Association between placental oxygen transport and fetal brain cortical development: a study in monochorionic diamniotic twins.

Normal cortical growth and the resulting folding patterns are crucial for normal brain function. Although cortical development is largely influenced by genetic factors, environmental factors in fetal life can modify the gene expression associated with brain development. As the placenta plays a vital role in shaping the fetal environment, affecting fetal growth through the exchange of oxygen and nutrients, placental oxygen transport might be one of the environmental factors that also affect early human cortical growth. In this study, we aimed to assess the placental oxygen transport during maternal hyperoxia and its impact on fetal brain development using MRI in identical twins to control for genetic and maternal factors. We enrolled 9 pregnant subjects with monochorionic diamniotic twins (30.03 ± 2.39 gestational weeks [mean ± SD]). We observed that the fetuses with slower placental oxygen delivery had reduced volumetric and surface growth of the cerebral cortex. Moreover, when the difference between placenta oxygen delivery increased between the twin pairs, sulcal folding patterns were more divergent. Thus, there is a significant relationship between placental oxygen transport and fetal brain cortical growth and folding in monochorionic twins.

Local SAR management strategies to use two-channel RF shimming for fetal MRI at 3 T.

PURPOSE: This study evaluates the imaging performance of two-channel RF-shimming for fetal MRI at 3 T using four different local specific absorption rate (SAR) management strategies. METHODS: Due to the ambiguity of safe local SAR levels for fetal MRI, local SAR limits for RF shimming were determined based on either each individual's own SAR levels in standard imaging mode (CP mode) or the maximum SAR level observed across seven pregnant body models in CP mode. Local SAR was constrained either indirectly by further constraining the whole-body SAR (wbSAR) or directly by using subject-specific local SAR models. Each strategy was evaluated by the improvement of the transmit field efficiency (average |B1 + |) and nonuniformity (|B1 + | variation) inside the fetus compared with CP mode for the same wbSAR. RESULTS: Constraining wbSAR when using RF shimming decreases B1 + efficiency inside the fetus compared with CP mode (by 12%-30% on average), making it inefficient for SAR management. Using subject-specific models with SAR limits based on each individual's own CP mode SAR value, B1 + efficiency and nonuniformity are improved on average by 6% and 13% across seven pregnant models. In contrast, using SAR limits based on maximum CP mode SAR values across seven models, B1 + efficiency and nonuniformity are improved by 13% and 25%, compared with the best achievable improvement without SAR constraints: 15% and 26%. CONCLUSION: Two-channel RF-shimming can safely and significantly improve the transmit field inside the fetus when subject-specific models are used with local SAR limits based on maximum CP mode SAR levels in the pregnant population.

Cross-Sectional Observational Study of Typical in utero Fetal Movements Using Machine Learning.

Early variations of fetal movements are the hallmark of a healthy developing central nervous system. However, there are no automatic methods to quantify the complex 3D motion of the developing fetus in utero. The aim of this prospective study was to use machine learning (ML) on in utero MRI to perform quantitative kinematic analysis of fetal limb movement, assessing the impact of maternal, placental, and fetal factors. In this cross-sectional, observational study, we used 76 sets of fetal (24-40 gestational weeks [GW]) blood oxygenation level-dependent (BOLD) MRI scans of 52 women (18-45 years old) during typical pregnancies. Pregnant women were scanned for 5-10 min while breathing room air (21% O2) and for 5-10 min while breathing 100% FiO2 in supine and/or lateral position. BOLD acquisition time was 20 min in total with effective temporal resolution approximately 3 s. To quantify upper and lower limb kinematics, we used a 3D convolutional neural network previously trained to track fetal key points (wrists, elbows, shoulders, ankles, knees, hips) on similar BOLD time series. Tracking was visually assessed, errors were manually corrected, and the absolute movement time (AMT) for each joint was calculated. To identify variables that had a significant association with AMT, we constructed a mixed-model ANOVA with interaction terms. Fetuses showed significantly longer duration of limb movements during maternal hyperoxia. We also found a significant centrifugal increase of AMT across limbs and significantly longer AMT of upper extremities <31 GW and longer AMT of lower extremities >35 GW. In conclusion, using ML we successfully quantified complex 3D fetal limb motion in utero and across gestation, showing maternal factors (hyperoxia) and fetal factors (gestational age, joint) that impact movement. Quantification of fetal motion on MRI is a potential new biomarker of fetal health and neuromuscular development.

Safety and imaging performance of two-channel RF shimming for fetal MRI at 3T.

PURPOSE: This study investigates whether two-channel radiofrequency (RF) shimming can improve imaging without increasing specific absorption rate (SAR) for fetal MRI at 3T. METHODS: Transmit field ( B1+ ) average and variation in the fetus was simulated in seven numerical pregnant body models. Safety was quantified by maternal and fetal peak local SAR and fetal average SAR. The shim parameter space was divided into improved B1+ (magnitude and homogeneity) and improved SAR regions, and an overlap where RF shimming improved both classes of metrics compared with birdcage mode was assessed. Additionally, the effect of fetal position, tissue detail, and dielectric properties on transmit field and SAR was studied. RESULTS: A region of subject-specific RF shim parameter space improving both B1+ and SAR metrics was found for five of the seven models. Optimizing only B1+ metrics improved B1+ efficiency across models by 15% on average and 28% for the best-case model. B1+ variation improved by 26% on average and 49% for the best case. However, for these shim settings, fetal SAR increased by up to 106%. The overlap region, where both B1+ and SAR metrics improve, showed an average B1+ efficiency improvement of 6% on average across models and 19% for the best-case model. B1+ variation improved by 13% on average and 40% for the best case. RFS could also decrease maternal/fetal SAR by up to 49%/58%. CONCLUSION: RF shimming can improve imaging compared with birdcage mode without increasing fetal and maternal SAR when a patient-specific SAR model is incorporated into the shimming procedure.

Individual variation in simulated fetal SAR assessed in multiple body models.

PURPOSE: We generate 12 models from 4 pregnant individuals to evaluate individual differences in local specific absorption rate (SAR) for differing body habitus and fetal and maternal positions. METHODS: Structural MR images from 4 pregnant subjects (including supine and left-lateral maternal positions) were manually segmented to create 12 body models by rotating the fetus, modifying the fat content, and altering the maternal arm position in 1 of the subjects. Electromagnetic simulations modeled at 3 Tesla determined the average and peak local SAR in the maternal trunk, fetus, fetal brain, and amniotic fluid. RESULTS: We observed a significant range of fetal and maternal peak local SAR across the models (maternal trunk: 19.14-44.03 watts/kg, fetus: 9.93-18.79 watts/kg, fetal brain 3.36-10.3 watts/kg). We found that maternal body habitus changes introduced a significant variation in the maternal peak local SAR but not the fetal local SAR. However, the maternal position (either rotating the mother to left-lateral position or altering the arm position) introduced changes in fetal peak local SAR (range: 11.9-17.9 watts/kg). Rotating the fetus also introduced variation in the fetal and fetal brain peak local SAR. CONCLUSION: The observed variation in SAR emphasizes the need for more anatomical models to enable better safety management of individuals during fetal MRI, including a wider range of gestational ages.

Exploring early human brain development with structural and physiological neuroimaging.

Early brain development, from the embryonic period to infancy, is characterized by rapid structural and functional changes. These changes can be studied using structural and physiological neuroimaging methods. In order to optimally acquire and accurately interpret this data, concepts from adult neuroimaging cannot be directly transferred. Instead, one must have a basic understanding of fetal and neonatal structural and physiological brain development, and the important modulators of this process. Here, we first review the major developmental milestones of transient cerebral structures and structural connectivity (axonal connectivity) followed by a summary of the contributions from ex vivo and in vivo MRI. Next, we discuss the basic biology of neuronal circuitry development (synaptic connectivity, i.e. ensemble of direct chemical and electrical connections between neurons), physiology of neurovascular coupling, baseline metabolic needs of the fetus and the infant, and functional connectivity (defined as statistical dependence of low-frequency spontaneous fluctuations seen with functional magnetic resonance imaging (fMRI)). The complementary roles of magnetic resonance imaging (MRI), electroencephalography (EEG), magnetoencephalography (MEG), and near-infrared spectroscopy (NIRS) are discussed. We include a section on modulators of brain development where we focus on the placenta and emerging placental MRI approaches. In each section we discuss key technical limitations of the imaging modalities and some of the limitations arising due to the biology of the system. Although neuroimaging approaches have contributed significantly to our understanding of early brain development, there is much yet to be done and a dire need for technical innovations and scientific discoveries to realize the future potential of early fetal and infant interventions to avert long term disease.

Change in T2* measurements of placenta and fetal organs during Braxton Hicks contractions.

Maternal-placental perfusion can be temporarily compromised by Braxton Hicks (BH) uterine contractions. Although prior studies have employed T2* changes to investigate the effect of BH contractions on placental oxygen, the effect of these contractions on the fetus has not been fully characterized. We investigated the effect of BH contractions on quantitative fetal organ T2* across gestation together with the birth information. We observed a slight but significant decrease in fetal brain and liver T2* during contractions.

Placental MRI: Effect of maternal position and uterine contractions on placental BOLD MRI measurements.

INTRODUCTION: Before using blood-oxygen-level-dependent magnetic resonance imaging (BOLD MRI) during maternal hyperoxia as a method to detect individual placental dysfunction, it is necessary to understand spatiotemporal variations that represent normal placental function. We investigated the effect of maternal position and Braxton-Hicks contractions on estimates obtained from BOLD MRI of the placenta during maternal hyperoxia. METHODS: For 24 uncomplicated singleton pregnancies (gestational age 27-36 weeks), two separate BOLD MRI datasets were acquired, one in the supine and one in the left lateral maternal position. The maternal oxygenation was adjusted as 5 min of room air (21% O2), followed by 5 min of 100% FiO2. After datasets were corrected for signal non-uniformities and motion, global and regional BOLD signal changes in R2* and voxel-wise Time-To-Plateau (TTP) in the placenta were measured. The overall placental and uterine volume changes were determined across time to detect contractions. RESULTS: In mothers without contractions, increases in global placental R2* in the supine position were larger compared to the left lateral position with maternal hyperoxia. Maternal position did not alter global TTP but did result in regional changes in TTP. 57% of the subjects had Braxton-Hicks contractions and 58% of these had global placental R2* decreases during the contraction. CONCLUSION: Both maternal position and Braxton-Hicks contractions significantly affect global and regional changes in placental R2* and regional TTP. This suggests that both factors must be taken into account in analyses when comparing placental BOLD signals over time within and between individuals.

Placental MRI: Developing Accurate Quantitative Measures of Oxygenation.

The Human Placenta Project has focused attention on the need for noninvasive magnetic resonance imaging (MRI)-based techniques to diagnose and monitor placental function throughout pregnancy. The hope is that the management of placenta-related pathologies would be improved if physicians had more direct, real-time measures of placental health to guide clinical decision making. As oxygen alters signal intensity on MRI and oxygen transport is a key function of the placenta, many of the MRI methods under development are focused on quantifying oxygen transport or oxygen content of the placenta. For example, measurements from blood oxygen level-dependent imaging of the placenta during maternal hyperoxia correspond to outcomes in twin pregnancies, suggesting that some aspects of placental oxygen transport can be monitored by MRI. Additional methods are being developed to accurately quantify baseline placental oxygenation by MRI relaxometry. However, direct validation of placental MRI methods is challenging and therefore animal studies and ex vivo studies of human placentas are needed. Here we provide an overview of the current state of the art of oxygen transport and quantification with MRI. We suggest that as these techniques are being developed, increased focus be placed on ensuring they are robust and reliable across individuals and standardized to enable predictive diagnostic models to be generated from the data. The field is still several years away from establishing the clinical benefit of monitoring placental function in real time with MRI, but the promise of individual personalized diagnosis and monitoring of placental disease in real time continues to motivate this effort.

Preliminary evaluation of dynamic glucose enhanced MRI of the human placenta during glucose tolerance test.

BACKGROUND: To investigate dynamic glucose enhanced (DGE) chemical exchange saturation transfer (CEST) MRI as a means to non-invasively image glucose transport in the human placenta. METHODS: Continuous wave (CW) CEST MRI was performed at 3.0 Tesla. The glucose contrast enhancement (GCE) was calculated based on the magnetization transfer asymmetry (MTRasym), and the DGE was calculated with the positive side of Z-spectra in reference to the first time point. The glucose CEST (GlucoCEST) was optimized using a glucose solution phantom. Glucose solution perfused ex vivo placenta tissue was used to demonstrate GlucoCEST MRI effect. The vascular density of ex vivo placental tissue was evaluated with yellow dye after MRI scans. Finally, we preliminarily demonstrated GlucoCEST MRI in five pregnant subjects who received a glucose tolerance test. For human studies, the dynamic R2* change was captured with T2*-weighted echo planar imaging (EPI). RESULTS: The GCE effect peaks at a saturation B1 field of about 2 µT, and the GlucoCEST effect increases linearly with the glucose concentration between 4-20 mM. In ex vivo tissue, the GlucoCEST MRI was sensitive to the glucose perfusate and the placenta vascular density. Although the in vivo GCE baseline was sensitive to field inhomogeneity and motion artifacts, the temporal evolution of the GlucoCEST effect showed a consistent and positive response after oral glucose tolerance drink. CONCLUSIONS: Despite the challenges of placental motion and field inhomogeneity, our study demonstrated the feasibility of DGE placenta MRI at 3.0 Tesla.

In Vivo Quantification of Placental Insufficiency by BOLD MRI: A Human Study.

Fetal health is critically dependent on placental function, especially placental transport of oxygen from mother to fetus. When fetal growth is compromised, placental insufficiency must be distinguished from modest genetic growth potential. If placental insufficiency is present, the physician must trade off the risk of prolonged fetal exposure to placental insufficiency against the risks of preterm delivery. Current ultrasound methods to evaluate the placenta are indirect and insensitive. We propose to use Blood-Oxygenation-Level-Dependent (BOLD) MRI with maternal hyperoxia to quantitatively assess mismatch in placental function in seven monozygotic twin pairs naturally matched for genetic growth potential. In-utero BOLD MRI time series were acquired at 29 to 34 weeks gestational age. Maps of oxygen Time-To-Plateau (TTP) were obtained in the placentas by voxel-wise fitting of the time series. Fetal brain and liver volumes were measured based on structural MR images. After delivery, birth weights were obtained and placental pathological evaluations were performed. Mean placental TTP negatively correlated with fetal liver and brain volumes at the time of MRI as well as with birth weights. Mean placental TTP positively correlated with placental pathology. This study demonstrates the potential of BOLD MRI with maternal hyperoxia to quantify regional placental function in vivo.