Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the upper and lower motor neurons die. Most studies aimed at elucidating the cause of this disease have focused on the motor neuron cell body. However, recent work has suggested that the disease may begin in motor nerve terminals. The experiments described in Chapters 2-4 of this dissertation studied functional defects in motor nerve terminals of mice expressing mutant human superoxide dismutase 1 (SOD1-G93A, SOD1-G85R), models of familial ALS. In Chapter 2, the proximal hind limbs of SOD1-G93A mice were subjected to varying durations of a tourniquet-induced ischemia/reperfusion injury to determine whether these motor terminals were more vulnerable to this stress than wild-type terminals. Confocal imaging of yellow fluorescent protein (YFP expressed in neurons) and alpha-bungarotoxin (labels acetylcholine receptors on muscle) was used to determine endplate occupancy. In the distal hind limb of SOD1-G93A/YFP terminals innervating fast type muscles (extensor digitorum longus (EDL) and plantaris) were more vulnerable to ischemia/reperfusion injury than those occupying the slow type muscle (soleus). Increased vulnerability to endplate denervation was evident in presymptomatic mice as early as 31 days old. Experiments in Chapters 3 tested whether mitochondrial handling of Ca2+ loads is altered at presymptomatic stages. These experiements used rhodamine-123 to measure depolarization of the mitochondrial membrane potential (Ψm) evoked by trains of action potentials delivered to the motor nerve in levator auris longus motor terminals. These Ψm depolarizations depended on Ca2+ entry into motor terminals and were relatively small (~1-2 mV) in wild-type terminals. Consistent with the hypothesis that reduced ability to accelerate the electron transport chain (ETC) activity results in larger stimulation-induced Ψm depolarizations, presymptomatic SOD1-G93A (maintains dismutase activity) and SOD1-G85R (lacks dismutase activity) terminals displayed ~5 times greater depolarizations than wild-type terminals. Expression of normal human SOD1 or knockout of SOD1 did not significantly alter Ψm depolarizations. In the presence of a low concentration of rotenone (inhibits complex 1 of the ETC) wild-type terminals also displayed larger Ψm depolarizations. Experiments in Chapter 4 studied stimulation-induced Ψm depolarizations in terminals of older, symptomatic SOD1-G93A and SOD1-G85R mice. These depolarizations decayed more slowly than those in wild-type terminals and incremented with successive trains. Asynchronous depolarizations that were not time linked to the stimulus train were also noted. These behaviors were attenuated when opening of the mitochondrial permeability transition pore (mPTP) was inhibited with cyclosporin A or by replacing bath Ca2+ with Sr2+. Incrementing Ψm depolarizations could be elicited in wild-type terminals when subjected to an oxidative stress (diamide-induced depletion of glutathione). These findings indicate that motor terminals in mutant SOD1 mice display functional deficits even at presymptomatic ages, and that deficits associated with mitochondrial handling of stimulation-induced Ca2+ loads increase with age and may contribute to motor terminal degeneration in mutant SOD1 mice.

L'évaluation de la carcinose péritonéale (CP) reste difficile et peu standardisée. Nous avons évalué différentes techniques de suivi de la CP en imagerie fonctionnelle, afin de mieux comprendre l'évolution microcirculatoire de la maladie, la valeur des différents biomarqueurs disponibles et essayer de construite une méthodologie d'évaluation multiparamétrique fonctionnelle.Nous avons établi un modèle murin orthotopique de pseudomyxome péritonéale (PMP). Nous avons suivi la perfusion tumorale par échographie Doppler de l'artère mésentérique supérieure (AMS), et montré une accélération des flux au sein de l'AMS accompagnant le développement de la tumeur, ainsi qu'une diminution de ces flux chez les souris traitées par bévacizumab.Puis, nous avons évalué la microcirculation au sein même de la tumeur. Nous avons ainsi pu montrer dans le modèle murin de PMP et dans un modèle de carcinose murine une bonne reproductibilité pour mesurer la valeur du coefficient apparent de diffusion dans la tumeur ainsi que les paramètres de microcirculation extraits par la méthode Intra-Voxe Incoherent Motion (IVIM) en utilisant une séquence d'imagerie par résonance magnétique (IRM) de type HASTE avec un équipement clinique standard à 1.5T. Nous avons ensuite appliqué la méthode IVIM pour le suivi de PMP de souris traitée par anti-angiogénique (sorafénib).L'application de ces méthodes d'imagerie fonctionnelle, combinées entre elles pourraient permettre de construire des modèles prédictifs et de suivi chez les patients atteints de PMP et de proposer des stratégies thérapeutiques personnalisées très précocement au cours de la maladie.5 IRM de diffusion6 Echographie doppler3 Imagerie fonctionnelle 74 Pseudomyxome péritonéal / Assessment of peritoneal carcinomatosis (PC) remains difficult and not well standardized. We have evaluated different techniques for monitoring CP using functional imaging, in order to better understand the microcirculation and the evolution of the disease, the value of various biomarkers available and we tries to establish methodology for functional multiparametric evaluation of the disease.We have established an orthotopic model of peritoneal pseudomyxoma (PMP). We have monitored the tumor perfusion by Doppler ultrasound of the superior mesenteric artery (SMA), and showed an increase in blood flow velocities in the SMA accompanying the development of the tumor, as well as a decrease of these flows in mice treated with bevacizumab.Then, we evaluated the microcirculation within the tumor itself. We have thus shown in the murine model of PMP and in a murine model of PC a good reproducibility of the measurement of the value of the apparent diffusion coefficient in the tumor as well as the microcirculation parameters extracted by the Intra-Voxel Incoherent Motion technique (IVIM) Using a HASTE magnetic resonance imaging (MRI) sequence with standard clinical equipment at 1.5T. We then applied the IVIM method for the monitoring of anti-angiogenic (sorafenib) -treated mouse PMP.The combined application of these functional imaging methods, may allow to construct predictive and follow-up models in patients with PMP and to propose personalized therapeutic strategies very early in the evolution of the disease.

Congenital hypothyroidism (CH) is a pediatric endocrine disorder caused by an insufficiency of thyroid hormone. Despite treatment following newborn screening, CH is associated with persisting memory weaknesses. Given animal research has shown thyroid hormone plays a crucial role in the development of the hippocampus, a brain structure required for normal declarative memory, it is possible that altered hippocampally-dependent processes underlie the memory weakness associated with CH. Previous studies of individuals with CH have found reduced memory abilities and left hippocampal volumes but no study has thoroughly assessed memory abilities or how the hippocampus functions to support memory. Thus, the present study compared individuals with CH and typically developing adolescents using clinical memory tests and two associative memory tasks shown in adults to activate the hippocampus during functional magnetic resonance imaging (fMRI). Results indicated groups did not differ in memory accuracy on clinical measures or either fMRI task. However, fMRI revealed hippocampal activation differed between the groups when performing the associative memory tasks. The first task utilized a visuospatial paired associates novelty detection paradigm to show the CH group increased activation relative to controls in left hippocampus and recruited right hippocampus when controls did not. Since previous research suggested the left hippocampus and verbal memory were more vulnerable to the effects of CH, the second task utilized a verbal paired associates paradigm to demonstrate that when making old and new judgments about associations versus items, the CH group increased activation relative to controls in left hippocampus. Further investigation revealed that when recognizing old associations versus items, the CH group had increased bilateral posterior hippocampal activation whereas controls showed increased activation in right anterior hippocampus, a distinction noted in previous research with this paradigm which suggests individuals with CH may retrieve associations in a less flexible manner than controls. In addition, worse memory performance and increased hippocampal activation, particularly on the left, was predicted by severity of hypothyroidism experienced early in life. In conclusion, these studies demonstrate that early thyroid hormone insufficiency associated with CH alters the functioning of the hippocampus and engenders use of compensatory mechanisms to support associative memory functions.

Congenital hypothyroidism (CH) is a pediatric endocrine disorder caused by an insufficiency of thyroid hormone. Despite treatment following newborn screening, CH is associated with persisting memory weaknesses. Given animal research has shown thyroid hormone plays a crucial role in the development of the hippocampus, a brain structure required for normal declarative memory, it is possible that altered hippocampally-dependent processes underlie the memory weakness associated with CH. Previous studies of individuals with CH have found reduced memory abilities and left hippocampal volumes but no study has thoroughly assessed memory abilities or how the hippocampus functions to support memory. Thus, the present study compared individuals with CH and typically developing adolescents using clinical memory tests and two associative memory tasks shown in adults to activate the hippocampus during functional magnetic resonance imaging (fMRI). Results indicated groups did not differ in memory accuracy on clinical measures or either fMRI task. However, fMRI revealed hippocampal activation differed between the groups when performing the associative memory tasks. The first task utilized a visuospatial paired associates novelty detection paradigm to show the CH group increased activation relative to controls in left hippocampus and recruited right hippocampus when controls did not. Since previous research suggested the left hippocampus and verbal memory were more vulnerable to the effects of CH, the second task utilized a verbal paired associates paradigm to demonstrate that when making old and new judgments about associations versus items, the CH group increased activation relative to controls in left hippocampus. Further investigation revealed that when recognizing old associations versus items, the CH group had increased bilateral posterior hippocampal activation whereas controls showed increased activation in right anterior hippocampus, a distinction noted in previous research with this paradigm which suggests individuals with CH may retrieve associations in a less flexible manner than controls. In addition, worse memory performance and increased hippocampal activation, particularly on the left, was predicted by severity of hypothyroidism experienced early in life. In conclusion, these studies demonstrate that early thyroid hormone insufficiency associated with CH alters the functioning of the hippocampus and engenders use of compensatory mechanisms to support associative memory functions.

The Default Mode Network (DMN) is a large-scale brain network implicated in the control and monitoring of internal modes of cognition. The aim of this research was to investigate DMN function and its relationship to other large-scale cognitive control networks through functional connectivity analysis and analysis of combined electroencephalographic (EEG) recordings. Data utilised across a series of three experiments were obtained from combined EEG-functional Magnetic Resonance Imaging recordings acquired during technical development of a new scanner in the Clinical Research Centre, Ninewells Hospital, Dundee. Analyses were based on data acquired from neurologically healthy participants while they rested with their eyes-closed for five minutes. Following this, participants completed a 14-minute auditory attention task, designed to engage the dorsal and ventral attention networks. In this task, participants responded to task-relevant stimuli (odd/even numbers) and attempted to inhibit their responses to task-irrelevant ‘oddballs’ (the number ‘0’) and task-irrelevant/distractor stimuli (environment sounds). Experiment 1 utilised the simultaneous acquired EEG-fMRI resting-state data in order to establish whether EEG frequency content in the beta range (13-30 Hz) was a significant predictor of DMN activity (regions of which were identified on an individual basis using functional connectivity analysis). Results were comparable to existing literature showing there is inconsistency in establishing a reliable electrophysiological signature of the DMN. Experiment 1 also employed region-of-interest (ROI)-to-ROI functional connectivity analysis as a method of exploring the functional relationship between the DMN and: (1) a task-positive resting-state network; (2) other commonly identified DMN regions; and (3) regions covering the whole of the cerebral cortex. Results revealed networks were correlated at a component-based level and challenged existing literature which appears to over-generalise results from exploration of network interaction. Findings also revealed activation of specific DMN components were coupled with down-regulation of sensory-associated cortical regions. Experiment 2 analysed the fMRI data that were obtained from the auditory attention task in order to: (1) determine whether DMN activity was observed when participants were engaged in an externally-directed task; and (2) explore changes in DMN activity associated with increasing task duration. Results revealed that activation of the DMN was prominent and did not vary over three equal time periods. This supports existing research showing the DMN is a continuously active system (whose activity is modulated based on external-task demands). Results also hinted at the existence of possible relationships between the DMN and components of several other large-scale control networks. Therefore, in Experiment 3 potential interactions were explored using ROI-to-ROI functional connectivity analysis of the whole 14-minute time series. Firstly, functional connectivity within the dorsal/ventral attention, executive/frontoparietal control and salience networks was analysed; secondly, the relationships between putative regions of these networks and the DMN were analysed. Overall, results revealed that networks were functionally connected with one another at a component-based level only. This suggests flexible interaction between several large-scale control networks allows neurologically healthy participants to allocate resources to the simultaneous monitoring of the internal and external worlds.

Ces travaux de thèse portent sur les récents progrès de l’imagerie fonctionnelle par ultrasons et ses nouvelles applications en ophtalmologie. Dans le cadre d’un projet mêlant physique des ondes, imagerie, neurosciences et ophtalmologie, nous avons appliqué cette technologie à l’imagerie du système visuel et à l’étude préclinique de thérapies le ciblant. Au cours de ce projet, nous avons accompagné nos études précliniques de progrès constants dans notre imagerie.Un dispositif permettant l’imagerie du cerveau en 3 dimensions a été conçu. Cette imagerie a été réalisée en temps réel, ou à une fréquence ultrasonore de 30 MHz grâce au procédé d’entrelacement. Grâce à une connaissance a priori de l’architecture vasculaire cérébrale et de l’effet Doppler, il est possible de réaliser une décomposition spectrale des écoulements sanguins cérébraux selon leurs vitesses et de leurs orientations.Ceci a permis une étude des fonctions visuelles du rat et du primate non-humain. Nous avons imagé la rétine du primate en Doppler de puissance, mais sa forte mobilité en fait un organe délicat à imager en imagerie fonctionnelle. En revanche, nous avons réalisé une imagerie fonctionnelle de la rétine de rat à 30 MHz. Nous avons caractérisé en détail le système visuel cérébral de ce rongeur. Nous avons mis en évidence ses principales structures et redémontré leurs caractéristiques les plus connues, comme leur organisation rétinotopique ou leur différence de temps de réponse neurovasculaire à un stimulus. Des animaux traités par des thérapies de restauration visuelle a été imagée. La première imagerie de primates non-humains anesthésiés puis éveillés et exécutant une tâche comportementale, et la détection de variations de flux sanguins dues à des erreurs uniques ont été réalisées. Enfin, une étude préclinique aiguë et une étude chronique de traitements ayant des effets neurovasculaires ont été menées grâce au suivi du flux sanguin par nos procédés. / This thesis focuses on recent improvements in the functional ultrasound imaging (fUS) technique and their applications in the field of ophthalmology. Within the framework of a synergetic project blending waves physics, medical imaging, neuroscience and ophthalmology, fUS was shown to be capable of imaging and studying the visual system of healthy and diseased animals for the purpose of preclinical studies. To tackle these issues, constant upgrades in the fUS technique had to support the preclinical studies.An experimental set-up was built to image the visual pathway in three dimensions with fUS. Using a new imaging facility, fUS was proven to be feasible in real time and at high ultrasound frequencies such as 30 MHz. Interleaved sampling had to be implemented in that case. Furthermore, the a priori knowledge of the vascular cerebral architecture and the Doppler Effect were exploited to spectrally decompose cerebral blood flux and vessels according to their velocities and orientations.Leveraging these improvements, functional ultrasound imaging of rats and non-human primates was performed. Primate retina was imaged with Power Doppler, but proved to be too mobile to be functionally imaged. However, fUS has been performed on rat retina after 30 MHz fUS imaging had been implemented. The rat visual pathway has then been characterised with fUS. Some of its known features where highlighted such as its retinotopic organisation or the time response differences between some of its structures. The same set-up has been leveraged to map the cerebral activity of animal that underwent visual restauration therapies. These tools were then used to map cerebral activity in anesthetized and awake and behaving monkeys. Unique blood volume variations due to unique mistakes were detected. These tools were finally applied to two preclinical trials on a depressive state of the brain vascular contractility. Blood volume and blood velocity changes were highlighted throughout an acute and a chronical study.

The main function of the respiratory system is gas exchange. Since many disease or injury conditions can cause biomechanical or material property changes that can alter lung function, there is a great interest in measuring regional lung ventilation and regional mechanical changes. We describe a technique that uses multiple respiratory-gated CT images of the lung acquired at different levels of inflation with both breath-hold static scans and retrospectively reconstructed dynamic scans, along with non-rigid 3D image registration, to make local estimates of lung tissue expansion. The degree of regional lung expansion is measured using the Jacobian (a function of local partial derivatives) of the registration displacement field. We compare the ventral-dorsal patterns of lung expansion estimated across seven phase changes and three pressure changes to a xenon CT based measure of specific ventilation in four anesthetized sheep studied in the supine orientation. Using 3D image registration to match images acquired at 50% and 75% phase points of the inspiratory portion of the respiratory cycle and 20 cm H2O and 25 cm H2O airway pressures gave the best match between the average Jacobian and the xenon CT specific ventilation respectively (linear regression, average r2=0.85 and r2=0.84). We validate the registration accuracy by 200 semi-automatically matched landmarks and both the dynamic and static scans show landmark error on the order of 2mm.

We investigate the possibility of extracting accurate functional information such as local blood oxygenation level using multi-wavelength photoacoustic measurements. Photoacoustic microscope is utilized to acquire images of microvasculature in smallanimal skin. Owing to endogenous optical contrast, optical spectral information obtained from spectral photoacoustic measurements are successfully inverted to yield oxygenation level in blood. Analysis of error propagation from photoacoustic measurements to inverted quantities showed minimum inversion error in the optical wavelength region of 570-600 nm. To obtain accurate and vessel size independent blood oxygenation measurements, transducers with central frequency of more than 25 MHz are needed for the optical region of 570-600 nm used in this study. The effect of transducer focal position on accuracy of blood oxygenation level quantification was found to be negligible. To obtain accurate measurements in vivo, one needs to compensate for factors such as spectral dependent optical attenuation.

The search for the optimal choice of treatment time, dose and fractionation regimen is one of the major challenges in radiation therapy. Several aspects of the radiation response of tumours and normal tissues give different indications of how the parameters defining a fractionation schedule should be altered relative to each other which often results in contradictory conclusions. For example, the increased sensitivity to fractionation in late-reacting as opposed to early-reacting tissues indicates that a large number of fractions is beneficial, while the issue of accelerated repopulation of tumour cells starting at about three weeks into a radiotherapy treatment would suggest as short overall treatment time as possible. Another tumour-to-normal tissue differential relevant to the sensitivity as well as the fractionation and overall treatment time is the issue of tumour hypoxia and reoxygenation. The tumour oxygenation is one of the most influential factors impacting on the outcome of many types of treatment modalities. Hypoxic cells are up to three times as resistant to radiation as well-oxygenated cells, presenting a significant obstacle to overcome in radiotherapy as solid tumours often contain hypoxic areas as a result of their poorly functioning vasculature. Furthermore, the oxygenation is highly dynamic, with changes being observed both from fraction to  fraction and over a time period of weeks as a result of fast and slow reoxygenation of acute and chronic hypoxia. With an increasing number of patients treated with hypofractionated stereotactic body radiotherapy (SBRT), the clinical implications of a substantially reduced number of fractions and hence also treatment time thus have to be evaluated with respect to the oxygenation status of the tumour. One of the most promising tools available for the type of study aiming at determining the optimal radiotherapy approach with respect to fractionation is radiobiological modelling. With clinically validated in vitro-derived tissue-specific radiobiological parameters and well-established survival models, in silico modelling offers a wide range of opportunities to test various hypotheses with respect to time, dose, fractionation and details of the tumour microenvironment. Any type of radiobiological modelling study intended to provide a realistic representation of a clinical tumour should therefore take into account details of both the spatial and temporal tumour oxygenation. This thesis presents the results of three-dimensional radiobiological modelling of the response of tumours with heterogeneous oxygenation to various fractionation schemes, and oxygenation levels and dynamics using different survival models. The results of this work indicate that hypoxia and its dynamics play a major role in the outcome of radiotherapy, and that neglecting the oxygenation status of tumours treated with e.g. SBRT may compromise the treatment outcome substantially. Furthermore, the possibilities offered by incorporating modelling into the clinical routine are explored and demonstrated by the development of a new calibration function for converting the uptake of the hypoxia-PET tracer 18F-HX4 to oxygen partial pressure, and applying it for calculations of the doses needed to overcome hypoxia-induced radiation resistance. By hence demonstrating how the clinical impact of hypoxia on dose prescription and the choice of fractionation schedule can be investigated, this project will hopefully advance the evolution towards routinely incorporating functional imaging of hypoxia into treatment planning. This is ultimately expected to result in increased levels of local control with more patients being cured from their cancer. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 6: Manuscript.</p>

<p>Abstract</p><p>The goal of modern radiotherapy is to precisely deliver a prescribed radiation dose to delineated target volumes that contain a significant amount of tumor cells while sparing the surrounding healthy tissues/organs. Precise delineation of treatment and avoidance volumes is the key for the precision radiation therapy. In recent years, considerable clinical and research efforts have been devoted to integrate MRI into radiotherapy workflow motivated by the superior soft tissue contrast and functional imaging possibility. Dynamic contrast-enhanced MRI (DCE-MRI) is a noninvasive technique that measures properties of tissue microvasculature. Its sensitivity to radiation-induced vascular pharmacokinetic (PK) changes has been preliminary demonstrated. In spite of its great potential, two major challenges have limited DCE-MRI’s clinical application in radiotherapy assessment: the technical limitations of accurate DCE-MRI imaging implementation and the need of novel DCE-MRI data analysis methods for richer functional heterogeneity information. </p><p>This study aims at improving current DCE-MRI techniques and developing new DCE-MRI analysis methods for particular radiotherapy assessment. Thus, the study is naturally divided into two parts. The first part focuses on DCE-MRI temporal resolution as one of the key DCE-MRI technical factors, and some improvements regarding DCE-MRI temporal resolution are proposed; the second part explores the potential value of image heterogeneity analysis and multiple PK model combination for therapeutic response assessment, and several novel DCE-MRI data analysis methods are developed.</p><p>I. Improvement of DCE-MRI temporal resolution. First, the feasibility of improving DCE-MRI temporal resolution via image undersampling was studied. Specifically, a novel MR image iterative reconstruction algorithm was studied for DCE-MRI reconstruction. This algorithm was built on the recently developed compress sensing (CS) theory. By utilizing a limited k-space acquisition with shorter imaging time, images can be reconstructed in an iterative fashion under the regularization of a newly proposed total generalized variation (TGV) penalty term. In the retrospective study of brain radiosurgery patient DCE-MRI scans under IRB-approval, the clinically obtained image data was selected as reference data, and the simulated accelerated k-space acquisition was generated via undersampling the reference image full k-space with designed sampling grids. Two undersampling strategies were proposed: 1) a radial multi-ray grid with a special angular distribution was adopted to sample each slice of the full k-space; 2) a Cartesian random sampling grid series with spatiotemporal constraints from adjacent frames was adopted to sample the dynamic k-space series at a slice location. Two sets of PK parameters’ maps were generated from the undersampled data and from the fully-sampled data, respectively. Multiple quantitative measurements and statistical studies were performed to evaluate the accuracy of PK maps generated from the undersampled data in reference to the PK maps generated from the fully-sampled data. Results showed that at a simulated acceleration factor of four, PK maps could be faithfully calculated from the DCE images that were reconstructed using undersampled data, and no statistically significant differences were found between the regional PK mean values from undersampled and fully-sampled data sets. DCE-MRI acceleration using the investigated image reconstruction method has been suggested as feasible and promising. </p><p>Second, for high temporal resolution DCE-MRI, a new PK model fitting method was developed to solve PK parameters for better calculation accuracy and efficiency. This method is based on a derivative-based deformation of the commonly used Tofts PK model, which is presented as an integrative expression. This method also includes an advanced Kolmogorov-Zurbenko (KZ) filter to remove the potential noise effect in data and solve the PK parameter as a linear problem in matrix format. In the computer simulation study, PK parameters representing typical intracranial values were selected as references to simulated DCE-MRI data for different temporal resolution and different data noise level. Results showed that at both high temporal resolutions (<1s) and clinically feasible temporal resolution (~5s), this new method was able to calculate PK parameters more accurate than the current calculation methods at clinically relevant noise levels; at high temporal resolutions, the calculation efficiency of this new method was superior to current methods in an order of 102. In a retrospective of clinical brain DCE-MRI scans, the PK maps derived from the proposed method were comparable with the results from current methods. Based on these results, it can be concluded that this new method can be used for accurate and efficient PK model fitting for high temporal resolution DCE-MRI. </p><p>II. Development of DCE-MRI analysis methods for therapeutic response assessment. This part aims at methodology developments in two approaches. The first one is to develop model-free analysis method for DCE-MRI functional heterogeneity evaluation. This approach is inspired by the rationale that radiotherapy-induced functional change could be heterogeneous across the treatment area. The first effort was spent on a translational investigation of classic fractal dimension theory for DCE-MRI therapeutic response assessment. In a small-animal anti-angiogenesis drug therapy experiment, the randomly assigned treatment/control groups received multiple fraction treatments with one pre-treatment and multiple post-treatment high spatiotemporal DCE-MRI scans. In the post-treatment scan two weeks after the start, the investigated Rényi dimensions of the classic PK rate constant map demonstrated significant differences between the treatment and the control groups; when Rényi dimensions were adopted for treatment/control group classification, the achieved accuracy was higher than the accuracy from using conventional PK parameter statistics. Following this pilot work, two novel texture analysis methods were proposed. First, a new technique called Gray Level Local Power Matrix (GLLPM) was developed. It intends to solve the lack of temporal information and poor calculation efficiency of the commonly used Gray Level Co-Occurrence Matrix (GLCOM) techniques. In the same small animal experiment, the dynamic curves of Haralick texture features derived from the GLLPM had an overall better performance than the corresponding curves derived from current GLCOM techniques in treatment/control separation and classification. The second developed method is dynamic Fractal Signature Dissimilarity (FSD) analysis. Inspired by the classic fractal dimension theory, this method measures the dynamics of tumor heterogeneity during the contrast agent uptake in a quantitative fashion on DCE images. In the small animal experiment mentioned before, the selected parameters from dynamic FSD analysis showed significant differences between treatment/control groups as early as after 1 treatment fraction; in contrast, metrics from conventional PK analysis showed significant differences only after 3 treatment fractions. When using dynamic FSD parameters, the treatment/control group classification after 1st treatment fraction was improved than using conventional PK statistics. These results suggest the promising application of this novel method for capturing early therapeutic response. </p><p> The second approach of developing novel DCE-MRI methods is to combine PK information from multiple PK models. Currently, the classic Tofts model or its alternative version has been widely adopted for DCE-MRI analysis as a gold-standard approach for therapeutic response assessment. Previously, a shutter-speed (SS) model was proposed to incorporate transcytolemmal water exchange effect into contrast agent concentration quantification. In spite of richer biological assumption, its application in therapeutic response assessment is limited. It might be intriguing to combine the information from the SS model and from the classic Tofts model to explore potential new biological information for treatment assessment. The feasibility of this idea was investigated in the same small animal experiment. The SS model was compared against the Tofts model for therapeutic response assessment using PK parameter regional mean value comparison. Based on the modeled transcytolemmal water exchange rate, a biological subvolume was proposed and was automatically identified using histogram analysis. Within the biological subvolume, the PK rate constant derived from the SS model were proved to be superior to the one from Tofts model in treatment/control separation and classification. Furthermore, novel biomarkers were designed to integrate PK rate constants from these two models. When being evaluated in the biological subvolume, this biomarker was able to reflect significant treatment/control difference in both post-treatment evaluation. These results confirm the potential value of SS model as well as its combination with Tofts model for therapeutic response assessment. </p><p>In summary, this study addressed two problems of DCE-MRI application in radiotherapy assessment. In the first part, a method of accelerating DCE-MRI acquisition for better temporal resolution was investigated, and a novel PK model fitting algorithm was proposed for high temporal resolution DCE-MRI. In the second part, two model-free texture analysis methods and a multiple-model analysis method were developed for DCE-MRI therapeutic response assessment. The presented works could benefit the future DCE-MRI routine clinical application in radiotherapy assessment.</p> / Dissertation