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Highlights • Transient fetal structures are visible on T2 MRI in neonates and can be scored. • Radiologically, these structures are different in term and former preterm infants. • Maturity of crossroads and subplate particularly discriminates the two groups. • Prematurity affects white matter precursors in frontal and occipital areas. • At term age, some preterms show accelerated occipital white matter maturation., Background and purpose Currently available MRI scoring systems of cerebral maturation in term and preterm infant at term equivalent age do not include the changes of transient fetal compartments that persist to term age. We studied the visibility and the pattern of these structures in healthy term newborns compared to preterm infants at term equivalent age in order to investigate if they can be included in a new MRI score system. We hypothesized that transient fetal compartments are different in both groups, and that these differences can be characterized using the clinical T2-weighted MRIs. Materials and methods Using 3T MRI T2-weighted brain sequences of 21 full-term and 41 preterm infants (< 32 weeks), scanned at term equivalent age, 3 raters independently scored the maturation level of 3 transient fetal compartments: the periventricular crossroads, von Monakow segments of the white matter, and the subplate compartment. These 3 new items were included in a scoring system along with validated parameters of brain maturation (germinal matrix, bands of migration, subarachnoid space and quality of gyrification). A cumulative maturity score was calculated separately for both groups of newborns by adding together each item. More mature were the brain structures, higher was the cumulative maturity score. Results Cumulative maturity score distinguished full-term from preterm infants (mean score 41/60 ± 1.4 versus 37/60 ± 2.5 points, p < 0.001), with an increase of 0.5 points for each supplemental gestational week at birth (r = 0.5, 95% CI 0.5 – 0.85). While a majority of transient fetal compartments were less mature in preterm group at term equivalent age, von Monakow segments of the white matter and subplate compartment presented a more advanced maturational stage in the preterm group compared to the term group. No subject had all scored items in the most mature state. Except a slight intra-rater agreement for von Monakow segment II, inter- and intra-rater agreements were moderate to excellent indicating the potential of the developed scoring system in routine clinical practice. Conclusion Brain transient fetal structures can be assessed on regular T2-weighted MRI in newborns. Their appearance differs between term and preterm babies. However our results suggest a more complex situation, with both delayed and accelerated maturation pattern in preterm infants. It remains to be determined if these differences could be biomarkers of the future neurodevelopment of preterm infants.

Periventricular white matter injury is common in very preterm infants and it is associated with long term neurodevelopmental impairments. While evidence supports the protective effects of erythropoetin (EPO) in preventing injury, we currently lack the complete understanding of how EPO affects the emergence and maturation of anatomical brain connectivity and function. In this case-control study, connectomic analysis based on diffusion MRI tractography was applied to evaluate the effect of early high-dose EPO in preterm infants. A whole brain, network-level analysis revealed a sub-network of anatomical brain connections in which connectivity strengths were significantly stronger in the EPO group. This distributed network comprised connections predominantly in the frontal and temporal lobe bilaterally, and the effect of EPO was focused on peripheral and feeder connections of the core structural connectivity network. EPO resulted in a globally increased clustering coefficient, higher global and average local efficiency, while higher strength and increased clustering was found for regions in the frontal lobe and cingulate gyrus. The connectivity network most affected by the EPO treatment showed a steeper increase graph theoretical measures with age compared to the placebo group. Our results demonstrate a weak but widespread effect of EPO on the structural connectivity network and a possible trophic effect of EPO reflected by increasing network segregation, predominantly in local connections., Highlights • Erythropoietin (EPO) is a potential neuroprotective agent in very preterm infants. • EPO leads to increased structural brain connectivity in fronto-temporal regions. • Clustering coefficient, local and global efficiency increases after EPO treatment.

Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3-9% of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain, and is in consequence called brain sparing. Despite this, it is now apparent that brain sparing does not ensure normal brain development in growth-restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who had FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions.

Lactoferrin (Lf), component of maternal milk, has antioxidant, anti-inflammatory and antimicrobial properties. Neuroprotective effects of Lf on the immature brain have been recently shown in rodent models of intrauterine growth restriction and cerebral hypoxia/ischemia. Here we postulated that Lf could also have beneficial effects on preterm inflammatory brain injury. Lf was supplemented in maternal food during lactation and lipopolysaccharide (LPS) was injected in subcortical white matter of rat pups at postnatal day 3 (P3). Effect of maternal Lf supplementation was investigated 24 h (P4), 4 (P7), or 21 days (P24) after LPS injection mainly on the striatum. Lateral ventricle and brain structures volumes were quantified. Microstructure was evaluated by diffusion tensor imaging, neurite orientation dispersion and density imaging as well as electron microscopy. Neurochemical profile was measured by (1) H-magnetic resonance spectroscopy. GFAP protein, proinflammatory cytokines mRNA expression microglial activation were assessed. Lf displayed neuroprotective effects as shown by reduced LPS-induced ventriculomegaly, brain tissue loss, and microstructural modifications, including myelination deficit. (1) H-MRS neurochemical profile was less altered through an antioxidant action of Lf. Despite the lack of effect on LPS-induced proinflammatory cytokines genes expression and on reactive gliosis, microglia was less activated under Lf treatment. In conclusion, Lf supplemented in food during lactation attenuated acute and long-term cerebral LPS-induced alterations. This provides a new evidence for a promising use of Lf as a preventive neuroprotective approach in preterm encephalopathy. © 2016 BioFactors, 42(3):323-336, 2016.

Preterm birth is associated with a higher prevalence of neurodevelopmental deficits. Indeed, preterm children are at increased risk for cognitive, behavioral, and socio-emotional difficulties. There is currently an increasing interest in introducing music intervention in neonatal intensive care unit (NICU) care. Several studies have shown short-term beneficial effects. A recent study has shown that listening to a familiar music (heard daily during the NICU stay) enhanced preterm infants' functional connectivity between auditory cortices and subcortical brain regions at term-equivalent age. However, the long-term effects of music listening in the NICUs have never been explored. The aim of this study was to evaluate at 12 and 24 months the effects of music listening in the NICU on cognitive and emotional development in preterm children by comparing them to a preterm control group with no previous music exposure and to a full-term group. Participants were 44 children (17 full-term and 27 preterm). Preterm children were randomized to either music intervention or control condition (without music). The preterm-music group regularly listened to music from 33 weeks postconceptional age until hospital discharge or term-equivalent age. At 12 months, children were evaluated on the Bayley Scales of Infant and Toddler Development, Third Edition, then with 4 episodes of the Laboratory Temperament Assessment Battery (assessing expressions of joy, anger, and fear, and sustained attention). At 24 months, the children were evaluated with the same tests, and with 3 additional episodes of the Effortful Control Battery (assessing inhibition). Results showed that the scores of preterm children, music and control, differed from those of full-term children for fear reactivity at 12 months of age and for anger reactivity at 24 months of age. Interestingly, these significant differences were less important between the preterm-music and the full-term groups than between the preterm-control and the full-term groups. The present study provides preliminary, but promising, scientific findings on the beneficial long-term effects of music listening in the NICU on neurodevelopmental outcomes in preterm children, and more specifically on emotion mechanisms at 12 and 24 months of age. Our findings bring new insights for supporting early music intervention in the NICU.

AIM Hospitalised newborn infants may be stressed due to inappropriate sensory stimuli and early separation from their families, that can negatively impact their neurodevelopment. The French Group of Reflection and Evaluation of the Environment of Newborns (GREEN) issues guidelines based on environmental neonatology and family-centred care. The first recommendation focuses on private family rooms versus large shared rooms. METHODS These guidelines are based on a systematic evaluation of the literature providing different grades of evidence. Internal and external reviews by multidisciplinary experts examined the scientific evidence of all recommendations. The literature search was performed for the period January 1, 2000 to January 1, 2016 with the keywords 'single room' or 'private room' and 'neonatal intensive care unit'. RESULTS A total of 25 studies were retained. Most studies reported a positive impact of private rooms on the health of newborn infants and satisfaction of families. Private rooms could lead to sensory deprivation if there is low parental involvement with limited presence and to reduced interaction among caregivers. CONCLUSION We recommend that neonatal units should mostly have private rooms. With this architectural design, we recommend supporting the staff's needs for changes in the organisation and philosophy of care and to provide improved family support.

Aim This study assessed predictive values of fidgety movement assessment (FMA) in a large sample of infants born very preterm for developmental abnormalities, in particular for cerebral palsy (CP) at 2 years in an everyday clinical setting. Method This is a multicentre study of infants born preterm with gestational age lower than 32.0 weeks. FMA was performed at 3 months corrected age; neurodevelopment (Bayley Scales of Infant Development, 2nd edition) and neurological abnormalities were assessed at 2 years. Predictive values of FMA for the development of CP were calculated and combined with abnormalities at cerebral ultrasound. Results Five hundred and thirty-five infants (gestational age 28.2wks [standard deviation 1.3wks]) were included. Eighty-one percent showed normal fidgety movements and 19% atypical (82 absent, 21 abnormal) fidgety movements. Absent fidgety movements predicted CP at 2 years with an odds ratio (OR) of 8.9 (95% confidence interval [CI] 4.1–17.0), a combination of atypical fidgety movements and major brain lesion on cerebral ultrasound predicted it with an OR of 17.8 (95% CI 5.2–61.6). Mean mental developmental index of infants with absent fidgety movements was significantly lower (p=0.012) than with normal fidgety movements. Interpretation Detection of infants at risk for later CP through FMA was good, but less robust when performed in a routine clinical setting; prediction improved when combined with neonatal cerebral ultrasound.

Over the last decade, there has been a significant increase in the number of high-magnetic-field MRI magnets. However, the exact effect of a high magnetic field strength (B0 ) on diffusion-weighted MR signals is not yet fully understood. The goal of this study was to investigate the influence of different high magnetic field strengths (9.4 T and 14.1 T) and diffusion times (9, 11, 13, 15, 17 and 24 ms) on the diffusion-weighted signal in rat brain white matter. At a short diffusion time (9 ms), fractional anisotropy values were found to be lower at 14.1 T than at 9.4 T, but this difference disappeared at longer diffusion times. A simple two-pool model was used to explain these findings. The model describes the white matter as a first hindered compartment (often associated with the extra-axonal space), characterized by a faster orthogonal diffusion and a lower fractional anisotropy, and a second restricted compartment (often associated with the intra-axonal space), characterized by a slower orthogonal diffusion (i.e. orthogonal to the axon direction) and a higher fractional anisotropy. Apparent T2 relaxation time measurements of the hindered and restricted pools were performed. The shortening of the pseudo-T2 value from the restricted compartment with B0 is likely to be more pronounced than the apparent T2 changes in the hindered compartment. This study suggests that the observed differences in diffusion tensor imaging parameters between the two magnetic field strengths at short diffusion time may be related to differences in the apparent T2 values between the pools. Copyright © 2013 John Wiley & Sons, Ltd.

Objective To examine the relationships between intensity of delivery room resuscitation and short- and long-term outcomes of very low birth weight infants enrolled in the Caffeine for Apnea of Prematurity (CAP) Trial. Study design The CAP Trial enrolled 2006 infants with birthweights between 500 and 1250 g who were eligible for caffeine therapy. All levels of delivery room resuscitation were recorded in study participants. We divided infants in 4 groups of increasing intensity of resuscitation: minimal, n = 343; bag-mask ventilation, n = 372; endotracheal intubation, n = 1205; and cardiopulmonary resuscitation (chest compressions/epinephrine), n = 86. We used multivariable logistic regression models to compare outcomes across the 4 groups. Results The observed rates of death or disability, death, cerebral palsy, cognitive deficit, and hearing loss at 18 months increased with higher levels of resuscitation. Risk of bronchopulmonary dysplasia, severe retinopathy of prematurity, and brain injury also increased with higher levels of resuscitation. Adjustment for prognostic variables reduced the differences between the groups for most outcomes. Only the adjusted rates of bronchopulmonary dysplasia and severe retinopathy remained significantly higher after more intense resuscitation. Conclusions In CAP Trial participants, the risk of death or neurodevelopmental disability at 18 months did not increase substantially with increasing intensity of delivery room resuscitation.

Brain function is tightly linked to the development of the cortex. Until recently, assessing the human cortical development and folding was not possible in vivo. It is magnetic resonance imaging and new post-processing image analysis tools that have improved the understanding of cortical development. The combination of conventional magnetic resonance imaging and diffusion tensor imaging has further allowed depiction of the relationship of changes in intracortical layering and cortical folding. Being able to follow these early developmental processes has elucidated changes in early brain development due to changed environmental conditions in fetal life such as twinning and fetal growth restriction and postnatal conditions such as prematurity. This review further illustrates new data on brain structural asymmetries linked to the emergence of early language functions.

Objective To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the Caffeine for Apnea of Prematurity (CAP) trial. Study design Post-hoc subgroup analyses were performed on the basis of: (1) indication for commencement of study drug: treat apnea, prevent apnea, or facilitate extubation; (2) positive pressure ventilation (PPV) at randomization: endotracheal tube (ETT), noninvasive ventilation, or none; and (3) timing of commencement of study drug: early or late (≤3 versus >3 days). Outcomes assessed were those showing treatment effects in the original analyses. We investigated the consistency of caffeine effects by using regression models that incorporated treatment/subgroup factor interactions. Results There was little evidence of a differential treatment effect of caffeine in subgroups defined by the clinical indication for starting study drug. The size and direction of the caffeine effect on death or disability differed depending on PPV at randomization ( P = .03). Odds ratios (95% CI) were: no support, 1.32 (0.81-2.14); noninvasive support, 0.73 (0.52-1.03); and ETT, 0.73 (0.57-0.94). Adjustment for baseline factors strengthened this effect ( P = .02). Starting caffeine early resulted in larger reductions in days of respiratory support. Postmenstrual age at time of discontinuing PPV was shorter with earlier treatment ( P = .01). Mean differences (95% CI) were: early, 1.35 weeks (0.90-1.81); and late 0.55 weeks (–0.11-0.99). Adjustment for baseline factors weakened this effect ( P = .03). Conclusions There is evidence of variable beneficial effects of caffeine. Infants receiving respiratory support appeared to derive more neurodevelopmental benefits from caffeine than infants not receiving support. Earlier initiation of caffeine may be associated with a greater reduction in time on ventilation.

Within preterm-born children, being born male and at a lower gestational age (GA) have both been associated with a heightened risk for developmental difficulties. However, in this population little is known about the combined effect and the influence of these risk factors on cortical structures and executive control. In the present study, 58 preterm-born children (GA ranging from 24.0 to 35.1 weeks) were administered the computerized Child Attention Network Task at 6 years of age. Brain magnetic resonance imaging was performed and analyzed using Voxel-Based Morphometry (VBM) in all children. At a behavioral level, boys born28 weeks of GA had significantly less executive control than preterm-born girls28 weeks (p = .001) and preterm-born boys ≥28 (p = .003). The reduced executive control in preterm-born boys28 weeks gestation was related to lower cortical densities in the inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC). The current study links the higher incidence of reduced executive control in preterm-born boys to a higher degree of prematurity (low GA) and identifies brain structural abnormalities in the prefrontal cortex related to these deficits. The implications of these results are discussed.

Understanding human brain development from the fetal life to adulthood is of great clinical importance as many neurological and neurobehavioral disorders have their origin in early structural and functional cerebral maturation. The developing brain is particularly prone to being affected by endogenous and exogenous events through the fetal and early postnatal life. The concept of 'developmental plasticity or disruption of the developmental program' summarizes these events. Increases in white matter, which speed up communication between brain cells, growing complexity of neuronal networks suggested by gray and white matter changes, and environmentally sensitive plasticity are all essential aspects in a child's ability to mentalize and maintain the adaptive flexibility necessary for achieving high sociocognitive functioning. Advancement in neuroimaging has opened up new ways for examining the developing human brain in vivo, the study of the effects of early antenatal, perinatal and neonatal events on later structural and functional brain development resulting in developmental disabilities or developmental resilience. In this review, methods of quantitative assessment of human brain development, such as 3D-MRI with image segmentation, diffusion tensor imaging to assess connectivity and functional MRI to visualize brain function will be presented.

Development of brain functions and the structural-functional correlates of brain injury remain difficult to evaluate in the young infant. Thus, new noninvasive methods capable of early functional diagnosis are needed. This review describes the use of functional magnetic resonance imaging (fMRI) for studying localization of brain function in the developing brain when standard clinical investigations are not available or conclusive. This promising neuroimaging technique has been successfully used in healthy newborns and in newborns with brain injury using different paradigms, including passive visual, somato-sensorial, and auditory stimulation. We summarize the major findings of previous fMRI studies in young infants, describe ongoing methodological challenges, and propose exciting future developments in using resting-state protocols and functional connectivity techniques to assist in evaluating early life brain function and its recovery from injury.

Significant human brain growth occurs during the third trimester, with a doubling of whole brain volume and a fourfold increase of cortical gray matter volume. This is also the time period during which cortical folding and gyrification take place. Conditions such as intrauterine growth restriction, prematurity and cerebral white matter injury have been shown to affect brain growth including specific structures such as the hippocampus, with subsequent potentially permanent functional consequences. The use of 3D magnetic resonance imaging (MRI) and dedicated postprocessing tools to measure brain tissue volumes (cerebral cortical gray matter, white matter), surface and sulcation index can elucidate phenotypes associated with early behavior development. The use of diffusion tensor imaging can further help in assessing microstructural changes within the cerebral white matter and the establishment of brain connectivity. Finally, the use of functional MRI and resting-state functional MRI connectivity allows exploration of the impact of adverse conditions on functional brain connectivity in vivo. Results from studies using these methods have for the first time illustrated the structural impact of antenatal conditions and neonatal intensive care on the functional brain deficits observed after premature birth. In order to study the pathophysiology of these adverse conditions, MRI has also been used in conjunction with histology in animal models of injury in the immature brain. Understanding the histological substrate of brain injury seen on MRI provides new insights into the immature brain, mechanisms of injury and their imaging phenotype.

Understanding human brain development from the fetal life to adulthood is of great clinical importance as many neurological and neurobehavioral disorders have their origin in early structural and functional cerebral maturation. The developing brain is particularly prone to being affected by endogenous and exogenous events through the fetal and early postnatal life. The concept of 'developmental plasticity or disruption of the developmental program' summarizes these events. Increases in white matter, which speed up communication between brain cells, growing complexity of neuronal networks suggested by gray and white matter changes, and environmentally sensitive plasticity are all essential aspects in a child's ability to mentalize and maintain the adaptive flexibility necessary for achieving high sociocognitive functioning. Advancement in neuroimaging has opened up new ways for examining the developing human brain in vivo, the study of the effects of early antenatal, perinatal and neonatal events on later structural and functional brain development resulting in developmental disabilities or developmental resilience. In this review, methods of quantitative assessment of human brain development, such as 3D-MRI with image segmentation, diffusion tensor imaging to assess connectivity and functional MRI to visualize brain function will be presented.

Understanding early human brain development is of great clinical importance, as many neurological and neurobehavioral disorders have their origin in early structural and functional cerebral organization and maturation. Diffusion tensor imaging (DTI), a recent magnetic resonance (MR) modality which assesses water diffusion in biological tissues at a microstructural level, has revealed a powerful technique to explore the structural basis of normal brain development. In fact, the tissue organization can be probed non-invasively, and the age-related changes of diffusion parameters (mean diffusivity, anisotropy) reveal crucial maturational processes, such as white matter myelination. Nevertheless, the developing human brain presents several challenges for DTI applications compared with the adult brain. DTI may further be used to detect brain injury well before conventional MRI, as water diffusion changes are an early indicator of cellular injury. This is particularly critical in infants in the context of administration of neuroprotective therapies. Changes in diffusion characteristics further provide early evidence of both focal and diffuse white matter injury in association with periventricular leukomalacia in the preterm infant. Finally, with the development of 3D fiber tractography, the maturation of white matter connectivity can be followed throughout infant development into adulthood with the potential to study correlations between abnormalities on DTI and ultimate neurologic/cognitive outcome.

The human brain is susceptible to a wide variety of insults. The permanent residua of these abnormalities are represented in dysfunction of one or more areas of neurodevelopment. A full understanding of normal brain development, mechanisms of brain injury, and consequences for subsequent brain development is required to determine which infants are at risk for neurodevelopmental handicap, and to monitor the effects of new treatments and management regimens designed to prevent these disabilities. Advanced magnetic resonance techniques, such as quantitative morphometric magnetic resonance techniques, diffusion-weighted magnetic resonance techniques, and magnetic resonance spectroscopy applied to the study of early human brain development have given us a better understanding of the pathophysiologic mechanisms of brain injury and its effects on subsequent brain development. Magnetic resonance imaging has provided an invaluable tool for the study of the fetal and newborn brain in vivo.