This paper deals with the effect of the MR pulse sequences on the temperature of the measured object. The theoretical part is dedicated to basic principle of magnetic resonance, the selected pulse sequences and risks that are connected with MRI. There is also described the draft of the testing phantom and information about the measurement and record of temperature during MR measurement. In the experimental part the effect of RF coils, pulse sequences and parameters of pulse sequences are tested on drafted phantom with experimental MR device located at the Institut of Scientific Instruments of the AS CR in Brno. These findings are then tested on live laboratory mouse. All results are analyzed and used as default data for developed simulation program.

An MRI’s superior soft tissue contrast and ability to perform parametric scanning make it a powerful tool for use during medical procedures; from surgery to rehabilitation. However, the MRI’s strong static magnetic field, fast switching gradients and constrained space make accomplishing procedures within it difficult. Recent advances in the field of robotics have enabled the creation of devices capable of assisting medical practitioners in this environment. In this work, technologies to enable the use and control of robotic assistive devices for MRI interventions are presented. This includes a modular controller that is designed, built and used to control two surgical systems with minimal effect on image quality. Progressive improvements to an MRI conditional actuator including the construction of a first of a kind plastic piezoelectric resonant motor stator that improves the motor’s compatibility with the MRI is presented. Finally, control algorithms are evaluated for real-time functional MRI based control of a rehabilitation robot which includes the use of a robot for controlling brain activity of a subject in an online experiment.

L'imagerie par résonance magnétique dynamique (IRM-dynamique) consiste en l'observation de la distribution dans le temps d'un agent de contraste à l'aide de l'IRM. L'une des approches très répandues est d'analyser les données à l'aide de modèles mathématiques qui décrivent la pharmacocinétique de cet agent dans les tissus. L'une des hypothèses utilisées par l'ensemble des modèles présentés dans la littérature à ce jour est que les images d'IRM-dynamique peuvent être analysées pixel-par-pixel ce qui néglige implicitement la possibilité de diffusion de l'agent à l'intérieur des tissus. Dans ce mémoire, un nouveau modèle est proposé dans lequel la diffusion de l'agent est explicitement incluse dans un modèle à deux compartiments. Les deux paramètres couramment utilisés dans la littérature sont : K[indice supérieur trans] , le taux de transfert transcapillaire, et [nu]e, la fraction de volume extravasculaire extracellulaire. Deux méthodes d'optimisation stochastique ont été évaluées pour le lissage avec le modèle proposé à cause de la très grande taille de l'espace des solutions. Le modèle a été caractérisé avec des données simulées incluant la diffusion de l'agent de contraste et des données expérimentales montrant des signes de diffusion à l'intérieur du tissu tumoral. Les résultats avec les données simulées montrent que le modèle peut retrouver de façon fiable les valeurs des paramètres utilisés pour générer ces données (erreur relative moyenne de 16% pour K trans et 17% pour [nu]e) même lorsqu'un niveau de bruit raisonnable est ajouté. Le modèle standard à deux compartiments négligeant la diffusion retourne des distributions de valeurs de K[indice supérieur trans] erronées (erreur relative moyenne de 43%) qui sont moyennée sur le tissu. Lorsque les données expérimentales sont ajustées avec le modèle standard, les valeurs de K[indice supérieur trans] retournées montrent une perfusion moyennée sur l'ensemble du tissu, ce qui n'est pas en accord avec le rehaussement initial du signal qui est observé. À l'opposé, le modèle proposé retourne des cartes de K[indice supérieur trans] ayant une démarcation franche entre les zones bien perfusées et celles très peu perfusées en accord avec ce qui est observé sur les images d'IRM. De plus, le modèle standard à deux compartiments assigne des valeurs n'ayant pas de sens physique à [nu]e ([nu]e [supérieur à] 1) dans le centre des tumeurs où l'agent parvient par diffusion à partir de la périphérie bien vascularisée. De son côté, le modèle proposé trouve des valeurs plausibles de [nu]e pour l'ensemble du tissu.

Electroconvulsive therapy (ECT) is used worldwide to treat severe mental disorders. The most common mental disorder, and the third leading cause of disease burden in the world is depression. The clinical efficacy of ECT for severe depression is well-established. However, both the pathophysiology of depression and the mechanism of action of ECT remain elusive. The main aims of this thesis are to address the following issues: 1) the use and practice of ECT in Sweden has not been systematically evaluated since 1975, 2) cognitive side-effects (memory disturbances) are a major concern with ECT and 3) the mechanism of action of ECT remain elusive. The neurobiological aspects of ECT focus on two hypotheses. First, the recent years´ preclinical studies that have provided evidence that ECT induces hippocampal cell proliferation, including neurogenesis. Second, that enhanced functional inhibition of neuronal activity is a key feature. Current use and practice of ECT in Sweden (paper I) is based on data from the national quality register for ECT, the mandatory patient register of the National Board of Health and Welfare and a survey. Treated person rate (TPR) in Sweden 2013 was found to be 41 individuals / 100 000, and thus unchanged since the latest systematic investigation in Sweden 1975. In more than 70% of treatment series the indication was a depressive episode. The selection of patients for ECT and treatment technique in Sweden was similar to that in other western countries, but the consent procedure and the involvement of nurses and nursing assistants in the delivery of ECT differ. Data also shows that there is room for improvement in both the specificity of use and availability of ECT. The second study in this thesis is a longitudinal observational trial where 12 (paper II and III) and 14 (paper IV) patients with depression referred for ECT were investigated. Patients underwent a 3 T MRI structural scanning and DSC-MRI perfusion, a neuropsychological test battery and clinical ratings before ECT, within one to two weeks after ECT and after 6 and 12 months.  In line with preclinical findings and the plasticity hypothesis of mechanism of action of ECT, the hippocampal volume increased after ECT in patients with depression. However, this increase was transient and returned to baseline levels within 6 months. No correlation was found between volumetric changes and clinical effect or cognitive outcome. Instead our results suggested an association to the number of treatments, without relation to the side of stimulation. A right-sided decrease in frontal blood flow distinguished remission from non-remission after ECT. There were significant impairments in verbal episodic memory and verbal fluency within one week after ending the ECT course, but these impairments were transient and no persistent cognitive impairments were seen during the follow-up. In summary, this thesis present the first update on the use and practice of ECT in Sweden in the last 40 years as well as a pioneering MRI-study on the hippocampal volume increase in the treatment of depression with ECT. Supportive to earlier findings we also found the cognitive side-effects that are measurable after ECT to be transient. Furthermore, we found that a decreased frontal blood flow is of importance for the anti-depressive response to ECT.

Background Superparamagnetic particles of iron oxide (SPIO) are part of a novel and exciting class of ‘smart’ magnetic resonance imaging (MRI) contrast agents that are taken up by inflammatory cells. Ultrasmall SPIO (USPIO; ~30 nm diameter) can be used to assess cellular tissue inflammation and SPIO (80-150 nm) have the potential to be used to label cells ex vivo for in vivo cell tracking studies. Objectives The aims of the thesis were therefore (i) to develop and validate quantitative MRI methodology for assessing SPIO uptake within tissues, (ii) to demonstrate USPIO accumulation within the aortic wall and its implications in patients with abdominal aortic aneurysms (AAA), and (iii) to develop and apply a Good Manufacturing Practice (GMP) compliant method of SPIO cell labelling in healthy volunteers. Methods Patients with asymptomatic AAA >4.0 cm in diameter were recruited. Imaging sequences were optimised in eight patients using a 3 tesla MRI scanner. Data were analysed using the decay constant for multi echo T2* weighted (T2*W) sequences (T2*) or its inverse (R2*) and the repeatability of these measurements was established. A further twenty-nine patients underwent MRI scanning before and 24- 36 hours after administration of USPIO. T2 and multi echo T2*W sequences were performed and ultrasound-based growth rate data were collected. Operative aortic wall tissue samples were obtained from patients undergoing open surgical aneurysm repair. A GMP compliant protocol was developed for labelling cells with SPIO for clinical cell tracking studies. The effects of SPIO-labelling on cell viability and function were assessed in vitro. A phased-dosing protocol was used to establish the safety of intravenous administration of SPIO-labelled cells in healthy volunteers. The feasibility of imaging cells at a target site in vivo following local or systemic administration was assessed. Tracking of SPIO-labelled cells to a target site was investigated by inducing an iatrogenic inflammatory focus in the skin of the anterior thigh of healthy volunteers, following which autologous SPIO-labelled cells were administered and their accumulation was assessed using MRI scanning and histology of skin biopsies. Results Robust and semi-quantitative data acquisition and image analysis methodology was developed for the assessment of SPIO accumulation in tissues. In patients with AAA, histological analysis of aortic wall tissue samples confirmed USPIO accumulation in areas of cellular inflammation. USPIO-enhanced MRI detected aortic wall inflammation and mural USPIO uptake was associated with a 3-fold higher aneurysm expansion rate. Human mononuclear cells were labelled with SPIO under GMP compliant conditions without affecting cell viability or function. Both local and intravenous administration of SPIO-labelled cells was safe and cells were detectable in vitro and in vivo using a clinical MRI scanner. SPIO-labelled cells tracked to a focal iatrogenic inflammatory focus following intravenous administration in humans and were detectable on MRI scanning and histological examination of skin biopsies. Conclusions SPIO contrast agents have an extensive range of potential clinical applications. USPIO uptake in the wall of AAA appears to identify cellular inflammation and predict accelerated aneurysm expansion. This is therefore a promising investigative tool for stratifying the risk of disease progression in patients with AAA, and may also be considered as a biomarker for response to novel pharmacological agents. The ability to label cells for non-invasive cell tracking studies would facilitate the further development of novel cell-based therapies and would enable assessment of dynamic inflammatory processes through inflammatory cell tracking.

As humans age, specific mental faculties deteriorate even in the absence of dementia. Age related cognitive decline affects quality of life, and has significant implications from a socio-economic perspective; however not everyone declines to equal degrees, at equal rates, or from the same baseline. This PhD examined a large sample of community-dwelling older adults called the Lothian Birth Cohort 1936, most of whom completed an intelligence test at age 11 years, and again around age 73 as part of a detailed assessment that also included detailed brain magnetic resonance imaging (N range = 700-866). I investigated the independent effects of two linked genetic loci which have been associated with greater risk of Alzheimer’s disease – the APOE ε haplotype (commonly ‘genotype’) and a poly-T repeat in the TOMM40 gene. Are 'risk' variants in these loci associated with specific measures of cognitive ageing and brain structure - specifically white matter microstructural integrity, hippocampal volumes, white matter lesions or cerebral microbleeds – in this sample? Firstly, a pilot study aimed to replicate significant associations between the ADRB2 gene and brain imaging/cognitive phenotypes, that had previously been reported in a smaller subsample of the cohort that had by that time undergone MRI (n = 132). Previously reported significant associations were not significant in the larger, full LBC1936 sample (n = 700-866), but novel significant associations were found (P < 0.05). Specifically, integrity of the left arcuate fasciculus white matter tract significantly mediated part of the association between specific genetic variations at ADRB2, and the Digit Symbol Coding task of information processing speed. These findings indicated that this approach – testing three-way genetic/brain imaging/cognitive associations for mediation - was viable for the main APOE/TOMM40 analyses. Results in the main APOE/TOMM40 analyses showed that specific variants in the APOE and TOMM40 gene loci were statistically significantly associated (at raw P value <0.05) with white matter tract microstructural integrity, but not white matter lesions, hippocampal volume or cerebral microbleeds. Inconsistencies with previous, positive reports showing significant associations between APOE ε and these latter phenotypes may reflect a degree of type 1 error or more study-specific discrepancies (which are detailed throughout). APOE ε was significantly associated with average scores on a large proportion of cognitive tests, independent of age 11 intelligence (i.e. ‘cognitive ageing’; Deary et al., 2004). These associations were partly – but not completely – mediated by white matter tract microstructural integrity. TOMM40 poly-T repeat genotype was associated with cognitive ageing to a much lesser extent. A range of brain phenotypes may form the anatomical basis for significant associations between APOE genotype and cognitive ageing, among which includes white matter tract microstructural integrity.

While diffusion MRI promises an insight into white matter microstructure in vivo, the axonal pathways that connect different brain regions together can only partially be segmented using current methods. Here we present a novel method for estimating the tissue composition of each voxel in the brain from diffusion MRI data, thereby providing a foundation for computing the volume of different pathways in both health and disease. With the tissue dependent diffusion model described in this thesis, white matter is segmented by removing the ambiguity caused by the isotropic partial volumes: both grey matter and cerebrospinal fluid. Apart from the volume fractions of all three tissue types, we also obtain estimates of fibre orientations for tractography as well as diffusivity and anisotropy parameters which serve as proxy indices of pathway coherence. We assume Gaussian diffusion of water molecules for each tissue type. The resulting three-tensor model comprises one anisotropic (white matter) compartment modelled by a cylindrical tensor and two isotropic compartments (grey matter and cerebrospinal fluid). We model the measurement noise using a Rice distribution. Markov chain Monte Carlo sampling techniques are used to estimate posterior distributions over the model’s parameters. In particular, we employ a Metropolis Hastings sampler with a custom burn-in and proposal adaptation to ensure good mixing and efficient exploration of the high-probability region. This way we obtain not only point estimates of quantities of interest, but also a measure of their uncertainty (posterior variance). The model is evaluated on synthetic data and brain images: we observe that the volume maps produced with our method show plausible and well delineated structures for all three tissue types. Estimated white matter fibre orientations also agree with known anatomy and align well with those obtained using current methods. Importantly, we are able to disambiguate the volume and anisotropy information thus alleviating partial volume effects and providing measures superior to the currently ubiquitous fractional anisotropy. These improved measures are then applied to study brain differences in a cohort of healthy volunteers aged 25-65 years. Lastly, we explore the possibility of using prior knowledge of the spatial variability of our parameters in the brain to further improve the estimation by pooling information among neighbouring voxels.

The in vivo detection of enzyme activity is a significant biomarker in tumorigenesis. Assessment of enzyme activity relative to enzyme concentration can serve as quite an accurate measurement of several disease states. Chemical Exchange Saturation Transfer (CEST) MRI is a non-invasive imaging technique that can be used to evaluate enzyme activity. Compared to other contrast agents CEST MRI agents have a slower chemical exchange rate and thus have greater specificity for detecting the intended biomarker. Chapter 1 provides an overview of the advances made in the field of molecular imaging for detection of cancer biomarkers. The molecular mechanism of each technique is explained with specific examples and advantages as well as disadvantages of each technique. Chapter 2 investigates the specific example of detection of an enzyme, γ-glutamyl transferase (GGT) in ovarian cancer tumor models using a catalyCEST MRI contrast agent. This chapter discusses the step-by step evaluation of the non-metallic contrast agent, from synthesis to evaluation of its catalytic efficiency with Michaelis Menten kinetics studies and finally in vivo GGT detection in ovarian tumor models of OVCAR-8 and OVCAR-3. Chapter 3 investigates the enzyme, Kallikrein-6 and its detection in HCT116 colon cancer tumor model. In addition to enzyme detection, enzyme inhibition using Antithrombin III inhibitor has also been explored within in vitro media and in vivo HCT116 tumor model. Chapter 4 introduces the catalyCEST agent for detection of sulfatase enzyme. This chapter discusses the synthesis of this agent and its ability to detect sulfatase in bacterial cell suspension and mammalian cell suspension. These examples portray catalyCEST MRI as a platform technology for enzyme activity detection. Finally in Chapter 5 future ideas have been proposed to improve the in vivo detection and broaden the applications of catalyCEST MRI in the field of enzyme studies.

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