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

Prenatal alcohol exposure reduces magnetic susceptibility contrast and anisotropy in the white matter of mouse brains

Prenatal alcohol exposure can result in long-term cognitive and behavioral deficits. Fetal alcohol spectrum disorder (FASD) refers to a range of permanent birth defects caused by prenatal alcohol exposure, and is the most common neurodevelopmental disorder in the US. Studies by autopsy and conventional structural MRI indicate that the midline structures of the brain are particularly vulnerable to prenatal alcohol exposure. Diffusion tensor imaging (DTI) has shown that abnormalities in brain white matter especially the corpus callosum are very common in FASD. Quantitative susceptibility mapping (QSM) is a novel technique that measures tissue’s magnetic property. Such magnetic property is affected by tissue microstructure and molecular composition including that of myelin in the white matter. In this work, we studied three major white matter fiber bundles of a mouse model of FASD and compared it to control mice using both QSM and DTI. QSM revealed clear and significant abnormalities in anterior commissure, corpus callosum, and hippocampal commissure, which were likely due to reduced myelination. Our data also suggested that QSM may be even more sensitive than DTI for examining changes due to prenatal alcohol exposure. Although this is a preclinical study, the technique of QSM is readily translatable to human brain

20-αHydroxycholesterol, an oxysterol in human breast milk, reverses mouse neonatal white matter injury through Gli-dependent oligodendrogenesis.

White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth

Advances in noninvasive myelin imaging

Myelin is important for the normal development and healthy function of the nervous system. Recent developments in MRI acquisition and tissue modeling aim to provide a better characterization and more specific markers for myelin. This allows for specific monitoring of myelination longitudinally and noninvasively in the healthy brain as well as assessment of treatment and intervention efficacy. Here, we offer a nontechnical review of MRI techniques developed to specifically monitor myelin such as magnetization transfer (MT) and myelin water imaging (MWI). We further summarize recent studies that employ these methods to measure myelin in relation to development and aging, learning and experience, and neuropathology and psychiatric disorders

Quantitative Susceptibility Mapping by Inversion of a Perturbation Field Model: Correlation With Brain Iron in Normal Aging

There is increasing evidence that iron deposition occurs in specific regions of the brain in normal aging and neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's disease. Iron deposition changes the magnetic susceptibility of tissue, which alters the MR signal phase, and allows estimation of susceptibility differences using quantitative susceptibility mapping (QSM). We present a method for quantifying susceptibility by inversion of a perturbation model, or “QSIP.” The perturbation model relates phase to susceptibility using a kernel calculated in the spatial domain, in contrast to previous Fourier-based techniques. A tissue/air susceptibility atlas is used to estimate B[subscript 0] inhomogeneity. QSIP estimates in young and elderly subjects are compared to postmortem iron estimates, maps of the Field-Dependent Relaxation Rate Increase, and the L1-QSM method. Results for both groups showed excellent agreement with published postmortem data and in vivo FDRI: statistically significant Spearman correlations ranging from Rho=0.905 to Rho=1.00 were obtained. QSIP also showed improvement over FDRI and L1-QSM: reduced variance in susceptibility estimates and statistically significant group differences were detected in striatal and brainstem nuclei, consistent with age-dependent iron accumulation in these regions.National Institutes of Health (U.S.) (Grant P41EB015902)National Institutes of Health (U.S.) (Grant P41RR013218)National Institutes of Health (U.S.) (Grant P41EB015898)National Institutes of Health (U.S.) (Grant P41RR019703)National Institutes of Health (U.S.) (Grant T32EB0011680-06)National Institutes of Health (U.S.) (Grant K05AA017168)National Institutes of Health (U.S.) (Grant R01AA012388

On Nature of the Gradient Echo MR Signal and Its Application to Monitoring Multiple Sclerosis

Multiple Sclerosis is a common disease, affecting 2.5 million people world-wide. The clinical course is heterogeneous, ranging from benign disease in which patients live an almost normal life to severe and devastating disease that may shorten life. Despite much research, a fully effective treatment for MS is still unavailable and diagnostic techniques for monitoring MS disease evolution are much needed. As a non-invasive tool, Magnetic resonance imaging: MRI) plays a key role in MS diagnosis. Numerous MRI techniques have been proposed over the years. Among most widely used are conventional T1-weighted: T1W), T2-weighted: T2W) and FLuid Attenuated Inversion Recovery: FLAIR) imaging techniques. However their results do not correlate well with neurological findings. Several advanced MRI techniques are also used as research tools to study MS. Among them are magnetization transfer contrast imaging: MT), MR spectroscopy: MRS), and Diffusion Tensor Imaging: DTI) but they have not penetrated to clinical arena yet. Gradient Echo Plural Contrast Imaging: GEPCI) developed in our laboratory is a post processing technique based on multi-echo gradient echo sequence. It offers basic contrasts such as T1W images and T2* maps obtained from magnitude of GEPCI signal, and frequency maps obtained from GEPCI signal phase. Phase information of Gradient Echo MR signal has recently attracted much attention of the MR community since it manifests superior gray matter/ white matter contrast and sub-cortical contrast, especially at high field: 7 T) MRI. However the nature of this contrast is under intense debates. Our group proposed a theoretical framework - Generalized Lorentzian Approach - which emphasizes that, contrary to a common-sense intuition, phase contrast in brain tissue is not directly proportional to the tissue bulk magnetic susceptibility but is rather determined by the geometrical arrangement of brain tissue components: lipids, proteins, iron, etc.) at the cellular and sub-cellular levels - brain tissue magnetic architecture . In this thesis we have provide first direct prove of this hypothesis by measurement of phase contrast in isolated optic nerve. We have also provided first quantitative measurements of the contribution to phase contrast from the water-macromolecule exchange effect. Based on our measurement in protein solutions, we demonstrated that the magnitude of exchange effect is 1/2 of susceptibility effect and to the opposite sign. GEPCI technique also offers a scoring method for monitoring Multiple Sclerosis based on the quantitative T2* maps generated from magnitude information of gradient echo signal. Herein we demonstrated a strong agreement between GEPCI quantitative scores and traditional lesion load assessment. We also established a correlation between GEPCI scores and clinical tests for MS patients. We showed that this correlation is stronger than that found between traditional lesion load and clinical tests. Such studies will be carried out for longer period and on MS subjects with broader range of disease severity in the future. We have also demonstrated that the magnitude and phase information available from GEPCI experiment can be combined in multiple ways to generate novel contrasts that can help with visualization of neurological brain abnormalities beyond Multiple Sclerosis. In summary, in this study, we 1) propose novel contrasts for GEPCI from its basic images; 2) investigate the biophysical mechanisms behind phase contrast; 3) evaluate the benefits of quantitative T2* map offered by GEPCI in monitoring disease of Multiple Sclerosis by comparing GEPCI results to clinical standard techniques; 4) apply our theoretical framework - Generalized Lorentzian Approach - to better understand phase contrast in MS lesions

定量磁化率成像重建方法及其应用

磁共振成像(MRI)中,相位图像包含丰富的组织磁化率变化信息,获取相位图像不需要额外的扫描时间.组织中的顺磁性物质会影响组织磁化率差异,从而导致局部磁场不均匀.对组织内顺磁性物质的定量有利于许多脑血管疾病和神经系统疾病的诊断,但利用局部相位信息重建组织磁化率分布是一个不适定逆问题,目前仍然有许多问题亟待解决.该文着重介绍定量磁化率成像(QSM)的原理、重建方法及其在MRI中的应用.国家自然科学基金资助项目(81171331,11174239);中央高校基本业务费资助项目(2010121101

The Larmor frequency shift of a white matter magnetic microstructure model with multiple sources

Magnetic susceptibility imaging may provide valuable information about chemical composition and microstructural organization of tissue. However, its estimation from the MRI signal phase is particularly difficult as it is sensitive to magnetic tissue properties ranging from the molecular to macroscopic scale. The MRI Larmor frequency shift measured in white matter (WM) tissue depends on the myelinated axons and other magnetizable sources such as iron-filled ferritin. We have previously derived the Larmor frequency shift arising from a dense media of cylinders with scalar susceptibility and arbitrary orientation dispersion. Here we extend our model to include microscopic WM susceptibility anisotropy as well as spherical inclusions with scalar susceptibility to represent subcellular structures, biologically stored iron etc. We validate our analytical results with computer simulations and investigate the feasibility of estimating susceptibility using simple iterative linear least squares without regularization or preconditioning. This is done in a digital brain phantom synthesized from diffusion MRI (dMRI) measurements of an ex vivo mouse brain at ultra-high field.Comment: 70 pages, 14 figure

임상연구를 위한 신경수초물영상

학위논문 (박사)-- 서울대학교 대학원 : 공과대학 전기·정보공학부, 2019. 2. 이종호.신경수초는 몸 안의 전기적 신호를 전달하는데 있어 중요한 역할을 한다. 신경퇴행성질환은 신경수초 손상과 연관성이 있으며 이는 전기적 신호 전달의 손실을 유발한다. 병원에서 사용하는 자기 공명 영상법인 T1, T2 강조영상들은 신경수초의 양을 정량화 할 수 없고 신경퇴행성질환 환자의 신경수초의 손상된 정도를 확인 할 수 없다. 본 연구에서는 신경수초의 손상된 정도를 예측하기 위해 새롭게 개발 된 신경수초물영상을 신경퇴행성질환에 적용하였다. 이를 위해 신경다발의 물교환 및 머리로 유입되는 혈류로 인한 신경수초물영상법에 미치는 영향에 대하여 탐구하였다. 또한, 신경수초물영상법을 이용한 임상적 연구를 위하여 분석 파이프라인을 개발하였다. 첫째로 신경다발의 생물, 물리적학적 특성을 시뮬레이션화한 Monte-Carlo 시뮬레이션 모델을 개발하였다. 시뮬레이션에서 계산된 신경수초물의 거주 시간을 이용하여 신경수초물영상법이 신경수초물을 측정하고 있는 것을 검증하였다. 둘째로 본 연구에서는 머리로 유입되는 혈류로 인한 artifact을 제거하기 위해 혈류 시뮬레이션 모델을 개발하였다. 혈류 시뮬레이션 모델을 통하여 유입되는 혈류로 인한 artifact을 최소화 하는 혈류포화펄스의 최적 시간을 제안하였다. 최종적으로, 신경수초물 영상의 임상연구 적용을 위하여 분석 파이프 라인을 개발 및 요약하였다. 이를 이용하여 신경퇴행성질환인 다발성경화증, 시신경척수염, 외상성 뇌손상 환자의 정상으로 보이는 영역에서 신경수초물변화를 관찰하였다. 본 연구의 결과는 추후 수초관련 뇌 질환의 진단, 치료의 효용성 및 예후 평가뿐 아니라 학습에 의한 뇌 가소성 연구 및 재활 치료 효과 평가에 이용될 수 있을 것이라 사료된다.Myelin plays an important role in transmitting electrical signals in the body. Neurodegenerative diseases are associated with myelin damage and induce a loss of the electrical signals. The conventional T1 and T2 weighted imaging, used in clinics, cannot quantify the amount of myelin and confirm the degree of myelin damage in patients with neurodegenerative diseases. This thesis applied newly developed myelin water imaging, named ViSTa, to the neurodegenerative diseases to estimate changes in myelin. To utilize ViSTa myelin water imaging in clinical studies, I explored the effects of water exchange and inflow in ViSTa myelin water imaging. Then, I developed new data analysis pipelines to apply ViSTa myelin water imaging for the clinical studies. First, the Monte-Carlo simulation model that has the biological and physical properties of white matter fiber was developed for myelin water residence time. The simulation model validated the origin of ViSTa as myelin water. Second, the thesis developed a flow simulation model to compensate artifacts from inflow blood in ViSTa myelin water imaging. The flow simulation model suggested the optimal timing of flow saturation pulse(s) to suppress the inflow of blood. Finally, I summarized new data analysis pipelines for clinical applications. Using the analysis pipelines, ViSTa myelin water imaging revealed reduced apparent myelin water fraction in normal-appearing white matter for three prominent brain diseases and injury (neurodegenerative diseases): multiple sclerosis, neuromyelitis optica spectrum disorders, and traumatic brain injury. The developments in this thesis can be utilized not only in the diagnosis, treatment, and prognosis of various diseases but also in neuroplasticity and rehabilitation studies to explore the answer for the questions related to myelin issues.Chapter 1. Introduction 1 1.1 Myelin 1 1.2 Myelin Water 1 1.3 ViSTa Myelin Water Imaging 4 1.4 Purpose of Study 7 Chapter 2. Water Exchange Model 8 2.1 Introduction 8 2.2 Methods 8 2.3 Results 14 2.4 Discussion 16 Chapter 3. Blood Flow Simulation Model 17 3.1 Introduction 17 3.2 Methods 18 3.3 Results 25 3.4 Discussion 30 Chapter 4. Clinical Applications 32 4.1 Multiple Sclerosis 32 4.1.1 Introduction 32 4.1.2 Methods 33 4.1.3 Results 42 4.1.4 Discussion 52 4.2 Neuromyelitis Optica Spectrum Disorder 56 4.2.1 Introduction 56 4.2.2 Methods 57 4.2.3 Results 60 4.2.4 Discussion 65 4.3 Traumatic Brain Injury 68 4.3.1 Introduction 68 4.3.2 Methods 69 4.3.3 Results 75 4.3.4 Discussion 80 Chapter 5. Conclusion 84 Reference 85 Abstract 100Docto