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

Towards in vivo g-ratio mapping using MRI: unifying myelin and diffusion imaging

The g-ratio, quantifying the comparative thickness of the myelin sheath encasing an axon, is a geometrical invariant that has high functional relevance because of its importance in determining neuronal conduction velocity. Advances in MRI data acquisition and signal modelling have put in vivo mapping of the g-ratio, across the entire white matter, within our reach. This capacity would greatly increase our knowledge of the nervous system: how it functions, and how it is impacted by disease. This is the second review on the topic of g-ratio mapping using MRI. As such, it summarizes the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches. Using simulations based on recently published data, this review demonstrates the relevance of the calibration step for three myelin-markers (macromolecular tissue volume, myelin water fraction, and bound pool fraction). It highlights the need to estimate both the slope and offset of the relationship between these MRI-based markers and the true myelin volume fraction if we are really to achieve the goal of precise, high sensitivity g-ratio mapping in vivo. Other challenges discussed in this review further evidence the need for gold standard measurements of human brain tissue from ex vivo histology. We conclude that the quest to find the most appropriate MRI biomarkers to enable in vivo g-ratio mapping is ongoing, with the potential of many novel techniques yet to be investigated.Comment: Will be published as a review article in Journal of Neuroscience Methods as parf of the Special Issue with Hu Cheng and Vince Calhoun as Guest Editor

On the track of the brain's microstructure : myelin water imaging using quantitative MRI

Conventional quantitative magnetic resonance imaging (MRI), for example monoexponential determination of the relaxation times T1 and T2, is sensitive to the various pathologies of myelinated tissue in the brain. However, it gives relatively unspecific information about the underlying nature of the disease. A parameter that directly correlates with the integrity of the myelin sheath is the so-called myelin water fraction (MWF). Based on multi-component analysis of non-invasive quantitative MRI measurements, mapping of the MWF becomes feasible and proved to be useful for studying demyelination and remyelination processes in the course of multiple sclerosis (MS) and other myelin related pathologies. Common myelin water imaging techniques often suffer from a lack of volume coverage due to their 2D acquisition schemes. This thesis focuses on the development of new myelin water mapping procedures, especially on fast 3D MRI measurements that provide whole brain coverage. In chapter 2, an MWF mapping technique based on balanced steady-state free precession (bSSFP) sequences is introduced. An extended bSSFP signal equation, which is based on a two-pool water model describing brain tissue, is derived to determine typical multi-compartment parameters, including the MWF, of healthy subjects. Possible influences of magnetization transfer effects, infinite radiofrequency pulses and B0/B1 inhomogeneities are discussed extensively. Chapter 3 introduces a 3D acquisition scheme based on multi-gradient-echo (mGRE) pulse sequences that is applied for sampling multi-component T2* decays in the human brain of healthy volunteers and MS patients. Quantitative myelin water maps are generated based on analysis of T2* spectra. Chapter 4 discusses possible adaptations and modifications of the proposed procedure from chapter 3 when moving to higher main magnetic field strengths. The effects of B0 inhomogeneities on the data sets and possible correction methods are additionally covered in this part of the thesis. Finally, the crucial role of accurate B1 and B0 imaging and the influences on myelin water imaging are revisited in chapter 5. A solution to simultaneous mapping of B1 and B0 is presented that might help to overcome systematic error sources in MWF mapping in the future

Reduced Myelin Water in the White Matter Tracts of Patients with Niemann-Pick Disease Type C

SUMMARY: Previous studies using diffusion tensor imaging to examine white matter in Niemann-Pick disease type C have produced mixed results. However, diffusion tensor imaging does not directly measure myelin and may be affected by other structural changes. We used myelin water imaging to more directly examine demyelination in 2 patients with Niemann-Pick disease type C. The results suggest that this technique may be useful for identifying regional changes in myelination in this condition

Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies

Backward Walking: A Novel Marker Of Fall Risk, Cognitive Dysfunction, And Myelin Damage In Persons With Multiple Sclerosis

Multiple sclerosis (MS) is a progressive, neurologic disease of the central nervous system that causes debilitating motor, sensory and cognitive impairments. As a result, persons with MS are at an increased risk for falls and falls represent a serious public health concern for the MS population. The current clinical measures used to assess fall risk in MS patients lack sensitivity and predictive validity for falls and are limited in their ability to capture to multiple functional domains (i.e., motor, sensory, cognitive and pathological domains) that are impaired by MS. Backward walking sensitively detects falls in the elderly and other neurologic diseases. However, backward walking and falls has never been explored in the MS population and the underlying reasons as to why backward walking sensitively detects falls remains unknown. Identification of a quick, simply and clinically feasible fall risk measures related to multiple functions impacted by MS and related to fall risk, which can detect falls before they occur is critical for fall prevention and timely and targeted intervention. Therefore, this dissertation examines backward walking as a novel marker of fall risk and its cognitive and pathological underpinnings to support its clinical utility. Our results indicate that backward walking is a sensitive marker of fall risk in the MS population, regardless of co-morbid cognitive deficits, and that examining underlying brain regions likely to contribute to backward walking performance including the corticospinal tract, corpus callosum and cerebellum, with neuroimaging tools sensitive to myelin (i.e., Myelin Water Imaging) demonstrate potential to identify underlying mechanisms of backward walking performance in the MS population. This work is the critical first step in establishing backward walking as a sensitive marker of fall risk for the MS population and leads the way to more personalized fall prevention therapies and interventions to improve clinical outcomes and decrease fall rates in the MS population