Unique longitudinal contributions of sulcal interruptions to reading acquisition in children.

A growing body of literature indicates strong associations between indentations of the cerebral cortex (i.e., sulci) and individual differences in cognitive performance. Interruptions, or gaps, of sulci (historically known as pli de passage) are particularly intriguing as previous work suggests that these interruptions have a causal effect on cognitive development. Here, we tested how the presence and morphology of sulcal interruptions in the left posterior occipitotemporal sulcus (pOTS) longitudinally impact the development of a culturally-acquired skill: reading. Forty-three children were successfully followed from age 5 in kindergarten, at the onset of literacy instruction, to ages 7 and 8 with assessments of cognitive, pre-literacy, and literacy skills, as well as MRI anatomical scans at ages 5 and 8. Crucially, we demonstrate that the presence of a left pOTS gap at 5 years is a specific and robust longitudinal predictor of better future reading skills in children, with large observed benefits on reading behavior ranging from letter knowledge to reading comprehension. The effect of left pOTS interruptions on reading acquisition accumulated through time, and was larger than the impact of benchmark cognitive and familial predictors of reading ability and disability. Finally, we show that increased local U-fiber white matter connectivity associated with such sulcal interruptions possibly underlie these behavioral benefits, by providing a computational advantage. To our knowledge, this is the first quantitative evidence supporting a potential integrative gray-white matter mechanism underlying the cognitive benefits of macro-anatomical differences in sulcal morphology related to longitudinal improvements in a culturally-acquired skill.

Event-related variability is modulated by task and development.

In carefully designed experimental paradigms, cognitive scientists interpret the mean event-related potentials (ERP) in terms of cognitive operations. However, the huge signal variability from one trial to the next, questions the representability of such mean events. We explored here whether this variability is an unwanted noise, or an informative part of the neural response. We took advantage of the rapid changes in the visual system during human infancy and analyzed the variability of visual responses to central and lateralized faces in 2-to 6-month-old infants compared to adults using high-density electroencephalography (EEG). We observed that neural trajectories of individual trials always remain very far from ERP components, only moderately bending their direction with a substantial temporal jitter across trials. However, single trial trajectories displayed characteristic patterns of acceleration and deceleration when approaching ERP components, as if they were under the active influence of steering forces causing transient attraction and stabilization. These dynamic events could only partly be accounted for by induced microstate transitions or phase reset phenomena. Importantly, these structured modulations of response variability, both between and within trials, had a rich sequential organization, which in infants, was modulated by the task difficulty and age. Our approaches to characterize Event Related Variability (ERV) expand on classic ERP analyses and provide the first evidence for the functional role of ongoing neural variability in human infants.

Exploring the emergence of morphological asymmetries around the brain's Sylvian fissure: a longitudinal study of shape variability in preterm infants.

Brain folding patterns vary within the human species, but some folding properties are common across individuals, including the Sylvian fissure's inter-hemispheric asymmetry. Contrarily to the other brain folds (sulci), the Sylvian fissure develops through the process of opercularization, with the frontal, parietal, and temporal lobes growing over the insular lobe. Its asymmetry may be related to the leftward functional lateralization for language processing, but the time course of these asymmetries' development is still poorly understood. In this study, we investigated refined shape features of the Sylvian fissure and their longitudinal development in 71 infants born extremely preterm (mean gestational age at birth: 26.5 weeks) and imaged once before and once at term-equivalent age (TEA). We additionally assessed asymmetrical sulcal patterns at TEA in the perisylvian and inferior frontal regions, neighbor to the Sylvian fissure. While reproducing renowned strong asymmetries in the Sylvian fissure, we captured an early encoding of its main asymmetrical shape features, and we observed global asymmetrical shape features representative of a more pronounced opercularization in the left hemisphere, contrasting with the previously reported right hemisphere advance in sulcation around birth. This added novel insights about the processes governing early-life brain folding mechanisms, potentially linked to the development of language-related capacities.

Early structural connectivity within the sensorimotor network: Deviations related to prematurity and association to neurodevelopmental outcome.

Consisting of distributed and interconnected structures that interact through cortico-cortical connections and cortico-subcortical loops, the sensorimotor (SM) network undergoes rapid maturation during the perinatal period and is thus particularly vulnerable to preterm birth. However, the impact of prematurity on the development and integrity of the emerging SM connections and their relationship to later motor and global impairments are still poorly understood. In this study we aimed to explore to which extent the early microstructural maturation of SM white matter (WM) connections at term-equivalent age (TEA) is modulated by prematurity and related with neurodevelopmental outcome at 18 months corrected age. We analyzed 118 diffusion MRI datasets from the developing Human Connectome Project (dHCP) database: 59 preterm (PT) low-risk infants scanned near TEA and a control group of full-term (FT) neonates paired for age at MRI and sex. We delineated WM connections between the primary SM cortices (S1, M1 and paracentral region) and subcortical structures using probabilistic tractography, and evaluated their microstructure with diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. To go beyond tract-specific univariate analyses, we computed a maturational distance related to prematurity based on the multi-parametric Mahalanobis distance of each PT infant relative to the FT group. Our results confirmed the presence of microstructural differences in SM tracts between PT and FT infants, with effects increasing with lower gestational age at birth. Maturational distance analyses highlighted that prematurity has a differential effect on SM tracts with higher distances and thus impact on (i) cortico-cortical than cortico-subcortical connections; (ii) projections involving S1 than M1 and paracentral region; and (iii) the most rostral cortico-subcortical tracts, involving the lenticular nucleus. These different alterations at TEA suggested that vulnerability follows a specific pattern coherent with the established WM caudo-rostral progression of maturation. Finally, we highlighted some relationships between NODDI-derived maturational distances of specific tracts and fine motor and cognitive outcomes at 18 months. As a whole, our results expand understanding of the significant impact of premature birth and early alterations on the emerging SM network even in low-risk infants, with possible relationship with neurodevelopmental outcomes. This encourages further exploration of these potential neuroimaging markers for prediction of neurodevelopmental disorders, with special interest for subtle neuromotor impairments frequently observed in preterm-born children.

Concurrent mapping of brain ontogeny and phylogeny within a common space: Standardized tractography and applications.

Developmental and evolutionary effects on brain organization are complex, yet linked, as evidenced by the correspondence in cortical area expansion across these vastly different time scales. However, it is still not possible to study concurrently the ontogeny and phylogeny of cortical areal connections, which is arguably more relevant to brain function than allometric measurements. Here, we propose a novel framework that allows the integration of structural connectivity maps from humans (adults and neonates) and nonhuman primates (macaques) onto a common space. We use white matter bundles to anchor the common space and use the uniqueness of cortical connection patterns to these bundles to probe area specialization. This enabled us to quantitatively study divergences and similarities in connectivity over evolutionary and developmental scales, to reveal brain maturation trajectories, including the effect of premature birth, and to translate cortical atlases between diverse brains. Our findings open new avenues for an integrative approach to imaging neuroanatomy.

Shape variability of the central sulcus in the developing brain: A longitudinal descriptive and predictive study in preterm infants.

Despite growing evidence of links between sulcation and function in the adult brain, the folding dynamics, occurring mostly before normal-term-birth, is vastly unknown. Looking into the development of cortical sulci in infants can give us keys to address fundamental questions: what is the sulcal shape variability in the developing brain? When are the shape features encoded? How are these morphological parameters related to further functional development? In this study, we aimed to investigate the shape variability of the developing central sulcus, which is the frontier between the primary somatosensory and motor cortices. We studied a cohort of 71 extremely preterm infants scanned twice using MRI - once around 30 weeks post-menstrual age (w PMA) and once at term-equivalent age, around 40w PMA -, in order to quantify the sulcus's shape variability using manifold learning, regardless of age-group or hemisphere. We then used these shape descriptors to evaluate the sulcus's variability at both ages and to assess hemispheric and age-group specificities. This led us to propose a description of ten shape features capturing the variability in the central sulcus of preterm infants. Our results suggested that most of these features (8/10) are encoded as early as 30w PMA. We unprecedentedly observed hemispheric asymmetries at both ages, and the one captured at term-equivalent age seems to correspond with the asymmetry pattern previously reported in adults. We further trained classifiers in order to explore the predictive value of these shape features on manual performance at 5 years of age (handedness and fine motor outcome). The central sulcus's shape alone showed a limited but relevant predictive capacity in both cases. The study of sulcal shape features during early neurodevelopment may participate to a better comprehension of the complex links between morphological and functional organization of the developing brain.

MRI of the Neonatal Brain: A Review of Methodological Challenges and Neuroscientific Advances.

In recent years, exploration of the developing brain has become a major focus for researchers and clinicians in an attempt to understand what allows children to acquire amazing and unique abilities, as well as the impact of early disruptions (eg, prematurity, neonatal insults) that can lead to a wide range of neurodevelopmental disorders. Noninvasive neuroimaging methods such as MRI are essential to establish links between the brain and behavioral changes in newborns and infants. In this review article, we aim to highlight recent and representative studies using the various techniques available: anatomical MRI, quantitative MRI (relaxometry, diffusion MRI), multiparametric approaches, and functional MRI. Today, protocols use 1.5 or 3T MRI scanners, and specialized methodologies have been put in place for data acquisition and processing to address the methodological challenges specific to this population, such as sensitivity to motion. MR sequences must be adapted to the brains of newborns and infants to obtain relevant good soft-tissue contrast, given the small size of the cerebral structures and the incomplete maturation of tissues. The use of age-specific image postprocessing tools is also essential, as signal and contrast differ from the adult brain. Appropriate methodologies then make it possible to explore multiple neurodevelopmental mechanisms in a precise way, and assess changes with age or differences between groups of subjects, particularly through large-scale projects. Although MRI measurements only indirectly reflect the complex series of dynamic processes observed throughout development at the molecular and cellular levels, this technique can provide information on brain morphology, structural connectivity, microstructural properties of gray and white matter, and on the functional architecture. Finally, MRI measures related to clinical, behavioral, and electrophysiological markers have a key role to play from a diagnostic and prognostic perspective in the implementation of early interventions to avoid long-term disabilities in children. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 1.

Anatomo-functional correlates of auditory development in infancy.

Infant brain development incorporates several intermingled mechanisms leading to intense and asynchronous maturation across cerebral networks and functional modalities. Combining electroencephalography (EEG) and diffusion magnetic resonance imaging (MRI), previous studies in the visual modality showed that the functional maturation of the event-related potentials (ERP) during the first postnatal semester relates to structural changes in the corresponding white matter pathways. Here investigated similar issues in the auditory modality. We measured ERPs to syllables in 1- to 6-month-old infants and related them to the maturational properties of underlying neural substrates measured with diffusion tensor imaging (DTI). We first observed a decrease in the latency of the auditory P2, and in the diffusivities in the auditory tracts and perisylvian regions with age. Secondly, we highlighted some of the early functional and structural substrates of lateralization. Contralateral responses to monoaural syllables were stronger and faster than ipsilateral responses, particularly in the left hemisphere. Besides, the acoustic radiations, arcuate fasciculus, middle temporal and angular gyri showed DTI asymmetries with a more complex and advanced microstructure in the left hemisphere, whereas the reverse was observed for the inferior frontal and superior temporal gyri. Finally, after accounting for the age-related variance, we correlated the inter-individual variability in P2 responses and in the microstructural properties of callosal fibers and inferior frontal regions. This study combining dedicated EEG and MRI approaches in infants highlights the complex relation between the functional responses to auditory stimuli and the maturational properties of the corresponding neural network.

Connectivity between the visual word form area and the parietal lobe improves after the first year of reading instruction: a longitudinal MRI study in children.

Shortly after reading instruction, a region in the ventral occipital temporal cortex (vOTC) of the left hemisphere, the Visual Word Form Area (VWFA), becomes specialized for written words. Its reproducible location across scripts suggests important anatomical constraints, such as specific patterns of connectivity, notably to spoken language areas. Here, we explored the structural connectivity of the emerging VWFA in terms of its specificity relative to other ventral visual regions and its stability throughout the process of reading instruction in ten children studied longitudinally over 2 years. Category-specific regions for words, houses, faces, and tools were identified in the left vOTC of each subject with functional MRI. With diffusion MRI and tractography, we reconstructed the connections of these regions at two time points (mean age ± standard deviation: 6.2 ± 0.3, 7.2 ± 0.4 years). We first showed that the regions for each visual category harbor their own specific connectivity, all of which precede reading instruction and remain stable throughout development. The most specific connections of the VWFA were to the dorsal posterior parietal cortex. We then showed that microstructural changes in these connections correlated with improvements in reading scores over the first year of instruction but not 1 year later in a subsample of eight children (age: 8.4 ± 0.3 years). These results suggest that the VWFA location depends on its connectivity to distant regions, in particular, the left inferior parietal region which may play a crucial role in visual field maps and eye movement dynamics in addition to attentional control in letter-by-letter reading and disambiguation of mirror-letters during the first stages of learning to read.

Delineation of early brain development from fetuses to infants with diffusion MRI and beyond.

Dynamic macrostructural and microstructural changes take place from the mid-fetal stage to 2 years after birth. Delineating structural changes of the brain during early development provides new insights into the complicated processes of both typical development and the pathological mechanisms underlying various psychiatric and neurological disorders including autism, attention deficit hyperactivity disorder and schizophrenia. Decades of histological studies have identified strong spatial and functional maturation gradients in human brain gray and white matter. The recent improvements in magnetic resonance imaging (MRI) techniques, especially diffusion MRI (dMRI), relaxometry imaging, and magnetization transfer imaging (MTI) have provided unprecedented opportunities to non-invasively quantify and map the early developmental changes at whole brain and regional levels. Here, we review the recent advances in understanding early brain structural development during the second half of gestation and the first two postnatal years using modern MR techniques. Specifically, we review studies that delineate the emergence and microstructural maturation of white matter tracts, as well as dynamic mapping of inhomogeneous cortical microstructural organization unique to fetuses and infants. These imaging studies converge into maturational curves of MRI measurements that are distinctive across different white matter tracts and cortical regions. Furthermore, contemporary models offering biophysical interpretations of the dMRI-derived measurements are illustrated to infer the underlying microstructural changes. Collectively, this review summarizes findings that contribute to charting spatiotemporally heterogeneous gray and white matter structural development, offering MRI-based biomarkers of typical brain development and setting the stage for understanding aberrant brain development in neurodevelopmental disorders.

The dynamics of cortical folding waves and prematurity-related deviations revealed by spatial and spectral analysis of gyrification.

In the human brain, the appearance of cortical sulci is a complex process that takes place mostly during the second half of pregnancy, with a relatively stable temporal sequence across individuals. Since deviant gyrification patterns have been observed in many neurodevelopmental disorders, mapping cortical development in vivo from the early stages on is an essential step to uncover new markers for diagnosis or prognosis. Recently this has been made possible by MRI combined with post-processing tools, but the reported results are still fragmented. Here we aimed to characterize the typical folding progression ex utero from the pre- to the post-term period, by considering 58 healthy preterm and full-term newborns and infants imaged between 27 and 62 weeks of post-menstrual age. Using a method of spectral analysis of gyrification (SPANGY), we detailed the spatial-frequency structure of cortical patterns in a quantitative way. The modeling of developmental trajectories revealed three successive waves that might correspond to primary, secondary and tertiary folding. Some deviations were further detected in 10 premature infants without apparent neurological impairment and imaged at term equivalent age, suggesting that our approach is sensitive enough to highlight the subtle impact of preterm birth and extra-uterine life on folding.

Early asymmetric inter-hemispheric transfer in the auditory network: insights from infants with corpus callosum agenesis.

The left hemisphere specialization for language is a well-established asymmetry in the human brain. Structural and functional asymmetries are observed as early as the prenatal period suggesting genetically determined differences between both hemispheres. The corpus callosum is a large tract connecting mostly homologous areas; some have proposed that it might participate in an enhancement of the left-hemispheric advantage to process speech. To investigate its role in early development, we compared 13 3-4-month-old infants with an agenesis of the corpus callosum ("AgCC") with 18 typical infants using high-density electroencephalography in an auditory task. We recorded event-related potentials for speech stimuli (syllables and babbling noise), presented binaurally (same syllable in both ears), monaurally (babbling noise in one ear) and dichotically (syllable in one ear and babbling noise in the other ear). In response to these stimuli, both groups developed an anterior positivity synchronous with a posterior negativity, yet the topography significantly differed between groups likely due to the atypical gyration of the medial surface in AgCC. In particular, the anterior positivity was lateral in AgCC infants while it covered the midline in typical infants. We then measured the latencies of the main auditory response (P2 at this age) for the different conditions on the symmetrical left and right clusters. The main difference between groups was a ~ 60 ms delay in typical infants relative to AgCC, for the ipsilateral response (i.e. left hemisphere) to babbling noise presented in the left ear, whereas no difference was observed in the case of right-ear stimulation. We suggest that our results highlight an asymmetrical callosal connectivity favoring the right-to-left hemisphere direction in typical infants. This asymmetry, similar to recent descriptions in adults, might contribute to an enhancement of left lateralization for language processing beyond the initial cortical left-hemisphere advantage.

Right but not left hemispheric discrimination of faces in infancy.

The ontogeny of the functional asymmetries of the human brain is poorly understood. Are they a consequence of differential development based on competition mechanisms, or are they constitutive of the human brain architecture from the start? Using structural magnetic resonance imaging and a face-discrimination electroencephalography paradigm with lateralized presentation of faces, we studied face perception in infants over the first postnatal semester. We showed that the corpus callosum is sufficiently mature to transfer visual information across hemispheres, but the inter-hemispheric transfer time of early visual responses is modulated by callosal fibre myelination. We also revealed that only the right hemisphere shows evidence of face discrimination when presented in the left visual hemifield. This capability improved throughout the first semester with no evidence of discrimination in the left hemisphere. Face-processing lateralization is thus a characteristic of the infant's extra-striate visual cortex, highlighting the differential left-right organization of the human brain already established in infanthood.

A New Strategy for Fast MRI-Based Quantification of the Myelin Water Fraction: Application to Brain Imaging in Infants.

The volume fraction of water related to myelin (fmy) is a promising MRI index for in vivo assessment of brain myelination, that can be derived from multi-component analysis of T1 and T2 relaxometry signals. However, existing quantification methods require rather long acquisition and/or post-processing times, making implementation difficult both in research studies on healthy unsedated children and in clinical examinations. The goal of this work was to propose a novel strategy for fmy quantification within acceptable acquisition and post-processing times. Our approach is based on a 3-compartment model (myelin-related water, intra/extra-cellular water and unrestricted water), and uses calibrated values of inherent relaxation times (T1c and T2c) for each compartment c. Calibration was first performed on adult relaxometry datasets (N = 3) acquired with large numbers of inversion times (TI) and echo times (TE), using an original combination of a region contraction approach and a non-negative least-square (NNLS) algorithm. This strategy was compared with voxel-wise fitting, and showed robust estimation of T1c and T2c. The accuracy of fmy calculations depending on multiple factors was investigated using simulated data. In the testing stage, our strategy enabled fast fmy mapping, based on relaxometry datasets acquired with reduced TI and TE numbers (acquisition <6 min), and analyzed with NNLS algorithm (post-processing <5min). In adults (N = 13, mean age 22.4±1.6 years), fmy maps showed variability across white matter regions, in agreement with previous studies. In healthy infants (N = 18, aged 3 to 34 weeks), asynchronous changes in fmy values were demonstrated across bundles, confirming the well-known progression of myelination.

Relation between clinical risk factors, early cortical changes, and neurodevelopmental outcome in preterm infants.

Cortical folding mainly takes place in the third trimester of pregnancy and may therefore be influenced by preterm birth. The aim of this study was to evaluate the development of specific cortical structures between early age (around 30weeks postmenstrual age) and term-equivalent age (TEA, around 40weeks postmenstrual age) in 71 extremely preterm infants, and to associate this to clinical characteristics and neurodevelopmental outcome at two years of age. First, analysis showed that the central sulcus (CS), lateral fissure (LF) and insula (INS) were present at early MRI in all infants, whereas the other sulci (post-central sulcus [PCS], superior temporal sulcus [STS], superior [SFS] and inferior [IFS] frontal sulcus) were only seen in part of the infants. Relative growth from early to TEA examination was largest in the SFS. A rightward asymmetry of the surface area was seen in development between both examinations except for the LF, which showed a leftward asymmetry at both time points. Second, lower birth weight z-score, multiple pregnancy and prolonged mechanical ventilation showed negative effects on cortical folding of the CS, LF, INS, STS and PCS, mainly on the first examination, suggesting that sulci developing the earliest were the most affected by clinical factors. Finally, in this cohort, a clear association between cortical folding and neurodevelopmental outcome at two years corrected age was found, particularly for receptive language.

Altered hemispheric lateralization of white matter pathways in developmental dyslexia: Evidence from spherical deconvolution tractography.

This study examines the structural integrity and the hemispheric lateralization patterns of four major association fiber pathways in a group of French dyslexic children and age-matched controls (from 9 to 14 years), using high angular diffusion imaging combined with spherical deconvolution tractography. Compared with age-matched controls, dyslexic children show increased hindrance-modulated oriented anisotropy (HMOA) in the right superior longitudinal fasciculus (SLF). They also show a reduced leftward asymmetry of the inferior fronto-occipital fasciculus (IFOF) and an increased rightward asymmetry of the second branch of the SLF (SLF II). The lateralization pattern of IFOF and SLF II also accounts for individual differences in dyslexic children's reading abilities. These data provide evidence for an abnormal lateralization of occipito-frontal and parieto-frontal pathways in developmental dyslexia.

Are Developmental Trajectories of Cortical Folding Comparable Between Cross-sectional Datasets of Fetuses and Preterm Newborns?

Magnetic resonance imaging has proved to be suitable and efficient for in vivo investigation of the early process of brain gyrification in fetuses and preterm newborns but the question remains as to whether cortical-related measurements derived from both cases are comparable or not. Indeed, the developmental folding trajectories drawn up from both populations have not been compared so far, neither from cross-sectional nor from longitudinal datasets. The present study aimed to compare features of cortical folding between healthy fetuses and early imaged preterm newborns on a cross-sectional basis, over a developmental period critical for the folding process (21-36 weeks of gestational age [GA]). A particular attention was carried out to reduce the methodological biases between the 2 populations. To provide an accurate group comparison, several global parameters characterizing the cortical morphometry were derived. In both groups, those metrics provided good proxies for the dramatic brain growth and cortical folding over this developmental period. Except for the cortical volume and the rate of sulci appearance, they depicted different trajectories in both groups suggesting that the transition from into ex utero has a visible impact on cortical morphology that is at least dependent on the GA at birth in preterm newborns.

Exploring the Early Organization and Maturation of Linguistic Pathways in the Human Infant Brain.

Linguistic processing is based on a close collaboration between temporal and frontal regions connected by two pathways: the "dorsal" and "ventral pathways" (assumed to support phonological and semantic processing, respectively, in adults). We investigated here the development of these pathways at the onset of language acquisition, during the first post-natal weeks, using cross-sectional diffusion imaging in 21 healthy infants (6-22 weeks of age) and 17 young adults. We compared the bundle organization and microstructure at these two ages using tractography and original clustering analyses of diffusion tensor imaging parameters. We observed structural similarities between both groups, especially concerning the dorsal/ventral pathway segregation and the arcuate fasciculus asymmetry. We further highlighted the developmental tempos of the linguistic bundles: The ventral pathway maturation was more advanced than the dorsal pathway maturation, but the latter catches up during the first post-natal months. Its fast development during this period might relate to the learning of speech cross-modal representations and to the first combinatorial analyses of the speech input.

MRI and M/EEG studies of the White Matter Development in Human Fetuses and Infants: Review and Opinion.

Already during the last trimester of gestation, functional responses are recorded in foetuses and preterm newborns, attesting an already complex cerebral architecture. Then throughout childhood, anatomical connections are further refined but at different rates and over asynchronous periods across functional networks. Concurrently, infants gradually achieve new psychomotor and cognitive skills. Only the recent use of non-invasive techniques such as magnetic resonance imaging (MRI) and magneto- and electroencephalography (M/EEG) has opened the possibility to understand the relationships between brain maturation and skills development in vivo. In this review, we describe how these techniques have been applied to study the white matter maturation. At the structural level, the early architecture and myelination of bundles have been assessed with diffusion and relaxometry MRI, recently integrated in multi-compartment models and multi-parametric approaches. Nevertheless, technical limitations prevent us to map major developmental mechanisms such as fibers growth and pruning, and the progressive maturation at the bundle scale in case of mixing trajectories. At the functional level, M/EEG have been used to record different visual, somatosensory and auditory evoked responses. Because the conduction velocity of neural impulses increases with the myelination of connections, major changes in the components latency are observed throughout development. But so far, only a few studies have related structural and functional markers of white matter myelination. Such multi-modal approaches will be a major challenge in future research, not only to understand normal development, but also to characterize early mechanisms of pathologies and the influence of fetal and perinatal interventions on later outcome.