Cortical morphology at birth reflects spatiotemporal patterns of gene expression in the fetal human 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 magnetic resonance imaging (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 postconceptional weeks [pcw]). 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 (PCA) of 6 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 with 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.

Predicting age and clinical risk from the neonatal connectome.

The development of perinatal brain connectivity underpins motor, cognitive and behavioural abilities in later life. Diffusion MRI allows the characterisation of subtle inter-individual differences in structural brain connectivity. Individual brain connectivity maps (connectomes) are by nature high in dimensionality and complex to interpret. Machine learning methods are a powerful tool to uncover properties of the connectome which are not readily visible and can give us clues as to how and why individual developmental trajectories differ. In this manuscript we used Deep Neural Networks and Random Forests to predict demographic and neurodevelopmental characteristics from neonatal structural connectomes in a large sample of babies (n = 524) from the developing Human Connectome Project. We achieved an accurate prediction of post menstrual age (PMA) at scan in term-born infants (mean absolute error (MAE) = 0.72 weeks, r = 0.83 and p < 0.001). We also achieved good accuracy when predicting gestational age at birth in a cohort of term and preterm babies scanned at term equivalent age (MAE = 2.21 weeks, r = 0.82, p < 0.001). We subsequently used sensitivity analysis to obtain feature relevance from our prediction models, with the most important connections for prediction of PMA and GA found to predominantly involve frontal and temporal regions, thalami, and basal ganglia. From our models of PMA at scan for infants born at term, we computed a brain maturation index (predicted age minus actual age) of individual preterm neonates and found a significant correlation between this index and motor outcome at 18 months corrected age. Our results demonstrate the applicability of machine learning techniques in analyses of the neonatal connectome and suggest that a neural substrate of brain maturation with implications for future neurodevelopment is detectable at term equivalent age from the neonatal connectome.

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

The Developing Human Connectome Project is an Open Science project that provides the first large sample of neonatal functional MRI data with high temporal and spatial resolution. These data enable 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 organization in humans. Here, we characterize 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 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 found a robust, modular, symmetrical functional brain organization 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.

Phenotyping the Preterm Brain: Characterizing Individual Deviations From Normative Volumetric Development in Two Large Infant Cohorts.

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 characterizing brain volumetric development in 274 term-born infants, modeling for age at scan and sex. We then compared 89 preterm infants scanned at term-equivalent age with these normative charts, relating individual deviations from typical volumetric development to perinatal risk factors and later neurocognitive scores. To test generalizability, we used a second independent dataset comprising of 253 preterm infants scanned using different acquisition parameters and scanner. We describe rapid, nonuniform 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 disguises a large degree of individual differences. We provide a method and normative dataset that offer a more precise characterization of the cerebral consequences of preterm birth by profiling the individual neonatal brain.

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

INTRODUCTION: The 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. METHODS: We 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 = 259). Then we offer a comprehensive characterization of the cortical consequences of preterm birth in 76 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. RESULTS: In the term-born neonatal brain, we observed heterogeneous and regionally specific associations between age at scan and measures of cortical morphology and microstructure, including rapid surface expansion, greater cortical thickness, lower cortical anisotropy and higher 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. CONCLUSION: We showed that preterm birth alters cortical micro- and macrostructural maturation near the time of full-term birth. Deviations from normative development were highly variable between individual preterm infants.

Modelling brain development to detect white matter injury in term and preterm born neonates.

Premature birth occurs during a period of rapid brain growth. In this context, interpreting clinical neuroimaging can be complicated by the typical changes in brain contrast, size and gyrification occurring in the background to any pathology. To model and describe this evolving background in brain shape and contrast, we used a Bayesian regression technique, Gaussian process regression, adapted to multiple correlated outputs. Using MRI, we simultaneously estimated brain tissue intensity on T1- and T2-weighted scans as well as local tissue shape in a large cohort of 408 neonates scanned cross-sectionally across the perinatal period. The resulting model provided a continuous estimate of brain shape and intensity, appropriate to age at scan, degree of prematurity and sex. Next, we investigated the clinical utility of this model to detect focal white matter injury. In individual neonates, we calculated deviations of a neonate's observed MRI from that predicted by the model to detect punctate white matter lesions with very good accuracy (area under the curve > 0.95). To investigate longitudinal consistency of the model, we calculated model deviations in 46 neonates who were scanned on a second occasion. These infants' voxelwise deviations from the model could be used to identify them from the other 408 images in 83% (T2-weighted) and 76% (T1-weighted) of cases, indicating an anatomical fingerprint. Our approach provides accurate estimates of non-linear changes in brain tissue intensity and shape with clear potential for radiological use.

Development of Microstructural and Morphological Cortical Profiles in the Neonatal Brain.

Interruptions to neurodevelopment during the perinatal period may have long-lasting consequences. However, to be able to investigate deviations in the foundation of proper connectivity and functional circuits, we need a measure of how this architecture evolves in the typically developing brain. To this end, in a 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 postmenstrual 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 regions became more morphometrically similar with increasing age, while peri-cingulate and medial temporal regions became more dissimilar. Network strength was associated with age: Within-network similarity increased over age suggesting emerging network distinction. These changes in cortical network architecture over an 8-week period are consistent with, and likely underpin, the highly dynamic processes occurring during this critical period. The resulting cortical profiles might provide normative reference to investigate atypical early brain development.

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 20-45 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.

Multimodal surface matching with higher-order smoothness constraints.

In brain imaging, accurate alignment of cortical surfaces is fundamental to the statistical sensitivity and spatial localisation of group studies, and cortical surface-based alignment has generally been accepted to be superior to volume-based approaches at aligning cortical areas. However, human subjects have considerable variation in cortical folding, and in the location of functional areas relative to these folds. This makes alignment of cortical areas a challenging problem. The Multimodal Surface Matching (MSM) tool is a flexible, spherical registration approach that enables accurate registration of surfaces based on a variety of different features. Using MSM, we have previously shown that driving cross-subject surface alignment, using areal features, such as resting state-networks and myelin maps, improves group task fMRI statistics and map sharpness. However, the initial implementation of MSM's regularisation function did not penalize all forms of surface distortion evenly. In some cases, this allowed peak distortions to exceed neurobiologically plausible limits, unless regularisation strength was increased to a level which prevented the algorithm from fully maximizing surface alignment. Here we propose and implement a new regularisation penalty, derived from physically relevant equations of strain (deformation) energy, and demonstrate that its use leads to improved and more robust alignment of multimodal imaging data. In addition, since spherical warps incorporate projection distortions that are unavoidable when mapping from a convoluted cortical surface to the sphere, we also propose constraints that enforce smooth deformation of cortical anatomies. We test the impact of this approach for longitudinal modelling of cortical development for neonates (born between 31 and 43 weeks of post-menstrual age) and demonstrate that the proposed method increases the biological interpretability of the distortion fields and improves the statistical significance of population-based analysis relative to other spherical methods.

Construction of a neonatal cortical surface atlas using Multimodal Surface Matching in the Developing Human Connectome Project.

We propose a method for constructing a spatio-temporal cortical surface atlas of neonatal brains aged between 36 and 44 weeks of post-menstrual age (PMA) at the time of scan. The data were acquired as part of the Developing Human Connectome Project (dHCP), and the constructed surface atlases are publicly available. The method is based on a spherical registration approach: Multimodal Surface Matching (MSM), using cortical folding for driving the alignment. Templates have been generated for the anatomical cortical surface and for the cortical feature maps: sulcal depth, curvature, thickness, T1w/T2w myelin maps and cortical regions. To achieve this, cortical surfaces from 270 infants were first projected onto the sphere. Templates were then generated in two stages: first, a reference space was initialised via affine alignment to a group average adult template. Following this, templates were iteratively refined through repeated alignment of individuals to the template space until the variability of the average feature sets converged. Finally, bias towards the adult reference was removed by applying the inverse of the average affine transformations on the template and de-drifting the template. We used temporal adaptive kernel regression to produce age-dependant atlases for 9 weeks (36-44 weeks PMA). The generated templates capture expected patterns of cortical development including an increase in gyrification as well as an increase in thickness and T1w/T2w myelination with increasing age.

The developing human connectome project: A minimal processing pipeline for neonatal cortical surface reconstruction.

The Developing Human Connectome Project (dHCP) seeks to create the first 4-dimensional connectome of early life. Understanding this connectome in detail may provide insights into normal as well as abnormal patterns of brain development. Following established best practices adopted by the WU-MINN Human Connectome Project (HCP), and pioneered by FreeSurfer, the project utilises cortical surface-based processing pipelines. In this paper, we propose a fully automated processing pipeline for the structural Magnetic Resonance Imaging (MRI) of the developing neonatal brain. This proposed pipeline consists of a refined framework for cortical and sub-cortical volume segmentation, cortical surface extraction, and cortical surface inflation, which has been specifically designed to address considerable differences between adult and neonatal brains, as imaged using MRI. Using the proposed pipeline our results demonstrate that images collected from 465 subjects ranging from 28 to 45 weeks post-menstrual age (PMA) can be processed fully automatically; generating cortical surface models that are topologically correct, and correspond well with manual evaluations of tissue boundaries in 85% of cases. Results improve on state-of-the-art neonatal tissue segmentation models and significant errors were found in only 2% of cases, where these corresponded to subjects with high motion. Downstream, these surfaces will enhance comparisons of functional and diffusion MRI datasets, supporting the modelling of emerging patterns of brain connectivity.

Multi-eigenmode control for high material contrast in bimodal and higher harmonic atomic force microscopy.

High speed imaging and mapping of nanomechanical properties in atomic force microscopy (AFM) allows the observation and characterization of dynamic sample processes. Recent developments involve several cantilever frequencies in a multifrequency approach. One method actuates the first eigenmode for topography imaging and records the excited higher harmonics to map nanomechanical properties of the sample. To enhance the higher frequencies' response two or more eigenmodes are actuated simultaneously, where the higher eigenmode(s) are used to quantify the nanomechanics. In this paper, we combine each imaging methodology with a novel control approach. It modifies the Q factor and resonance frequency of each eigenmode independently to enhance the force sensitivity and imaging bandwidth. It allows us to satisfy the different requirements for the first and higher eigenmode. The presented compensator is compatible with existing AFMs and can be simply attached with minimal modifications. Different samples are used to demonstrate the improvement in nanomechanical contrast mapping and imaging speed of tapping mode AFM in air. The experiments indicate most enhanced nanomechanical contrast with low Q factors of the first and high Q factors of the higher eigenmode. In this scenario, the cantilever topography imaging rate can also be easily improved by a factor of 10.

The interaction between neuromuscular forces, aerodynamic forces, and anatomical motion in the upper airway predicts the severity of pediatric OSA.

Upper airway neuromuscular response to air pressure during inhalation is an important factor in assessing pediatric subjects with obstructive sleep apnea (OSA). The neuromuscular response's strength, timing, and duration all contribute to the potential for airway collapses and the severity of OSA. This study quantifies these factors at the soft palate, tongue, and epiglottis to assess the relationship between neuromuscular control and OSA severity in 20 pediatric subjects with and without trisomy 21, under dexmedetomidine-induced sedation. The interaction between neuromuscular force and airflow pressure force was assessed based on power transferred between the airway wall and airflow calculated from airway wall motion (from cine magnetic resonance images) and air pressure acting on the airway wall (from computational fluid dynamics simulations). Airway wall motion could be asynchronous with pressure forces due to neuromuscular activation, or synchronous with pressure forces, indicating a passive response to airflow. The obstructive apnea-hypopnea index (oAHI) quantified OSA severity. During inhalation, the normalized work done through asynchronous dilation of the airway at the soft palate, tongue, and epiglottis correlated significantly with oAHI (Spearman's ρ = 0.54, 0.50, 0.64; P = 0.03, 0.03, 0.003). Synchronous collapse at the epiglottis correlated significantly with oAHI (ρ = 0.52; P = 0.02). Temporal order of synchronous and asynchronous epiglottis motion during inhalation predicted the severity of OSA (moderate vs. severe) with 100% sensitivity and 70% specificity. Subjects with severe OSA and/or trisomy 21 have insufficient neuromuscular activation during inhalation, leading to collapse and increased neuromuscular activation. Airflow-driven airway wall motion during late inhalation likely is the main determinant of OSA severity.NEW & NOTEWORTHY This is the first study that combines cine MRI and computational fluid dynamics with in vivo synchronous respiratory flow measurement to quantify the interaction between airway neuromuscular forces, aerodynamic forces, and airway anatomy noninvasively in pediatric patients with obstructive sleep apnea (OSA). The results indicate power transfer predicts OSA severity.

Structural and functional asymmetry of the neonatal cerebral cortex.

Features of brain asymmetry have been implicated in a broad range of cognitive processes; however, their origins are still poorly understood. Here we investigated cortical asymmetries in 442 healthy term-born neonates using structural and functional magnetic resonance images from the Developing Human Connectome Project. Our results demonstrate that the neonatal cortex is markedly asymmetric in both structure and function. Cortical asymmetries observed in the term cohort were contextualized in two ways: by comparing them against cortical asymmetries observed in 103 preterm neonates scanned at term-equivalent age, and by comparing structural asymmetries against those observed in 1,110 healthy young adults from the Human Connectome Project. While associations with preterm birth and biological sex were minimal, significant differences exist between birth and adulthood.

Atlas-ISTN: Joint segmentation, registration and atlas construction with image-and-spatial transformer networks.

Deep learning models for semantic segmentation are able to learn powerful representations for pixel-wise predictions, but are sensitive to noise at test time and may lead to implausible topologies. Image registration models on the other hand are able to warp known topologies to target images as a means of segmentation, but typically require large amounts of training data, and have not widely been benchmarked against pixel-wise segmentation models. We propose the Atlas Image-and-Spatial Transformer Network (Atlas-ISTN), a framework that jointly learns segmentation and registration on 2D and 3D image data, and constructs a population-derived atlas in the process. Atlas-ISTN learns to segment multiple structures of interest and to register the constructed atlas labelmap to an intermediate pixel-wise segmentation. Additionally, Atlas-ISTN allows for test time refinement of the model's parameters to optimize the alignment of the atlas labelmap to an intermediate pixel-wise segmentation. This process both mitigates for noise in the target image that can result in spurious pixel-wise predictions, as well as improves upon the one-pass prediction of the model. Benefits of the Atlas-ISTN framework are demonstrated qualitatively and quantitatively on 2D synthetic data and 3D cardiac computed tomography and brain magnetic resonance image data, out-performing both segmentation and registration baseline models. Atlas-ISTN also provides inter-subject correspondence of the structures of interest.

Computational assessment of upper airway muscular activity in obstructive sleep apnea - In vitro validation.

Neuromuscular control of the upper airway contributes to obstructive sleep apnea (OSA). An accurate, non-invasive method to assess neuromuscular function is needed to improve surgical treatment outcomes. Currently, surgical approaches for OSA are based on airway anatomy and are often not curative. When the airway surface moves, the power transferred between air in the airway lumen and the structures of the upper airway may be a measure of airway neuromuscular activity. The aim of this study was to validate power transfer as a measure of externally applied forces, representing neuromuscular activity, through cine computed tomography (CT) imaging and computational fluid dynamics (CFD) analysis in a 3D-printed airway model. A hollow elastic airway model was manufactured. An insufflation/exsufflation device generated airflow within the model lumen. The model was contained in an airtight chamber that could be positively or negatively pressurized to represent muscular forces. These forces were systematically applied to dilate and collapse the model. Cine CT imaging captured airway wall movement during respiratory cycles with and without externally applied forces. Power transfer was calculated from the product of wall movement and internal aerodynamic pressure forces using CFD simulations. Cross-correlation peaks between power transfer and changes in externally applied pressure during exhalation and inhalation were -0.79 and 0.95, respectively. Power transfer calculated via cine CT imaging and CFD was an accurate surrogate measure of externally applied forces representing airway muscular activity. In the future, power transfer may be used in clinical practice to phenotype patients with OSA and select personalized therapies.

Predicting tracheal work of breathing in neonates based on radiological and pulmonary measurements.

Tracheomalacia is an airway condition in which the trachea excessively collapses during breathing. Neonates diagnosed with tracheomalacia require more energy to breathe, and the effect of tracheomalacia can be quantified by assessing flow-resistive work of breathing (WOB) in the trachea using computational fluid dynamics (CFD) modeling of the airway. However, CFD simulations are computationally expensive; the ability to instead predict WOB based on more straightforward measures would provide a clinically useful estimate of tracheal disease severity. The objective of this study is to quantify the WOB in the trachea using CFD and identify simple airway and/or clinical parameters that directly relate to WOB. This study included 30 neonatal intensive care unit subjects (15 with tracheomalacia and 15 without tracheomalacia). All subjects were imaged using ultrashort echo time (UTE) MRI. CFD simulations were performed using patient-specific data obtained from MRI (airway anatomy, dynamic motion, and airflow rates) to calculate the WOB in the trachea. Several airway and clinical measurements were obtained and compared with the tracheal resistive WOB. The maximum percent change in the tracheal cross-sectional area (ρ = 0.560, P = 0.001), average glottis cross-sectional area (ρ = -0.488, P = 0.006), minute ventilation (ρ = 0.613, P < 0.001), and lung tidal volume (ρ = 0.599, P < 0.001) had significant correlations with WOB. A multivariable regression model with three independent variables (minute ventilation, average glottis cross-sectional area, and minimum of the eccentricity index of the trachea) can be used to estimate WOB more accurately (R2 = 0.726). This statistical model may allow clinicians to estimate tracheal resistive WOB based on airway images and clinical data.NEW & NOTEWORTHY The work of breathing due to resistance in the trachea is an important metric for quantifying the effect of tracheal abnormalities such as tracheomalacia, but currently requires complex dynamic imaging and computational fluid dynamics simulation to calculate it. This study produces a method to predict the tracheal work of breathing based on readily available imaging and clinical metrics.

Neonatal multi-modal cortical profiles predict 18-month developmental outcomes.

Developmental delays in infanthood often persist, turning into life-long difficulties, and coming at great cost for the individual and community. By examining the developing brain and its relation to developmental outcomes we can start to elucidate how the emergence of brain circuits is manifested in variability of infant motor, cognitive and behavioural capacities. In this study, we examined if cortical structural covariance at birth, indexing coordinated development, is related to later infant behaviour. We included 193 healthy term-born infants from the Developing Human Connectome Project (dHCP). An individual cortical connectivity matrix derived from morphological and microstructural features was computed for each subject (morphometric similarity networks, MSNs) and was used as input for the prediction of behavioural scores at 18 months using Connectome-Based Predictive Modeling (CPM). Neonatal MSNs successfully predicted social-emotional performance. Predictive edges were distributed between and within known functional cortical divisions with a specific important role for primary and posterior cortical regions. These results reveal that multi-modal neonatal cortical profiles showing coordinated maturation are related to developmental outcomes and that network organization at birth provides an early infrastructure for future functional skills.

Neonates With Tracheomalacia Generate Auto-Positive End-Expiratory Pressure via Glottis Closure.

BACKGROUND: In pediatrics, tracheomalacia is an airway condition that causes tracheal lumen collapse during breathing and may lead to the patient requiring respiratory support. Adult patients can narrow their glottis to self-generate positive end-expiratory pressure (PEEP) to raise the pressure in the trachea and prevent collapse. However, auto-PEEP has not been studied in newborns with tracheomalacia. The objective of this study was to measure the glottis cross-sectional area throughout the breathing cycle and to quantify total pressure difference through the glottis in patients with and without tracheomalacia. RESEARCH QUESTION: Do neonates with tracheomalacia narrow their glottises? How does the glottis narrowing affect the total pressure along the airway? STUDY DESIGN AND METHODS: Ultrashort echo time MRI was performed in 21 neonatal ICU patients (11 with tracheomalacia, 10 without tracheomalacia). MRI scans were reconstructed at four different phases of breathing. All patients were breathing room air or using noninvasive respiratory support at the time of MRI. Computational fluid dynamics simulations were performed on patient-specific virtual airway models with airway anatomic features and motion derived via MRI to quantify the total pressure difference through the glottis and trachea. RESULTS: The mean glottis cross-sectional area at peak expiration in the patients with tracheomalacia was less than half that in patients without tracheomalacia (4.0 ± 1.1 mm2 vs 10.3 ± 4.4 mm2; P = .002). The mean total pressure difference through the glottis at peak expiration was more than 10 times higher in patients with tracheomalacia compared with patients without tracheomalacia (2.88 ± 2.29 cm H2O vs 0.26 ± 0.16 cm H2O; P = .005). INTERPRETATION: Neonates with tracheomalacia narrow their glottises, which raises pressure in the trachea during expiration, thereby acting as auto-PEEP.