Low back pain (LBP) is the leading cause of disability globally and is most commonly associated with pathologies of the intervertebral disc (IVD), including spinal stenosis, disc herniation, and IVD degeneration. IVD cells within the local degenerative disc environment are known to produce abundant inflammatory cytokines and chemokines, leading to recruitment of immune cells, such as macrophages. The presence of both IVD cells and macrophages in the pro-inflammatory microenvironment further exacerbates the degenerative cascade, leading to production of additional inflammatory cytokines and catabolic enzymes that compromise the IVD ECM structural integrity. However, the individual contributions of IVD cells and macrophages on degeneration, as well as the impact of crosstalk between the cell types remains unknown. A systemic inflammatory response is also common in cases of chronic LBP, defined as lasting longer than 3 months. While systemic inflammation in the serum of patients with LBP has been widely observed in comparison to healthy controls, the impact of pain and disability severity on systemic inflammation has not been determined. Additionally, both the local and systemic inflammatory responses associated with IVD injury and LBP have been characterized independently; however, the connection between these responses and their role in the progression of pain has not been studied. This thesis addresses these questions through a variety of methodologies including characterization of clinical samples, in vivo injury modeling, and an in vitro co-culture system. First, transcriptomic analysis of whole blood from patients with chronic LBP and spine pathologies was performed to determine the signaling mechanisms contributing to pain and disability severity systemically. Circulating immune cell senescence, and decreased complement activation and Type I interferon signaling were shown to contribute to greater severity of disability in patients with LBP. Next, an inflammation-driven in vivo injury model utilizing intradiscal injection of the inflammatory stimulus, lipopolysaccharide (LPS), was developed to investigate the role of local inflammation in the progression of IVD degeneration. Intradiscal inflammatory stimulation increased degeneration, macrophage infiltration, and innervation, ultimately leading to a pain phenotype. RNA sequencing analysis of the AF and whole blood after injection was also performed to determine signaling mechanisms mediating the local and systemic inflammatory responses. Type I interferon signaling was commonly upregulated in both the AF and blood, indicating a direct connection between local and systemic inflammation. Additionally, an inverse relationship between the complement activation and neuronal signaling pathways provides an interesting parallel with the relationship observed between the complement system and disability severity clinically. An in vitro macrophage-IVD explant co-culture model was also created to gain understanding of the contributions of macrophages in the inflammatory microenvironment of the degenerating IVD. Using a transwell system limiting communication to paracrine signaling, pro-inflammatory M1 macrophages were shown to have detrimental effects increasing inflammation, while M2 macrophage were protective, decreasing production of inflammatory cytokines. Inflammatory-stimulated IVDs also polarized M0 macrophages towards an M1-like phenotype, further exacerbating inflammation and degradation. Taken together, this thesis indicates a key role for macrophages in the modulation of the local inflammatory environment. Local inflammation severity also directly regulates the systemic inflammatory response, contributing to a pain phenotype. Finally, in cases of chronic LBP clinically, systemic inflammation is dependent on pain and disability severity.

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.i / ACKNOWLEDGEMENTS --- p.vi / LIST OF FIGURES --- p.viii / LIST OF TABLES --- p.xvi / LIST OF ABBREVIATIONS --- p.xvii / CONTENTS --- p.xxi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Conventional Magnetic Resonance Imaging --- p.1 / Chapter 1.1.1 --- Basic Principle of Conventional Magnetic Resonance Imaging --- p.1 / Chapter 1.1.2 --- T1 Relaxation --- p.2 / Chapter 1.1.3 --- T2 Relaxation --- p.3 / Chapter 1.2 --- T1rho Magnetic Resonance Imaging --- p.3 / Chapter 1.2.1 --- T1rho Relaxation --- p.3 / Chapter 1.2.2 --- Principle of T1rho Magnetic Resonance Imaging --- p.4 / Chapter 1.2.3 --- Radiofrequency Pulse for T1rho Magnetic Resonance Imaging --- p.5 / Chapter 1.2.4 --- T1rho-weighted Contrast Imaging and Application --- p.10 / Chapter 1.2.5 --- Quantitative T1rho Mapping and Application --- p.11 / Chapter 1.2.6 --- T1rho Dispersion and Application --- p.13 / Chapter 1.3 --- Thesis Overview --- p.14 / Chapter Chapter 2 --- T1rho MRI in brain aging of animal model --- p.19 / Chapter 2.1 --- Introduction --- p.19 / Chapter 2.2 --- Materials and Methods --- p.20 / Chapter 2.2.1 --- Animal Model of Brain Aging --- p.20 / Chapter 2.2.2 --- T1rho Data Acquisition --- p.21 / Chapter 2.2.3 --- T1rho Data Processing --- p.23 / Chapter 2.2.4 --- T1rho Measurement and Statistical Analysis --- p.24 / Chapter 2.3 --- Results --- p.27 / Chapter 2.4 --- Discussion --- p.38 / Chapter 2.5 --- Summary --- p.42 / Chapter Chapter 3 --- T1rho MRI in lumbar disc degeneration of human subjects --- p.43 / Chapter 3.1 --- Introduction --- p.43 / Chapter 3.2 --- Methods --- p.45 / Chapter 3.2.1 --- Subjects --- p.45 / Chapter 3.2.2 --- MR Image Acquisition --- p.46 / Chapter 3.2.2.1 --- T2-weighted MRI --- p.46 / Chapter 3.2.2.2 --- T2 Mapping Imaging --- p.47 / Chapter 3.2.2.3 --- T1rho MRI --- p.47 / Chapter 3.2.3 --- Data Processing --- p.49 / Chapter 3.2.4 --- Data Measurement and Statistical Analysis --- p.49 / Chapter 3.3 --- Results --- p.52 / Chapter 3.3.1 --- Range of T1rho/T2 Values for Discs --- p.52 / Chapter 3.3.2 --- The Relationship between NP T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.52 / Chapter 3.3.3 --- The Relationship between NP T1rho/T2 Values and 5-level Degeneration Grading of Discs --- p.55 / Chapter 3.3.4 --- The Relationship between AF T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.58 / Chapter 3.3.5 --- The Relationship between AF T1rho/T2 Values and 8-level Degeneration Grading of Discs --- p.61 / Chapter 3.4 --- Discussion --- p.64 / Chapter 3.5 --- Summary --- p.69 / Chapter Chapter 4 --- T1rho MRI in rat liver fibrosis model induced by CCl4 insult --- p.71 / Chapter 4.1 --- Introduction --- p.71 / Chapter 4.2 --- Materials and Methods --- p.73 / Chapter 4.2.1 --- Animal Preparation --- p.73 / Chapter 4.2.2 --- MR Image Acquisition --- p.74 / Chapter 4.2.2.1 --- T2-weighted MRI --- p.75 / Chapter 4.2.2.2 --- T1rho MRI --- p.75 / Chapter 4.2.3 --- Data Processing --- p.76 / Chapter 4.2.4 --- Data Measurement and Statistical Analysis --- p.78 / Chapter 4.2.5 --- Histology Analysis --- p.79 / Chapter 4.3 --- Results --- p.80 / Chapter 4.3.1 --- T1rho Measurement Reproducibility --- p.80 / Chapter 4.3.2 --- Rat Liver T1rho Values at Different Time Phase --- p.81 / Chapter 4.3.3 --- Relative Rat Liver Signal Intensity on T2WI at Different Time Phase --- p.83 / Chapter 4.3.4 --- Histology Results --- p.84 / Chapter 4.4 --- Discussion --- p.86 / Chapter 4.5 --- Summary --- p.91 / Chapter Chapter 5 --- T1rho MRI in liver of healthy human subjects --- p.93 / Chapter 5.1 --- Introduction --- p.93 / Chapter 5.2 --- Methods --- p.95 / Chapter 5.2.1 --- Subjects --- p.95 / Chapter 5.2.2 --- MR Image Acquisition --- p.96 / Chapter 5.2.2.1 --- T2-weighted MRI --- p.96 / Chapter 5.2.2.2 --- T1rho MRI --- p.97 / Chapter 5.2.3 --- T1rho Data Processing --- p.99 / Chapter 5.2.4 --- T1rho Measurement --- p.100 / Chapter 5.3 --- Results --- p.102 / Chapter 5.3.1 --- T1rho Measurement Reproducibility --- p.105 / Chapter 5.3.2 --- T1rho Value Agreement of the Fasting Status with Post Meal Status --- p.105 / Chapter 5.3.3 --- T1rho Value Agreement for T1rho Maps Constructed by Different Spin-lock Time Points --- p.106 / Chapter 5.3.4 --- T1rho Value Range of Healthy Human Subjects --- p.108 / Chapter 5.4 --- Discussion --- p.108 / Chapter 5.5 --- Summary --- p.113 / Chapter Chapter 6 --- General discussion and further work --- p.115 / References: --- p.119 / LIST OF PUBLICATIONS --- p.138