Cortical overgrowth in fetuses with isolated ventriculomegaly.

Mild cerebral ventricular enlargement is associated with schizophrenia, autism, epilepsy, and attention-deficit/hyperactivity disorder. Fetal ventriculomegaly is the most common central nervous system (CNS) abnormality affecting 1% of fetuses and is associated with cognitive, language, and behavioral impairments in childhood. Neurodevelopmental outcome is partially predictable by the 2-dimensional size of the ventricles in the absence of other abnormalities. We hypothesized that isolated fetal ventriculomegaly is a marker of altered brain development characterized by relative overgrowth and aimed to quantify brain growth using volumetric magnetic resonance imaging (MRI) in fetuses with isolated ventriculomegaly. Fetal brain MRI (1.5 T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly, across a gestational age range of 22-38 weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3-dimensional reconstructed datasets. Fetuses with isolated ventriculomegaly had increased brain parenchyma volumes when compared with the control cohort (9.6%, P < 0.0001) with enlargement restricted to the cortical gray matter (17.2%, P = 0.002). The extracerebral cerebrospinal fluid and third and fourth ventricles were also enlarged. White matter, basal ganglia, and thalamic volumes were not significantly different between cohorts. The presence of relative cortical overgrowth in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language, and behavioral deficits in these children.

Correlation of fetal lung area with MRI derived pulmonary volume.

BACKGROUND: Neonatal chest-Xray (CXR)s are commonly performed as a first line investigation for the evaluation of respiratory complications. Although lung area derived from CXRs correlates well with functional assessments of the neonatal lung, it is not currently utilised in clinical practice, partly due to the lack of reference ranges for CXR-derived lung area in healthy neonates. Advanced MR techniques now enable direct evaluation of both fetal pulmonary volume and area. This study therefore aims to generate reference ranges for pulmonary volume and area in uncomplicated pregnancies, evaluate the correlation between prenatal pulmonary volume and area, as well as to assess the agreement between antenatal MRI-derived and neonatal CXR-derived pulmonary area in a cohort of fetuses that delivered shortly after the antenatal MRI investigation. METHODS: Fetal MRI datasets were retrospectively analysed from uncomplicated term pregnancies and a preterm cohort that delivered within 72 h of the fetal MRI. All examinations included T2 weighted single-shot turbo spin echo images in multiple planes. In-house pipelines were applied to correct for fetal motion using deformable slice-to-volume reconstruction. An MRI-derived lung area was manually segmented from the average intensity projection (AIP) images generated. Postnatal lung area in the preterm cohort was measured from neonatal CXRs within 24 h of delivery. Pearson correlation coefficient was used to correlate MRI-derived lung volume and area. A two-way absolute agreement was performed between the MRI-derived AIP lung area and CXR-derived lung area. RESULTS: Datasets from 180 controls and 10 preterm fetuses were suitable for analysis. Mean gestational age at MRI was 28.6 ± 4.2 weeks for controls and 28.7 ± 2.7 weeks for preterm neonates. MRI-derived lung area correlated strongly with lung volumes (p < 0.001). MRI-derived lung area had good agreement with the neonatal CXR-derived lung area in the preterm cohort [both lungs = 0.982]. CONCLUSION: MRI-derived pulmonary area correlates well with absolute pulmonary volume and there is good correlation between MRI-derived pulmonary area and postnatal CXR-derived lung area when delivery occurs within a few days of the MRI examination. This may indicate that fetal MRI derived lung area may prove to be useful reference ranges for pulmonary areas derived from CXRs obtained in the perinatal period.

A bimodal 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 bimodal distribution of sulci on a linear-to-complex dimension. Linear sulci were more heritable and typically located in unimodal cortex, and 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.

Automated body organ segmentation, volumetry and population-averaged atlas for 3D motion-corrected T2-weighted fetal body MRI.

Structural fetal body MRI provides true 3D information required for volumetry of fetal organs. However, current clinical and research practice primarily relies on manual slice-wise segmentation of raw T2-weighted stacks, which is time consuming, subject to inter- and intra-observer bias and affected by motion-corruption. Furthermore, there are no existing standard guidelines defining a universal approach to parcellation of fetal organs. This work produces the first parcellation protocol of the fetal body organs for motion-corrected 3D fetal body MRI. It includes 10 organ ROIs relevant to fetal quantitative volumetry studies. We also introduce the first population-averaged T2w MRI atlas of the fetal body. The protocol was used as a basis for training of a neural network for automated organ segmentation. It showed robust performance for different gestational ages. This solution minimises the need for manual editing and significantly reduces time. The general feasibility of the proposed pipeline was also assessed by analysis of organ growth charts created from automated parcellations of 91 normal control 3T MRI datasets that showed expected increase in volumetry during 22-38 weeks gestational age range.

Structural and functional fetal cardiac imaging using low field (0.55†T) MRI.

Purpose: This study aims to investigate the feasibility of using a commercially available clinical 0.55 T MRI scanner for comprehensive structural and functional fetal cardiac imaging. Methods: Balanced steady-state free precession (bSSFP) and phase contrast (PC) sequences were optimized by in utero studies consisting of 14 subjects for bSSFP optimization and 9 subjects for PC optimization. The signal-to-noise ratio (SNR) of the optimized sequences were investigated. Flow measurements were performed in three vessels, umbilical vein (UV), descending aorta (DAo), and superior vena cava (SVC) using the PC sequences and retrospective gating. The optimized bSSFP, PC and half-Fourier single shot turbo spin-echo (HASTE) sequences were acquired in a cohort of 21 late gestation-age fetuses (>36 weeks) to demonstrate the feasibility of a fetal cardiac exam at 0.55 T. The HASTE stacks were reconstructed to create an isotropic reconstruction of the fetal thorax, followed by automatic great vessel segmentations. The intra-abdominal UV blood flow measurements acquired with MRI were compared to ultrasound UV free-loop flow measurements. Results: Using the parameters from 1.5 T as a starting point, the bSSFP sequences were optimized at 0.55 T, resulting in a 1.6-fold SNR increase and improved image contrast compared to starting parameters, as well as good visibility of most cardiac structures as rated by two experienced fetal cardiologists. The PC sequence resulted in increased SNR and reduced scan time, subsequent retrospective gating enabled successful blood flow measurements. The reconstructions and automatic great vessel segmentations showed good quality, with 18/21 segmentations requiring no or minor refinements. Blood flow measurements were within the expected range. A comparison of the UV measurements performed with ultrasound and MRI showed agreement between the two sets of measurements, with better correlation observed at lower flows. Conclusion: We demonstrated the feasibility of low-field (0.55 T) MRI for fetal cardiac imaging. The reduced SNR at low field strength can be effectively compensated for by strategically optimizing sequence parameters. Major fetal cardiac structures and vessels were consistently visualized, and flow measurements were successfully obtained. The late gestation study demonstrated the robustness and reproducibility at low field strength. MRI performed at 0.55 T is a viable option for fetal cardiac examination.

Automated Craniofacial Biometry with 3D T2w Fetal MRI.

Objectives: Evaluating craniofacial phenotype-genotype correlations prenatally is increasingly important; however, it is subjective and challenging with 3D ultrasound. We developed an automated landmark propagation pipeline using 3D motion-corrected, slice-to-volume reconstructed (SVR) fetal MRI for craniofacial measurements. Methods: A literature review and expert consensus identified 31 craniofacial biometrics for fetal MRI. An MRI atlas with defined anatomical landmarks served as a template for subject registration, auto-labelling, and biometric calculation. We assessed 108 healthy controls and 24 fetuses with Down syndrome (T21) in the third trimester (29-36 weeks gestational age, GA) to identify meaningful biometrics in T21. Reliability and reproducibility were evaluated in 10 random datasets by four observers. Results: Automated labels were produced for all 132 subjects with a 0.03% placement error rate. Seven measurements, including anterior base of skull length and maxillary length, showed significant differences with large effect sizes between T21 and control groups (ANOVA, p<0.001). Manual measurements took 25-35 minutes per case, while automated extraction took approximately 5 minutes. Bland-Altman plots showed agreement within manual observer ranges except for mandibular width, which had higher variability. Extended GA growth charts (19-39 weeks), based on 280 control fetuses, were produced for future research. Conclusion: This is the first automated atlas-based protocol using 3D SVR MRI for fetal craniofacial biometrics, accurately revealing morphological craniofacial differences in a T21 cohort. Future work should focus on improving measurement reliability, larger clinical cohorts, and technical advancements, to enhance prenatal care and phenotypic characterisation.

Multidimensional analysis of fetal posterior fossa in health and disease.

Fetal magnetic resonance imaging (MRI) is now routinely used to further investigate cerebellar malformations detected with ultrasound. However, the lack of 2D and 3D biometrics in the current literature hinders the detailed characterisation and classification of cerebellar anomalies. The main objectives of this fetal neuroimaging study were to provide normal posterior fossa growth trajectories during the second and third trimesters of pregnancy via semi-automatic segmentation of reconstructed fetal brain MR images and to assess common cerebellar malformations in comparison with the reference data. Using a 1.5-T MRI scanner, 143 MR images were obtained from 79 normal control and 53 fetuses with posterior fossa abnormalities that were grouped according to the severity of diagnosis on visual MRI inspections. All quantifications were performed on volumetric datasets, and supplemental outcome information was collected from the surviving infants. Normal growth trajectories of total brain, cerebellar, vermis, pons and fourth ventricle volumes showed significant correlations with 2D measurements and increased in second-order polynomial trends across gestation (Pearson r, p < 0.05). Comparison of normal controls to five abnormal cerebellum subgroups depicted significant alterations in volumes that could not be detected exclusively with 2D analysis (MANCOVA, p < 0.05). There were 15 terminations of pregnancy, 8 neonatal deaths, and a spectrum of genetic and neurodevelopmental outcomes in the assessed 24 children with cerebellar abnormalities. The given posterior fossa biometrics enhance the delineation of normal and abnormal cerebellar phenotypes on fetal MRI and confirm the advantages of utilizing advanced neuroimaging tools in clinical fetal research.

Exploring the role of a time-efficient MRI assessment of the placenta and fetal brain in uncomplicated pregnancies and these complicated by placental insufficiency.

INTRODUCTION: The development of placenta and fetal brain are intricately linked. Placental insufficiency is related to poor neonatal outcomes with impacts on neurodevelopment. This study sought to investigate whether simultaneous fast assessment of placental and fetal brain oxygenation using MRI T2* relaxometry can play a complementary role to US and Doppler US. METHODS: This study is a retrospective case-control study with uncomplicated pregnancies (n = 99) and cases with placental insufficiency (PI) (n = 49). Participants underwent placental and fetal brain MRI and contemporaneous ultrasound imaging, resulting in quantitative assessment including a combined MRI score called Cerebro-placental-T2*-Ratio (CPTR). This was assessed in comparison with US-derived Cerebro-Placental-Ratio (CPR), placental histopathology, assessed using the Amsterdam criteria [1], and delivery details. RESULTS: Pplacental and fetal brain T2* decreased with increasing gestational age in both low and high risk pregnancies and were corrected for gestational-age alsosignificantly decreased in PI. Both CPR and CPTR score were significantly correlated with gestational age at delivery for the entire cohort. CPTR was, however, also correlated independently with gestational age at delivery in the PI cohort. It furthermore showed a correlation to birth-weight-centile in healthy controls. DISCUSSION: This study indicates that MR analysis of the placenta and brain may play a complementary role in the investigation of fetal development. The additional correlation to birth-weight-centile in controls may suggest a role in the determination of placental health even in healthy controls. To our knowledge, this is the first study assessing quantitatively both placental and fetal brain development over gestation in a large cohort of low and high risk pregnancies. Future larger prospective studies will include additional cohorts.

Characterisation of ASD traits among a cohort of children with isolated fetal ventriculomegaly.

Fetal ventriculomegaly is the most common antenatally-diagnosed brain abnormality. Imaging studies in antenatal isolated ventriculomegaly demonstrate enlarged ventricles and cortical overgrowth which are also present in children with autism-spectrum disorder/condition (ASD). We investigate the presence of ASD traits in a cohort of children (n = 24 [20 males/4 females]) with isolated fetal ventriculomegaly, compared with 10 controls (n = 10 [6 males/4 females]). Neurodevelopmental outcome at school age included IQ, ASD traits (ADOS-2), sustained attention, neurological functioning, behaviour, executive function, sensory processing, co-ordination, and adaptive behaviours. Pre-school language development was assessed at 2 years. 37.5% of children, all male, in the ventriculomegaly cohort scored above threshold for autism/ASD classification. Pre-school language delay predicted an ADOS-2 autism/ASD classification with 73.3% specificity/66.7% sensitivity. Greater pre-school language delay was associated with more ASD symptoms. In this study, the neurodevelopment of children with isolated fetal ventriculomegaly, associated with altered cortical development, includes ASD traits, difficulties in sustained attention, working memory and sensation-seeking behaviours.

3D T2w fetal body MRI: automated organ volumetry, growth charts and population-averaged atlas.

Structural fetal body MRI provides true 3D information required for volumetry of fetal organs. However, current clinical and research practice primarily relies on manual slice-wise segmentation of raw T2-weighted stacks, which is time consuming, subject to inter- and intra-observer bias and affected by motion-corruption. Furthermore, there are no existing standard guidelines defining a universal approach to parcellation of fetal organs. This work produces the first parcellation protocol of the fetal body organs for motion-corrected 3D fetal body MRI. It includes 10 organ ROIs relevant to fetal quantitative volumetry studies. We also introduce the first population-averaged T2w MRI atlas of the fetal body. The protocol was used as a basis for training of a neural network for automated organ segmentation. It showed robust performance for different gestational ages. This solution minimises the need for manual editing and significantly reduces time. The general feasibility of the proposed pipeline was also assessed by analysis of organ growth charts created from automated parcellations of 91 normal control 3T MRI datasets that showed expected increase in volumetry during 22-38 weeks gestational age range. In addition, the results of comparison between 60 normal and 12 fetal growth restriction datasets revealed significant differences in organ volumes.

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.

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.

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.

BOUNTI: Brain vOlumetry and aUtomated parcellatioN for 3D feTal MRI.

Fetal MRI is widely used for quantitative brain volumetry studies. However, currently, there is a lack of universally accepted protocols for fetal brain parcellation and segmentation. Published clinical studies tend to use different segmentation approaches that also reportedly require significant amounts of time-consuming manual refinement. In this work, we propose to address this challenge by developing a new robust deep learning-based fetal brain segmentation pipeline for 3D T2w motion corrected brain images. At first, we defined a new refined brain tissue parcellation protocol with 19 regions-of-interest using the new fetal brain MRI atlas from the Developing Human Connectome Project. This protocol design was based on evidence from histological brain atlases, clear visibility of the structures in individual subject 3D T2w images and the clinical relevance to quantitative studies. It was then used as a basis for developing an automated deep learning brain tissue parcellation pipeline trained on 360 fetal MRI datasets with different acquisition parameters using semi-supervised approach with manually refined labels propagated from the atlas. The pipeline demonstrated robust performance for different acquisition protocols and GA ranges. Analysis of tissue volumetry for 390 normal participants (21-38 weeks gestational age range), scanned with three different acquisition protocols, did not reveal significant differences for major structures in the growth charts. Only minor errors were present in < 15% of cases thus significantly reducing the need for manual refinement. In addition, quantitative comparison between 65 fetuses with ventriculomegaly and 60 normal control cases were in agreement with the findings reported in our earlier work based on manual segmentations. These preliminary results support the feasibility of the proposed atlas-based deep learning approach for large-scale volumetric analysis. The created fetal brain volumetry centiles and a docker with the proposed pipeline are publicly available online at https://hub.docker.com/r/fetalsvrtk/segmentation (tag brain_bounti_tissue).

Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm.

Elucidating the gene regulatory networks that govern pharyngeal arch artery (PAA) development is an important goal, as such knowledge can help to identify new genes involved in cardiovascular disease. The transcription factor Tbx1 plays a vital role in PAA development and is a major contributor to cardiovascular disease associated with DiGeorge syndrome. In this report, we used various genetic approaches to reveal part of a signalling network by which Tbx1 controls PAA development in mice. We investigated the crucial role played by the homeobox-containing transcription factor Gbx2 downstream of Tbx1. We found that PAA formation requires the pharyngeal surface ectoderm as a key signalling centre from which Gbx2, in response to Tbx1, triggers essential directional cues to the adjacent cardiac neural crest cells (cNCCs) en route to the caudal PAAs. Abrogation of this signal generates cNCC patterning defects leading to PAA abnormalities. Finally, we showed that the Slit/Robo signalling pathway is activated during cNCC migration and that components of this pathway are affected in Gbx2 and Tbx1 mutant embryos at the time of PAA development. We propose that the spatiotemporal control of this tightly orchestrated network of genes participates in crucial aspects of PAA development.

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.

The Developing Human Connectome Project Neonatal Data Release.

The Developing Human Connectome Project has created a large open science resource which provides researchers with data for investigating typical and atypical brain development across the perinatal period. It has collected 1228 multimodal magnetic resonance imaging (MRI) brain datasets from 1173 fetal and/or neonatal participants, together with collateral demographic, clinical, family, neurocognitive and genomic data from 1173 participants, together with collateral demographic, clinical, family, neurocognitive and genomic data. All subjects were studied in utero and/or soon after birth on a single MRI scanner using specially developed scanning sequences which included novel motion-tolerant imaging methods. Imaging data are complemented by rich demographic, clinical, neurodevelopmental, and genomic information. The project is now releasing a large set of neonatal data; fetal data will be described and released separately. This release includes scans from 783 infants of whom: 583 were healthy infants born at term; as well as preterm infants; and infants at high risk of atypical neurocognitive development. Many infants were imaged more than once to provide longitudinal data, and the total number of datasets being released is 887. We now describe the dHCP image acquisition and processing protocols, summarize the available imaging and collateral data, and provide information on how the data can be accessed.

Brain volumetry in fetuses that deliver very preterm: An MRI pilot study.

BACKGROUND: Infants born preterm are at increased risk of neurological complications resulting in significant morbidity and mortality. The exact mechanism and the impact of antenatal factors has not been fully elucidated, although antenatal infection/inflammation has been implicated in both the aetiology of preterm birth and subsequent neurological sequelae. It is therefore hypothesized that processes driving preterm birth are affecting brain development in utero. This study aims to compare MRI derived regional brain volumes in fetuses that deliver < 32 weeks with fetuses that subsequently deliver at term. METHODS: Women at high risk of preterm birth, with gestation 19.4-32 weeks were recruited prospectively. A control group was obtained from existing study datasets. Fetal MRI was performed on a 1.5 T or 3 T MRI scanner: T2-weighted images were obtained of the fetal brain. 3D brain volumetric datsets were produced using slice to volume reconstruction and regional segmentations were produced using multi-atlas approaches for supratentorial brain tissue, lateral ventricles, cerebellum cerebral cortex and extra-cerebrospinal fluid (eCSF). Statistical comparison of control and high-risk for preterm delivery fetuses was performed by creating normal ranges for each parameter from the control datasets and then calculating gestation adjusted z scores. Groups were compared using t-tests. RESULTS: Fetal image datasets from 24 pregnancies with delivery < 32 weeks and 87 control pregnancies that delivered > 37 weeks were included. Median gestation at MRI of the preterm group was 26.8 weeks (range 19.4-31.4) and control group 26.2 weeks (range 21.7-31.9). No difference was found in supra-tentorial brain volume, ventricular volume or cerebellar volume but the eCSF and cerebral cortex volumes were smaller in fetuses that delivered preterm (p < 0.001 in both cases). CONCLUSION: Fetuses that deliver preterm have a reduction in cortical and eCSF volumes. This is a novel finding and needs further investigation. If alterations in brain development are commencing antenatally in fetuses that subsequently deliver preterm, this may present a window for in utero therapy in the future.

Early alterations in cortical and cerebellar regional brain growth in Down Syndrome: An in vivo fetal and neonatal MRI assessment.

Down Syndrome (DS) is the most frequent genetic cause of intellectual disability with a wide spectrum of neurodevelopmental outcomes. At present, the relationship between structural brain morphology and the spectrum of cognitive phenotypes in DS, is not well understood. This study aimed to quantify the development of the fetal and neonatal brain in DS participants, with and without a congenital cardiac defect compared with a control population using dedicated, optimised and motion-corrected in vivo magnetic resonance imaging (MRI). We detected deviations in development and altered regional brain growth in the fetus with DS from 21 weeks' gestation, when compared to age-matched controls. Reduced cerebellar volume was apparent in the second trimester with significant alteration in cortical growth becoming evident during the third trimester. Developmental abnormalities in the cortex and cerebellum are likely substrates for later neurocognitive impairment, and ongoing studies will allow us to confirm the role of antenatal MRI as an early biomarker for subsequent cognitive ability in DS. In the era of rapidly developing technologies, we believe that the results of this study will assist counselling for prospective parents.

Cardiac phenotyping in ex vivo murine embryos using microMRI.

Microscopic MRI (microMRI) is an emerging technique for high-throughput phenotyping of transgenic mouse embryos, and is capable of visualising abnormalities in cardiac development. To identify cardiac defects in embryos, we have optimised embryo preparation and MR acquisition parameters to maximise image quality and assess the phenotypic changes in chromodomain helicase DNA-binding protein 7 (Chd7) transgenic mice. microMRI methods rely on tissue penetration with a gadolinium chelate contrast agent to reduce tissue T(1), thus improving signal-to-noise ratio (SNR) in rapid gradient echo sequences. We investigated 15.5 days post coitum (dpc) wild-type CD-1 embryos fixed in gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) solutions for either 3 days (2 and 4 mM) or 2 weeks (2, 4, 8 and 16 mM). To assess penetration of the contrast agent into heart tissue and enable image contrast simulations, T(1) and T(*) (2) were measured in heart and background agarose. Compared to 3-day, 2-week fixation showed reduced mean T(1) in the heart at both 2 and 4 mM concentrations (p < 0.0001), resulting in calculated signal gains of 23% (2 mM) and 29% (4 mM). Using T(1) and T(*) (2) values from 2-week concentrations, computer simulation of heart and background signal, and ex vivo 3D gradient echo imaging, we demonstrated that 2-week fixed embryos in 8 mM Gd-DTPA in combination with optimised parameters (TE/TR/alpha/number of averages: 9 ms/20 ms/60 degrees /7) produced the largest SNR in the heart (23.2 +/- 1.0) and heart chamber contrast-to-noise ratio (CNR) (27.1 +/- 1.6). These optimised parameters were then applied to an MRI screen of embryos heterozygous for the gene Chd7, implicated in coloboma of the eye, heart defects, atresia of the choanae, retardation of growth, genital/urinary abnormalities, ear abnormalities and deafness (CHARGE) syndrome (a condition partly characterised by cardiovascular birth defects in humans). A ventricular septal defect was readily identified in the screen, consistent with the human phenotype.