Distinct brain regions process innocuous vibration and cutaneous heat pain. The role of these areas in the perception of pain is still a matter of debate; and the role of these areas in the mediation of memory of somatosensory stimuli is uncertain and has not been studied with brain imaging in healthy human volunteers. All experiments described here, involved an experimental design, which included a delayed-discrimination paradigm and functional magnetic resonance imaging (fMRI). In manuscript #1, we aimed at unraveling the cerebral correlates of attention and spatial localization of innocuous vibrotactile stimuli applied to the right volar surface of the forearm. In this study, we report that increased degrees of attention to the vibrotactile stimuli were associated with heightened levels of activation in several brain areas. In manuscript #2, we investigated the short-term memory for sensory aspects (intensity and location) of cutaneous heat pain delivered to two areas (thenar and hypothenar eminences) of the palm of the right hand. In this experiment, the memory and control trials were presented in blocks, whereby the subjects could predict what trials were going to follow. This study revealed that the presentation of painful stimuli evoked activation in different brain regions than those activated during the online maintenance (interstimulus interval or ISI) of the intensity and spatial features of those stimuli; a process, which I will refer to short-term memory. In manuscript #3, we investigated again short-term memory for sensory aspects of heat pain (as in manuscript #2), but in this case, the memory and control trials were presented in a randomized order. In this study, we found that the perception and short-term memory of pain were processed by a comparable network of areas. The predictability of the memory and control trials may have contributed to these findings. / La vibration inoffensive ainsi que la chaleur douloureuse cutanée sont traitées pardifférentes régions du cerveau. Le rôle de ces régions dans la perception de la douleurest controversé; et le rôle de ces régions dans la mémoire des stimuli somatosensorielsest incertain et n'a jamais encore été étudié en imagerie cérébrale chez des sujetshumains sains. Le design expérimental de toutes les études décrites ici comprenait unparadigme de 'delayed-discrimination' et l'imagerie par résonance magnétiquefonctionnelle (IRMf). L'étude #1 visait à élucider les corrélats cérébraux de l'attention etde la localisation spatiale des stimuli vibrotactiles inoffensifs présentés à la faceantérieure de l'avant-bras droit. Dans cette étude, nous avons trouvé que des degrésélevés d'attention portée aux stimuli vibrotactiles étaient associés à des niveaux accrusd'activation dans plusieurs zones du cerveau. Dans l'étude #2, nous avons enquêté surla mémoire à court-terme des caractéristiques sensorielles (intensité et emplacement)de la chaleur douloureuse cutanée présentée à deux endroits (éminences thénar ethypothénar) de la paume de la main droite. Dans cette étude, les essais mémoire etcontrôle étaient présentés en bloc, ou de sorte que les participants pouvaient prévoir dequel type serait le prochain essai. Cette étude a révélé que la présentation des stimulidouloureux a évoqué une activation de différentes régions cérébrales que celles quiétaient activées lors de la rétention de l'intensité et de l'emplacement des stimulationsdurant l'intervalle inter-stimuli (liS); un processus que je qualifierai de mémoire à courtterme.Dans l'étude #3, nous avons également enquêté sur la 'mémoire à court-termedes aspects sensoriels de la chaleur douloureuse (tout comme dans l'étude #2), maisdans ce cas, les essais mémoire et contrôle étaient présentés de façon aléatoire. Danscette étude, nous avons trouvé que la perception de la douleur ainsi que la mémoire àcourt-terme de la douleur étaient traitées par un réseau de régions semblable. Laprévisibilité des essais mémoire et contrôle peut avoir contribué à ce résultat.

While providing non-invasive tissue detection, magnetic resonance imaging (MRI) presently possesses limited sensitivity for protein target recognition. This limitation was addressed for the target beta-galactosidase (beta-gal) by constructing three beta-gal-specific MRI probes. The probes are based on a bipartite design in which a vasoactive moiety known as a diazeniumdiolate (NONOate) is bound to a specifier, specifically galactose. Upon galactose' interaction with beta-gal, the NONOate is cleaved from galactose, and actively generates nitric oxide (NO). The released NO leads to microvascular permeability changes in surrounding tissues affecting localized T1 measurements. These changes serve as a quantitative index of beta-gal detection. The three beta-gal-specific NO-releasing probes constructed include GALPYRNONO, GALPIPNONO and a 'bi-functional' probe, which is similar to the first two but with glucose additionally incorporated so that the third probe may easily cross cellular membranes. Synthesis and characterization of this novel class of MRI probes are described in this work. / Keywords: non-invasive detection, magnetic resonance imaging (MRI), nitric oxide (NO), diazeniumdiolates (NONOates), NO-releasing compounds, novel MRI probes, molecular targets, protein targets, specifier, vasoactive, vasodilation, microvascular permeability, tissue localization, bipartite systems, bifunctional probes, blood-brain barrier, cell membrane trafficking, saccharide-bound NONOates, sugar diazeniumdiolates, glycosylated diazeniumdiolates, galactose, beta-galactosidase, glucose, glucose transporters, thermal & photolytic degradation, half-life optimization, Griess test, rat serum, stability.

Background: Functional magnetic resonance imaging (fMRI) can require extensive preprocessing to minimize noise and maximize signal. There is evidence suggesting that fixed-subject preprocessing pipelines, the current standard in fMRI preprocessing, are suboptimal compared to individual-subject pipelines. Aim: We sought to test if individual-subject preprocessing pipeline optimization, compared to fixed, resulted in stronger and more reliable brain-patterns in episodic recognition. Methodology: 27 young healthy controls were scanned via fMRI while performing forced-choice episodic recognition. Several sets of fMRI preprocessing pipelines were tested and optimized in a fixed and individual-subject manner, using methods outlined by Churchill et al. (2011). Results: Individual-subject pipeline optimization, compared to fixed, significantly increased reproducibility, significantly increased the detection of positively and negatively activated voxels, and resulted in a brain-pattern with significant correlation to a task behavioral measure. Conclusions: Individual-subject pipeline optimization, compared to fixed, led to stronger and more reliable brain-patterns that are significantly correlated with behavior.

Background: Functional magnetic resonance imaging (fMRI) can require extensive preprocessing to minimize noise and maximize signal. There is evidence suggesting that fixed-subject preprocessing pipelines, the current standard in fMRI preprocessing, are suboptimal compared to individual-subject pipelines. Aim: We sought to test if individual-subject preprocessing pipeline optimization, compared to fixed, resulted in stronger and more reliable brain-patterns in episodic recognition. Methodology: 27 young healthy controls were scanned via fMRI while performing forced-choice episodic recognition. Several sets of fMRI preprocessing pipelines were tested and optimized in a fixed and individual-subject manner, using methods outlined by Churchill et al. (2011). Results: Individual-subject pipeline optimization, compared to fixed, significantly increased reproducibility, significantly increased the detection of positively and negatively activated voxels, and resulted in a brain-pattern with significant correlation to a task behavioral measure. Conclusions: Individual-subject pipeline optimization, compared to fixed, led to stronger and more reliable brain-patterns that are significantly correlated with behavior.

Cirrhosis is a leading cause of death in the United States and has severe and costly complications. Because of the clinical significance of cirrhosis, it is important that noninvasive methods be developed to detect cirrhosis early and to monitor its progression with advancing liver disease. Previous studies on portal venous hemodynamics have been performed mainly with ultrasound with mixed results. Magnetic Resonance Imaging offers several advantages over ultrasound including acquisition of both high quality anatomical and hemodynamic information. Phase-Contrast MR was used to gather velocity data for the portal venous system. Methods were developed to perform registration, segmentation and isolation of the portal vein geometries and velocity data. Computational Fluid Dynamics was also employed to further investigate the flow within the portal vein. Velocity data for the portal vein, superior mesenteric vein, splenic vein and the right or left portal vein was acquired in varying numbers for both data sets. Even with the limited number of subjects a few parameters were significant. Patients with cirrhosis had a significantly increased portal vein area and a significantly decreased average velocity per liver volume and velocity variance. Patients with cirrhosis had a significantly increased splenic vein area and average flow rate per liver volume. While these results are preliminary due to small sample size, they are promising and require further investigation and more subjects including varying stages of disease.

The non-invasive cardiovascular imaging modalities, cardiovascular magnetic resonance (CMR) and multi-detector computer tomography (MDCT) are playing an increasing role in both clinical and research settings. CMR is a unique imaging modality due to unsurpassed contrast between soft tissue structures that is non-invasive, does not use ionising radiation and is able to provide high-resolution information about cardiac anatomy, function, flow, perfusion, viability and metabolism. It has provided the gold standard in imaging in congenital heart disease. Recent advances in this technology have led to images of high spatial and temporal resolution that has made the characterisation of atheroma possible. While currently spatial resolution still limits its ability to characterise atheroma in native human coronary arteries in living patients, CMR imaging of the coronary arteries has future potential with further technological and sequence advances. MDCT has been used in clinical settings to measure of the amount of calcification in the coronary arteries with “coronary artery calcium scoring” of the coronary tree a surrogate marker of atherosclerosis. MDCT has also become the gold standard for angiographic imaging in most arterial beds such as the carotid and peripheral vascular systems. In the coronary arteries in particular, there have been major advances in the accuracy of coronary MDCT angiography, particularly with regards to its negative predictive value, although excessive calcification and blooming artefacts still limit the diagnostic accuracy of the technique for assessing stenotic severity. In this thesis, our aims were to address some specific novel areas advancing the utility of these imaging modalities in two major areas of interest, namely congenital heart disease and atheroma imaging. Our first step was to validate the accuracy and reproducibility of CMR, the main imaging modality we utilised. To achieve this, we assessed MR imaging of cardiac volumes and function in a normal adult Australian population with a specific focus on the reproducibility of the technique. In confirming that this technique in our hands is both accurate and reproducible, we would then be in a position to be able to confidently use this technique in our future chapters. However, more than this, we sought to establish some normal ranges for left and right atrial and ventricular parameters in our local population. This would be crucial background information for us to be able to make comparisons with future studies in patients with congenital heart disease. Having established our technique and reference ranges, we would then explore the two specific issues in the ensuing two chapters using CMR in one area of congenital heart disease, atrial septal defect. Atrial septal defect is the most common congenital heart defect first diagnosed in adults. The traditional method of assessment of these patients and for suitability for ASD closure involves semiinvasive investigation with transoesophageal echocardiography (TOE) for measurement of the defect size and atrial septal margins. MRI assessment of patients prior to percutaneous device closure compared to TOE assessment would provide information on the accuracy of TOE assessment and provide information of the utility of cardiac MRI as an alternative to TOE for the work-up of these patients prior to ASD closure. In our third original research chapter, we utilised CMR to understand the effects of percutaneous ASD closure on cardiac chamber volumes. We achieved this by assessing with cardiac MRI pre-closure and post-closure atrial and ventricular cardiac volumes. Longstanding right heart dilatation in the setting of an ASD may lead to complications including right heart failure, pulmonary hypertension and arrhythmia. Closure of the ASD should reduce right heart volumes by removing left-to-right shunting and lead to normalisation of ventricular volumes. The assessment of atrial volume changes with ASD closure may be important in furthering our understanding in its contribution to arrhythmia. Having assessed the ability of CMR to assess both the ASD dimensions, and therefore suitability for percutaneous closure, as well as the effects of ASD closure on cardiac chamber size, we look in the final two original research chapters to move to another area of research development with these highresolution imaging technologies, atherosclerosis imaging. Two particular areas we wished to focus on included the potential of high-resolution MR imaging to monitor effects of HDL infusion on atherosclerosis, and secondly to explore mechanisms behind limitations in MDCT imaging of atherosclerosis, specifically calcification and blooming artifacts. For assessing the effects of HDL infusion on atherosclerosis, we utilised a cholesterol-fed rabbit model of atherosclerosis. The abdominal aorta of the rabbit is comparable in size to the human coronary artery. Previous work with the rabbit model of atherosclerosis and magnetic resonance imaging of the aortic wall has shown that it can provide information about atherosclerotic composition as well as provide serial data of the arterial wall. While high intensity lipid-lowering with statins remains the first line management of at risk individuals, modest manipulations of serum HDL levels are associated with a significant impact on cardiovascular risk. Thus, we assessed the effect of HDL infusion and atorvastatin in a rabbit model of using MRI aortic atherosclerosis as the endpoint. In our fifth and final original research chapter, we assessed the accuracy of quantification of atherosclerotic calcification with MDCT in the carotid arteries of patients undergoing carotid endarterectomy, and sought to identify algorithms or techniques that may improve quantification of calcification. This would potentially lead to an improvement in the ability of MDCT techniques to quantify stenotic severity in coronary arteries that were calcified. To achieve these we utilised MDCT in vivo and in comparison with carotid endarterectomy specimen micro-CT. Importantly, as part of this study, we undertook a thorough assessment of reproducibility of these techniques. Thus, in summary, we have been able to confirm the accuracy and reproducibility of CMR and MDCT in the areas of a specific congenital defect (ASD) and atherosclerosis imaging, and utilised these techniques to advance our understanding of these disease states. This thesis identifies strengths and weaknesses of these techniques that will allow us to more appropriately use them for future purposes in cardiovascular disease. Future work directly stemming from this thesis has already begun, and now looks to address issues of whether CMR and MDCT may provide complimentary information about atherosclerotic lesions that may benefit outcomes in certain conditions. Specifically the work in this thesis has led to studies commencing in carotid atherosclerosis and saphenous vein graft atherosclerosis and using these imaging techniques to potentially predict adverse future outcomes. / Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2008

[Truncated abstract] Clinical magnetic resonance imaging (MRI) scanners were used to investigate the measurement and imaging of ferrimagnetic particle concentrations in biological tissues in vivo. The presence of ferrimagnetic particles tends to increase the proton transverse relaxation rate (R2) of water protons in tissue. A quantitative image of R2 can be generated using a series of single spin echo magnetic resonance images acquired using clinical MRI scanners and analysing the images using techniques based on that reported by Clark and St. Pierre (2000). If ferrimagnetic particles have a high enough concentration, there is a monotonic relationship between particle concentration and R2; therefore an image of R2 gives a map of the ferrimagnetic particle concentration in the tissue. These techniques were used to investigate the feasibility of in vivo measurement of the concentration and distribution of both synthetic and biogenic ferrimagnetic particles in tissue. Rabbit liver was loaded with ferrimagnetic particles of ?-Fe2O3 (designed for magnetic hyperthermia treatment of liver tumours) by injecting various doses of a suspension of the particles into the hepatic artery in vivo. R2 images of the livers in vivo, excised, and dissected were generated from a series of single spin-echo images. Mean R2 values for samples of ferrimagnetic-particle-loaded liver dissected into approximate 1 cm cubes were found to linearly correlate with tissue iron concentration over the range from approximately 0.1 to at least 2.7 mg Fe/g dry tissue when measured at room temperature. Changing the temperature of ferrimagnetic-particle-loaded samples of liver from 1?C to 37?C had no observable effect on tissue R2 values. However, a small but significant decrease in R2 was found for control samples containing no ferrimagnetic material on raising the temperature from 1?C to 37?C. Both chemically measured iron ii concentrations and mean R2 values for rabbit livers with implanted tumours tended to be higher than those measured for tumour-free liver. This study indicates that tissue R2 measurement and imaging by nuclear magnetic resonance may have a useful role in magnetic hyperthermia therapy protocols for the treatment of liver cancer. In order to investigate the use of clinical MRI scanners to measure biogenic ferrimagnetic particle concentrations in human brain tissue, agar gel based phantoms containing ferrimagnetic particles were made in order to determine the lower concentration detection limit for such particles in a homogenous medium. Magnetite/maghemite nanoparticles were synthesized in the presence of either dextran or polyvinyl alcohol, yielding cluster- and necklace-like aggregates, respectively. Magnetization, Mossbauer spectroscopy, and microscopy measurements indicated that the arrangement of the particles within the aggregates affects the magnetic properties of the particles resulting in smaller particles in the clusters having higher superparamagnetic blocking temperatures than larger particles in the necklaces.

Magnetic resonance imaging (MRI) has increasingly become the preferred imaging modality in modern day research to study disease. MRI presents an imaging technique that is practically non-invasive and without any ionizing radiation. This dissertation presents the use of contrast agents in MRI studies to differentiate compartments, to study dose dependence of relaxation times, and to characterize tumors using signal amplifying enzymes in the brain. Differentiating compartments in the brain can be useful in diffusion studies to detect stroke at an early stage. Diffusion-weighted NMR techniques have established that the apparent diffusion coefficient (ADC) of cerebral tissue water decreases during ischemia. However, it is unclear whether the ADC change occurs due to changes in the intracellular (IC) space, extracellular (EC) space, or both. To better understand the mechanism of water ADC changes in response to ischemic injury, making IC and EC compartment specific measurements of water diffusion is essential. The first study was done where manganese (Mn2+) was used as an IC contrast agent. Mn2+ uptake by cells causes shortening of the T1 relaxation time of IC water. The relative difference in T1 relaxation times between the IC and EC compartments can be used to discriminate between the MR signals arising from water in the respective compartments. Mn2+ is also widely used in manganese-enhanced MRI (MEMRI) studies to visualize functional neural tracts and anatomy in the brain in vivo. In animal studies, the goal is to use a dose of Mn2+ that will maximize the contrast while minimizing its toxic effects. The goal of dose study was to investigate the MRI dose response of Mn2+ in rat brain following SC administration of Mn2+. The dose dependence and temporal dynamics of Mn2+ after SC injection can prove useful for longitudinal in vivo studies that require brain enhancement to persist for a long period of time to visualize neuroarchitecture like in neurodegenerative disease studies. Contrast agents, in addition to their use in compartmental differentiation and dose studies, can be used for imaging tumors. The last study in this dissertation focuses on imaging EGF receptors in brain tumors. We tested a novel pretargeting imaging approach that includes the administration of humanized monoclonal antibody (anti-EGFR mAb, EMD72000) linked to enzymes with complementing activities that use a low-molecular weight paramagnetic molecule (diTyr-GdDTPA) as a reducing substrate administered following the mAb conjugates. We analyzed the differential MR tumor signal decay in vivo using orthotopic models of human glioma. The patterns of MR signal change following substrate administration revealed differences in elimination patterns that allowed distinguishing between non-specific and specific modes of MR signal decay.

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