Mapping the asynchrony of cortical maturation in the infant brain: A MRI multi-parametric clustering approach.

While the main neural networks are in place at term birth, intense changes in cortical microstructure occur during early infancy with the development of dendritic arborization, synaptogenesis and fiber myelination. These maturational processes are thought to relate to behavioral acquisitions and the development of cognitive abilities. Nevertheless, in vivo investigations of such relationships are still lacking in healthy infants. To bridge this gap, we aimed to study the cortical maturation using non-invasive Magnetic Resonance Imaging, over a largely unexplored period (1-5 post-natal months). In a first univariate step, we focused on different quantitative parameters: longitudinal relaxation time (T1), transverse relaxation time (T2), and axial diffusivity from diffusion tensor imaging (λ//) These individual maps, acquired with echo-planar imaging to limit the acquisition time, showed spatial distortions that were first corrected to reliably match the thin cortical ribbon identified on high-resolution T2-weighted images. Averaged maps were also computed over the infants group to summarize the parameter characteristics during early infancy. In a second step, we considered a multi-parametric approach that leverages parameters complementarity, avoids reliance on pre-defined regions of interest, and does not require spatial constraints. Our clustering strategy allowed us to group cortical voxels over all infants in 5 clusters with distinct microstructural T1 and λ// properties The cluster maps over individual cortical surfaces and over the group were in sound agreement with benchmark post mortem studies of sub-cortical white matter myelination, showing a progressive maturation of 1) primary sensori-motor areas, 2) adjacent unimodal associative cortices, and 3) higher-order associative regions. This study thus opens a consistent approach to study cortical maturation in vivo.

Anatomical correlations of the international 10-20 sensor placement system in infants.

Developmental research, as well as paediatric clinical activity crucially depends on non-invasive and painless brain recording techniques, such as electroencephalography (EEG), and near infrared spectroscopy (NIRS). However, both of these techniques measure cortical activity from the scalp without precise knowledge of the recorded cerebral structures. An accurate and reliable mapping between external anatomical landmarks and internal cerebral structures is therefore fundamental to localise brain sources in a non-invasive way. Here, using MRI, we examined the relations between the 10-20 sensor placement system and cerebral structures in 16 infants (3-17 weeks post-term). We provided an infant template parcelled in 94 regions on which we reported the variability of sensors locations, concurrently with the anatomical variability of six main cortical sulci (superior and inferior frontal sulcus, central sulcus, sylvian fissure, superior temporal sulcus, and intraparietal sulcus) and of the distances between the sensors and important cortical landmarks across these infants. The main difference between infants and adults was observed for the channels O1-O2, T5-T6, which projected over lower structures than in adults. We did not find any asymmetry in the distances between the scalp and the brain envelope. However, because of the Yakovlean torque pushing dorsally and frontally the right sylvian fissure, P3-P4 were not at the same distance from the posterior end of this structure. This study should help to refine hypotheses on functional cognitive development by providing an accurate description of the localization of standardised channels relative to infants' brain structures. Template and atlas are publicly available on our Web site (http://www.unicog.org/pm/pmwiki.php/Site/InfantTemplate).

Interoperable atlases of the human brain.

The last two decades have seen an unprecedented development of human brain mapping approaches at various spatial and temporal scales. Together, these have provided a large fundus of information on many different aspects of the human brain including micro- and macrostructural segregation, regional specialization of function, connectivity, and temporal dynamics. Atlases are central in order to integrate such diverse information in a topographically meaningful way. It is noteworthy, that the brain mapping field has been developed along several major lines such as structure vs. function, postmortem vs. in vivo, individual features of the brain vs. population-based aspects, or slow vs. fast dynamics. In order to understand human brain organization, however, it seems inevitable that these different lines are integrated and combined into a multimodal human brain model. To this aim, we held a workshop to determine the constraints of a multi-modal human brain model that are needed to enable (i) an integration of different spatial and temporal scales and data modalities into a common reference system, and (ii) efficient data exchange and analysis. As detailed in this report, to arrive at fully interoperable atlases of the human brain will still require much work at the frontiers of data acquisition, analysis, and representation. Among them, the latter may provide the most challenging task, in particular when it comes to representing features of vastly different scales of space, time and abstraction. The potential benefits of such endeavor, however, clearly outweigh the problems, as only such kind of multi-modal human brain atlas may provide a starting point from which the complex relationships between structure, function, and connectivity may be explored.

A robust cerebral asymmetry in the infant brain: the rightward superior temporal sulcus.

In order to understand how genetic mutations might have favored language development in our species, we need a better description of the human brain at the beginning of life. As the linguistic network mainly involves the left perisylvian regions in adults, we used anatomical MRI to study the structural asymmetries of these regions in 14 preverbal infants. Our results show four significant asymmetries. First and foremost, they stress an important but little-known asymmetry: the larger depth of the right superior temporal sulcus (STS) at the base of Heschl's gyrus. Then, we characterized the early forward and upward shift of the posterior end of the right Sylvian fissure, the elongation of the left planum temporale as well as the thickening of the left Heschl's gyrus. The rightward bias of the STS is robust and large, and is not correlated with the leftward asymmetries of the planum and Heschl's gyrus, suggesting that different morphogenetic factors drive these asymmetries. As this sulcus is engaged in multiple high-level functions (e.g. language and theory of mind), and has been spotted as abnormal in several developmental disorders (e.g. schizophrenia, autism), this early rightward asymmetry should be further explored as a target for a genetic evolutionary pressure.

Structural asymmetries in the infant language and sensori-motor networks.

Both language capacity and strongly lateralized hand preference are among the most intriguing particularities of the human species. They are associated in the adult brain with functional and anatomical hemispheric asymmetries in the speech perception-production network and in the sensori-motor system. Only studies in early life can help us to understand how such asymmetries arise during brain development, and to which point structural left-right differences are the source or the consequence of functional lateralization. In this study, we aimed to provide new in vivo structural markers of hemispheric asymmetries in infants from 1 to 4 months of age, with diffusion tensor imaging. We used 3 complementary analysis methods based on local diffusion indices and spatial localizations of tracts. After a prospective approach over the whole brain, we demonstrated early leftward asymmetries in the arcuate fasciculus and in the cortico-spinal tract. These results suggest that the early macroscopic geometry, microscopic organization, and maturation of these white matter bundles are related to the development of later functional lateralization.

A lateral-to-mesial organization of human ventral visual cortex at birth.

In human adults, ventral extra-striate visual cortex contains a mosaic of functionally specialized areas, some responding preferentially to natural visual categories such as faces (fusiform face area) or places (parahippocampal place area) and others to cultural inventions such as written words and numbers (visual word form and number form areas). It has been hypothesized that this mosaic arises from innate biases in cortico-cortical connectivity. We tested this hypothesis by examining functional resting-state correlation at birth using fMRI data from full-term human newborns. The results revealed that ventral visual regions are functionally connected with their contra-lateral homologous regions and also exhibit distinct patterns of long-distance functional correlation with anterior associative regions. A mesial-to-lateral organization was observed, with the signal of the more lateral regions, including the sites of visual word and number form areas, exhibiting higher correlations with voxels of the prefrontal, inferior parietal and temporal cortices, including language areas. Finally, we observed hemispheric asymmetries in the functional correlation of key areas of the language network that may influence later adult hemispheric lateralization. We suggest that long-distance circuits present at birth constrain the subsequent functional differentiation of the ventral visual cortex.

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.

Abstract representations of numbers in the animal and human brain.

There is evidence to suggest that animals, young infants and adult humans possess a biologically determined, domain-specific representation of number and of elementary arithmetic operations. Behavioral studies in infants and animals reveal number perception, discrimination and elementary calculation abilities in non-verbal organisms. Lesion and brain-imaging studies in humans indicate that a specific neural substrate, located in the left and right intraparietal area, is associated with knowledge of numbers and their relations ('number sense'). The number domain is a prime example where strong evidence points to an evolutionary endowment of abstract domain-specific knowledge in the brain because there are parallels between number processing in animals and humans.The numerical distance effect, which refers to the finding that the ability to discriminate between two numbers improves as the numerical distance between them increases, has been demonstrated in humans and animals, as has the number size effect,which refers to the finding that for equal numerical distance,discrimination of two numbers worsens as their numerical size increases.

Cross-linguistic approaches to speech processing.

Recent advances in the field of speech processing indicate that speakers of differing languages process speech relying on units that are appropriate to the rhythmical properties of their maternal tongue. Studies with young infants suggest that the acquisition of these processing routines takes place before the end of the first year of life. Further evidence shows that the left hemisphere initially processes any language and gradually becomes specialized for the maternal language.

Spatial normalization of brain images and beyond.

The deformable atlas paradigm has been at the core of computational anatomy during the last two decades. Spatial normalization is the variant endowing the atlas with a coordinate system used for voxel-based aggregation of images across subjects and studies. This framework has largely contributed to the success of brain mapping. Brain spatial normalization, however, is still ill-posed because of the complexity of the human brain architecture and the lack of architectural landmarks in standard morphological MRI. Multi-atlas strategies have been developed during the last decade to overcome some difficulties in the context of segmentation. A new generation of registration algorithms embedding architectural features inferred for instance from diffusion or functional MRI is on the verge to improve the architectural value of spatial normalization. A better understanding of the architectural meaning of the cortical folding pattern will lead to use some sulci as complementary constraints. Improving the architectural compliance of spatial normalization may impose to relax the diffeomorphic constraint usually underlying atlas warping. A two-level strategy could be designed: in each region, a dictionary of templates of incompatible folding patterns would be collected and matched in a way or another using rare architectural information, while individual subjects would be aligned using diffeomorphisms to the closest template. Manifold learning could help to aggregate subjects according to their morphology. Connectivity-based strategies could emerge as an alternative to deformation-based alignment leading to match the connectomes of the subjects rather than images.

The Infancy of the Human Brain.

The human infant brain is the only known machine able to master a natural language and develop explicit, symbolic, and communicable systems of knowledge that deliver rich representations of the external world. With the emergence of noninvasive brain imaging, we now have access to the unique neural machinery underlying these early accomplishments. After describing early cognitive capacities in the domains of language and number, we review recent findings that underline the strong continuity between human infants' and adults' neural architecture, with notably early hemispheric asymmetries and involvement of frontal areas. Studies of the strengths and limitations of early learning, and of brain dynamics in relation to regional maturational stages, promise to yield a better understanding of the sources of human cognitive achievements.

Electrophysiological evidence of statistical learning of long-distance dependencies in 8-month-old preterm and full-term infants.

Using electroencephalography, we examined 8-month-old infants' ability to discover a systematic dependency between the first and third syllables of successive words, concatenated into a monotonous speech stream, and to subsequently generalize this regularity to new items presented in isolation. Full-term and preterm infants, while exposed to the stream, displayed a significant entrainment (phase-locking) to the syllabic and word frequencies, demonstrating that they were sensitive to the word unit. The acquisition of the systematic dependency defining words was confirmed by the significantly different neural responses to rule-words and part-words subsequently presented during the test phase. Finally, we observed a correlation between syllabic entrainment during learning and the difference in phase coherence between the test conditions (rule-words vs part-words) suggesting that temporal processing of the syllable unit might be crucial in linguistic learning. No group difference was observed suggesting that non-adjacent statistical computations are already robust at 8 months, even in preterm infants, and thus develop during the first year of life, earlier than expected from behavioral studies.

Multi-parametric evaluation of the white matter maturation.

In vivo evaluation of the brain white matter maturation is still a challenging task with no existing gold standards. In this article we propose an original approach to evaluate the early maturation of the white matter bundles, which is based on comparison of infant and adult groups using the Mahalanobis distance computed from four complementary MRI parameters: quantitative qT1 and qT2 relaxation times, longitudinal λ║ and transverse λ⊥ diffusivities from diffusion tensor imaging. Such multi-parametric approach is expected to better describe maturational asynchrony than conventional univariate approaches because it takes into account complementary dependencies of the parameters on different maturational processes, notably the decrease in water content and the myelination. Our approach was tested on 17 healthy infants (aged 3- to 21-week old) for 18 different bundles. It finely confirmed maturational asynchrony across the bundles: the spino-thalamic tract, the optic radiations, the cortico-spinal tract and the fornix have the most advanced maturation, while the superior longitudinal and arcuate fasciculi, the anterior limb of the internal capsule and the external capsule have the most delayed maturation. Furthermore, this approach was more reliable than univariate approaches as it revealed more maturational relationships between the bundles and did not violate a priori assumptions on the temporal order of the bundle maturation. Mahalanobis distances decreased exponentially with age in all bundles, with the only difference between them explained by different onsets of maturation. Estimation of these relative delays confirmed that the most dramatic changes occur during the first post-natal year.

Electrophysiological correlates of categorical phoneme perception in adults.

Event-related potentials, recorded through a 128-electrode net, were used to study phonemic processing in the human auditory system. Within a stream of identical syllables, acoustic deviants were introduced that either crossed a phonetic boundary or remained within the same category. Two phonetic boundaries were explored, one present and the other absent in the subjects' native language. A large mismatch negativity was induced by native phonetic deviants, but not by non-native or within-category deviants. We suggest that a language-specific phonemic code has a separate neural representation in sensory memory and can serve as the basis for auditory mismatch detection. The subjects' inability to discriminate non-native phonetic contrasts does not seem related to a late attentional filter, but rather to a genuine loss of auditory discrimination abilities.

Electrophysiological evidence for automatic phonetic processing in neonates.

At least two fundamental properties should be present in a network computing a phonetic representation: categorical perception and normalization across different utterances. Normalization processes were studied at birth by recording high density evoked potentials to strings of syllables in sleeping neonates. We compared the response to a change of phoneme when irrelevant speaker variation was present or absent. A mismatch response was recorded at the same latency in both cases, suggesting that relevant phonetic information was extracted from the irrelevant variation. Combined with our previous work showing that the mismatch response is sensitive to categorical perception in infants, this result suggests that a phonetic network like that of adults, is already present in the infant brain. Furthermore, efficient phonetic processing does not require attention.

A phonological representation in the infant brain.

In adults, neural networks for phonological processing distinct from those involved in acoustical processing are located in the left temporal lobe. We now report that by the age of 3 months, infants display phonological processing devices analogous to those found in adults. Within a stream of identical syllables, acoustic deviants were introduced, either crossing a phonetic boundary or remaining within the same category. Event-related potentials were recorded using a 64-electrode net. Although the acoustical change was of similar amplitude in the two deviants, the electrophysiological response was larger for a phonological change and involved a more posterior and dorsal temporal region than for an acoustical change. These results demonstrate that infants, like adults, already possess a dedicated neuronal network for phonetic processing.

Phoneme perception in a neonate with a left sylvian infarct.

We report the case of a neonate tested three weeks after a neonatal left sylvian infarct. We studied her perception of speech and non-speech stimuli with high-density event-related potentials. The results show that she was able to discriminate not only a change of timbre in tones but also a vowel change, and even a place of articulation contrast in stop consonants. Moreover, a discrimination response to stop consonants was observed even when syllables were produced by different speakers. Her intact right hemisphere was thus able to extract relevant phonetic information in spite of irrelevant acoustic variation. These results suggest that both hemispheres contribute to phoneme perception during the first months of life and confirm our previous findings concerning bilateral responses in normal infants.

The early development of brain white matter: a review of imaging studies in fetuses, newborns and infants.

Studying how the healthy human brain develops is important to understand early pathological mechanisms and to assess the influence of fetal or perinatal events on later life. Brain development relies on complex and intermingled mechanisms especially during gestation and first post-natal months, with intense interactions between genetic, epigenetic and environmental factors. Although the baby's brain is organized early on, it is not a miniature adult brain: regional brain changes are asynchronous and protracted, i.e. sensory-motor regions develop early and quickly, whereas associative regions develop later and slowly over decades. Concurrently, the infant/child gradually achieves new performances, but how brain maturation relates to changes in behavior is poorly understood, requiring non-invasive in vivo imaging studies such as magnetic resonance imaging (MRI). Two main processes of early white matter development are reviewed: (1) establishment of connections between brain regions within functional networks, leading to adult-like organization during the last trimester of gestation, (2) maturation (myelination) of these connections during infancy to provide efficient transfers of information. Current knowledge from post-mortem descriptions and in vivo MRI studies is summed up, focusing on T1- and T2-weighted imaging, diffusion tensor imaging, and quantitative mapping of T1/T2 relaxation times, myelin water fraction and magnetization transfer ratio.

[Brain development of infant and MRI by diffusion tensor imaging]. / Neurophysiologie clinique : développement cérébral du nourrisson et imagerie par résonance magnétique.

Studying how the brain develops and becomes functional is important to understand how the man has been able to develop specific cognitive abilities, and to comprehend the complexity of some developmental pathologies. Thanks to magnetic resonance imaging (MRI), it is now possible to image the baby's immature brain and to consider subtle correlations between the brain anatomical development and the early acquisition of cognitive functions. Dedicated methodologies for image acquisition and post-treatment must then be used because the size of cerebral structures and the image contrast are very different in comparison with the adult brain, and because the examination length is a major constraint. Two recent studies have evaluated the developing brain under an original perspective. The first one has focused on cortical folding in preterm newborns, from 6 to 8 months of gestational age, assessed with T2-weighted conventional MRI. The second study has mapped the organization and maturation of white matter fiber bundles in 1- to 4-month-old healthy infants with diffusion tensor imaging (DTI). Both studies have enabled to highlight spatio-temporal differences in the brain regions' maturation, as well as early anatomical asymmetries between cerebral hemispheres. These studies emphasize the potential of MRI to evaluate brain development compared with the infant's psychomotor acquisitions after birth.

Language or music, mother or Mozart? Structural and environmental influences on infants' language networks.

Understanding how language emerged in our species calls for a detailed investigation of the initial specialization of the human brain for speech processing. Our earlier research demonstrated that an adult-like left-lateralized network of perisylvian areas is already active when infants listen to sentences in their native language, but did not address the issue of the specialization of this network for speech processing. Here we used fMRI to study the organization of brain activity in two-month-old infants when listening to speech or to music. We also explored how infants react to their mother's voice relative to an unknown voice. The results indicate that the well-known structural asymmetry already present in the infants' posterior temporal areas has a functional counterpart: there is a left-hemisphere advantage for speech relative to music at the level of the planum temporale. The posterior temporal regions are thus differently sensitive to the auditory environment very early on, channelling speech inputs preferentially to the left side. Furthermore, when listening to the mother's voice, activation was modulated in several areas, including areas involved in emotional processing (amygdala, orbito-frontal cortex), but also, crucially, a large extent of the left posterior temporal lobe, suggesting that the mother's voice plays a special role in the early shaping of posterior language areas. Both results underscore the joint contributions of genetic constraints and environmental inputs in the fast emergence of an efficient cortical network for language processing in humans.