Towards Deciphering the Fetal Foundation of Normal Cognition and Cognitive Symptoms From Sulcation of the Cortex.

Growing evidence supports that prenatal processes play an important role for cognitive ability in normal and clinical conditions. In this context, several neuroimaging studies searched for features in postnatal life that could serve as a proxy for earlier developmental events. A very interesting candidate is the sulcal, or sulco-gyral, patterns, macroscopic features of the cortex anatomy related to the fold topology-e.g., continuous vs. interrupted/broken fold, present vs. absent fold-or their spatial organization. Indeed, as opposed to quantitative features of the cortical sheet (e.g., thickness, surface area or curvature) taking decades to reach the levels measured in adult, the qualitative sulcal patterns are mainly determined before birth and stable across the lifespan. The sulcal patterns therefore offer a window on the fetal constraints on specific brain areas on cognitive abilities and clinical symptoms that manifest later in life. After a global review of the cerebral cortex sulcation, its mechanisms, its ontogenesis along with methodological issues on how to measure the sulcal patterns, we present a selection of studies illustrating that analysis of the sulcal patterns can provide information on prenatal dispositions to cognition (with a focus on cognitive control and academic abilities) and cognitive symptoms (with a focus on schizophrenia and bipolar disorders). Finally, perspectives of sulcal studies are discussed

Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multi-modal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey index to provide a fine-grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development at term-equivalent age. Compared to term-born controls, preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion.Keywords: feature similarity gradients, neonatal brain, preterm birth, MRI, neonatal corte

Semi-automatic GUI platform to characterize brain development in preterm children using ultrasound images

The third trimester of pregnancy is the most critical period for human brain development, during which significant changes occur in the morphology of the brain. The development of sulci and gyri allows for a considerable increase in the brain surface. In preterm newborns, these changes occur in an extrauterine environment that may cause a disruption of the normal brain maturation process. We hypothesize that a normalized atlas of brain maturation with cerebral ultrasound images from birth to term equivalent age will help clinicians assess these changes. This work proposes a semi-automatic Graphical User Interface (GUI) platform for segmenting the main cerebral sulci in the clinical setting from ultrasound images. This platform has been obtained from images of a cerebral ultrasound neonatal database images provided by two clinical researchers from the Hospital Sant Joan de Déu in Barcelona, Spain. The primary objective is to provide a user-friendly design platform for clinicians for running and visualizing an atlas of images validated by medical experts. This GUI offers different segmentation approaches and pre-processing tools and is user-friendly and designed for running, visualizing images, and segmenting the principal sulci. The presented results are discussed in detail in this paper, providing an exhaustive analysis of the proposed approach’s effectiveness.Peer ReviewedPostprint (published version

The Developing Human Connectome Project: typical and disrupted perinatal functional connectivity

The Developing Human Connectome Project (dHCP) is an Open Science project which provides the first large sample of neonatal functional MRI (fMRI) data with high temporal and spatial resolution. This data enables mapping of intrinsic functional connectivity between spatially distributed brain regions under normal and adverse perinatal circumstances, offering a framework to study the ontogeny of large-scale brain organisation in humans. Here, we characterise in unprecedented detail the maturation and integrity of resting-state networks (RSNs) at term-equivalent age in 337 infants (including 65 born preterm). First, we applied group independent component analysis (ICA) to define 11 RSNs in term-born infants scanned at 43.5-44.5 weeks postmenstrual age (PMA). Adult-like topography was observed in RSNs encompassing primary sensorimotor, visual and auditory cortices. Among six higher-order, association RSNs, analogues of the adult networks for language and ocular control were identified, but a complete default mode network precursor was not. Next, we regressed the subject-level datasets from an independent cohort of infants scanned at 37-43.5 weeks PMA against the group-level RSNs to test for the effects of age, sex and preterm birth. Brain mapping in term-born infants revealed areas of positive association with age across four of six association RSNs, indicating active maturation in functional connectivity from 37 to 43.5 weeks PMA. Female infants showed increased connectivity in inferotemporal regions of the visual association network. Preterm birth was associated with striking impairments of functional connectivity across all RSNs in a dose-dependent manner; conversely, connectivity of the superior parietal lobules within the lateral motor network was abnormally increased in preterm infants, suggesting a possible mechanism for specific difficulties such as developmental coordination disorder which occur frequently in preterm children. Overall, we find a robust, modular, symmetrical functional brain organisation at normal term age. A complete set of adult-equivalent primary RSNs is already instated, alongside emerging connectivity in immature association RSNs, consistent with a primary-to-higher-order ontogenetic sequence of brain development. The early developmental disruption imposed by preterm birth is associated with extensive alterations in functional connectivity

A bipolar taxonomy of adult human brain sulcal morphology related to timing of fetal sulcation and trans-sulcal gene expression gradients

We developed a computational pipeline (now provided as a resource) for measuring morphological similarity between cortical surface sulci to construct a sulcal phenotype network (SPN) from each magnetic resonance imaging (MRI) scan in an adult cohort (N=34,725; 45-82 years). Networks estimated from pairwise similarities of 40 sulci on 5 morphological metrics comprised two clusters of sulci, represented also by the bipolar distribution of sulci on a linear-to-complex dimension. Linear sulci were more heritable and typically located in unimodal cortex; complex sulci were less heritable and typically located in heteromodal cortex. Aligning these results with an independent fetal brain MRI cohort (N=228; 21-36 gestational weeks), we found that linear sulci formed earlier, and the earliest and latest-forming sulci had the least between-adult variation. Using high-resolution maps of cortical gene expression, we found that linear sulcation is mechanistically underpinned by trans-sulcal gene expression gradients enriched for developmental processes.</p

Physics of Brain Folding

The human brain is characterized by its folded structure, being the most folded brain among all primates. The process by which these folds emerge, called gyrogenesis, is still not fully understood. The brain is divided into an outer region, called gray matter, which grows at a faster rate than the inner region, called white matter. It is hypothesized that this imbalance in growth -- and the mechanical stress thereby generated -- drives gyrogenesis, which is the focus of this thesis. Finite element simulations are performed where the brain is modeled as a non-linear elastic and growth is introduced via a multiplicative decomposition. A small section of the brain, represented by a rectangular slab, is analyzed. This slab is divided into a thin hard upper layer mimicking the gray matter, and a soft substrate, mimicking the white matter. The top layer is then grown tangentially, while the underlying substrate does not grow. JuFold, the software developed to perform these simulations, is introduced, and its design is explained. An overview of its capabilities, and examples of simulation possibilities are shown. Additionally, one patent-leading application of JuFold in the realm of material science showcases its flexibility. Simulations are first performed by minimizing the elastic energy, corresponding to the slow growth regime. Systems with homogeneous cortices are studied, where growth initially compresses, and then buckles the cortical region, which generates wavy patterns with wavelength proportional to cortical thickness. After buckling, the sulcal regions (i.e. the valleys of the system) are thinner than the gyral regions (i.e. the hills). Introducing thickness inhomogeneities along the cortex lead to new and localized configurations, which are strongly dependent not only on the thickness of the region, but also on its gradient. Furthermore, cortical landmarks appear sequentially, consistent with the hierarchical folding observed during gestation. A linear stability theory is developed based on thin plate theory and is compared with homogeneous and inhomogeneous systems. Next, we turn to more physically stringent dynamic simulations. For slow growth rate and time-constant thickness, the results obtained through energy minimization are recovered, justifying previous literature. For faster growth, an overshoot of the wavenumber and a broad wavenumber spectrum are observed immediately after buckling. After a relaxation period, where the average wavenumber decreases and the wavenumber spectrum narrows, it is observed that the system stabilizes into a finite spectrum, whose average wavelength is smaller than that expected from energy minimization arguments. Cortical inhomogeneities are further explored in this new regime. Systems with inhomogeneous cortical thickness are revisited, with effects similar to the homogeneous cortex (i.e., results are consistent between the slow growth and the quasistatic regimes, and overshoot is observed in the fast growth regimes). Systems with inhomogeneous cortical growth are simulated, with this new type of inhomogeneity inducing fissuration and localized folding. The interplay between these two inhomogeneities is studied, and their interaction is shown to be nonlinear, with each inhomogeneity type inhibiting the folding effects of the other. That is, the folding profile of each individual region emerges as a result of the local inhomogeneity, and the system does not display an intermediate behavior. Finally, these results are compared with an extended linear stability theory. Taken together, our simulations and analytical theory expose new phenomena predicted by an incremented buckling hypothesis for folding and show a series of new avenues which could give rise to the important cortical features in the mammalian brain, especially those related to higher-order folding

Brain morphological and functional correlates of genetic, psychological, prenatal and prodromal risk for major mental disorders and their behavioural links

Cross-sectional mri-studies comparing psychiatric patients with healthy individuals have shown that patients show brain morphometric as well as functional changes. However, it is unclear whether these are pathological factors or whether these neurobiological changes are simply a risk factor for mental disorders, a consequence of therapy, only occur in certain subgroups. Therefore, the influence of a broad spectrum of different risk factors for mental disorders on brain morphometry as well as function was investigated in the present study: polygenic risk scores for psychiatric disorders, temporal perspective, shortened prenatal development as well as an extremely high risk for the development of psychosis. It can be shown that these risk factors significantly influence brain structural parameters as well as brain function. Some of these changes also correlated with behavioural changes such as poorer cognitive performance. These behavioural correlates could be valuable diagnostic or prognostic markers and could also be important research targets for the development of new therapeutic approaches

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

Time resolved functional brain networks : a novel method and developmental perspective

Functional neuroimaging has helped elucidating the complexity of brain function in ever more detail during the last 30 years. In this time the concepts used to understand how the brain works has also developed from a focus on regional activation to a network based whole brain perspective (Deco et al., 2015). The understanding that the brain is not just merely responding to external demands but is itself a co-creator of its perceived reality is now the default perspective (Buzsáki and Fernández-Ruiz, 2019). This means that the brain is never resting and its intrinsic architecture is the basis for any task related modulation (Cole et al., 2014). As often in science, understanding and technological advances go hand in hand. For the advancement of the functional neuroimaging field during the last decade, methods that are able to track, capture and model time resolved connectivity changes has been essential (Lurie et al., 2020). This development is an ongoing process. Part of the work presented in this thesis is a small contribution to this collective endeavor. The first theme in the thesis is time resolved connectivity of functional brain networks. This theme is present in Study I which presents a novel method for analysis of time resolved connectivity using BOLD fMRI data. With this method, subnetworks in the brain are defined dynamically. It allows for connectivity changes to be tracked from time point to time point while respecting the temporal ordering of the data. It also provides relational properties in terms of differences in phase coherence between simultaneously integrated networks and their gradual change. The method can be used see how whole brain connectivity configurations recure in quasi-cyclic patterns. Finally, the method is able to estimate flexibility and modularity of individual brain areas. The method is applied in Study III in order to understand how premature birth effects flexibility and modularity of intrinsic functional brain networks. Beyond the purely scientific endeavor to understand how the brain creates cognition, consciousness, perception and supports motor function, neuroimaging research has also been helpful in elucidating normal brain development and neurodevelopmental disorders. The second theme in this thesis is brain development in extremely preterm born children at school age. This theme is the focus of Study II & III. Study II investigates the prevalence of discrete white matter abnormalities at school age in children born extremely preterm and the relationship to neuro-motor outcome. The prevalence of white matter abnormalities was high but there was no relationship to an unfavorable outcome. Also, a longitudinal association to neonatal white matter injury was seen. While discrete white matter abnormalities were not correlated to quantitative measures of white matter volume and white matter integrity, neonatal white matter injury was associated with lower volume and integrity at age 8- 11 years. Moreover, neonatal white matter injury was associated with lower processing speed at 12 years. The third and final study investigated flexibility and modularity as well as lateralization of intrinsic networks in children born extremely preterm at age 8-11 years. No significant differences in either flexibility or modularity was seen for any intrinsic network after correcting for multiple comparisons. However, at the level of individual brain areas, preterm children showed decreased flexibility in both the basal ganglia and thalamus. Also, children born extremely preterm had a decreased level of lateralization in most networks

Emotion and motor function: a clinical and developmental perspective

The idea that emotions and physical actions are strongly intertwined has been widely accepted for quite some time. Yet surprisingly, in both the affective neuroscience and movement neuroscience literature, relatively little empirical attention has been paid to the (psycho)neurophysiological processes underpinning emotion-motor interactions. This body of work provides new insights into emotion-motor interactions by furthering our understanding of the temporal relationship between emotion and motor preparation and motor output during different stages of brain maturation as well as the neurobiological correlates of abnormal motor output in the form of non-epileptic seizures