Maturational networks of human fetal brain activity reveal emerging connectivity patterns prior to ex-utero exposure.

A key feature of the fetal period is the rapid emergence of organised patterns of spontaneous brain activity. However, characterising this process in utero using functional MRI is inherently challenging and requires analytical methods which can capture the constituent developmental transformations. Here, we introduce a novel analytical framework, termed "maturational networks" (matnets), that achieves this by modelling functional networks as an emerging property of the developing brain. Compared to standard network analysis methods that assume consistent patterns of connectivity across development, our method incorporates age-related changes in connectivity directly into network estimation. We test its performance in a large neonatal sample, finding that the matnets approach characterises adult-like features of functional network architecture with a greater specificity than a standard group-ICA approach; for example, our approach is able to identify a nearly complete default mode network. In the in-utero brain, matnets enables us to reveal the richness of emerging functional connections and the hierarchy of their maturational relationships with remarkable anatomical specificity. We show that the associative areas play a central role within prenatal functional architecture, therefore indicating that functional connections of high-level associative areas start emerging prior to exposure to the extra-utero environment.

Spatiotemporal tissue maturation of thalamocortical pathways in the human fetal brain.

The development of connectivity between the thalamus and maturing cortex is a fundamental process in the second half of human gestation, establishing the neural circuits that are the basis for several important brain functions. In this study, we acquired high-resolution in utero diffusion magnetic resonance imaging (MRI) from 140 fetuses as part of the Developing Human Connectome Project, to examine the emergence of thalamocortical white matter over the second to third trimester. We delineate developing thalamocortical pathways and parcellate the fetal thalamus according to its cortical connectivity using diffusion tractography. We then quantify microstructural tissue components along the tracts in fetal compartments that are critical substrates for white matter maturation, such as the subplate and intermediate zone. We identify patterns of change in the diffusion metrics that reflect critical neurobiological transitions occurring in the second to third trimester, such as the disassembly of radial glial scaffolding and the lamination of the cortical plate. These maturational trajectories of MR signal in transient fetal compartments provide a normative reference to complement histological knowledge, facilitating future studies to establish how developmental disruptions in these regions contribute to pathophysiology.

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.

Spatial gradients of healthy aging: a study of myelin-sensitive maps.

Protracted development of a brain network may entail greater susceptibility to aging decline, supported by evidence of an earlier onset of age-related changes in late-maturing anterior areas, that is, an anterior-to-posterior gradient of brain aging. Here we analyzed the spatiotemporal features of age-related differences in myelin content across the human brain indexed by magnetization transfer (MT) concentration in a cross-sectional cohort of healthy adults. We described age-related spatial gradients in MT, which may reflect the reversal of patterns observed in development. We confirmed an anterior-to-posterior gradient of age-related MT decrease and also showed a lateral-to-ventral gradient inversely mirroring the sequence of connectivity development and myelination. MT concentration in the lateral white matter regions continued to increase up to the age of 45 years and decreased moderately following a peak. In contrast, ventral white matter regions reflected life-long stable MT concentration levels, followed by a rapid decrease at a later age. We discussed our findings in relation with existing theories of brain aging, including the lack of support for the proposal that areas which mature later decline at an accelerated rate.

The architecture of functional lateralisation and its relationship to callosal connectivity in the human brain.

Functional lateralisation is a fundamental principle of the human brain. However, a comprehensive taxonomy of functional lateralisation and its organisation in the brain is missing. Here, we report the first complete map of functional hemispheric asymmetries in the human brain, reveal its low dimensional structure, and its relationship with structural inter-hemispheric connectivity. Our results suggest that the lateralisation of brain functions is distributed along four functional axes: symbolic communication, perception/action, emotion, and decision-making. The similarity between this finding and recent work on neurological symptoms give rise to new hypotheses on the mechanisms that support brain recovery after a brain lesion. We also report that cortical regions showing asymmetries in task-evoked activity have reduced connections with the opposite hemisphere. This latter result suggests that during evolution, brain size expansion led to functional lateralisation to avoid excessive conduction delays between the hemispheres.

Probing the architecture of visual number sense with parietal tRNS.

Theoretical accounts of the visual number sense (VNS), i.e., an ability to discriminate approximate numerosities, remain controversial. A proposal that the VNS represents a process of numerosity extraction, leading to an abstract number representation in the brain, has been challenged by the view that the VNS is non-numerical in its essence and amounts to a weighted integration of continuous magnitude features that typically change with numerosity. In the present study, using two-alternative forced-choice paradigm, we aimed to distinguish between these proposals by probing brain areas implicated in the VNS with transcranial random noise stimulation (tRNS). We generated predictions for the stimulation-related changes in behavioural performance which would be compatible with alternative mechanisms proposed for the VNS. First, we investigated whether the superior parietal (SP) area hosts a numerosity code or whether its function is to modulate weighting of continuous stimulus features. We predicted that stimulation may affect the VNS precision if the SP role is representational, and that it may affect decision threshold if its role is modulatory. Second, we investigated whether the intraparietal (IP) area hosts a numerosity code independently of codes for continuous stimulus features, or whether their representations overlap. If the numerosity code is independent, we predicted that IP stimulation may improve the VNS but not continuous magnitude judgements. Our results were consistent with the hypotheses of a modulatory role of the SP and of the independence of the numerosity code in the IP, whereby suggesting that VNS is an emergent abstract property based on continuous magnitude statistics.

The effect of perinatal brain injury on dopaminergic function and hippocampal volume in adult life.

Perinatal brain injuries, including hippocampal lesions, cause lasting changes in dopamine function in rodents, but it is not known if this occurs in humans. We compared adults who were born very preterm with perinatal brain injury to those born very preterm without perinatal brain injury, and age-matched controls born at full term using [18F]-DOPA PET and structural MRI. Dopamine synthesis capacity was reduced in the perinatal brain injury group relative to those without brain injury (Cohen's d = 1.36, p=0.02) and the control group (Cohen's d = 1.07, p=0.01). Hippocampal volume was reduced in the perinatal brain injury group relative to controls (Cohen's d = 1.17, p=0.01) and was positively correlated with striatal dopamine synthesis capacity (r = 0.344, p=0.03). This is the first evidence in humans linking neonatal hippocampal injury to adult dopamine dysfunction, and provides a potential mechanism linking early life risk factors to adult mental illness.

Volumetric grey matter alterations in adolescents and adults born very preterm suggest accelerated brain maturation.

Previous research investigating structural neurodevelopmental alterations in individuals who were born very preterm demonstrated a complex pattern of grey matter changes that defy straightforward summary. Here we addressed this problem by characterising volumetric brain alterations in individuals who were born very preterm from adolescence to adulthood at three hierarchically related levels - global, modular and regional. We demarcated structural components that were either particularly resilient or vulnerable to the impact of very preterm birth. We showed that individuals who were born very preterm had smaller global grey matter volume compared to controls, with subcortical and medial temporal regions being particularly affected. Conversely, frontal and lateral parieto-temporal cortices were relatively resilient to the effects of very preterm birth, possibly indicating compensatory mechanisms. Exploratory analyses supported this hypothesis by showing a stronger association between lateral parieto-temporal volume and IQ in the very preterm group compared to controls. We then related these alterations to brain maturation processes. Very preterm individuals exhibited a higher maturation index compared to controls, indicating accelerated brain maturation and this was specifically associated with younger gestational age. We discuss how the findings of accelerated maturation might be reconciled with evidence of delayed maturation at earlier stages of development.

Reinforcement of the Brain's Rich-Club Architecture Following Early Neurodevelopmental Disruption Caused by Very Preterm Birth.

The second half of pregnancy is a crucial period for the development of structural brain connectivity, and an abrupt interruption of the typical processes of development during this phase caused by the very preterm birth (<33 weeks of gestation) is likely to result in long-lasting consequences. We used structural and diffusion imaging data to reconstruct the brain structural connectome in very preterm-born adults. We assessed its rich-club organization and modularity as 2 characteristics reflecting the capacity to support global and local information exchange, respectively. Our results suggest that the establishment of global connectivity patterns is prioritized over peripheral connectivity following early neurodevelopmental disruption. The very preterm brain exhibited a stronger rich-club architecture than the control brain, despite possessing a relative paucity of white matter resources. Using a simulated lesion approach, we also investigated whether putative structural reorganization takes place in the very preterm brain in order to compensate for its anatomical constraints. We found that connections between the basal ganglia and (pre-) motor regions, as well as connections between subcortical regions, assumed an altered role in the structural connectivity of the very preterm brain, and that such alterations had functional implications for information flow, rule learning, and verbal IQ.