Simulating local deformations in the human cortex due to blood flow-induced changes in mechanical tissue properties: Impact on functional magnetic resonance imaging

Investigating human brain tissue is challenging due to the complexity and the manifold interactions between structures across different scales. Increasing evidence suggests that brain function and microstructural features including biomechanical features are related. More importantly, the relationship between tissue mechanics and its influence on brain imaging results remains poorly understood. As an important example, the study of the brain tissue response to blood flow could have important theoretical and experimental consequences for functional magnetic resonance imaging (fMRI) at high spatial resolutions. Computational simulations, using realistic mechanical models can predict and characterize the brain tissue behavior and give us insights into the consequent potential biases or limitations of in vivo, high-resolution fMRI. In this manuscript, we used a two dimensional biomechanical simulation of an exemplary human gyrus to investigate the relationship between mechanical tissue properties and the respective changes induced by focal blood flow changes. The model is based on the changes in the brain’s stiffness and volume due to the vasodilation evoked by neural activity. Modeling an exemplary gyrus from a brain atlas we assessed the influence of different potential mechanisms: (i) a local increase in tissue stiffness (at the level of a single anatomical layer), (ii) an increase in local volume, and (iii) a combination of both effects. Our simulation results showed considerable tissue displacement because of these temporary changes in mechanical properties. We found that the local volume increase causes more deformation and consequently higher displacement of the gyrus. These displacements introduced considerable artifacts in our simulated fMRI measurements. Our results underline the necessity to consider and characterize the tissue displacement which could be responsible for fMRI artifacts

Magnetic resonance imaging of the Amine-Proton EXchange (APEX) dependent contrast

Chemical exchange between water and labile protons from amino-acids, proteins and other molecules can be exploited to provide tissue contrast with magnetic resonance imaging (MRI) techniques. Using an offresonance Spin-Locking (SL) scheme for signal preparation is advantageous because the image contrast can be tuned to specific exchange rates by adjusting SL pulse parameters. While the amide-proton transfer (APT) contrast is obtained optimally with steady-state preparation, using a low power and long irradiation pulse, image contrast from the faster amine-water proton exchange (APEX) is optimized in the transient state with a higher power and a shorter SL pulse. Our phantom experiments show that the APEX contrast is sensitive to protein and amino acid concentration, as well as pH. In vivo 9.4-T SL MRI data of rat brains with irradiation parameters optimized to slow exchange rates have a sharp peak at 3.5 ppm and also broad peak at − 2 to − 5 ppm, inducing negative contrast in APT-weighted images, while the APEX image has large positive signal resulting from a weighted summation of many different amine-groups. Brain ischemia induced by cardiac arrest decreases pure APT signal from~1.7% to~0%, and increases the APEX signal from~8% to~16%. In the middle cerebral artery occlusion (MCAO) model, the APEX signal shows different spatial and temporal patterns with large inter-animal variations compared to APT and water diffusion maps. Because of the similarity between the chemical exchange saturation transfer (CEST) and SL techniques, APEX contrast can also be obtained by a CEST approach using similar irradiation parameters. APEX may provide useful information for many diseases involving a change in levels of proteins, peptides, amino-acids, or pH, and may serve as a sensitive neuroimaging biomarker

Development of a Multimodal MRI Study to Characterize Morpho-Functional Features in Rodent Models of Alzheimer's Disease

Alzheimer’s Disease (AD) is the most common form of dementia, recognized by the World Health Organization as a global public health priority. It is a complex pathology characterized by the accumulation of the Amyloid-β (Aβ) peptide as extracellular plaques and of the intracellullar neuro fibrillary tangles (NFT) alongside with different events, such as chronic neuroinflammation and astrogliosis. None of the existing biomarkers is simultaneously specific for the pathology and sensitive to its progression. Metabolic and functional alterations are the earliest events described in the AD pathological cascade but shared with other form of dementia, while specific structural alterations occurs in a later stage of the disease. The use of transgenic models could simplify the development of new imaging biomarkers that would enable early diagnosis and making new treatments more effective. The objective of this work was to develop a multi-modal panel of magnetic resonance imaging (MRI) techniques and automated analysis pipelines, characterized by a high translational impact, in order to investigate the metabolic, functional and structural alterations in the brains of AD transgenic models. Results obtained in the APP23 transgenic mouse show that chemical exchange saturation transfer (CEST) imaging can be used to detect alterations in the brain uptake of the glucose analogue 2-deoxy-d-glucose (2DG) with a better resolution than PET and without the need of radioactive tracers. Moreover, a longitudinal study highlighted that significant structural and metabolic alterations can be found only in a late stage of the pathology. Furthermore, an advanced pipeline for the analysis of the rodent brain functional connectivity has been developed. This thesis demonstrates that the advantage to the experimental design adopted is simplifying longitudinal studies of the same animal cohort. The translation of the analysis pipelines adopted in human studies enables more powerful results and reduces the number of animals involved in research

T1rho MRI in brain aging, lumbar disc degeneration, and liver fibrosis: clinical and experimental studies.

T1rho弛豫是旋轉坐標系中的自旋晶格弛豫，它決定橫向磁化向量在存有自旋鎖定射頻脈衝情況下的衰減，自旋鎖定脈衝與橫向磁化向量同向。T1rho磁共振成像對於低頻運動過程敏感，故可研究水與其周大分子物質環境間的交互作用，有鑒別組織內早期生化改變的潛力。衰老與慢性高血壓是常見腦退行性疾病的兩個主要危險因素。但是正常腦衰老過程及慢性高血壓兩個因素與腦組織T1rho是否有相關性，尚缺乏研究。序貫性測量SD老鼠自5至15月齡、WKY（血壓正常）和SHR（患有自發性高血壓）老鼠自6至12月齡的雙側丘腦、海馬、和皮質的腦組織T1rho值。發現三組老鼠的丘腦、海馬及皮質的T1rho均隨年齡增長而增高；且SHR的顯著高於WKY老鼠。T1rho值與椎間盤退變等級的相關性已有報導。但相比T2值，T1rho在評價椎間盤退變方面是否優於或如何優於T2值尚缺乏研究。將椎間盤髓核及纖維環的T1rho和T2值與5級和8級椎間盤退變等級系統做比較；發現髓核的T1rho及T2與椎間盤退變等級的相關性均呈二次函數降低，且無顯著差別(P=0.40)。纖維環的T1rho及T2與椎間盤退變等級的相關性呈線性函數降低，T2降低的斜率明顯比T1rho降低的斜率要平坦(P<0.001)。故T1rho值比T2值更加適合評價纖維環退變，而兩者在評價髓核時相似。肝纖維化是幾乎所有慢性肝病的常見特徵，包括大分子物質在細胞外基質的沉積。選用四氯化碳CCl4腹腔注射6周來製造肝纖維化模型。肝臟T1rho在注射後的第二天輕度上升，然後持續上升，直到注射六周後T1rho達最高值，此後T1rho隨CCl4注射停止而降低。顯示T1rho磁共振成像對於監測慢性注射CCl4誘導的肝纖維化及肝損傷有價值。當沒有明顯肝纖維化時，肝T1rho輕微受水腫及急性炎症的影響。為將肝臟T1rho磁共振成像轉化到臨床使用，我們研究了其可行性，以及正常志願者肝臟T1rho值分佈範圍。發現採用六個自旋鎖定時間來測量健康志願者肝T1rho，結果有較高的可重複性和一致性，肝T1rho平均值為42.5ms，分佈範圍為38.8到46.5ms。採用三個自鎖鎖定時間點掃描，可以減少一半掃描時間，且可以得到可信的肝T1rho值，但採用兩個自旋鎖定時間點則不行。T1rho relaxation is spin-lattice relaxation in the rotating frame. It determines the decay of the transverse magnetization in the presence of a spin-lock radiofrequency pulse, which applied along the transverse magnetization. T1rho MRI is sensitive to low frequency motional processes, so it can be used to investigate the interaction between water molecules and their macromolecular environment. T1rho imaging is suggested to have the potential to identify early biochemical changes in tissues.Aging and chronic hypertension are two major risk factors for common neurodegenerative disease. However, whether normal brain aging and chronic spontaneous hypertensive are associated with brain T1rho values changes were not reported. We longitudinally measured the T1rho value in rat brain of Sprague-Dawley (SD) rats from 5-month to 15-month, and spontaneous hypertensive rats (SHR) with Wistar Kyoto (WKY) rats from 6-month to 12-month. The T1rho values in three brain regions of thalamus, hippocampus, and cortices increased with aging process, and were significantly higher in SHR than WKY rats.For intervertebral disc, the correlation between T1rho and degenerative grade has been reported. However, whether and how T1rho specifically offer better evaluation of disc degeneration compared with T2 was not studied previously. T1rho and T2 value of nucleus pulposus (NP) and annulus fibrosus (AF) was compared with reference to the five-level and eight-level semi-quantitative disc degeneration grading systems. For NP, T1rho and T2 decreased quadratically with disc degeneration grades and had no significant trend difference (P=0.40). In NP, T1rho and T2 decrease in a similar pattern following disc degeneration. For AF, T1rho and T2 decreased linearly and the slopes of T2 were significantly flatter than those of T1rho (P<0.001). Therefore, the T1rho is better suited for evaluating AF in degenerated disc than T2.Liver fibrosis, a common feature of almost all causes of chronic liver disease, involves macromolecules accumulated within the extracellular matrix. Male Sprague-Dawley rats received intraperitoneal injection of 2 ml/kg CCl4 twice weekly for up to 6 weeks. Then CCl4 was withdrawn for recovery. The liver T1rho values increased slightly on day 2, then increased further and were highest at week 6 post CCl4 insults, and decreased upon the withdrawal of the CCl4 insult. This study demonstrated that T1rho MRI is a valuable imaging biomarker for liver injury and fibrosis induced by CCl4. Liver T1rho value was only mildly affected by edema and acute inflammation when there was no apparent fibrosis.To translate liver T1rho MRI to clinical application, the technical feasibility of T1rho MRI in human liver was explored and the normal range of T1rho values in healthy volunteers was determined. We found it is feasible to obtain consistent liver T1rho measurement for healthy human liver with six spin-lock time (SLT) points of 1, 10, 20, 30, 40, and 50ms; the mean liver T1rho value of the healthy subjects was 42.5ms, with a range of 38.8-46.5ms. Adopting 3-SLT points of 1, 20, and 50ms for T1rho measurement could provide reliable measurement and reduce the scanning time, while 2-SLT points of 1 and 50ms do not provide reliable measurement.Detailed summary in vernacular field only.Detailed summary in vernacular field only.Detailed summary in vernacular field only.Detailed summary in vernacular field only.Detailed summary in vernacular field only.Zhao, Feng.Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.Includes bibliographical references (leaves 119-143).Abstracts also in Chinese.ABSTRACT --- p.iACKNOWLEDGEMENTS --- p.viLIST OF FIGURES --- p.viiiLIST OF TABLES --- p.xviLIST OF ABBREVIATIONS --- p.xviiCONTENTS --- p.xxiChapter Chapter 1 --- Introduction --- p.1Chapter 1.1 --- Conventional Magnetic Resonance Imaging --- p.1Chapter 1.1.1 --- Basic Principle of Conventional Magnetic Resonance Imaging --- p.1Chapter 1.1.2 --- T1 Relaxation --- p.2Chapter 1.1.3 --- T2 Relaxation --- p.3Chapter 1.2 --- T1rho Magnetic Resonance Imaging --- p.3Chapter 1.2.1 --- T1rho Relaxation --- p.3Chapter 1.2.2 --- Principle of T1rho Magnetic Resonance Imaging --- p.4Chapter 1.2.3 --- Radiofrequency Pulse for T1rho Magnetic Resonance Imaging --- p.5Chapter 1.2.4 --- T1rho-weighted Contrast Imaging and Application --- p.10Chapter 1.2.5 --- Quantitative T1rho Mapping and Application --- p.11Chapter 1.2.6 --- T1rho Dispersion and Application --- p.13Chapter 1.3 --- Thesis Overview --- p.14Chapter Chapter 2 --- T1rho MRI in brain aging of animal model --- p.19Chapter 2.1 --- Introduction --- p.19Chapter 2.2 --- Materials and Methods --- p.20Chapter 2.2.1 --- Animal Model of Brain Aging --- p.20Chapter 2.2.2 --- T1rho Data Acquisition --- p.21Chapter 2.2.3 --- T1rho Data Processing --- p.23Chapter 2.2.4 --- T1rho Measurement and Statistical Analysis --- p.24Chapter 2.3 --- Results --- p.27Chapter 2.4 --- Discussion --- p.38Chapter 2.5 --- Summary --- p.42Chapter Chapter 3 --- T1rho MRI in lumbar disc degeneration of human subjects --- p.43Chapter 3.1 --- Introduction --- p.43Chapter 3.2 --- Methods --- p.45Chapter 3.2.1 --- Subjects --- p.45Chapter 3.2.2 --- MR Image Acquisition --- p.46Chapter 3.2.2.1 --- T2-weighted MRI --- p.46Chapter 3.2.2.2 --- T2 Mapping Imaging --- p.47Chapter 3.2.2.3 --- T1rho MRI --- p.47Chapter 3.2.3 --- Data Processing --- p.49Chapter 3.2.4 --- Data Measurement and Statistical Analysis --- p.49Chapter 3.3 --- Results --- p.52Chapter 3.3.1 --- Range of T1rho/T2 Values for Discs --- p.52Chapter 3.3.2 --- The Relationship between NP T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.52Chapter 3.3.3 --- The Relationship between NP T1rho/T2 Values and 5-level Degeneration Grading of Discs --- p.55Chapter 3.3.4 --- The Relationship between AF T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.58Chapter 3.3.5 --- The Relationship between AF T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.61Chapter 3.4 --- Discussion --- p.64Chapter 3.5 --- Summary --- p.69Chapter Chapter 4 --- T1rho MRI in rat liver fibrosis model induced by CCl4 insult --- p.71Chapter 4.1 --- Introduction --- p.71Chapter 4.2 --- Materials and Methods --- p.73Chapter 4.2.1 --- Animal Preparation --- p.73Chapter 4.2.2 --- MR Image Acquisition --- p.74Chapter 4.2.2.1 --- T2-weighted MRI --- p.75Chapter 4.2.2.2 --- T1rho MRI --- p.75Chapter 4.2.3 --- Data Processing --- p.76Chapter 4.2.4 --- Data Measurement and Statistical Analysis --- p.78Chapter 4.2.5 --- Histology Analysis --- p.79Chapter 4.3 --- Results --- p.80Chapter 4.3.1 --- T1rho Measurement Reproducibility --- p.80Chapter 4.3.2 --- Rat Liver T1rho Values at Different Time Phase --- p.81Chapter 4.3.3 --- Relative Rat Liver Signal Intensity on T2WI at Different Time Phase --- p.83Chapter 4.3.4 --- Histology Results --- p.84Chapter 4.4 --- Discussion --- p.86Chapter 4.5 --- Summary --- p.91Chapter Chapter 5 --- T1rho MRI in liver of healthy human subjects --- p.93Chapter 5.1 --- Introduction --- p.93Chapter 5.2 --- Methods --- p.95Chapter 5.2.1 --- Subjects --- p.95Chapter 5.2.2 --- MR Image Acquisition --- p.96Chapter 5.2.2.1 --- T2-weighted MRI --- p.96Chapter 5.2.2.2 --- T1rho MRI --- p.97Chapter 5.2.3 --- T1rho Data Processing --- p.99Chapter 5.2.4 --- T1rho Measurement --- p.100Chapter 5.3 --- Results --- p.102Chapter 5.3.1 --- T1rho Measurement Reproducibility --- p.105Chapter 5.3.2 --- T1rho Value Agreement of the Fasting Status with Post Meal Status --- p.105Chapter 5.3.3 --- T1rho Value Agreement for T1rho Maps Constructed by Different Spin-lock Time Points --- p.106Chapter 5.3.4 --- T1rho Value Range of Healthy Human Subjects --- p.108Chapter 5.4 --- Discussion --- p.108Chapter 5.5 --- Summary --- p.113Chapter Chapter 6 --- General discussion and further work --- p.115References: --- p.119LIST OF PUBLICATIONS --- p.13

Myelin imaging and characterization by magnetic resonance imaging

280 p.Los axones neuronales están recubiertos de una membrana lipídica llamada mielina, que protege a los axones y posibilita una transmisión rápida y eficiente del impulso eléctrico. En ciertas patologías como la lesión cerebral traumática, la isquemia o principalmente, en la esclerosis múltiple, la pérdida de mielina o desmielinización da lugar a la muerte neuronal y por consiguiente a la pérdida de capacidades cognitivas. Este estado puede ser revertido por medio de la remielinización, en la que los oligodendrocitos mielinizantes del sistema nervioso central regeneran la vaina de mielina, evitando la degeneración de las neuronas. En los últimos años se ha realizado un esfuerzo considerable en el desarrollo de terapias remielinizantes. Para ello, es imprescindible el desarrollo de técnicas para la evaluación no-invasiva de estas terapias y una caracterización profunda de los procesos de desmielinización y remielinización. En este contexto, la imagen por resonancia magnética (IRM) juega un papel fundamental por su carácter no-invasivo, alta resolución y versatilidad.Los principales objetivos de esta tesis han sido el desarrollo de protocolos de IRM para la cuantificación de mielina y la caracterización de los procesos de remielinización y desmielinización a través de resonancia magnética funcional en reposo. Para ello se ha utilizado como base el modelo murinocuprizona, en la que la administración del tóxico da lugar a la desmielinización en el cerebro, seguido por la remielinización. Los datos y conclusiones obtenidas se han contrastado en otros modelos de ratón, como en modelos de Alzheimer o en ratones sanos envejecidos.A grandes rasgos, hemos podido concluir que la imagen ponderada en peso T2 es la más específica y sensible para la cuantificación de mielina en el modelo cuprizona. Por ello, en este trabajo se propone la utilización de la imagen ponderada en peso T2 para la evaluación de terapias remielinizantes en el modelo cuprizona. Sin embargo, el interés de realizar imagen multiparamétríca ha quedado al descubierto al realizar imagen de modelos de ratón de Alzheimer, pudiendo detectar patología no relacionada con pérdida de mielina en zonas de materia blanca.Así mismo, hemos podido comprobar como la desmielinización conlleva la pérdida de la conectividad y función cerebral y la remielinización posibilita la recuperación por medio de la resonancia magnética funcional en reposo. Además, el potencial agente remielinizante clemastina, ha demostrado su capacidad de promover la remielinización a nivel anatómico y funcional tras 2 semanas de tratamiento. Finalmente, se ha realizado un estudio para determinar el efecto del envejecimiento en la conectividad del cerebro. Hemos podido observar que en ratones sanos, se ha observado un incremento de la conectividad cerebral hasta el mes 8, seguido de un descenso hasta el mes 13, probablemente debido a la neurodegeneración.En este trabajo hemos contribuido al desarrollo de terapias remielinizantes, por un lado, desarrollando protocolos de imagen para la cuantificación de mielina en modelos animales y por otro lado, caracterizando la desmielinización y remielinización a nivel funcional y anatómico

Multimodal Investigation of Neuronal Responses

This thesis describes an investigation of neuronal responses with both magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). MEG and fMRI are widely used in neuroscience. However, aspects of the MEG and fMRI signal are still not well understood, particularly post-stimulus responses – responses which occur after a stimulus has ended. Post-stimulus responses have been shown to correlate with various illnesses and as a result, MEG and fMRI have yet to reach their full potential clinically. By developing carefully controlled experiments, MEG is used in this thesis to characterise post-stimulus responses to a grip-force task. The results showed that the beta-band post-stimulus response (post-movement beta rebound, PMBR) is modulated by task duration. Functional network analysis, using amplitude envelope correlation and a hidden Markov model, showed that the PMBR re-establishes networks after breaking down during a task, suggesting the PMBR is related to functional connectivity. The results of this thesis provide new information about the nature of the PMBR, demonstrating that it can be systematically controlled by task parameters and provides insight into its generation. It is hoped this research will contribute to a deeper understanding of the PMBR and provide a step forward for its use clinically. In fMRI, the origin of the post-stimulus response is also poorly understood. To investigate fMRI post-stimulus responses, an MR pulse sequence was developed and optimised to measure blood flow, volume and oxygenation changes simultaneously at 7 T. This was implemented with the grip-force task, allowing direct comparison between MEG and fMRI. This study provides new insights into the fMRI post-stimulus undershoot which warrant further investigation. Understanding the link between fMRI and MEG signals will help further understanding of both modalities and how they relate to neuronal activity. Finally, the applications of fMRI were explored by comparing fMRI responses in patients with focal hand dystonia (FHD) with healthy controls. 7 T fMRI was used to map cortical fingertip representations and measures were developed to compare overlap of digit representations between patients and healthy controls. This project provided an important opportunity to advance the understanding of FHD and was the first study to use fMRI to explore the effects of treatment on patients with FHD

Multimodal Investigation of Neuronal Responses

This thesis describes an investigation of neuronal responses with both magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). MEG and fMRI are widely used in neuroscience. However, aspects of the MEG and fMRI signal are still not well understood, particularly post-stimulus responses – responses which occur after a stimulus has ended. Post-stimulus responses have been shown to correlate with various illnesses and as a result, MEG and fMRI have yet to reach their full potential clinically. By developing carefully controlled experiments, MEG is used in this thesis to characterise post-stimulus responses to a grip-force task. The results showed that the beta-band post-stimulus response (post-movement beta rebound, PMBR) is modulated by task duration. Functional network analysis, using amplitude envelope correlation and a hidden Markov model, showed that the PMBR re-establishes networks after breaking down during a task, suggesting the PMBR is related to functional connectivity. The results of this thesis provide new information about the nature of the PMBR, demonstrating that it can be systematically controlled by task parameters and provides insight into its generation. It is hoped this research will contribute to a deeper understanding of the PMBR and provide a step forward for its use clinically. In fMRI, the origin of the post-stimulus response is also poorly understood. To investigate fMRI post-stimulus responses, an MR pulse sequence was developed and optimised to measure blood flow, volume and oxygenation changes simultaneously at 7 T. This was implemented with the grip-force task, allowing direct comparison between MEG and fMRI. This study provides new insights into the fMRI post-stimulus undershoot which warrant further investigation. Understanding the link between fMRI and MEG signals will help further understanding of both modalities and how they relate to neuronal activity. Finally, the applications of fMRI were explored by comparing fMRI responses in patients with focal hand dystonia (FHD) with healthy controls. 7 T fMRI was used to map cortical fingertip representations and measures were developed to compare overlap of digit representations between patients and healthy controls. This project provided an important opportunity to advance the understanding of FHD and was the first study to use fMRI to explore the effects of treatment on patients with FHD