Relationship Between Early Functional and Structural Brain Developments and Brain Injury in Preterm Infants.

BACKGROUND: Recent studies explored the relationship between early brain function and brain morphology, based on the hypothesis that increased brain activity can positively affect structural brain development and that excitatory neuronal activity stimulates myelination. OBJECTIVE: To investigate the relationship between maturational features from early and serial aEEGs after premature birth and MRI metrics characterizing structural brain development and injury, measured around 30weeks postmenstrual age (PMA) and at term. Moreover, we aimed to verify whether previously developed maturational EEG features are related with PMA. DESIGN/METHODS: One hundred six extremely preterm infants received bedside aEEGs during the first 72h and weekly until week 5. 3T-MRIs were performed at 30weeks PMA and at term. Specific features were extracted to assess EEG maturation: (1) the spectral content, (2) the continuity [percentage of spontaneous activity transients (SAT%) and the interburst interval (IBI)], and (3) the complexity. Automatic MRI segmentation to assess volumes and MRI score was performed. The relationship between the maturational EEG features and MRI measures was investigated. RESULTS: Both SAT% and EEG complexity were correlated with PMA. IBI was inversely associated with PMA. Complexity features had a positive correlation with the cerebellar size at 30weeks, while event-based measures were related to the cerebellar size at term. Cerebellar width, cortical grey matter, and total brain volume at term were inversely correlated with the relative power in the higher frequency bands. CONCLUSIONS: The continuity and complexity of the EEG steadily increase with increasing postnatal age. Increasing complexity and event-based features are associated with cerebellar size, a structure with enormous development during preterm life. Brain activity is important for later structural brain development.

Longitudinal study of neonatal brain tissue volumes in preterm infants and their ability to predict neurodevelopmental outcome.

Premature birth has been associated with poor neurodevelopmental outcomes. However, the relation between such outcomes and brain growth in the neonatal period has not yet been fully elucidated. This study investigates longitudinal brain development between birth and term-equivalent age (TEA) by quantitative imaging in a cohort of premature infants born between 26 and 36 weeks gestational age (GA), to provide insight into the relation of brain growth with later neurodevelopmental outcomes. Longitudinal T2-weighted magnetic resonance images (MRI) of 84 prematurely born infants acquired shortly after birth and TEA were automatically segmented into cortical gray matter (CGM), unmyelinated white matter (UWM), subcortical gray matter (SGM), cerebellum (CB) and cerebrospinal fluid (CSF). General linear models and correlation analysis were used to study the relation between brain volumes and their growth, and perinatal variables. To investigate the ability of the brain volumes to predict children's neurodevelopmental outcome at 18-24 months and at 5 years of age, a linear discriminant analysis classifier was tested and several general linear models were fitted and compared by statistical tests. From birth to TEA, relative volumes of CGM, CB and CSF with respect to total intracranial volume increased, while relative volumes of UWM and SGM decreased. The fastest growing tissues between birth and TEA were found to be the CB and the CGM. Lower GA at birth was associated with lower growth rates of CGM, CB and total tissue. Among perinatal factors, persistent ductus arteriosus was associated with lower SGM, CB and IC growth rates, while sepsis was associated with lower CSF and intracranial volume growth rates. Model comparisons showed that brain tissue volumes at birth and at TEA contributed to the prediction of motor outcomes at 18-24 months, while volumes at TEA and volume growth rates contributed to the prediction of cognitive scores at 5 years of age. The family socio-economic status (SES) was not correlated with brain volumes at birth or at TEA, but was strongly associated with the cognitive outcomes at 18-24 months and 5 years of age. This study provides information about brain growth between birth and TEA in premature children with no focal brain lesions, and investigates their association with subsequent neurodevelopmental outcome. Parental SES was found to be a major determinant of neurodevelopmental outcome, unrelated to brain growth. However, further research is necessary in order to fully explain the variability of neurodevelopmental outcomes in this population.

Recommendation for hygiene and topical in neonatology from the French Neonatal Society.

We sought to establish guidelines for hygiene care in newborns based on a systematic review of the literature and grading of evidence using the Groupe de Réflexion et d'Evaluation de l'Environement des Nouveau-nés (GREEN) methodology. We examined 45 articles and 4 reports from safety agencies. These studies recommend a tub bath (rather than a sponge bath) for full-term infants and a swaddle bath for preterm newborns. They also recommend against daily cleansing of preterm infants. The literature emphasized that hygiene care must consider the clinical state of the newborn, including the level of awareness and behavioral responses. Hospitalized newborns treated with topical agents may also experience high exposure to potentially harmful excipients of interest. Caregivers should therefore be aware of the excipients present in the different products they use. In high-resource countries, the available data do not support the use of protective topical agents for preterm infants.Conclusions: We recommend individualization of hygiene care for newborns. There is increasing concern regarding the safety of excipients in topical agents that are used in neonatology. A multidisciplinary approach should be used to identify an approach that requires lower levels of excipients and alternative excipients. What is known: • Hygiene care is one of the most basic and widespread types of care received by healthy and sick newborns worldwide. • There is no current guideline on hygiene for preterm or hospitalized term newborn. What is new: • The French Group of Reflection and Evaluation of the environment of Newborns (GREEN) provided here guidelines based on the current body of evidence. • Caregivers should be aware of the many issues related to hygiene care of newborns including newborns' behavioral responses to hygiene care, exposition to excipients of interest, and the potential risk of protective topical agents in a preterm infant. provided here guidelines based on the current body of evidence. • Caregivers should be aware of the many issues related to hygiene care of newborns including newborns' possible behavioral responses to hygiene care, exposition to excipients of interest and the potential risk of protective topical agents in a preterm infant.

Neuroprocessing Mechanisms of Music during Fetal and Neonatal Development: A Role in Neuroplasticity and Neurodevelopment.

The primary aim of this viewpoint article is to examine recent literature on fetal and neonatal processing of music. In particular, we examine the behavioral, neurophysiological, and neuroimaging literature describing fetal and neonatal music perception and processing to the first days of term equivalent life. Secondly, in light of the recent systematic reviews published on this topic, we discuss the impact of music interventions on the potential neuroplasticity pathways through which the early exposure to music, live or recorded, may impact the fetal, preterm, and full-term infant brain. We conclude with recommendations for music stimuli selection and its role within the framework of early socioemotional development and environmental enrichment.

[Cerebral brain injury in preterm infants and the role of neuroimaging in predicting neurodevelopmental outcomes]. / Lésions cérébrales du prématuré et techniques d'imagerie à visée pronostique du développement neurocognitif.

Due to advances in neonatal intensive care over the last decades, the pattern of brain injury seen in very preterm infants has evolved in more subtle lesions that are still essential to diagnose in regard to neurodevelopmental outcome. While cranial ultrasound is still used at the bedside, magnetic resonance imaging (MRI) is becoming increasingly used in this population for the assessment of brain maturation and white and grey matter lesions. Therefore, MRI provides a better prognostic value for the neurodevelopmental outcome of these preterms. Furthermore, the development of new MRI techniques, such as diffusion tensor imaging, resting state functional connectivity and magnetic resonance spectroscopy, may further increase the prognostic value, helping to counsel parents and allocate early intervention services.

[Pediatrics. Developmental care in neonatology]. / Pédiatrie. 1. Les soins de soutien au développement en néonatologie.

Developmental care is a multidisciplinary approach aiming at improving the premature newborn's well-being through individualized observation and care, and at limiting environmental nociceptive stimuli. The aim is to lessen neonatal morbidity and enhance long-term psychomotor development in this population of high-risk newborns.

[Neurodevelopmental follow-up of premature children in Lausanne and Geneva]. / Suivi neurodéveloppemental de l'enfant né prématuré dans l'Arc lémanique.

Preterm children born before 32 weeks of gestation represent 1% of the annual births in Switzerland, and are the most at risk of neurodevelopmental disabilities. A neurological surveillance is thus implemented in the neonatal units, and multidisciplinary neurodevelopmental follow-up is offered to all our preterm patients. The follow-up clinics of the University hospitals in Lausanne and Geneva follow the Swiss guidelines for follow-up. An extended history and neurological examination is taken at each appointment, and a standardized test of development is performed. These examinations, which take place between the ages of 3 months and 9 years old, allow the early identification and treatment of developmental disorders frequent in this population, such as motor, cognitive or behavioral disorders, as well as the monitoring of the quality of neonatal care.

Structural asymmetries of perisylvian regions in the preterm newborn.

During the last trimester of human pregnancy, the cerebral cortex of foetuses becomes greatly and quickly gyrified, and post-mortem studies have demonstrated that hemispheres are already asymmetric at the level of Heschl gyrus, planum temporale and superior temporal sulcus (STS). Recently, magnetic resonance imaging (MRI) and dedicated post-processing tools enabled the quantitative study of brain development non-invasively in the preterm newborn. However, previous investigations were conducted either over the whole brain or in specific sulci. These approaches may consequently fail to highlight most cerebral sites, where anatomical landmarks are hard to delineate among individuals. In this cross-sectional study, we aimed to blindly and automatically map early asymmetries over the immature cortex. Voxel-based analyses of cortical and white matter masks were performed over a group of 25 newborns from 26 to 36 weeks of gestational age. Inter-individual variations associated with increasing age were first detected in large cerebral regions, with a prevalence of the right hemisphere in comparison with the left. Asymmetries were further highlighted in three specific cortical regions. Confirming previous studies, we observed deeper STS on the right side and larger posterior region of the sylvian fissure on the left side, close to planum temporale. For the first time, we also detected larger anterior region of the sylvian fissure on the left side, close to Broca's region. This study demonstrated that perisylvian regions are the only regions to be asymmetric from early on, suggesting their anatomical specificity for the emergence of functional lateralization in language processing prior to language exposure.

Diffusion-weighted spectroscopy: a novel approach to determine macromolecule resonances in short-echo time 1H-MRS.

Quantification of short-echo time proton magnetic resonance spectroscopy results in >18 metabolite concentrations (neurochemical profile). Their quantification accuracy depends on the assessment of the contribution of macromolecule (MM) resonances, previously experimentally achieved by exploiting the several fold difference in T(1). To minimize effects of heterogeneities in metabolites T(1), the aim of the study was to assess MM signal contributions by combining inversion recovery (IR) and diffusion-weighted proton spectroscopy at high-magnetic field (14.1 T) and short echo time (= 8 msec) in the rat brain. IR combined with diffusion weighting experiments (with δ/Δ = 1.5/200 msec and b-value = 11.8 msec/µm(2)) showed that the metabolite nulled spectrum (inversion time = 740 msec) was affected by residuals attributed to creatine, inositol, taurine, choline, N-acetylaspartate as well as glutamine and glutamate. While the metabolite residuals were significantly attenuated by 50%, the MM signals were almost not affected (< 8%). The combination of metabolite-nulled IR spectra with diffusion weighting allows a specific characterization of MM resonances with minimal metabolite signal contributions and is expected to lead to a more precise quantification of the neurochemical profile.

Attentional networks efficiency in preterm children.

Recent studies have reported specific executive and attentional deficits in preterm children. However, the majority of this research has used multidetermined tasks to assess these abilities, and the interpretation of the results lacks an explicit theoretical backdrop to better understand the origin of the difficulties observed. In the present study, we used the Child Attention Network Task (Child ANT; Rueda et al. 2004) to assess the efficiency of the alerting, orienting and executive control networks. We compared the performance of 25 preterm children (gestational age < or = 32 weeks) to 25 full-term children, all between 5(1/2) and 6(1/2) years of age. Results showed that, as compared to full-term children, preterm children were slower on all conditions of the Child ANT and had a specific deficit in executive control abilities. We also observed a significantly higher correlation between the orienting and executive control networks in the preterm group, suggesting less differentiation of these two networks in this population.

Morphine affects brain activity and volumes in preterms: An observational multi-center study.

OBJECTIVE: We hypothesized that morphine has a depressing effect on early brain activity, assessed using quantitative aEEG/EEG parameter and depressed activity will be associated with brain volumes at term in extremely preterm infants. STUDY DESIGN: 174 preterm infants were enrolled in 3 European tertiary NICUs (mean GA:26 ± 1wks) and monitored during the first 72 h after birth with continuous 2 channel aEEG. Six epochs of aEEG recordings were selected and minimum amplitude of aEEG (min aEEG), percentage of time amplitude <5 µV (% of time < 5 µV), spontaneous activity transients (SATrate) and interSAT interval (ISI) were calculated. For infants receiving morphine, the cumulative morphine dosage was calculated. In a subgroup of 58 infants, good quality MRI at term equivalent age (TEA) and the cumulative morphine dose until TEA were available. The effects of morphine administration and cumulative dose on aEEG/EEG measures and on brain volumes were investigated. RESULTS: Morphine administration had a significant effect on all quantitative aEEG/EEG measures, causing depression of early brain activity [longer ISI (ß 2.900), reduced SAT rate (ß -1.386), decreased min aEEG (ß -0.782), and increased % of time < 5 µV (ß 14.802)] in all epochs. A significant effect of GA and postnatal age on aEEG/EEG measures was observed. Cumulative morphine dose until TEA had a significant negative effect on total brain volume (TBV) (ß -8.066) and cerebellar volume (ß -1.080). CONCLUSIONS: Administration of sedative drugs should be considered when interpreting aEEG/EEG together with the negative dose dependent morphine impact on brain development.

Primary cortical folding in the human newborn: an early marker of later functional development.

In the human brain, the morphology of cortical gyri and sulci is complex and variable among individuals, and it may reflect pathological functioning with specific abnormalities observed in certain developmental and neuropsychiatric disorders. Since cortical folding occurs early during brain development, these structural abnormalities might be present long before the appearance of functional symptoms. So far, the precise mechanisms responsible for such alteration in the convolution pattern during intra-uterine or post-natal development are still poorly understood. Here we compared anatomical and functional brain development in vivo among 45 premature newborns who experienced different intra-uterine environments: 22 normal singletons, 12 twins and 11 newborns with intrauterine growth restriction (IUGR). Using magnetic resonance imaging (MRI) and dedicated post-processing tools, we investigated early disturbances in cortical formation at birth, over the developmental period critical for the emergence of convolutions (26-36 weeks of gestational age), and defined early 'endophenotypes' of sulcal development. We demonstrated that twins have a delayed but harmonious maturation, with reduced surface and sulcation index compared to singletons, whereas the gyrification of IUGR newborns is discordant to the normal developmental trajectory, with a more pronounced reduction of surface in relation to the sulcation index compared to normal newborns. Furthermore, we showed that these structural measurements of the brain at birth are predictors of infants' outcome at term equivalent age, for MRI-based cerebral volumes and neurobehavioural development evaluated with the assessment of preterm infant's behaviour (APIB).

Mapping the early cortical folding process in the preterm newborn brain.

In the developing human brain, the cortical sulci formation is a complex process starting from 14 weeks of gestation onward. The potential influence of underlying mechanisms (genetic, epigenetic, mechanical or environmental) is still poorly understood, because reliable quantification in vivo of the early folding is lacking. In this study, we investigate the sulcal emergence noninvasively in 35 preterm newborns, by applying dedicated postprocessing tools to magnetic resonance images acquired shortly after birth over a developmental period critical for the human cortex maturation (26-36 weeks of age). Through the original three-dimensional reconstruction of the interface between developing cortex and white matter and correlation with volumetric measurements, we document early sulcation in vivo, and quantify changes with age, gender, and the presence of small white matter lesions. We observe a trend towards lower cortical surface, smaller cortex, and white matter volumes, but equivalent sulcation in females compared with males. By precisely mapping the sulci, we highlight interindividual variability in time appearance and interhemispherical asymmetries, with a larger right superior temporal sulcus than the left. Thus, such an approach, included in a longitudinal follow-up, may provide early indicators on the structural basis of cortical functional specialization and abnormalities induced by genetic and environmental factors.

Network based statistics reveals trophic and neuroprotective effect of early high dose erythropoetin on brain connectivity in very 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.

[Intrauterine growth restriction: impact on brain development and function]. / Retard de croissance intra-utérin: impact sur le développement et tla fonction cérébrale.

Evidence exists that the developing organism adapts to the environment it finds itself. Short and long-term adjustments take place and will initially induce intrauterine growth retardation but will also have consequences that will appear later in life. These adjustments are referred as "programming". The use of advanced magnetic resonance imaging techniques in IUGR babies has delineated changes in the development of the central nervous system that correlate with altered neurodevelopment and could be implicated in the development of neuropsychiatric disorders in adult life. In this review, we will delineate some modifications of CNS development and functions that occur after exposition to adverse environment and that can now be studied in vivo with advanced imaging technology.

A framework based on sulcal constraints to align preterm, infant and adult human brain images acquired in vivo and post mortem.

Robust spatial alignment of post mortem data and in vivo MRI acquisitions from different ages, especially from the early developmental stages, into standard spaces is still a bottleneck hampering easy comparison with the mainstream neuroimaging results. In this paper, we test a landmark-based spatial normalization strategy as a framework for the seamless integration of any macroscopic dataset in the context of the Human Brain Project (HBP). This strategy stems from an approach called DISCO embedding sulcal constraints in a registration framework used to initialize DARTEL, the widely used spatial normalization approach proposed in the SPM software. We show that this strategy is efficient with a heterogeneous dataset including challenging data as preterm newborns, infants, post mortem histological data and a synthetic atlas computed from averaging the ICBM database, as well as more commonly studied data acquired in vivo in adults. We then describe some perspectives for a research program aiming at improving folding pattern matching for atlas inference in the context of the future HBP's portal.

Early assessment of brain maturation by MR imaging segmentation in neonates and premature infants.

PURPOSE: We evaluated the impact of premature extrauterine life on brain maturation. PATIENTS AND METHODS: Twelve neonates underwent MR imaging at 40 (39.64 +/- 0.98) weeks (full term). Fifteen premature infants underwent 2 MR imaging examinations, after birth (preterm at birth) and at 40 weeks (41.03 +/- 1.33) (preterm at term). A 3D MR imaging technique was used to measure brain volumes compared with intracranial volume: total brain volume, cortical gray matter, myelinated white matter, unmyelinated white matter, basal ganglia (BG), and CSF. RESULTS: The average absolute volume of intracranial volume (269.8 mL +/- 36.5), total brain volume (246.5 +/- 32.3), cortical gray matter (85.53 mL +/- 22.23), unmyelinated white matter (142.4 mL +/-14.98), and myelinated white matter (6.099 mL +/-1.82) for preterm at birth was significantly lower compared with that for the preterm at term: the average global volume of intracranial volume (431.7 +/- 69.98), total brain volume (391 +/- 66,1), cortical gray matter (179 mL +/- 41.54), unmyelinated white matter (185.3 mL +/- 30.8), and myelinated white matter (10.66 mL +/- 3.05). It was also lower compared with that of full-term infants: intracranial volume (427.4 mL +/- 53.84), total brain volume (394 +/- 49.22), cortical gray matter (181.4 +/- 29.27), unmyelinated white matter (183.4 +/- 27.37), and myelinated white matter (10.72 +/- 4.63). The relative volume of cortical gray matter (30.62 +/- 5.13) and of unmyelinated white matter (53.15 +/- 4.8) for preterm at birth was significantly different compared with the relative volume of cortical gray matter (41.05 +/- 5.44) and of unmyelinated white matter (43.22 +/- 5.11) for the preterm at term. Premature infants had similar brain tissue volumes at 40 weeks to full-term infants. CONCLUSION: MR segmentation techniques demonstrate that cortical neonatal maturation in moderately premature infants at term and term-born infants was similar.

Evolution of T1 Relaxation, ADC, and Fractional Anisotropy during Early Brain Maturation: A Serial Imaging Study on Preterm Infants.

BACKGROUND AND PURPOSE: The alteration of brain maturation in preterm infants contributes to neurodevelopmental disabilities during childhood. Serial imaging allows understanding of the mechanisms leading to dysmaturation in the preterm brain. The purpose of the present study was to provide reference quantitative MR imaging measures across time in preterm infants, by using ADC, fractional anisotropy, and T1 maps obtained by using the magnetization-prepared dual rapid acquisition of gradient echo technique. MATERIALS AND METHODS: We included preterm neonates born at <30 weeks of gestational age without major brain lesions on early cranial sonography and performed 3 MRIs (3T) from birth to term-equivalent age. Multiple measurements (ADC, fractional anisotropy, and T1 relaxation) were performed on each examination in 12 defined white and gray matter ROIs. RESULTS: We acquired 107 MRIs (35 early, 33 intermediary, and 39 at term-equivalent age) in 39 cerebral low-risk preterm infants. Measures of T1 relaxation time showed a gradual and significant decrease with time in a region- and hemispheric-specific manner. ADC values showed a similar decline with time, but with more variability than T1 relaxation. An increase of fractional anisotropy values was observed in WM regions and inversely a decrease in the cortex. CONCLUSIONS: The gradual change with time reflects the progressive maturation of the cerebral microstructure in white and gray matter. Our study provides reference trajectories from 25 to 40 weeks of gestation of T1 relaxation, ADC, and fractional anisotropy values in low-risk preterm infants. We speculate that deviation thereof might reflect disturbed cerebral maturation; the correlation of this disturbed maturation with neurodevelopmental outcome remains to be addressed.

Serum creatine-kinase-BB concentration in very low birth weight babies with posthemorrhagic ventricular dilatation.

The association between measurements of lateral ventricle dilatation determined by serial ultrasound and brain specific creatine-kinase isoenzyme patterns (CK-BB) is studied in 60 very low birth weight preterm neonates of 1,500 g birth weight or 32 weeks gestation or less. The patients were divided into three groups according to cranial ultrasonographic findings: Group A (n = 20) had isolated peri-intraventricular hemorrhage (PIVH); group B (n = 20) had PIVH and dilated ventricles (VM); group C (n = 20) were normal matched preterms and formed the control group. Compared to control babies or those with isolated PIVH, high serum concentrations of CK-BB were observed after birth in babies with persistent dilated ventricles at two weeks postnatal age (p less than 0.01). No difference was found between CK-BB levels of babies with isolated PIVH and control group (p greater than 0.05). We suggest that an elevated CK-BB value is found in babies with persistent ventricular dilatation suggesting severe and diffuse brain damage after post-hemorrhagic ventriculomegaly (VM).

MR imaging and spectroscopy of brain development.

MR imaging provides an invaluable tool for the study of brain development in vivo. Current MR imaging techniques allow noninvasive methodologies, without ionizing radiation, that provide a diversity of information on structure, metabolism, and function of the developing brain. This article focuses on the application of conventional and advanced MR imaging techniques, including quantitative morphometric MR imaging, diffusion-weighted, functional MR, and MR spectroscopic imaging to the study of early human brain development.