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.

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.

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.

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.

New human-specific brain landmark: the depth asymmetry of superior temporal sulcus.

Identifying potentially unique features of the human cerebral cortex is a first step to understanding how evolution has shaped the brain in our species. By analyzing MR images obtained from 177 humans and 73 chimpanzees, we observed a human-specific asymmetry in the superior temporal sulcus at the heart of the communication regions and which we have named the "superior temporal asymmetrical pit" (STAP). This 45-mm-long segment ventral to Heschl's gyrus is deeper in the right hemisphere than in the left in 95% of typical human subjects, from infanthood till adulthood, and is present, irrespective of handedness, language lateralization, and sex although it is greater in males than in females. The STAP also is seen in several groups of atypical subjects including persons with situs inversus, autistic spectrum disorder, Turner syndrome, and corpus callosum agenesis. It is explained in part by the larger number of sulcal interruptions in the left than in the right hemisphere. Its early presence in the infants of this study as well as in fetuses and premature infants suggests a strong genetic influence. Because this asymmetry is barely visible in chimpanzees, we recommend the STAP region during midgestation as an important phenotype to investigate asymmetrical variations of gene expression among the primate lineage. This genetic target may provide important insights regarding the evolution of the crucial cognitive abilities sustained by this sulcus in our species, namely communication and social cognition.

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.

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.

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.

Early Brain Activity Relates to Subsequent Brain Growth in Premature Infants.

Recent experimental studies have shown that early brain activity is crucial for neuronal survival and the development of brain networks; however, it has been challenging to assess its role in the developing human brain. We employed serial quantitative magnetic resonance imaging to measure the rate of growth in circumscribed brain tissues from preterm to term age, and compared it with measures of electroencephalographic (EEG) activity during the first postnatal days by 2 different methods. EEG metrics of functional activity were computed: EEG signal peak-to-peak amplitude and the occurrence of developmentally important spontaneous activity transients (SATs). We found that an increased brain activity in the first postnatal days correlates with a faster growth of brain structures during subsequent months until term age. Total brain volume, and in particular subcortical gray matter volume, grew faster in babies with less cortical electrical quiescence and with more SAT events. The present findings are compatible with the idea that (1) early cortical network activity is important for brain growth, and that (2) objective measures may be devised to follow early human brain activity in a biologically reasoned way in future research as well as during intensive care treatment.

Syllabic discrimination in premature human infants prior to complete formation of cortical layers.

The ontogeny of linguistic functions in the human brain remains elusive. Although some auditory capacities are described before term, whether and how such immature cortical circuits might process speech are unknown. Here we used functional optical imaging to evaluate the cerebral responses to syllables at the earliest age at which cortical responses to external stimuli can be recorded in humans (28- to 32-wk gestational age). At this age, the cortical organization in layers is not completed. Many neurons are still located in the subplate and in the process of migrating to their final location. Nevertheless, we observed several points of similarity with the adult linguistic network. First, whereas syllables elicited larger right than left responses, the posterior temporal region escaped this general pattern, showing faster and more sustained responses over the left than over the right hemisphere. Second, discrimination responses to a change of phoneme (ba vs. ga) and a change of human voice (male vs. female) were already present and involved inferior frontal areas, even in the youngest infants (29-wk gestational age). Third, whereas both types of changes elicited responses in the right frontal region, the left frontal region only reacted to a change of phoneme. These results demonstrate a sophisticated organization of perisylvian areas at the very onset of cortical circuitry, 3 mo before term. They emphasize the influence of innate factors on regions involved in linguistic processing and social communication in humans.

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.

Hydrocortisone treatment for bronchopulmonary dysplasia and brain volumes in preterm infants.

OBJECTIVE: To assess whether there was an adverse effect on brain growth after hydrocortisone (HC) treatment for bronchopulmonary dysplasia (BPD) in a large cohort of infants without dexamethasone exposure. STUDY DESIGN: Infants who received HC for BPD between 2005 and 2011 and underwent magnetic resonance imaging at term-equivalent age were included. Control infants born in Geneva (2005-2006) and Utrecht (2007-2011) were matched to the infants treated with HC according to segmentation method, sex, and gestational age. Infants with overt parenchymal pathology were excluded. Multivariable analysis was used to determine if there was a difference in brain volumes between the 2 groups. RESULTS: Seventy-three infants treated with HC and 73 matched controls were included. Mean gestational age was 26.7 weeks, and mean birth weight was 906 g. After correction for gestational age, postmenstrual age at time of scanning, the presence of intraventricular hemorrhage, and birth weight z-score, no differences were found between infants treated with HC and controls in total brain tissue or cerebellar volumes. CONCLUSIONS: In the absence of associated parenchymal brain injury, no reduction in brain tissue or cerebellar volumes could be found at term-equivalent age between infants with or without treatment with HC for BPD.

Early maturation of the linguistic dorsal pathway in human infants.

Human infants, unlike even closely related primates, exhibit a remarkable capacity for language learning. Yet how the underlying anatomical network matures remains largely unknown. The classical view is that of a largely immature brain comprising only a few islands of maturity in primary cortices. This view has favored a description of learning based on bottom-up algorithms and has tended to discard the role of frontal regions, which were assumed to be barely functional early on. Here, using an index based on the normalized T2-weighted magnetic resonance signal, we have quantified maturation within the linguistic network in fourteen 1- to 4-month-old infants. Our results show first that the ventral superior temporal sulcus (STS), and not the inferior frontal area, is the less mature perisylvian region. A significant difference of maturation in the STS favoring the right side is an early testimony of the distinctive left-right development of this structure observed during the whole life. Second, asymmetries of maturation in Broca's area were correlated with asymmetries in the posterior STS and in the parietal segment of the arcuate fasciculus, suggesting that an efficient frontotemporal dorsal pathway might provide infants with a phonological loop circuitry much earlier than expected.

Larger is twistier: spectral analysis of gyrification (SPANGY) applied to adult brain size polymorphism.

The description of cortical folding pattern (CFP) is challenging because of geometric complexity and inter-subject variability. On a cortical surface mesh, curvature estimation provides a good scalar proxy of CFP. The oscillations of this function can be studied using a Fourier-like analysis to produce a power spectrum representative of the spatial frequency composition of CFP. First, we introduce an original method for the SPectral ANalysis of GYrication (Spangy), which performs a spectral decomposition of the mean curvature of the grey/white interface mesh based on the Laplace-Beltrami operator eigenfunctions. Spangy produces an ordered 7 bands power spectrum of curvature (B0-B6) and provides an anatomically relevant segmentation of CFP based on local spectral composition. A spatial frequency being associated with each eigenfunction, the bandwidth design assumes frequency doubling between consecutive spectral bands. Next, we observed that the last 3 spectral bands (B4, 5 and 6) accounted for 93% of the analyzed spectral power and were associated with fold-related variations of curvature, whereas the lower frequency bands were related to global brain shape. The spectral segmentation of CFP revealed 1st, 2nd and 3rd order elements associated with B4, B5 and B6 respectively. These elements could be related to developmentally-defined primary, secondary and tertiary folds. Finally, we used allometric scaling of frequency bands power and segmentation to analyze the relationship between the spectral composition of CFP and brain size in a large adult dataset. Total folding power followed a positive allometric scaling which did not divide up proportionally between the bands: B4 contribution was constant, B5 increased like total folding power and B6 much faster. Besides, apparition of new elements of pattern with increasing size only concerned the 3rd order. Hence, we demonstrate that large brains are twistier than smaller ones because of an increased number of high spatial frequency folds, ramifications and kinks that accommodate the allometric increase of cortical surface.

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.

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.