Understanding development of jugular bulb stenosis in vein of galen malformations: identifying metrics of complex flow dynamics in the cerebral venous vasculature of infants.

Introduction: Computational fluid dynamics (CFD) assess biological systems based on specific boundary conditions. We propose modeling more advanced hemodynamic metrics, such as core line length (CL) and critical points which characterize complexity of flow in the context of cerebral vasculature, and specifically cerebral veins during the physiologically evolving early neonatal state of vein of Galen malformations (VOGM). CFD has not been applied to the study of arteriovenous shunting in Vein of Galen Malformations but could help illustrate the pathophysiology of this malformation. Methods: Three neonatal patients with VOGM at Boston Children's Hospital met inclusion criteria for this study. Structural MRI data was segmented to generate a mesh of the VOGM and venous outflow. Boundary condition flow velocity was derived from PC-MR sequences with arterial and venous dual velocity encoding. The mesh and boundary conditions were applied to model the cerebral venous flow. We computed flow variables including mean wall shear stress (WSSmean), mean OSI, CL, and the mean number of critical points (nCrPointsmean) for each patient specific model. A critical point is defined as the location where the shear stress vector field is zero (stationary point) and can be used to describe complexity of flow. Results: The division of flow into the left and right venous outflow was comparable between PC-MR and CFD modeling. A high complexity recirculating flow pattern observed on PC-MR was also identified on CFD modeling. Regions of similar WSSmean and OSImean (<1.3 fold) in the left and right venous outflow channels of a single patient have several-fold magnitude difference in higher order hemodynamic metrics (> 3.3 fold CL, > 1.7 fold nCrPointsmean). Specifically, the side which developed JBS in each model had greater nCrPointsmean compared to the jugular bulb with no stenosis (VOGM1: 4.49 vs. 2.53, VOGM2: 1.94 vs. 0, VOGM3: 1 vs. 0). Biologically, these regions had subsequently divergent development, with increased complexity of flow associating with venous stenosis. Discussion: Advanced metrics of flow complexity identified in computational models may reflect observed flow phenomena not fully characterized by primary or secondary hemodynamic parameters. These advanced metrics may indicate physiological states that impact development of jugular bulb stenosis in VOGM.

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.

Fetal Neuroimaging Updates.

MR imaging is used in conjunction with ultrasound screening for fetal brain abnormalities because it offers better contrast, higher resolution, and has multiplanar capabilities that increase the accuracy and confidence of diagnosis. Fetal motion still severely limits the MR imaging sequences that can be acquired. We outline the current acquisition strategies for fetal brain MR imaging and discuss the near term advances that will improve its reliability. Prospective and retrospective motion correction aim to make the complement of MR neuroimaging modalities available for fetal diagnosis, improve the performance of existing modalities, and open new horizons to understanding in utero brain development.

Quantitative T1 and T2 mapping by magnetic resonance fingerprinting (MRF) of the placenta before and after maternal hyperoxia.

INTRODUCTION: MR relaxometry has been used to assess placental exchange function, but methods to date are not sufficiently fast to be robust to placental motion. Magnetic resonance fingerprinting (MRF) permits rapid, voxel-wise, intrinsically co-registered T1 and T2 mapping. After characterizing measurement error, we scanned pregnant women during air and oxygen breathing to demonstrate MRF's ability to detect placental oxygenation changes. METHODS: The accuracy of FISP-based, sliding-window reconstructed MRF was tested on phantoms. MRF scans in 9-s breath holds were acquired at 3T in 31 pregnant women during air and oxygen breathing. A mixed effects model was used to test for changes in placenta relaxation times between physiological states, to assess the dependency on gestational age (GA), and the impact of placental motion. RESULTS: MRF estimates of known phantom relaxation times resulted in mean absolute errors for T1 of 92 ms (4.8%), but T2 was less accurate at 16 ms (13.6%). During normoxia, placental T1 = 1825 ± 141 ms (avg ± standard deviation) and T2 = 60 ± 16 ms (gestational age range 24.3-36.7, median 32.6 weeks). In the statistical model, placental T2 rose and T1 remained contant after hyperoxia, and no GA dependency was observed for T1 or T2. DISCUSSION: Well-characterized, motion-robust MRF was used to acquire T1 and T2 maps of the placenta. Changes with hyperoxia are consistent with a net increase in oxygen saturation. Toward the goal of whole-placenta quantitative oxygenation imaging over time, we aim to implement 3D MRF with integrated motion correction to improve T2 accuracy.

Placental MRI: Development of an MRI compatible ex vivo system for whole placenta dual perfusion.

PURPOSE: Placental dysfunction plays a key role in diseases that affect the fetus in utero and after birth. Aiming to develop a platform for validating in vivo placental MRI and investigations into placental physiology, we designed and built a prototype MRI-compatible perfusion chamber with an integrated MRI receive coil for high SNR ex vivo placental imaging. PRINCIPAL RESULTS: After optimizing placenta vascular clearing and perfusion protocols, we performed contrast enhanced MR angiography and MR relaxometry on eight carefully selected placentas while they were perfused via the umbilical arteries (UAs). Additionally, two of these placentas underwent maternal perfusion via the intervillous space (IVS). Despite striving for homogenous perfusion across the whole placenta, imaging results were highly heterogeneous for both UA and IVS perfused placentas. By histology, we observed blood congestion in the villi in regions that showed low UA perfusion during MRI. In two placentas prominent chorionic arteries followed by adjacent veins underwent contrast enhancement in the absence of villous capillary blush. The single placenta from a pregnancy affected by IUGR had the most homogeneous villous capillary perfusion. MAJOR CONCLUSIONS: A dual perfusion system for ex vivo placentas compatible with MRI permitted assessment of UA and IVS placental perfusion. We observed spatial UA perfusion heterogeneity and evidence for arteriovenous shunting in placentas from normal pregnancies and deliveries, but relative villous capillary perfusion homogeneity in a single IUGR placenta. Future work will focus on system optimization, followed by physiological manipulation and validation of in vivo placental MRI.

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.

Longitudinal Changes in Magnetic Resonance Spectroscopy in Pediatric Concussion: A Pilot Study.

Background: Nearly 20% of US adolescents report at least one lifetime concussion. Pathophysiologic models suggest that traumatic biomechanical forces caused by rotational deceleration lead to shear stress, which triggers a neurometabolic cascade beginning with excitotoxicity and leading to significant energy demands and a period of metabolic crisis for the injured brain. Proton magnetic resonance spectroscopy (1H MRS) offers a means for non-invasive measurement of neurometabolic changes after concussion. Objective: Describe longitudinal changes in metabolites measured in vivo in the brains of adolescent patients with concussion. Methods: We prospectively recruited 9 patients ages 11 to 20 who presented to a pediatric Emergency Department within 24 h of concussion. Patients underwent MRI scanning within 72 h (acute, n = 8), 2 weeks (subacute, n = 7), and at approximately 1 year (chronic, n = 7). Healthy, age and sex-matched controls were recruited and scanned once (n = 9). 1H MRS was used to measure N-acetyl-aspartate, choline, creatine, glutamate + glutamine, and myo-inositol concentrations in six regions of interest: left and right frontal white matter, posterior white matter and thalamus. Results: There was a significant increase in total thalamus glutamate+glutamine/choline at the subacute (p = 0.010) and chronic (p = 0.010) time points, and a significant decrease in total white matter myo-inositol/choline (p = 0.030) at the chronic time point as compared to controls. Conclusion: There are no differences in 1H MRS measurements in the acute concussive period; however, changes in glutamate+glutamine and myo-inositol concentrations detectable by 1H MRS may develop beyond the acute period.

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.

Functional oxygen extraction fraction (OEF) imaging with turbo gradient spin echo QUIXOTIC (Turbo QUIXOTIC).

PURPOSE: QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption (QUIXOTIC) is a recent technique that measures voxel-wise oxygen extraction fraction (OEF) but suffers from long scan times, limiting its application. We implemented multiecho QUIXOTIC dubbed turbo QUIXOTIC (tQUIXOTIC) that reduces scan time eightfold and then applied it in functional MRI. METHODS: tQUIXOTIC utilizes a novel turbo gradient spin echo readout enabling measurement of venular blood transverse relaxation rate in a single tag-control acquisition. Using tQUIXOTIC, we estimated cortical gray matter (GM) OEF, created voxel-by-voxel GM OEF maps, and quantified changes in visual cortex OEF during a blocked design flashing checkerboard visual stimulus. Contamination from cerebrospinal fluid partial volume averaging was estimated and corrected. RESULTS: The average cortical GM OEF was estimated as 0.38 ± 0.06 (n = 8) using a 3.4-min acquisition. The average OEF in the visual cortex was estimated as 0.43 ± 0.04 at baseline and 0.35 ± 0.05 during activation, with an average %ΔOEF of -20%. These values are consistent with those of past studies. CONCLUSION: tQUIXOTIC successfully estimated cortical GM OEF in clinical scan times and detected changes in OEF during blocked design visual stimulation. tQUIXOTIC will be useful to monitor regional OEF clinically and in blocked design or event-related functional MRI experiments. Magn Reson Med 79:2713-2723, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Assessing the effects of subject motion on T2 relaxation under spin tagging (TRUST) cerebral oxygenation measurements using volume navigators.

PURPOSE: Subject motion may cause errors in estimates of blood T2 when using the T2 -relaxation under spin tagging (TRUST) technique on noncompliant subjects like neonates. By incorporating 3D volume navigators (vNavs) into the TRUST pulse sequence, independent measurements of motion during scanning permit evaluation of these errors. METHODS: The effects of integrated vNavs on TRUST-based T2 estimates were evaluated using simulations and in vivo subject data. Two subjects were scanned with the TRUST+vNav sequence during prescribed movements. Mean motion scores were derived from vNavs and TRUST images, along with a metric of exponential fit quality. Regression analysis was performed between T2 estimates and mean motion scores. Also, motion scores were determined from independent neonatal scans. RESULTS: vNavs negligibly affected venous blood T2 estimates and better detected subject motion than fit quality metrics. Regression analysis showed that T2 is biased upward by 4.1 ms per 1 mm of mean motion score. During neonatal scans, mean motion scores of 0.6 to 2.0 mm were detected. CONCLUSION: Motion during TRUST causes an overestimate of T2 , which suggests a cautious approach when comparing TRUST-based cerebral oxygenation measurements of noncompliant subjects. Magn Reson Med 78:2283-2289, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Mitigation of partial volume effects in susceptibility-based oxygenation measurements by joint utilization of magnitude and phase (JUMP).

PURPOSE: Susceptibility-based blood oxygenation measurements in small vessels of the brain derive from gradient echo (GRE) phase and can provide localized assessment of brain function and pathology. However, when vessel diameter becomes smaller than the acquisition voxel size, partial volume effects compromise these measurements. The purpose of this study was to develop a technique to improve the reliability of vessel oxygenation estimates in the presence of partial volume effects. METHODS: Intravoxel susceptibility variations are present when a vessel and parenchyma experience partial volume effects, modifying the voxel's GRE phase signal and attenuating the GRE magnitude signal. Using joint utilization of magnitude and phase (JUMP), both vessel susceptibility and voxel partial volume fraction can be estimated, providing measurements of venous oxygen saturation ( Yv) in straight, nearly vertical vessels that have improved robustness to partial volume effects. RESULTS: JUMP was demonstrated by estimating vessel Yv in numerical and in vivo experiments. Deviations from ground truth of Yv measurements in vessels tilted up to 30° from B0 were reduced by over 50% when using JUMP compared with phase-only techniques. CONCLUSION: JUMP exploits both magnitude and phase data in GRE imaging to mitigate partial volume effects in estimation of vessel oxygenation. Magn Reson Med 77:1713-1727, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Regional quantification of cerebral venous oxygenation from MRI susceptibility during hypercapnia.

There is an unmet medical need for noninvasive imaging of regional brain oxygenation to manage stroke, tumor, and neurodegenerative diseases. Oxygenation imaging from magnetic susceptibility in MRI is a promising new technique to measure local venous oxygen extraction fraction (OEF) along the cerebral venous vasculature. However, this approach has not been tested in vivo at different levels of oxygenation. The primary goal of this study was to test whether susceptibility imaging of oxygenation can detect OEF changes induced by hypercapnia, via CO2 inhalation, within selected a priori brain regions. Ten healthy subjects were scanned at 3T with a 32-channel head coil. The end-tidal CO2 (ETCO2) was monitored continuously and inspired gases were adjusted to achieve steady-state conditions of eucapnia (41±3mmHg) and hypercapnia (50±4mmHg). Gradient echo phase images and pseudo-continuous arterial spin labeling (pcASL) images were acquired to measure regional OEF and CBF respectively during eucapnia and hypercapnia. By assuming constant cerebral oxygen consumption throughout both gas states, regional CBF values were computed to predict the local change in OEF in each brain region. Hypercapnia induced a relative decrease in OEF of -42.3% in the straight sinus, -39.9% in the internal cerebral veins, and approximately -50% in pial vessels draining each of the occipital, parietal, and frontal cortical areas. Across volunteers, regional changes in OEF correlated with changes in ETCO2. The reductions in regional OEF (via phase images) were significantly correlated (P<0.05) with predicted reductions in OEF derived from CBF data (via pcASL images). These findings suggest that susceptibility imaging is a promising technique for OEF measurements, and may serve as a clinical biomarker for brain conditions with aberrant regional oxygenation.