The purpose of this experiment is to study as a model the gelation phase transition of agarose solutions with transverse relaxation (T2) quantitative magnetic resonance imaging (qMRI). The focus is on the reduction of T2 of agarose solution upon gelation. The sol-to-gel phase transition of agarose may provide a useful and controllable experimental model of tissue formation. Furthermore, it may provide the basis for exact mathematical models useful for understanding the much reduced transverse relaxation times (T2) observed in solid tissues relative to simple liquids. In this context, the purpose of this work was to monitor dynamically with T2 quantitative MRI the liquid-to-gel phase transition of pure agarose as a function of gel concentration. Samples of agarose at various concentrations were allowed to cool down while scanning dynamically with T2 qMRI, 32 x 10milliseconds (ms) echoes, CarrPurcell-Meiboom-Gill (CPMG), 3Tesla.T2 versus; (temperature).curves of each agarose solution show a distinct phase transition region characterized by a sharp T2 reduction. Four agarose solutions were sequentially prepared by dissolving agarose powder in distilled water at concentrations of 1%, 2%, 3%, and 4% by weight/volume. Immediately after preparation and boiling at 98°C, each liquid agarose solution was poured into a plastic container and scanned dynamically at 3.0T as it cooled down with a whole body MRI scanner (Achieva, Philips Medical Systems, Cleveland, OH). A single axial slice multi spin echo CPMG pulse sequence with the following parameters was used: 32 echoes, 10ms echo spacing, 1.5s repetition time (TR), 160 x 160 matrix size, and 2 SENSE factor. The time per dynamic scan was 1minute. The DICOM images were further processed with an adaptive T2 qMRI algorithm programed in Mathcad (Parametric Technology Corporation, Needham, MA) whereby the number of echoes used in the semi-logarithmic linear regression varies automatically from pixel to pixel depending on noise level. The T2 values of agarose gels have been measured during the entire gelation phase transition process at four different concentrations. The T2 versus time (temperature) curves of all the four concentrations shows a rapid drop at about 24 minutes (T~40°C) at which time the gelation phase transition begins. At all temperatures, T2 decreases as a function of increasing agarose concentration. The data shows similar behaviors for all concentrations with a phase transition characterized by a drastic drop in T2 occurring while the temperature drops by approximately 8°C. These results may be useful for testing theoretical models of the Nuclear Magnetic Resonance (NMR) T2 relaxation properties during tissue formation. Quantitative magnetic resonance imaging (qMRI) differs sharply from conventional directly acquired MRI in that objective measures [such as the trio of the basis MR properties: longitudinal relaxation (T1), T2 and Proton Density (PD)] are used for analysis as well as further post-processing rather than relative signal intensities. Q-MRI portrays the spatial distribution of absolute biophysical parameter measurements on a pixel-by-pixel basis; Kevin J. Chang et al 2005

Yes / Background: Skeletal muscles undergo changes with ageing which can cause sarcopenia that can result in frailty. Quantitative MRI may detect the muscle-deficit component of frailty which could help improve the understanding of ageing muscles. Aims: To investigate whether quantitative MRI measures of T2, fat fraction (FF), diffusion tensor imaging and muscle volume can detect differences within the muscles between three age groups, and to assess how these measures compare with frailty index, gait speed and muscle power. Methods: 18 ‘young’ (18–30 years), 18 ‘middle-aged’ (31–68 years) and 18 ‘older’ (> 69 years) healthy participants were recruited. Participants had an MRI of their dominant thigh. Knee extension and flexion power and handgrip strength were measured. Frailty (English Longitudinal Study of Ageing frailty index) and gait speed were measured in the older participants. Results: Young participants had a lower muscle MRI T2, FF and mean diffusivity than middle-aged and older participants; middle-aged participants had lower values than older participants. Young participants had greater muscle flexion and extension power, muscle volume and stronger hand grip than middle-aged and older participants; middle-aged participants had greater values than the older participants. Quantitative MRI measurements correlated with frailty index, gait speed, grip strength and muscle power. Discussion: Quantitative MRI and strength measurements can detect muscle differences due to ageing. Older participants had raised T2, FF and mean diffusivity and lower muscle volume, grip strength and muscle power. Conclusions: Quantitative MRI measurements correlate with frailty and muscle function and could be used for identifying differences across age groups within muscle. / JDB is funded by a National Institute for Health Research (NIHR) (and Health Education England) Clinical Lectureship. This paper presents independent research funded/supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC). AC and LB are funded as part of the NIHR Collaboration for Leadership in Applied Health Research and Care, Yorkshire and Humber (NIHR CLAHRC YH).

Résumé : Imager la vascularisation cérébrale de la manière la plus exacte, précise et rapide possible représente un enjeu important pour plusieurs domaines de recherche. En plus d’aider à mieux comprendre le fonctionnement normal du cerveau, cela peut servir à caractériser diverses pathologies ou à développer de nouveaux traitements. Dans un premier temps, ce mémoire présente l’optimisation d’une technique d’angiographie cérébrale in vivo chez un modèle animal fréquemment utilisé, la souris. La technique emploie une séquence d’imagerie par résonance magnétique (IRM) 3D pondérée en susceptibilité ainsi qu’un agent de contraste, le Resovist. Les paramètres d’acquisition à l’IRM ont été optimisés à l’aide d’images acquises avant l’injection du Resovist. Ces paramètres permettent d’imager le cerveau entier en 41 minutes avec une résolution de 78 × 78 × 104 μm3. L’emploi d’une pondération en susceptibilité offre une excellente sensibilité aux petits vaisseaux (diamètre ≃ 40μm). L’analyse des images permet d’extraire des informations sur la morphologie vasculaire. Dans un second temps, la méthode de l’acquisition compressée (AcqC) a été implémentée dans le but d’accélérer l’acquisition des images angiographiques. La méthode de l’AcqC utilise des hypothèses de compressibilité des images pour diminuer la quantité de données acquise. L’AcqC a jusqu’à présent principalement été développée pour des images réelles (au sens des nombres complexes). Or, les images angiographiques obtenues présentent d’importantes variations de phase en raison de la pondération en susceptibilité. La présence de ces variations diminue d’une part la force des hypothèses de compressibilité habituelles et rend d’autre part l’espace-k moins propice au sous-échantillonnage requis par l’AcqC. En raison de ces deux facteurs, l’AcqC standard s’avère inefficace pour accélérer l’acquisition des images angiographiques acquises. Leur mise en lumière suggère cependant différentes pistes pour améliorer l’AcqC appliquée aux images comportant d’importantes variations de phase. / Abstract : Imaging neurovasculature with highest exactitude, precision and speed is of critical importance for several research fields. Beside providing an insight on normal brain activity, it can help characterize numerous pathologies or develop novel treatments. This thesis presents in its first part the optimization of a cerebral angiographic in vivo technique in a frequently used animal model, the mouse. The technique uses both a 3D magnetic resonance imaging (MRI) susceptibility weighted sequence and a strongly paramagnetic contrast agent, Resovist. MRI acquisition parameters were optimized using images acquired before contrast agent injection. Those parameters allow whole brain vascular imaging of the mouse brain in 41 minutes with a 78 × 78 × 104 μm3 resolution. Susceptibility weighting offers an excellent detection sensitivity for small vessels (diameter ≃ 40μm). Image treatment and analysis allow the extraction of vascular morphological information such as vessel size and vessel density. In the second part of this thesis, an attempt to accelerate angiographic images acquisition using the compressed sensing (CS) method is presented. CS method aims at reducing the acquired data by using compressibility hypothesis on images. Presently, CS is mainly developped for real images (within the meaning of complex numbers). However, the previously obtained angiographic images contain important phase variations due to the susceptibility weighting. First, those variations reduce the strength of the compressibility hypothesis normally used in CS. Second, those same variations make information distribution in k-space less appropriate for the undersampling required by CS. For those reasons, standard CS does not allow significant acceleration of the acquisition process for the presented angiographic technique. Studying those reasons however suggests new ways to increase CS efficiency when applied to images with important phase variations.

The work presented in this dissertation involves the development of parametric magnetic resonance imaging (MRI) techniques that can be used in a clinical set up. In the first chapter an introduction of basic magnetic resonance physics is given. The introduction covers the source to tissue magnetization, the origin of the detectable signal, the relaxation mechanisms, and the imaging principles. In the second chapter T₂ estimation - the main parametric MRI technique addressed in this work - is introduced and the problem associated with T₂ estimation from highly undersampled fast spin-echo (FSE) data is presented. In Chapter 3, a novel model-based algorithm with linearization by principal component analysis (REPCOM) is described. Based on simulations, physical phantom and in vivo data, the proposed algorithm is shown to produce accurate and stable T₂ estimates. In Chapter 4, the concept of indirect echoes associated with the acquisition of FSE data is introduced. Indirect echo correction using the extended phase graph approach is then studied for standard sampled data. A novel reconstruction algorithm (SERENADE) is presented for the reconstruction of decay curves with indirect echoes from highly undersampled data. The technique is evaluated using simulations, physical phantom and in vivo data; decay curves with indirect echoes are shown to be accurately recovered by this technique. Chapter 5 is dedicated to correcting the partial volume effect (PVE) in T₂ estimation. For the case of small lesions within a background tissue, PVE affects T₂ estimation which in turn affects lesion classification. A novel joint fitting algorithm is proposed and compared to conventional fitting algorithms using fully sampled spin-echo (SE) images. It is shown that the proposed algorithm is more accurate, robust, and insensitive to region of interest drawing than the conventional fitting algorithms. Because the acquisition of fully sampled SE images is long, the technique is combined with a thick refocusing slice approach in order to be able to use undersampled FSE data and reduce the acquisition time to a breath hold (~ 20 s). The final chapter summarizes the results presented in the dissertations and discusses areas for future work.

Dans cette thèse, nous avons proposé deux modèles multi-compartiments en IRM de relaxométrie T2 (MCT2) fournissant des informations sur la microstructure des tissus cérébraux. Trois compartiments de relaxométrie T2 ont été considérés dans chaque voxel représentant des tissus avec des temps de relaxation T2 courts, T2 moyens et T2 élevés. La complexité associée à l'estimation des paramètres de tels modèles paramétriques a ensuite été explorée. Le premier modèle MCT2 que nous avons proposé a estimé la représentation fractionnelle de compartiments T2 prédéfinis. Dans le second modèle, les représentations fractionnaires et le paramètre de relaxation moyenne ont été estimés pour le compartiment T2 moyen. Dans les deux modèles, le choix de l'approche était justifié par une analyse de la fonction de coût et un cadre d’estimation a été proposé. Le modèle MCT2 a été utilisé pour deux applications. Dans la première application, l’évolution des biomarqueurs de MCT2 a été étudiée dans les lésions de sclérose en plaques (SEP) présentant une prise de contraste gadolinium (Gd) ou non chez 10 patients présentant un syndrome cliniquement isolé. La seconde application a démontré le potentiel de combinaison des biomarqueurs MCT2 avec les informations de microstructure dérivées de l'IRM de diffusion pour identifier les régions présentant une prise de contraste Gd dans les lésions de SEP. Les résultats montrent que les biomarqueurs MCT2 proposés peuvent constituer des outils efficaces pour étudier l’état et l’évolution de la microstructure tissulaire dans le cerveau. La combinaison des biomarqueurs MCT2 avec les informations de microstructure dMRI nous a permis de progresser vers la résolution d’un problème critique et délicat consistant à limiter l'utilisation de gadolinium dans la détection de régions de lésion améliorantes dans les lésions de SEP. / In this thesis, we propose two multi-compartment T2 relaxometry (MCT2) models which provide information on brain tissue microstructure. Three T2 relaxometry compartments were considered in each voxel representing tissues with short T2, medium T2 and high T2 relaxation times. The complexity associated with the estimation of the parameters for such parametric models has then been explored. The first MCT2 model we propose computes the fractional representation of pre-defined T2 pools. In the next MCT2 model the fractional representations as well as T2 pool parameter were estimated for the medium T2 compartment. For both models the choice of approach was justified using a cost function analysis and a dedicated estimation framework was proposed.Our MCT2 model was used for two applications. In the first application the evolution of MCT2 biomarkers was studied in gadolinium (Gd) enhancing and nonenhancing regions of multiple sclerosis (MS) lesions in 10 patients with clinically isolated syndrome. The potential of combining the MCT2 biomarkers with diffusion MRI (dMRI) derived microstructure information to identify Gd enhancing regions in MS lesions was then demonstrated in the second application. The results show that the proposed MCT2 biomarkers can be effective tools to study the condition and evolution of tissue microstructures in the brain. Combining the MCT2 biomarkers with dMRI microstructure information enabled us to address a critical and challenging problem of limiting the use of gadolinium usage in detecting enhancing lesion regions in MS patients.

Hintergrund Das parametrische Mapping bietet durch die Erhebung absoluter Relaxationszeiten, welche die Gewebseigenschaften jedes Pixels widerspiegeln, das Potential, die nichtinvasive Gewebsdifferenzierung nach einem akuten Myokardinfarkt gegenüber dem heute als Goldstandard anzusehenden Late Gadolinium Enhancement (LGE) und der T2-gewichteten Short tau inversion recovery (T2-STIR) Sequenz weiter zu verbessern. Es galt das diagnostische Potential des parametrischen Mappings zur Differenzierung von Ödem, Nekrose, mikrovaskulärer Obstruktion (MVO), intramyokardialer Hämorrhagie (MH) und Remote Myokard unter Beweis zu stellen, Referenzwerte zu generieren und Schwellenwerte zur Differenzierung von pathologisch verändertem und gesundem Myokard abzuleiten. Die prognostische Relevanz der bestimmten Messwerte sollte durch Korrelation mit prognoserelevanten Faktoren ermittelt werden. Methoden In dieser retrospektiven Studie wurden 88 Patienten nach erlittenem ST Hebungsinfarkt (STEMI) oder Nicht-ST-Hebungsinfarkt (NSTEMI) untersucht, bei denen nach perkutaner koronarer Intervention eine Kardio-MRT (1,5 Tesla) durchgeführt wurde. Beim T1-Mapping kam eine modifizierte Look-Locker Inversion Recovery Sequenz nativ (T1 nativ), 1-2 min (EG-T1) und 15-18min (LG-T1) nach Gabe von 0,15mmol/kgKG Gadobutrol Kontrastmittel (KM) zum Einsatz. Beim T2-Mapping wurde eine Multi-Echo-Spin-Echo Sequenz und beim T2*-Mapping eine Gradient-Multiecho T2*-Sequenz verwendet. Das Extrazellularvolumen (EZV) leitete sich aus T1 nativ und LG-T1 ab. T2-STIR und LGE dienten als Referenzverfahren für Ödem und Nekrose. Die linksventrikuläre Pumpfunktion (LVEF) wurde mittels einer Steady-State Free Precession Sequenz bestimmt. Eine Voruntersuchung an N=14 Patienten, bei der Ödem und Nekrose anhand übertragener ROIs aus der T2-STIR und dem LGE definiert wurden, diente in Zusammenschau mit der Literatur zur Definition von visuellen Schwellenwerten für Ödem und Nekrose, an denen sich die visuellen Auswertungen dieser Arbeit orientierten (T1 nativ 1150ms, T2-Mapping 62ms, LG T1 350ms, MH 20ms). Es erfolgte eine visuelle Quantifizierung von Ödem, Nekrose, MVO, MH und Remote Myokard im T1 /T2- und T2*-Mapping bei allen N=88 Patienten. Die Ergebnisse wurden mit prognoserelevanten Parametern wie Infarktgröße, Myocardial Salvage Index (MSI), LVEF und EKG-Phänotyp (STEMI/NSTEMI) korreliert. Es wurden retrospektiv 1Standardabweichungs (SD)- und 2SD-Schwellenwerte vom Remote Myokard auf die erhobenen Messwerte angewendet. Ergebnisse Die Fläche des Ödems korrelierte in T1 nativ (r=0,82) und im T2-Mapping (r=0,85) in hohem Maße mit der T2-STIR Sequenz, wobei das Ödem durch das T1 nativ (p<0,01) signifikant und durch das T2-Mapping (p=0,048) grenzwertig signifikant unterschätzt wurde. In T1 nativ und im T2-Mapping konnten Referenzwerte für Ödem und Remote Myokard bestimmt werden (T1 nativ: 1249,0 ± 99,5ms vs. 1049,8 ± 77,7ms, p<0,01; T2-Mapping: 76,1± 8,9ms vs. 56,3 ± 4,2ms, p<0,01). Die T2 Zeit des Ödems korrelierte im Gegensatz zur T1-Zeit mit der LVEF und der Nekrosegröße. Die Fläche der Nekrose im LG-T1 und im LGE korrelierten höchstgradig miteinander (r=0,90). Im LG T1 lag die T1-Zeit der Nekrose bei 329,6 ± 37,9ms, die des Remote Myokards bei 430,1 ± 56,0ms (p<0,01). Das EZV im Infarktareal wurde mit 56,2 ± 8,6% und im Remote Myokard mit 34,6 ± 6,5% bestimmt (p<0,01). Das EG-T1 (N=37) zeigte sich bei der Darstellung der MVO gegenüber dem LG-T1 (N=36) leichtgradig sensitiver. In T1 nativ konnte zudem eine native MVO nachgewiesen werden (N=24). Für die MVO wurde in T1 nativ eine T1-Zeit von 972,6 ± 169,7ms, im EG-T1 von 636,2 ± 179,9ms und im LG-T1 von 456,3 ± 156,8ms bestimmt. Die T1 Zeit und Größe der MVO im EG-T1 und LG-T1 korrelierten mit der Nekrosegröße und der LVEF. Bei Nachweis einer MVO wiesen die Probanden einen geringeren MSI auf. Patienten mit MVO oder STEMI zeigten im T2 Mapping eine signifikant höhere T2 Zeit des Ödems. In T1 nativ und im LG T1 fanden sich hier hingegen keine signifikanten Unterschiede. Bei 21 der Probanden konnte eine MH nachgewiesen werden. Die T2*-Zeit der MH lag bei 17,5 ± 3,5ms. Das Auftreten einer MH stand im Zusammenhang mit einer größeren Nekrose, einem kleineren MSI und einer geringeren LVEF. Bei der retrospektiven Anwendung konnte ein +1SD Schwellenwert von 1127,5ms in T1 nativ und von 60,4ms im T2 Mapping das Ödem am besten differenzieren. Im LG T1 bevorzugten wir einen 1SD Schwellenwert von 374,1ms zur Differenzierung der Nekrose, wodurch diese jedoch im Vergleich zu den anderen Sequenzen häufiger nicht korrekt erkannt wurde. Auffällig war im LG-T1 eine höhere Variabilität der T1-Zeiten. Schlussfolgerung Das Ödem konnte mittels des nativen T1- und T2-Mappings dargestellt werden, wobei sich das T2-Mapping als überlegene Sequenz herausstellte. Es zeigte eine stärkere Übereinstimmung der bestimmten Ödemfläche mit dem Referenzverfahren. Die T2-Zeit des Ödems korrelierte im Gegensatz zur T1-Zeit mit prognoserelevanten Parametern wie der LVEF und der Nekrosegröße im LGE. Durch das LG-T1 gelang eine Quantifizierung der Nekrose, was eine höchstgradige Korrelation mit dem LGE belegte. Die MVO konnte nativ und im KM-verstärkten T1-Mapping nachgewiesen werden. Das EG-T1 zeigte sich hierbei dem LG-T1 leichtgradig überlegen. Im T2* Mapping gelang eine Darstellung der MH. Das Auftreten einer MVO oder MH standen im Zusammenhang mit prognoserelevanten Faktoren. Die T1 Zeit und Größe der MVO korrelierten zudem mit der LVEF und der Nekrosegröße. Patienten mit STEMI oder MVO zeigten signifikant höhere T2-Zeiten im Bereich des Ödems. Bei oben genannter Korrelation der T2-Zeit des Ödems mit der LVEF und der Nekrosegröße scheint somit die Höhe der T2-Zeit im Gegensatz zur T1-Zeit eine Aussage über das Ausmaß der Myokardschädigung zuzulassen. Ein +1SD-Schwellenwert stellte sich in T1 nativ und im T2-Mapping als zu favorisierender Schwellenwert zur Differenzierung des Ödems heraus. Eine höhere Variabilität der T1-Zeiten erschwerte im LG T1 eine schwellenwertbasierte Auswertung anhand eines 1SD Schwellenwertes.:1. Abkürzungsverzeichnis 1 2. Einleitung 2 2.1. Einführung 2 2.2. Der Myokardinfarkt 3 2.3. Grundlagen der Magnetresonanztomographie 4 2.4. Gewebscharakterisierung des akuten Myokardinfarkts 9 2.4.1. Das Ödem 9 2.4.2. Die Nekrose 10 2.4.3. Die mikrovaskuläre Obstruktion 12 2.4.4. Die intramyokardiale Hämorrhagie 13 2.5. Parametrisches Mapping 14 2.5.1. Parametrisches Mapping allgemein 14 2.5.2. T1-Mapping 15 2.5.3. Extrazellularvolumen 15 2.5.4. T2-Mapping 16 2.5.5. T2*-Mapping 17 2.6. Zielsetzung 17 3. Material und Methoden 18 3.1. Studienkollektiv 18 3.2. Datenakquisition 19 3.2.1. Datenakquisition des parametrischen Mappings 20 3.2.1.1. T1-Mapping 20 3.2.1.2. T2-Mapping 20 3.2.1.3. T2*-Mapping 20 3.2.2. Referenzverfahren 21 3.2.2.1. Ödemsensitive T2-gewichtete Bildgebung 21 3.2.2.2. Late Gadolinium Enhancement 21 3.2.3. Ergänzende Analysen 21 3.2.3.1. Linksventrikuläre Funktionsanalyse 21 3.3. Datenevaluation 22 3.3.1. Kalibrierende Voruntersuchung 23 3.3.2. Gewebscharakterisierung im parametrischen Mapping 23 3.3.2.1. T1-Mapping 23 3.3.2.2. T2-Mapping 25 3.3.2.3. T2*-Mapping 25 3.3.2.4. Schwellenwertbestimmung 26 3.3.3. Referenzverfahren 26 3.3.4. Ergänzende Analysen 27 3.3.4.1. Bestimmung der linksventrikulären Funktion 27 3.3.5. Abgeleitete Parameter 27 3.3.5.1. Myokardial Salvage Index 27 3.3.5.2. Extrazellularvolumen 27 3.4. Statistische Verfahren 28 4. Ergebnisse 29 4.1. Kalibrierende Voruntersuchung 29 4.2. Gewebscharakterisierung im parametrischen Mapping 32 4.2.1. Ergebnistabellen 32 4.2.2. Planimetrie der Gewebsdifferenzierung im parametrischen Mapping 33 4.2.2.1. Korrelation von parametrischem Mapping und Referenzverfahren 33 4.2.3. Relaxometrie der Gewebsdifferenzierung im parametrischen Mapping 37 4.2.3.1. Das Ödem im nativen T1- und T2-Mapping 37 4.2.3.2. Die Nekrose im kontrastmittelverstärkten T1-Mapping 43 4.2.3.3. Extrazellularvolumen 46 4.2.4. Mikrovaskuläre Obstruktion 46 4.2.5. Intramyokardiale Hämorrhagie 53 4.3. Schwellenwerte 57 4.4. Vergleich der EKG-Phänotypen STEMI vs. NSTEMI 63 5. Diskussion 64 5.1. Kalibrierende Voruntersuchung 64 5.2. Das Ödem im parametrischen Mapping 65 5.3. Die Nekrose im parametrischen Mapping 70 5.4. Extrazellularvolumen 74 5.5. Mikrovaskuläre Obstruktion 75 5.6. Intramyokardiale Hämorrhagie 79 5.7. Schwellenwerte 85 5.8. Schlussfolgerung 93 6. Zusammenfasssung der Arbeit 97 7. Literaturverzeichnis 100 8. Eigenständigkeitserklärung 111 9. Lebenslauf 112 10. Danksagung 113

Master of Science / Department of Statistics / Paul I. Nelson / Hotelling’s T2 test is the standard tool for inference about the mean of a multivariate normal population. However, this test may perform poorly when used on samples from multivariate distributions with highly skewed marginal distributions. The goal of our study was to investigate the type I error rate and power properties of Hotelling’s one sample test when sampling from a class of multivariate skew-normal (SN) distributions, which includes the multivariate normal distribution and, in addition to location and scale parameters, has a shape parameter to regulate skewness. Simulation results of tests carried out at nominal type I error rate 0.05 obtained from various levels of shape parameters, sample sizes, number of variables and fixed correlation matrix showed that Hotelling’s one sample test provides adequate control of type I error rates over the entire range of conditions studied. The test also produces suitable power levels for detecting departures from hypothesized values of a multivariate mean vector when data result from a random sample from a multivariate SN. The shape parameter of the SN family appears not to have much of an effect on the robustness of Hotelling’s test. However, surprisingly, it does have a positive impact on power.

This work proposes to look at the role of aesthetics within Christian theodicy. Though the recent theodicy literature has often displayed suspicion toward the inclusion of aesthetic criteria, I will argue that theological aesthetics can enrich the theodicy discourse and therefore should be used as a resource in responding to the problem of evil. In Part I, I will attempt to lay a foundation for an aesthetically informed theodicy by examining some of the philosophical frameworks that lie behind Christian theodicy, and seeking to illuminate a framework that allows theological aesthetics to helpfully contribute to the task of theodicy. By offering a preliminary account of theological aesthetics, I will aim to further lay a foundation for how the two areas of theology can interact. In Part II, I will look at three distinct aesthetic motifs or “themes” as they are developed by three different theodicists (one ancient and two contemporary): Augustine, Wendy Farley, and Marilyn McCord Adams. Each of the themes developed by these theodicists offers a different example of how aesthetics can reorient and enrich our perspective on theodicy. Though each, in and of itself, is incomplete, I will argue that they complement and critique one another in helpful ways, and therefore that all of them are useful for Christian theodicy.

<div> <p> Essential tremor (ET) is one of the most common movement disorders, characterized by kinetic tremor in the upper extremities with additional cranial tremor often present in the neck or jaw. While it is well established that ET is primarily a cerebellar disorder, recent investigations have shown more widespread pathological effects throughout the brain. Furthermore, the neurodegenerative nature of ET is still disputed and requires additional investigation. Additionally, the link between ET and Parkinson’s disease (PD) is of special interest, as it can be challenging to clinically differentiate these diseases.</p> <p> While post-mortem studies have helped to further the pathological understanding of these diseases, non-invasive in-vivo techniques allow for more accurate diagnosis in the clinic. With a more accurate diagnosis comes a more targeted treatment, and hopefully an improved remediation of the disease. My thesis seeks to further investigate the neurodegenerative hypothesis of ET as well as explore magnetic resonance imaging (MRI) biomarkers for potential differences in ET and PD. </p> <p>These aims will be accomplished in three steps. First, gray matter volume loss in the cerebellum was investigated using voxel-based morphometry and the Spatially Unbiased Infra-Tentorial Template (SUIT) atlas on a lobule level. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls. The cerebellum was segmented into 34 lobules using the SUIT atlas. Percent gray matter was calculated as the ratio of lobule gray matter volume divided by total lobule volume. No significant differences were identified between ET cases and controls in any of the 34 lobules. However, nine lobules had significantly decreased percent gray matter in ET cases with head or jaw tremor (n = 27) compared to controls. Also, 11 lobules had significantly decreased percent gray matter in ET cases with voice tremor (n = 22) compared to controls. This result confirms, with increased regional accuracy, gray matter volume loss in the cerebellum of ET cases.</p> <p>Second, gray matter volume loss beyond the cerebellum, in the cerebrum, was investigated using voxel-based morphometry. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls for processing in SPM12. The processing steps of SPM12 were updated to include a higher resolution atlas and set of tissue probability maps to optimize the segmentation and normalization of each subject image. After segmentation, normalization, and smoothing, a voxel-wise statistical analysis was performed to identify clusters of gray matter volume in ET cases compared to controls. ET cases showed decreased gray matter volume in the bilateral superior temporal region and the anterior and posterior cingulate cortex. These results, in combination with previous work provide support of wide-spread neurodegeneration in ET using optimized methodology.</p> <p>Third, we applied T2* mapping to determine relative iron concentrations in the substantia nigra (SN) and globus pallidus (GP) in ET and PD cases. Three separate studies were independently investigated to validate the reproducibility and detectability of group differences using T2* mapping. The first study (ET study) acquired T2* maps on 21 ET cases and 12 matched controls, the second study (PD study 1) acquired T2* maps on 10 PD cases and 7 controls, and the third study (PD study 2) acquired T2* maps on 21 PD cases and 17 controls. Regions of interest (ROIs) were manually placed in the SN and GP for each subject and group differences were calculated independently for each study using a linear regression model with age and sex as covariates. A significant decrease in T2* was found in PD study 1 and PD study 2 in the right SN in PD cases compared to their respective controls, indicating increased iron deposition. No significant difference was found in the ET group compared to their respective controls in the SN. No significant differences were found in any of the three studies in the GP. These results provide evidence for a difference in brain iron regulation in the pathology of ET and PD.</p> <p>Together, these thesis aims provide additional evidence in support of the neurodegenerative hypothesis of ET using updated methodology and present a quantitative imaging difference between groups of ET and PD cases. </p> </div> <br>

Perceptions of intelligence are strongly related to attractiveness and have a significant impact on first impressions. The introductory chapters (1 - 3) provide an overview of the literature on attractiveness, halo effects, and intelligence, while the experimental chapters (4 - 6) explore perceptions of cues to intelligence beyond attractiveness, individual differences in the susceptibility to the halo, and the accuracy of perceptions of competence. Chapter 4 investigated the malleable facial cues of eyelid-openness and mouth curvature and their influence on perceived intelligence. Attractiveness partially mediated intelligence impression, but effects of eyelid-openness and subtle smiling enhanced intelligence ratings independent of attractiveness. These effects were observed and replicated in between individual (cross-sectional) studies of natural images of adult faces, child faces, through digital manipulation of individual cues in the same faces, and in a within individual sleep-restricted sample. Chapter 5 investigated the relationship between perceived intelligence and attractiveness by exploring whether a raters' own intelligence may be related to a stronger endorsement of the perceived intelligence-attractiveness halo. The correlation between ratings of the perceived intelligence and attractiveness was found to be stronger for participants who scored higher on an intelligence test than participants with lower intelligence test scores. Chapter 6 investigated the limiting effects of attractiveness on perceptions of competence. When statistically controlling for the attractiveness halo, academic performance could be predicted from judgments of conscientiousness but not from ratings of intelligence. Thus this thesis demonstrates that malleable facial cues can influence perceptions of intelligence independent of attractiveness, identifies an individual difference that influences endorsement of the intelligence-attractiveness halo, and shows the limiting effects of the attractiveness halo on potentially accurate perceptions of academic performance. Collectively these findings provide evidence of the powerful influence of attractiveness on perceptions of intelligence; such work is necessary if we are to mitigate such bias.