Quantitative Susceptibility Imaging of Tissue Microstructure Using Ultra-High Field MRI

This thesis has used ultra-high field (UHF) magnetic resonance imaging (MRI) to investigate the fundamental relationships between tissue microstructure and such susceptibility-based contrast parameters as the apparent transverse relaxation rate (R2*), the local Larmor frequency shift (LFS) and quantitative volume magnetic susceptibility (QS). The interaction of magnetic fields with biological tissues results in shifts in the LFS which can be used to distinguish underlying cellular architecture. The LFS is also linked to the relaxation properties of tissues in a gradient echo MRI sequence. Equally relevant, histological analysis has identified iron and myelin as two major sources of the LFS. As a result, computation of LFS and the associated volume magnetic susceptibility from MRI phase data may serve as a significant method for in vivo monitoring of changes in iron and myelin associated with normal, healthy aging, as well as neurological disease processes. In this research, the cellular level underpinnings of the R2* and LFS signals were examined in a model rat brain system using 9.4 T MRI. The study was carried out using biophysical modeling and correlation with quantitative histology. For the first time, multiple biophysical modeling schemes were compared in both gray and white matter of excised rat brain tissue. Suprisingly, R2* dependence on tissue orientation has not been fully understood. Accordingly, scaling relations were derived for calculating the reversible, mesoscopic magnetic field component, R2\u27, of the apparent transverse relaxation rate from the orientation dependence in gray and white matter. Our results demonstrate that the orientation dependence of R2* and LFS in both white and cortical gray matter has a sinusoidal dependence on tissue orientation and a linear dependence on the volume fraction of myelin in the tissue. A susceptibility processing pipeline was also developed and applied to the calculation of phase-combined LFS and QS maps. The processing pipeline was subsequently used to monitor myelin and iron changes in multiple sclerosis (MS) patients compared to healthy, age and gender-matched controls. With the use of QS and R2* mapping, evidence of statistically significant increases in iron deposition in sub-cortical gray matter, as well as myelin degeneration along the white matter skeleton, were identified in MS patients. The magnetic susceptibility-based MRI methods were then employed as potential clinical biomarkers for disease severity monitoring of MS. It was demonstrated that the combined use of R2* and QS, obtained from multi-echo gradient echo MRI, could serve as an improved metric for monitoring both gray and white matter changes in early MS

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families

An Open Resource for Non-human Primate Imaging.

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets

Logistical analysis of the littoral combat ship

The purpose of the Littoral Combat Ship is to provide the Navy with an affordable, small, multi-mission ship capable of independent, interdependent and integrated operations inside the littorals. The Littoral Combat Ship will be designed to replace high-value Naval assets when conducting high-end missions such as littoral Anti-Submarine Warfare (ASW), Mine Warfare (MIW) and Anti-Surface Warfare (ASuW) as well as perform low-end missions such as Humanitarian Assistance (HA), Non-combatant Evacuation Operations (NEO) and Maritime Intercept Operations (MIO). In order to accomplish these missions and successfully counter the enemy's littoral denial strategy, the Navy has stated the Littoral Combat Ship must incorporate endurance, speed, payload capacity, sea-keeping, shallow-draft and mission reconfigurability into a small ship design. However, constraints in current ship design technology make this desired combination of design characteristics in small ships difficult to realize at any cost. This thesis (1) analyzes the relationship between speed, endurance, and payload to determine the expected displacement of the Littoral Combat Ship, (2) determines the impact of speed, displacement and significant wave height on Littoral Combat Ship fuel consumption and endurance, and (3) analyzes the implication of findings on Littoral Combat Ship logistics.http://archive.org/details/logisticalnalysi109451069Lieutenant Commander, Supply Corps, United States Naval ReserveApproved for public release; distribution is unlimited

Delineation of cortical pathology in multiple sclerosis using multi-surface magnetization transfer ratio imaging

The purpose of our study was to evaluate the utility of measurements of cortical surface magnetization transfer ratio (csMTR) on the inner, mid and outer cortical boundaries as clinically accessible biomarkers of cortical gray matter pathology in multiple sclerosis (MS). Twenty-five MS patients and 12 matched controls were recruited from the MS Clinic of the Montreal Neurological Institute. Anatomical and magnetization transfer ratio (MTR) images were acquired using 3 Tesla MRI at baseline and two-year time-points. MTR maps were smoothed along meshes representing the inner, mid and outer neocortical boundaries. To evaluate csMTR reductions suggestive of sub-pial demyelination in MS patients, a mixed model analysis was carried out at both the individual vertex level and in anatomically parcellated brain regions. Our results demonstrate that focal areas of csMTR reduction are most prevalent along the outer cortical surface in the superior temporal and posterior cingulate cortices, as well as in the cuneus and precentral gyrus. Additionally, age regression analysis identified that reductions of csMTR in MS patients increase with age but appear to hit a plateau in the outer caudal anterior cingulate, as well as in the precentral and postcentral cortex. After correction for the naturally occurring gradient in cortical MTR, the difference in csMTR between the inner and outer cortex in focal areas in the brains of MS patients correlated with clinical disability. Overall, our findings support multi-surface analysis of csMTR as a sensitive marker of cortical sub-pial abnormality indicative of demyelination in MS patients

Inter-echo variance as a weighting factor for multi-channel combination in multi-echo acquisition for local frequency shift mapping

© 2014 Wiley Periodicals, Inc. Purpose To develop and evaluate a local frequency shift (LFS) mapping method specifically designed for multi-echo acquisitions and multi-channel receive coils. Methods The proposed method uses the pixel-by-pixel inter-echo variance (IEV) as a weighting factor during channel-combination. Five healthy volunteers were scanned at 7 T. The IEV-weighted method was quantitatively compared to established (adaptive and Hermitian product) channel-combination methods with respect to IEV of LFS over the entire brain. Results In all experiments, the IEV-weighted method generated LFS maps free of artifacts caused by unwrapping errors. Based on measurements of the inter-echo frequency variance throughout the whole brain, the IEV-weighted method produced the lowest variation and the best contrast at the edge of the brain. Conclusion The primary finding of the present study is that accurate LFS maps are achievable if the data from each channel is processed independently prior to combination followed by a weighted combination using IEV as the weighting term. The software is freely available to the scientific community