Biology subjects

O'Muircheartaigh, J.

Publications and source records attributed to O'Muircheartaigh, J..

29 records · Page 2Linked to original sources

bioRxiv2021

Preterm birth alters the development of cortical microstructure and morphology at term-equivalent age

IntroductionThe dynamic nature and complexity of the cellular events that take place during the last trimester of pregnancy make the developing cortex particularly vulnerable to perturbations. Abrupt interruption to normal gestation can lead to significant deviations to many of these processes, resulting in atypical trajectory of cortical maturation in preterm birth survivors. MethodsWe sought to first map typical cortical micro and macrostructure development using invivo MRI in a large sample of healthy term-born infants scanned after birth (n=270). Then we offer a comprehensive characterisation of the cortical consequences of preterm birth in 78 preterm infants scanned at term-equivalent age (37-44 weeks postmenstrual age). We describe the group-average atypicality, the heterogeneity across individual preterm infants, and relate individual deviations from normative development to age at birth and neurodevelopment at 18 months. ResultsIn the term-born neonatal brain, we observed regionally specific age-associated changes in cortical morphology and microstructure, including rapid surface expansion, cortical thickness increase, reduction in cortical anisotropy and increase in neurite orientation dispersion. By term-equivalent age, preterm infants had on average increased cortical tissue water content and reduced neurite density index in the posterior parts of the cortex, and greater cortical thickness anteriorly compared to term-born infants. While individual preterm infants were more likely to show extreme deviations (over 3.1 standard deviations) from normative cortical maturation compared to term-born infants, these extreme deviations were highly variable and showed very little spatial overlap between individuals. Measures of regional cortical development were associated with age at birth, but not with neurodevelopment at 18 months. ConclusionWe showed that preterm birth alters cortical micro and macrostructural maturation near the time of fullterm birth. Deviations from normative development were highly variable between individual preterm infants.

neuroscience↗

bioRxiv2021

Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies

Multiple studies have demonstrated less favourable childhood outcomes in infants born in early term (37-38 weeks gestation) compared to those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain and subsequent neurodevelopment in term-born babies. Here we characterise structural brain correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome. We used T2 and diffusion weighted Magnetic Resonance Images acquired in the neonatal period from a cohort (n=454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor based morphometry (TBM) and tract based spatial statistics (TBSS). Neurodevelopment was subsequently assessed at age 18 months using the Bayley-III Scales of Infant and Toddler Development, and the effects of gestational age at birth and related neuroimaging findings on outcome were analysed with linear regression. Infants born earlier had areas of higher relative ventricular volume, and lower relative brain volume in the basal ganglia, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Linear regression models predicting outcome from gestational age at birth were significantly improved by adding neuroimaging features associated with gestational age at birth. This work adds to the growing body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.

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bioRxiv2020

Individualized characterization of volumetric development in the preterm brain

The diverse cerebral consequences of preterm birth create significant challenges for understanding pathogenesis or predicting later outcome. Instead of focusing on describing effects common to the group, comparing individual infants against robust normative data offers a powerful alternative to study brain maturation. Here we used Gaussian process regression to create normative curves characterising brain volumetric development in 274 term-born infants, modelling for age at scan and sex. We then compared 89 preterm infants scanned at termequivalent age to these normative charts, relating individual deviations from typical volumetric development to perinatal risk factors and later neurocognitive scores. To test generalisability, we used a second independent dataset comprising of 253 preterm infants scanned using different acquisition parameters and scanner. We describe rapid, non-uniform brain growth during the neonatal period. In both preterm cohorts, cerebral atypicalities were widespread, often multiple, and varied highly between individuals. Deviations from normative development were associated with respiratory support, nutrition, birth weight, and later neurocognition, demonstrating their clinical relevance. Group-level understanding of the preterm brain disguise a large degree of individual differences. We provide a method and normative dataset that offer a more precise characterisation of the cerebral consequences of preterm birth by profiling the individual neonatal brain.

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bioRxiv2020

Cortical morphology at birth reflects spatio-temporal patterns of gene expression in the fetal brain

Interruption to gestation through preterm birth can significantly impact cortical development and have long-lasting adverse effects on neurodevelopmental outcome. We compared cortical morphology captured by high-resolution, multimodal MRI in n=292 healthy newborn infants (mean age at birth=39.9 weeks) with regional patterns of gene expression in the fetal cortex across gestation (n=156 samples from 16 brains, aged 12 to 37 post-conceptional weeks). We tested the hypothesis that noninvasive measures of cortical structure at birth mirror areal differences in cortical gene expression across gestation, and in a cohort of n=64 preterm infants (mean age at birth = 32.0 weeks), we tested whether cortical alterations observed after preterm birth were associated with altered gene expression in specific developmental cell populations. Neonatal cortical structure was aligned to differential patterns of cell-specific gene expression in the fetal cortex. Principal component analysis of six measures of cortical morphology and microstructure showed that cortical regions were ordered along a principal axis, with primary cortex clearly separated from heteromodal cortex. This axis was correlated to estimated tissue maturity, indexed by differential expression of genes expressed by progenitor cells and neurons; and engaged in stem cell differentiation, neuron migration and forebrain development. Preterm birth was associated with altered regional MRI metrics and patterns of differential gene expression in glial cell populations. The spatial patterning of gene expression in the developing cortex was thus mirrored by regional variation in cortical morphology and microstructure at term, and this was disrupted by preterm birth. This work provides a framework to link molecular mechanisms to noninvasive measures of cortical development in early life and highlights novel pathways to injury in neonatal populations at increased risk of neurodevelopmental disorder.

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bioRxiv2020

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

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 normal term 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.

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bioRxiv2020

Development of Microstructural and Morphological Cortical Profiles in the Neonatal Brain

In the perinatal brain, regional cortical architecture and connectivity lay the foundations for functional circuits and emerging behaviour. Interruptions or atypical development during or before this period may therefore have long-lasting consequences. However, to be able to investigate these deviations, we need a measure of how this architecture evolves in the typically developing brain. To this end, in a large cohort of 241 term-born infants we used Magnetic Resonance Imaging to estimate cortical profiles based on morphometry and microstructure over the perinatal period (37-44 weeks post-menstrual age, PMA). Using the covariance of these profiles as a measure of inter-areal network similarity (Morphometric Similarity Networks; MSN), we clustered these networks into distinct modules. The resulting modules were consistent and symmetric, and corresponded to known functional distinctions, including sensory-motor, limbic and association regions and were spatially mapped onto known cytoarchitectonic tissue classes. Posterior (parietal, occipital) regions became more morphometrically similar with increasing PMA, while peri-cingulate and medial temporal regions became more dissimilar. Network strength was associated with PMA: Within-network similarity increased over PMA suggesting emerging network distinction. These changes in cortical network architecture over an eight-week period are consistent with, and likely underpin, the highly dynamic behavioural and cognitive development occurring during this critical period. The resulting cortical profiles might provide normative reference to investigate atypical early brain development.

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bioRxiv2019

The developing Human Connectome Project (dHCP) automated resting-state functional processing framework for newborn infants.

The developing Human Connectome Project (dHCP) aims to create a detailed 4-dimensional connectome of early life spanning 20 to 45 weeks post-menstrual age. This is being achieved through the acquisition of multi-modal MRI data from over 1000 in- and ex-utero subjects combined with the development of optimised pre-processing pipelines. In this paper we present an automated and robust pipeline to minimally pre-process highly confounded neonatal resting-state fMRI data, robustly, with low failure rates and high quality-assurance. The pipeline has been designed to specifically address the challenges that neonatal data presents including low and variable contrast and high levels of head motion. We provide a detailed description and evaluation of the pipeline which includes integrated slice-to-volume motion correction and dynamic susceptibility distortion correction, a robust multimodal registration approach, bespoke ICA-based denoising, and an automated QC framework. We assess these components on a large cohort of dHCP subjects and demonstrate that processing refinements integrated into the pipeline provide substantial reduction in movement related distortions, resulting in significant improvements in SNR, and detection of high quality RSNs from neonates. HighlightsO_LIAn automated and robust pipeline to minimally pre-process highly confounded neonatal fMRI data C_LIO_LIIncludes integrated dynamic distortion and slice-to-volume motion correction C_LIO_LIA robust multimodal registration approach which includes custom neonatal templates C_LIO_LIIncorporates an automated and self-reporting QC framework to quantify data quality and identify issues for further inspection C_LIO_LIData analysis of 538 infants imaged at 26-45 weeks post-menstrual age C_LI

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bioRxiv2019

The heterogeneous functional architecture of the posteromedial cortex is associated with selective functional connectivity differences in Alzheimer’s disease

The posteromedial cortex (PMC) is a key region involved in the development and progression of Alzheimers disease (AD). Previous studies have demonstrated a heterogenous functional architecture of the region, with different subdivisions reflecting distinct connectivity profiles. However, little is understood about PMC functional connectivity and its differential vulnerability to AD pathogenesis. Using a data-driven approach, we applied a constrained independent component analysis (ICA) on healthy adults from the Human Connectome Project (HCP) to characterise the distinct functional subdivisions and unique functional-anatomic connectivity patterns of the PMC. These connectivity profiles were subsequently quantified in the Alzheimers Disease Neuroimaging Initiative (ADNI) study, to examine functional connectivity differences in (1) AD patients and cognitively normal (CN) participants and (2) the entire AD pathological spectrum, ranging from CN participants and participants with subjective memory complaints (SMC), through to those with mild cognitive impairment (MCI), and finally, patients diagnosed with AD. Our findings revealed decreased functional connectivity in the anterior precuneus, dorsal posterior cingulate cortex, and the central precuneus in AD patients compared to CN participants. Functional abnormalities in these subdivisions were also related to high amyloid burden and lower hippocampal volumes. Across the entire AD spectrum, functional connectivity of the central precuneus was associated with disease progression and specific deficits in memory and executive function. These findings provide new evidence showing that specific vulnerabilities in PMC functional connectivity are associated with large-scale network disruptions in AD and that these patterns may be useful for elucidating potential biomarkers for measuring disease progression in future work.

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bioRxiv2019

Sustained perturbation in functional connectivity induced by cold pain

Functional connectivity (FC) perturbations have been reported in multiple chronic pain phenotypes, but the nature of reported changes is varied and inconsistent between cohorts. Increases and decreases in connectivity strength in task negative and positive networks, for example, the default mode and salience networks (DMN/SN), respectively, have been described, but how other networks are effected, for example, descending pain control networks, remains unknown. Whether connectivity changes relate to peripherally-mediated nociceptive afferent input, represent coping strategies or are sequelae of chronic pain, e.g. anxiety/depression, is also unknown. Here, we examined FC changes in response to experimentally-administered tonic cold pain in healthy volunteers as a means of disambiguating the nature of connectivity changes. We assessed FC prior to, during, and following tonic cold painful stimulation in four seed regions: ventromedial prefrontal cortex (vmPFC), rostral anterior insula (rAI), subgenual anterior cingulate cortex (ACC) and periaqueductal grey (PAG) and recorded subjectively reported pain using a computerised visual analogue scale. We saw DMN FC changes during painful stimulation and that inter-network communication between the rAI and sgACC seeds with the vmPFC became less anti-correlated during pain, whereas PAG-precuneus FC decreased. Pain-induced FC alterations largely persisted during a 6-minute recovery period following cessation of the painful stimulus. Observed FC changes related to the magnitude of individuals subjectively reported pain. We provide new insights into FC changes during and following tonic cold-pain and suggest that some FC changes observed in chronic pain patients may relate to the presence of an ongoing afferent peripheral drive.

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bioRxiv2018

Abnormal microstructural development of the cerebral cortex in neonates with congenital heart disease is associated with impaired cerebral oxygen delivery

BackgroundAbnormal macrostructural development of the cerebral cortex has been associated with hypoxia in infants with congenital heart disease (CHD). Animal studies have suggested that hypoxia results in cortical dysmaturation at the cellular level. New magnetic resonance imaging (MRI) techniques offer the potential to investigate the relationship between cerebral oxygen delivery and microstructural development of the cortex in newborn infants with CHD.\n\nMethodsWe measured macrostructural and microstructural properties of the cortex in 48 newborn infants with complex CHD and 48 age-matched healthy controls. Cortical volume and gyrification index were calculated from high resolution structural MRI. Neurite density and orientation dispersion indices were modelled using high angular resolution diffusion MRI. Cerebral oxygen delivery was estimated in infants with CHD using phase contrast MRI and pre-ductal pulse oximetry. We used tract-based spatial statistics to examine voxel-wise group differences in cortical microstructure.\n\nResultsMicrostructural development of the cortex was abnormal in 48 infants with CHD, with regions of increased fractional anisotropy (FA) and reduced orientation dispersion index (ODI) compared to 48 healthy controls, correcting for gestational age at birth and scan (FWE-corrected for multiple comparisons at P<0.05). Regions of reduced cortical ODI in infants with CHD were related to impaired cerebral oxygen delivery (R2=0.637, n=39). Cortical ODI was associated with gyrification index (R2=0.589, P<0.0001, n=48).\n\nConclusionsThis study suggests that the primary component of cerebral cortex dysmaturation in CHD is impaired dendritic arborisation, which may underlie abnormal macrostructural findings reported in this population. The degree of impairment was related to cerebral oxygen delivery, supporting the hypothesis that maternal oxygen therapy may be beneficial in this population.

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bioRxiv2018

Emergence of Human Amygdala Functional Networks: 3 Months to 5 Years of Age

Although the amygdalas role in shaping social behavior is especially important during early post-natal development, very little is known of human amygdala functional development before childhood. To address this important gap, this study used resting-state fMRI to examine early functional network development of the amygdala and its subregions in 80 participants from 3-months to 5-years of age. Whole brain functional connectivity with the whole amygdala and its laterobasal and superficial nuclear groups were largely similar to those seen in older children and adults, and functional distinctions between subregion networks exist already. These patterns suggest many amygdala functional circuits are intact from infancy, especially those that are part of larger motor, visual, auditory and subcortical (basal ganglia especially) networks. Notably, these observed robust amygdala functional networks in infancy precede reports to date of elicited amygdala reactivity in development. Developmental changes in connectivity were observed between the laterobasal nucleus and bilateral ventral temporal and motor cortex as well as between the superficial nuclei and medial thalamus, occipital cortex and a different region of motor cortex. These results show amygdala-subcortical and sensory-cortex connectivity begins refinement prior to childhood, though connectivity changes with associative and frontal cortical areas, seen after early childhood, were not evident in this age range. These findings represent early steps in understanding amygdala network dynamics across infancy through early childhood, an important period of emotional and cognitive development.

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