Maternal mortality in the United States: research gaps, opportunities, and priorities.

Maternal mortality and severe maternal morbidity are urgent issues in the United States. It is important to establish priority areas to address these public health crises. On April 8, 2019, and May 2 to 3, 2019, the Eunice Kennedy Shriver National Institute of Child Health and Human Development organized and invited experts with varied perspectives to 2 meetings, a community engagement forum and a scientific workshop, to discuss underlying themes involved in the rising incidence of maternal mortality in the United States. Experts from diverse disciplines reviewed current data, ongoing activities, and identified research gaps focused on data measurement and reporting, obstetrical and health system factors, social determinants and disparities, and the community perspective and engagement. Key scientific opportunities to reduce maternal mortality and severe maternal morbidity include improved data quality and measurement, understanding the populations affected as well as the numerous etiologies, clinical research to confirm preventive and interventional strategies, and engagement of community participation in research that will lead to the reduction of maternal mortality in the United States. This article provides a summary of the workshop presentations and discussions.

Quantitative magnetic susceptibility mapping without phase unwrapping using WASSR.

The magnetic susceptibility of tissue within and around an image voxel affects the magnetic field and thus the local frequency in that voxel. Recently, it has been shown that spatial maps of frequency can be used to quantify local susceptibility if the contributions of surrounding tissue can be deconvolved. Currently, such quantitative susceptibility mapping (QSM) methods employ gradient recalled echo (GRE) imaging to measure spatial differences in the signal phase evolution as a function of echo time, from which frequencies can be deduced. Analysis of these phase images, however, is complicated by phase wraps, despite the availability and usage of various phase unwrapping algorithms. In addition, lengthy high-resolution GRE scanning often heats the magnet bore, causing the magnetic field to drift over several Hertz, which is on the order of the frequency differences between tissues. Here, we explore the feasibility of applying the WAter Saturation Shift Referencing (WASSR) method for 3D whole brain susceptibility imaging. WASSR uses direct saturation of water protons as a function of frequency irradiation offset to generate frequency maps without phase wraps, which can be combined with any image or spectroscopy acquisition. By utilizing a series of fast short-echo-time direct saturation images with multiple radiofrequency offsets, a frequency correction for field drift can be applied based on the individual image phases. Regions of interest were delineated with an automated atlas-based method, and the average magnetic susceptibilities calculated from frequency maps obtained from WASSR correlated well with those from the phase-based multi-echo GRE approach at 3T.

Human brain atlas for automated region of interest selection in quantitative susceptibility mapping: application to determine iron content in deep gray matter structures.

The purpose of this paper is to extend the single-subject Eve atlas from Johns Hopkins University, which currently contains diffusion tensor and T1-weighted anatomical maps, by including contrast based on quantitative susceptibility mapping. The new atlas combines a "deep gray matter parcellation map" (DGMPM) derived from a single-subject quantitative susceptibility map with the previously established "white matter parcellation map" (WMPM) from the same subject's T1-weighted and diffusion tensor imaging data into an MNI coordinate map named the "Everything Parcellation Map in Eve Space," also known as the "EvePM." It allows automated segmentation of gray matter and white matter structures. Quantitative susceptibility maps from five healthy male volunteers (30 to 33 years of age) were coregistered to the Eve Atlas with AIR and Large Deformation Diffeomorphic Metric Mapping (LDDMM), and the transformation matrices were applied to the EvePM to produce automated parcellation in subject space. Parcellation accuracy was measured with a kappa analysis for the left and right structures of six deep gray matter regions. For multi-orientation QSM images, the Kappa statistic was 0.85 between automated and manual segmentation, with the inter-rater reproducibility Kappa being 0.89 for the human raters, suggesting "almost perfect" agreement between all segmentation methods. Segmentation seemed slightly more difficult for human raters on single-orientation QSM images, with the Kappa statistic being 0.88 between automated and manual segmentation, and 0.85 and 0.86 between human raters. Overall, this atlas provides a time-efficient tool for automated coregistration and segmentation of quantitative susceptibility data to analyze many regions of interest. These data were used to establish a baseline for normal magnetic susceptibility measurements for over 60 brain structures of 30- to 33-year-old males. Correlating the average susceptibility with age-based iron concentrations in gray matter structures measured by Hallgren and Sourander (1958) allowed interpolation of the average iron concentration of several deep gray matter regions delineated in the EvePM.

Mapping magnetic susceptibility anisotropies of white matter in vivo in the human brain at 7 T.

High-resolution magnetic resonance phase- or frequency-shift images acquired at high field show contrast related to magnetic susceptibility differences between tissues. Such contrast varies with the orientation of the organ in the field, but the development of quantitative susceptibility mapping (QSM) has made it possible to reproducibly image the intrinsic tissue susceptibility contrast. However, recent studies indicate that magnetic susceptibility is anisotropic in brain white matter and, as such, needs to be described by a symmetric second-rank tensor( ̅χ). To fully determine the elements of this tensor, it would be necessary to acquire frequency data at six or more orientations. Assuming cylindrical symmetry of the susceptibility tensor in myelinated white matter fibers, we propose a simplified method to reconstruct the susceptibility tensor in terms of a mean magnetic susceptibility, MMS=(χ(//)+2 χ(⊥))/3 and a magnetic susceptibility anisotropy, MSA=χ(//)-χ(⊥), where χ(//) and χ(⊥) are susceptibility parallel and perpendicular to the white matter fiber direction, respectively. Computer simulations show that with a practical head rotation angle of around 20°-30°, four head orientations suffice to reproducibly reconstruct the tensor with good accuracy. We tested this approach on whole brain 1 × 1 × 1 mm(3) frequency data acquired from five healthy subjects at 7 T. The frequency information from phase images collected at four head orientations was combined with the fiber direction information extracted from diffusion tensor imaging (DTI) to map the white matter susceptibility tensor. The MMS and MSA were quantified for regions in several large white matter fiber structures, including the corona radiata, posterior thalamic radiation and corpus callosum. MMS ranged from -0.037 to -0.053 ppm (referenced to CSF being about zero). MSA values could be quantified without the need for a reference and ranged between 0.004 and 0.029 ppm, in line with the expectation that the susceptibility perpendicular to the fiber is more diamagnetic than the one parallel to it.

Multi-parametric neuroimaging reproducibility: a 3-T resource study.

Modern MRI image processing methods have yielded quantitative, morphometric, functional, and structural assessments of the human brain. These analyses typically exploit carefully optimized protocols for specific imaging targets. Algorithm investigators have several excellent public data resources to use to test, develop, and optimize their methods. Recently, there has been an increasing focus on combining MRI protocols in multi-parametric studies. Notably, these have included innovative approaches for fusing connectivity inferences with functional and/or anatomical characterizations. Yet, validation of the reproducibility of these interesting and novel methods has been severely hampered by the limited availability of appropriate multi-parametric data. We present an imaging protocol optimized to include state-of-the-art assessment of brain function, structure, micro-architecture, and quantitative parameters within a clinically feasible 60-min protocol on a 3-T MRI scanner. We present scan-rescan reproducibility of these imaging contrasts based on 21 healthy volunteers (11 M/10 F, 22-61 years old). The cortical gray matter, cortical white matter, ventricular cerebrospinal fluid, thalamus, putamen, caudate, cerebellar gray matter, cerebellar white matter, and brainstem were identified with mean volume-wise reproducibility of 3.5%. We tabulate the mean intensity, variability, and reproducibility of each contrast in a region of interest approach, which is essential for prospective study planning and retrospective power analysis considerations. Anatomy was highly consistent on structural acquisition (~1-5% variability), while variation on diffusion and several other quantitative scans was higher (~<10%). Some sequences are particularly variable in specific structures (ASL exhibited variation of 28% in the cerebral white matter) or in thin structures (quantitative T2 varied by up to 73% in the caudate) due, in large part, to variability in automated ROI placement. The richness of the joint distribution of intensities across imaging methods can be best assessed within the context of a particular analysis approach as opposed to a summary table. As such, all imaging data and analysis routines have been made publicly and freely available. This effort provides the neuroimaging community with a resource for optimization of algorithms that exploit the diversity of modern MRI modalities. Additionally, it establishes a baseline for continuing development and optimization of multi-parametric imaging protocols.

Altered functional connectivity between sub-regions in the thalamus and cortex in schizophrenia patients measured by resting state BOLD fMRI at 7T.

The thalamus is a small brain structure that relays neuronal signals between subcortical and cortical regions. Abnormal thalamocortical connectivity in schizophrenia has been reported in previous studies using blood-oxygenation-level-dependent (BOLD) functional MRI (fMRI) performed at 3T. However, anatomically the thalamus is not a single entity, but is subdivided into multiple distinct nuclei with different connections to various cortical regions. We sought to determine the potential benefit of using the enhanced sensitivity of BOLD fMRI at ultra-high magnetic field (7T) in exploring thalamo-cortical connectivity in schizophrenia based on subregions in the thalamus. Seeds placed in thalamic subregions of 14 patients and 14 matched controls were used to calculate whole-brain functional connectivity. Our results demonstrate impaired thalamic connectivity to the prefrontal cortex and the cerebellum, but enhanced thalamic connectivity to the motor/sensory cortex in schizophrenia. This altered functional connectivity significantly correlated with disease duration in the patients. Remarkably, comparable effect sizes observed in previous 3T studies were detected in the current 7T study with a heterogeneous and much smaller cohort, providing evidence that ultra-high field fMRI may be a powerful tool for measuring functional connectivity abnormalities in schizophrenia. Further investigation with a larger cohort is merited to validate the current findings.

Abnormal Grey Matter Arteriolar Cerebral Blood Volume in Schizophrenia Measured With 3D Inflow-Based Vascular-Space-Occupancy MRI at 7T.

Metabolic dysfunction and microvascular abnormality may contribute to the pathogenesis of schizophrenia. Most previous studies of cerebral perfusion in schizophrenia measured total cerebral blood volume (CBV) and cerebral blood flow (CBF) in the brain, which reflect the ensemble signal from the arteriolar, capillary, and venular compartments of the microvasculature. As the arterioles are the most actively regulated blood vessels among these compartments, they may be the most sensitive component of the microvasculature to metabolic disturbances. In this study, we adopted the inflow-based vascular-space-occupancy (iVASO) MRI approach to investigate alterations in the volume of small arterial (pial) and arteriolar vessels (arteriolar cerebral blood volume [CBVa]) in the brain of schizophrenia patients. The iVASO approach was extended to 3-dimensional (3D) whole brain coverage, and CBVa was measured in the brains of 12 schizophrenia patients and 12 matched controls at ultra-high magnetic field (7T). Significant reduction in grey matter (GM) CBVa was found in multiple areas across the whole brain in patients (relative changes of 14%-51% and effect sizes of 0.7-2.3). GM CBVa values in several regions in the temporal cortex showed significant negative correlations with disease duration in patients. GM CBVa increase was also found in a few brain regions. Our results imply that microvascular abnormality may play a role in schizophrenia, and suggest GM CBVa as a potential marker for the disease. Further investigation is needed to elucidate whether such effects are due to primary vascular impairment or secondary to other causes, such as metabolic dysfunction.

Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A (1)H MRS Study at 7 Tesla.

The extent of age-related changes in glutamate and other neurometabolites in the anterior cingulate cortex (ACC) in individuals with schizophrenia remain unclear. Magnetic resonance spectroscopy (MRS) at 7 T, which yields precise measurements of various metabolites and can distinguish glutamate from glutamine, was used to determine levels of ACC glutamate and other metabolites in 24 individuals with schizophrenia and 24 matched controls. Multiple regression analysis revealed that ACC glutamate decreased with age in patients but not controls. No changes were detected in levels of glutamine, N-acetylaspartate, N-acetylaspartylglutamic acid, myo-inositol, GABA, glutathione, total creatine, and total choline. These results suggest that age may be an important modifier of ACC glutamate in schizophrenia.