic curve (AUC) of 0.78 for low cognitive outcome, and an AUC of 0.80 for low motor outcome. Identification based on the change of the descriptors between 30 and 40 weeks PMA (n = 66) resulted in an AUC of 0.80 for low cognitive outcome and an AUC of 0.85 for low motor outcome. This study provides evidence of the feasibility of identification of preterm infants at risk of cognitive and motor impairments based on descriptors automatically computed from images acquired at 30 and 40 weeks PMA.