Mapping Primary Gyrogenesis During Fetal Development in Primate Brains: High-Resolution in Utero Structural MRI of Fetal Brain Development in Pregnant Baboons

The global and regional changes in the fetal cerebral cortex in primates were mapped during primary gyrification (PG; weeks 17–25 of 26 weeks total gestation). Studying pregnant baboons using high-resolution MRI in utero, measurements included cerebral volume, cortical surface area, gyrification index and length and depth of 10 primary cortical sulci. Seven normally developing fetuses were imaged in two animals longitudinally and sequentially. We compared these results to those on PG that from the ferret studies and analyzed them in the context of our recent studies of phylogenetics of cerebral gyrification. We observed that in both primates and non-primates, the cerebrum undergoes a very rapid transformation into the gyrencephalic state, subsequently accompanied by an accelerated growth in brain volume and cortical surface area. However, PG trends in baboons exhibited some critical differences from those observed in ferrets. For example, in baboons, the growth along the long (length) axis of cortical sulci was unrelated to the growth along the short (depth) axis and far outpaced it. Additionally, the correlation between the rate of growth along the short sulcal axis and heritability of sulcal depth was negative and approached significance (r = −0.60; p < 0.10), while the same trend for long axis was positive and not significant (p = 0.3; p = 0.40). These findings, in an animal that shares a highly orchestrated pattern of PG with humans, suggest that ontogenic processes that influence changes in sulcal length and depth are diverse and possibly driven by different factors in primates than in non-primates

The application of in utero magnetic resonance imaging in the study of the metabolic and cardiovascular consequences of the developmental origins of health and disease

Observing fetal development in utero is vital to further the understanding of later-life diseases. Magnetic resonance imaging (MRI) offers a tool for obtaining a wealth of information about fetal growth, development, and programming not previously available using other methods. This review provides an overview of MRI techniques used to investigate the metabolic and cardiovascular consequences of the developmental origins of health and disease (DOHaD) hypothesis. These methods add to the understanding of the developing fetus by examining fetal growth and organ development, adipose tissue and body composition, fetal oximetry, placental microstructure, diffusion, perfusion, flow, and metabolism. MRI assessment of fetal growth, organ development, metabolism, and the amount of fetal adipose tissue could give early indicators of abnormal fetal development. Noninvasive fetal oximetry can accurately measure placental and fetal oxygenation, which improves current knowledge on placental function. Additionally, measuring deficiencies in the placenta\u27s transport of nutrients and oxygen is critical for optimizing treatment. Overall, the detailed structural and functional information provided by MRI is valuable in guiding future investigations of DOHaD

In utero diffusion tensor imaging of the fetal brain: a reproducibility study

Our purpose was to evaluate the within-subject reproducibility of in utero diffusion tensor imaging (DTI) metrics and the visibility of major white matter structures. Images for 30 fetuses (20-33. postmenstrual weeks, normal neurodevelopment: 6 cases, cerebral pathology: 24 cases) were acquired on 1.5 T or 3.0 T MRI. DTI with 15 diffusion-weighting directions was repeated three times for each case, TR/TE: 2200/63 ms, voxel size: 1 ∗ 1 mm, slice thickness: 3-5 mm, b-factor: 700 s/mm(2). Reproducibility was evaluated from structure detectability, variability of DTI measures using the coefficient of variation (CV), image correlation and structural similarity across repeated scans for six selected structures. The effect of age, scanner type, presence of pathology was determined using Wilcoxon rank sum test. White matter structures were detectable in the following percentage of fetuses in at least two of the three repeated scans: corpus callosum genu 76%, splenium 64%, internal capsule, posterior limb 60%, brainstem fibers 40% and temporooccipital association pathways 60%. The mean CV of DTI metrics ranged between 3% and 14.6% and we measured higher reproducibility in fetuses with normal brain development. Head motion was negatively correlated with reproducibility, this effect was partially ameliorated by motion-correction algorithm using image registration. Structures on 3.0 T had higher variability both with- and without motion correction. Fetal DTI is reproducible for projection and commissural bundles during mid-gestation, however, in 16-30% of the cases, data were corrupted by artifacts, resulting in impaired detection of white matter structures. To achieve robust results for the quantitative analysis of diffusivity and anisotropy values, fetal-specific image processing is recommended and repeated DTI is needed to ensure the detectability of fiber pathways

Quantification of total fetal brain volume using 3D MR imaging data acquired in utero.

Objective: Interpretation of magnetic resonance (MR) imaging of the fetal brain in utero is primarily undertaken using 2D images to provide anatomical information about structural abnormalities. It is now possible to obtain 3D image acquisitions that allow measurement of fetal brain volumes that are potentially useful clinically. The aim of our current work is to provide reference values of total brain volumes obtained from a cohort of low risk fetuses with no abnormalities on ante-natal ultrasonography and in utero MR imaging. Method: Images from volume MR acquisitions of 132 fetuses were used to extract brain volumes by manual segmentation. Reproducibility and reliability were assessed by analysis of the results of two subgroups who had repeated measurements made by the primary and a secondary observer. Results: Intra-observer and inter-observer agreement was high with no statistically significant differences between and within observers (p = 0.476 and p = 0.427, respectively). The results of the brain volume assessments are presented graphically with mean and 95% prediction limits alongside estimates of normal growth rates. Conclusion: We have shown that fetal brain volumes can be reliably extracted from in utero MR (iuMR) imaging 3D datasets with a high degree of reproducibility. The resultant data could potentially be used as a reference tool in the clinical setting

Mri Methods For Imaging The Feto-Placental Vasculature And Blood

Fetal magnetic resonance imaging (MRI) in recent times has become a well-established adjunct to ultrasound (US) in routine clinical prenatal care and diagnostics. The majority of fetal MRI is restricted to T2-weighted scans, where the diagnosis is based on the appearance of normal and abnormal tissue. Although there have been many advancements in MRI and a plethora of sequences, that probe different anatomical and different physiological process, the adaptation of these in fetal imaging has been rather slow. Many of these can extract quantitative parameters that can throw light on the underlying tissue’s normal/patho-physiology. But the use of such quantitative MRI methods has been extremely limited in fetal imaging due to its unique and dynamic physiological milieu that pose several technical challenges including low signal to noise and/or resolution, artifacts associated with abdominal imaging and most importantly fetal motion. These limitations are expected to be overcome by (a) optimizing and (b) developing novel MR imaging sequences, both of which constitute the primary aim of my work. This work develops a framework that allows for vascular imaging in the fetus and placenta. This includes both qualitative vascular imaging and blood flow quantification. Towards this, three broad directions were explored (a) Moving to higher field imaging, while optimizing parameters for low energy deposition and (b) application of non-gated phase contrast MRI and (c) optimization of conventional time-of-flight angiography for fetal applications

3D global and regional patterns of human fetal subplate growth determined in utero

The waiting period of subplate evolution is a critical phase for the proper formation of neural connections in the brain. During this time, which corresponds to 15 to 24 postconceptual weeks (PCW) in the human fetus, thalamocortical and cortico-cortical afferents wait in and are in part guided by molecules embedded in the extracellular matrix of the subplate. Recent advances in fetal MRI techniques now allow us to study the developing brain anatomy in 3D from in utero imaging. We describe a reliable segmentation protocol to delineate the boundaries of the subplate from T2-W MRI. The reliability of the protocol was evaluated in terms of intra-rater reproducibility on a subset of the subjects. We also present the first 3D quantitative analyses of temporal changes in subplate volume, thickness, and contrast from 18 to 24 PCW. Our analysis shows that firstly, global subplate volume increases in proportion with the supratentorial volume; the subplate remained approximately one-third of supratentorial volume. Secondly, we found both global and regional growth in subplate thickness and a linear increase in the median and maximum subplate thickness through the waiting period. Furthermore, we found that posterior regions—specifically the occipital pole, ventral occipito-temporal region, and planum temporale—of the developing brain underwent the most statistically significant increases in subplate thickness. During this period, the thickest region was the developing somatosensory/motor cortex. The subplate growth patterns reported here may be used as a baseline for comparison to abnormal fetal brain development

Magnetic Resonance Imaging of the Brain in Moving Subjects. Application of Fetal, Neonatal and Adult Brain Studies

Imaging in the presence of subject motion has been an ongoing challenge for magnetic resonance imaging (MRI). Motion makes MRI data inconsistent, causing artifacts in conventional anatomical imaging as well as invalidating diffusion tensor imaging (DTI) reconstruction. In this thesis some of the important issues regarding the acquisition and reconstruction of anatomical and DTI imaging of moving subjects are addressed; methods to achieve high resolution and high signalto- noise ratio (SNR) volume data are proposed. An approach has been developed that uses multiple overlapped dynamic single shot slice by slice imaging combined with retrospective alignment and data fusion to produce self consistent 3D volume images under subject motion. We term this method as snapshot MRI with volume reconstruction or SVR. The SVR method has been performed successfully for brain studies on subjects that cannot stay still, and in some cases were moving substantially during scanning. For example, awake neonates, deliberately moved adults and, especially, on fetuses, for which no conventional high resolution 3D method is currently available. Fine structure of the in-utero fetal brain is clearly revealed for the first time with substantially improved SNR. The SVR method has been extended to correct motion artifacts from conventional multi-slice sequences when the subject drifts in position during data acquisition. Besides anatomical imaging, the SVR method has also been further extended to DTI reconstruction when there is subject motion. This has been validated successfully from an adult who was deliberately moving and then applied to inutero fetal brain imaging, which no conventional high resolution 3D method is currently available. Excellent fetal brain 3D apparent diffusion coefficient (ADC) maps in high resolution have been achieved for the first time as well as promising fractional Anisotropy (FA) maps. Pilot clinical studies using SVR reconstructed data to study fetal brain development in-utero have been performed. Growth curves for the normally developing fetal brain have been devised by the quantification of cerebral and cerebellar volumes as well as some one dimensional measurements. A Verhulst model is proposed to describe these growth curves, and this approach has achieved a correlation over 0.99 between the fitted model and actual data

Maternal Nutrient Restriction with Fetal Growth Restriction in Guinea Pigs Impacts Brain Development and Neuroimaging Correlates in Neonatal Offspring

Aberrant brain development in utero accompanied by fetal growth restriction (FGR) increases the risk of neurodevelopmental disorders in later life. However there are limited non-invasive biomarkers in the brain for the early identification of said neurodevelopmental disorders in an animal model of FGR. Guinea pig sows were fed either ad libitum (Control) or 70% of the control diet pre-pregnancy, increasing to 90% at mid-pregnancy (MNR) creating appropriately grown (AGA) Control and FGR-MNR neonates, respectively. Three to four weeks corrected post-natal age, neonates were imaged using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques, and were killed 48-72 hours later for histological analysis. FGR-MNR neonates had smaller brain weights, whole brain volume, hippocampal volume and lateral ventricle volume, which correlate to histological findings. While there is a reduction in the hippocampal volume, there are no differences in hippocampus metabolite ratios between the AGA-Control and FGR-MNR neonates. Interestingly, there was a reduction in the width of the stratum oriens and stratum radiatum in the hippocampus proper, as well as the width of the polymorphic layer in the dentate gyrus, with no changes in pyramidal and granule cell number in the FGR-MNR neonates compared to AGA-Control neonates. In conclusion, MNR in guinea pigs produces FGR neonates that display catch up growth and structural differences in the brains while no changes in the metabolite levels in the hippocampal region of the brain. Together these results involve MRI and MRS as reliable imaging tools to detect the presence of brain injury for the future use of biomarkers for neurodevelopmental disorders and potential therapeutic interventions

Tracking Development of the Corpus Callosum in Fetal and Early Postnatal Baboons Using Magnetic Resonance Imaging

Although the maturation of the corpus callosum (CC) can serve as a sensitive marker for normative antenatal and postnatal brain development, little is known about its development across this critical period. While high-resolution magnetic resonance imaging can provide an opportunity to examine normative brain development in humans, concerns remain over the exposure of developing fetuses to non-essential imaging. Nonhuman primates can provide a valuable model for normative brain maturation. Baboons share several important developmental characteristics with humans, including a highly orchestrated pattern of cerebral development. Developmental changes in total CC area and its subdivisions were examined across the antenatal (weeks 17 – 26 of 28 weeks total gestation) and early postnatal (to week 32) period in baboons (Papio hamadryas anubis). Thirteen fetal and sixteen infant baboons were studied using high-resolution MRI. During the period of primary gyrification, the total area of the CC increased by a magnitude of five. By postnatal week 32, the total CC area attained only 51% of the average adult area. CC subdivisions showed non-uniform increases in area, throughout development. The splenium showed the most maturation by postnatal week 32, attaining 55% of the average adult value. The subdivisions of the genu and anterior midbody showed the least maturation by postnatal week 32, attaining 50% and 49% of the average adult area. Thus, the CC of baboons shows continued growth past the postnatal period. These age-related changes in the developing baboon CC are consistent with the developmental course in humans