Doctor of Philosophy (PhD) / Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide, and which typically has a devastating effect on the lives of its sufferers. The characteristic symptoms of the disease include hallucinations, delusions, disorganized thought and reduced emotional expression. While many of the early theories of schizophrenia focused on its psychosocial foundations, more recent theories have focused on the neurobiological underpinnings of the disease. This thesis has four primary aims: 1) to use magnetic resonance imaging (MRI) to identify the structural brain abnormalities present in patients suffering from their first episode of schizophrenia (FES), 2) to elucidate whether these abnormalities were static or progressive over the first 2-3 years of patients’ illness, 3) to identify the relationship between these neuroanatomical abnormalities and patients’ clinical profile, and 4) to identify the normative relationship between longitudinal changes in neuroanatomy and electrophysiology in healthy participants, and to compare this to the relationship observed between these two indices in patients with FES. The aim of Chapter 2 was to use MRI to identify the neuroanatomical changes that occur over adolescence in healthy participants, and to identify the normative relationship between the neuroanatomical changes and electrophysiological changes associated with healthy periadolescent brain maturation. MRI and electroencephalographic (EEG) scans were acquired from 138 healthy participants between the ages of 10 and 30 years. The MRI scans were segmented into grey matter (GM) and white matter (WM) images, before being parcellated into the frontal, temporal, parietal and occipital lobes. Absolute EEG power was calculated for the slow-wave, alpha and beta frequency bands, for the corresponding cortical regions. The age-related changes in regional tissue volumes and regional EEG power were inferred with a regression model. The results indicated that the healthy participants experienced accelerated GM loss, EEG power loss and WM gain in the frontal and parietal lobes between the ages of 10 and 20 years, which decelerated between the ages of 20 and 30 years. A linear relationship was also observed between the maturational changes in regional GM volumes and EEG power in the frontal and parietal lobes. These results indicate that the periadolescent period is a time of great structural and electrophysiological change in the healthy human brain. The aim of Chapter 3 was to identify the GM abnormalities present in patients with FES, both at the time of their first presentation to mental health services (baseline), and over the first 2-3 years of their illness (follow-up). MRI scans were acquired from 41 patients with FES at baseline, and 47 matched healthy control subjects. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. The analysis technique of voxel-based morphometry (VBM) was used in conjunction with the Statistical Parametric Mapping (SPM) software package in order to identify the regions of GM difference between the groups at baseline. The related analysis technique of tensor-based morphometry (TBM) was used to identify subjects’ longitudinal GM change over the follow-up interval. Relative to the healthy controls, the FES patients were observed to exhibit widespread GM reductions in the frontal, parietal and temporal cortices and cerebellum at baseline, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES patients lost considerably more GM over the follow-up interval than the controls, particularly in the parietal and temporal cortices. These results indicate that patients with FES exhibit significant structural brain abnormalities very early in the course of their illness, and that these abnormalities progress over the first few years of their illness. Chapter 4 employed the same methodology to investigate the white matter abnormalities exhibited by the FES subjects relative to the controls, both at baseline and over the follow-up interval. Compared to controls, the FES patients exhibited volumetric WM deficits in the frontal and temporal lobes at baseline, as well as volumetric increases at the fronto-parietal junction bilaterally. Furthermore, the FES patients lost considerably more WM over the follow-up interval than did the controls in the middle and inferior temporal cortex bilaterally. While there is substantial evidence indicating that abnormalities in the maturational processes of myelination play a significant role in the development of WM abnormalities in FES, the observed longitudinal reductions in WM were consistent with the death of a select population of temporal lobe neurons over the follow-up interval. The aim of Chapter 5 was to investigate the clinical correlates of the GM abnormalities exhibited by the FES patients at baseline. The volumes of four distinct cerebral regions where 31 patients with FES exhibited reduced GM volumes relative to 30 matched controls were calculated and correlated with patients’ scores on three primary symptom dimensions: Disorganization, Reality Distortion and Psychomotor Poverty. The results indicated that the greater the degree of atrophy exhibited by the FES patients in three of these four ‘regions-of-reduction’, the less severe their degree of Reality Distortion. These results suggest that an excessive amount of GM atrophy may in fact preclude the formation of hallucinations or highly systematized delusions in patients with FES. The aim of Chapter 6 was to identify the relationship between the longitudinal changes in brain structure and brain electrophysiology exhibited by 19 FES patients over the first 2-3 years of their illness, and to compare it to the normative relationship between the two indices reported in Chapter 2. The methodology employed for the parcellation of the MRI and EEG data was identical to Chapter 2. The results indicated that, in contrast to the healthy controls, the longitudinal reduction in GM volume exhibited by the FES patients was not associated with a corresponding reduction in EEG power in any brain lobe. In contrast, EEG power was observed to be maintained or even to increase over the follow-up interval in these patients. These results were consistent with the FES patients experiencing an abnormal elevation of neural synchrony. Such an abnormality in neural synchrony could potentially form the basis of the dysfunctional neural connectivity that has been widely proposed to underlie the functional deficits present in patients with schizophrenia. The primary aim of Chapter 7 was to assimilate the findings from the preceding empirical chapters with the theoretical framework provided in the literature, into an integrated and testable model of schizophrenia. The model emphasized dysfunctions in brain maturation, specifically in the normative processes of synaptic ‘pruning’ and axonal myelination, as playing a key role in the development of disintegrated neural activity and the subsequent onset of schizophrenic symptoms. The model concluded with the novel proposal that disintegrated neural activity arises from abnormal elevations in the synchrony of synaptic activity in patients with first-episode schizophrenia.

Porous ceramic-metal composites, or cermets, such as nickel zirconia (Ni-YSZ), are widely used as the anode material in solid oxide fuel cells (SOFC). These materials need to enable electrochemical reactions and provide the mechanical support for the layered cell structure. Thus, for the anode supported planar cells, the thermomechanical behavior of the porous cermet directly affects the reliability of the cell. Porous cermets can be viewed as three-phase composites with a random heterogeneous microstructure. While random in nature, the effective properties and overall behavior of such composites can still be linked to specific stochastic functions that describe the microstructure. The main objective of this research was to develop the relationship between the thermomechanical behavior of porous cermets and their random microstructure. The research consists of three components. First, a stochastic reconstruction scheme was developed for the three-phase composite. From this multiple realizations with identical statistical descriptors were constructed for analysis. Secondly, a finite element model was implemented to obtain the effective properties of interest including thermal expansion coefficient, thermal conductivity, and elastic modulus. Lastly, nonlinear material behaviors were investigated, such as damage, plasticity, and creep behavior. It was shown that the computational model linked the statistical features of the microstructure to its overall properties and behavior. Such a predictive computational tool will enable the design of SOFCs with higher reliability and lower costs.

Prostate cancer is the most common malignancy afflicting Canadian men in 2011. Physicians use digital rectal exams (DRE), blood tests for prostate specific antigen (PSA) and transrectal ultrasound (TRUS)-guided biopsies for the initial diagnosis of prostate cancer. None of these tests detail the spatial extent of prostate cancer - information critical for using new therapies that can target cancerous prostate. With an MRI technique called proton magnetic resonance spectroscopic imaging (1H-MRSI), biochemical analysis of the entire prostate can be done without the need for biopsy, providing detailed information beyond the non-specific changes in hardness felt by an experienced urologist in a DRE, the presence of PSA in blood, or the “blind-guidance” of TRUS-guided biopsy. A hindrance to acquiring high quality 1H-MRSI data comes from signal originating from fatty tissue surrounding prostate that tends to mask or distort signal from within the prostate, thus reducing the overall clinical usefulness of 1H-MRSI data. This thesis has three major areas of focus: 1) The development of an optimized 1H-MRSI technique, called conformal voxel magnetic resonance spectroscopy (CV-MRS), to deal the with removal of unwanted lipid contaminating artifacts at short and long echo times. 2) An in vivo human study to test the CV-MRS technique, including healthy volunteers and cancer patients scheduled for radical prostatectomy or radiation therapy. 3) A study to determine the efficacy of using the 1H-MRSI data for optimized radiation treatment planning using modern delivery techniques like intensity modulated radiation treatment. Data collected from the study using the optimized CV-MRS method show significantly reduced lipid contamination resulting in high quality spectra throughout the prostate. Combining the CV-MRS technique with spectral-spatial excitation further reduced lipid contamination and opened up the possibility of detecting metabolites with short T2 relaxation times. Results from the in vivo study were verified with post-histopathological data. Lastly, 1H-MRSI data was incorporated into the radiation treatment planning software and used to asses tumour control by escalating the radiation to prostate lesions that were identified by 1H-MRSI. In summary, this thesis demonstrates the clinical feasibility of using advanced spectroscopic imaging techniques for improved diagnosis and treatment of prostate cancer.

Parkinson’s disease patients present with the highest risk of dementia development. The thalamus, integral to several functions and behaviours is involved in the pathophysiology of Parkinson’s disease. The aim of this thesis was to determine if anatomical abnormalities in the thalamus are associated with the development of dementia in Parkinson’s disease. We examined the thalamus using macro and microstructural techniques and the white matter pathways that connect the thalamus with areas of the surrounding cortex using diffusion tensor imaging (DTI) based tractography. T1-weighted magnetic resonance and DT images were collected in 56 Parkinson’s disease patients with no cognitive impairment, 19 patients with mild cognitive impairment, 17 patients with dementia and 25 healthy individuals who acted as control subjects. An established automated segmentation procedure (FIRST FSL) was used to delineate the thalamus and a modified k-means clustering algorithm applied to segment the thalamus into clusters assumed to represent thalamic nuclei. Fibre tracts were determined using DTI probabilistic tracking methods available in FIRST. Microstructural integrity was quantified by fractional anisotropy and mean diffusivity (MD) DTI measures. Results show that microstructural measures of thalamic integrity are more sensitive to cognitive dysfunction in PD than macrostructural measures. For the first time we showed a progressive worsening of cellular integrity (MD) in the groups who had greater levels of cognitive dysfunction. Thalamic degeneration was regionally specific and most advanced in the limbic thalamic nuclei which influenced executive function and attention, areas of cognition that are known to be affected in the earliest stages of PD. The integrity of the fibre tracts corresponding to these thalamic regions was also compromised. Degeneration of fibre tracts was most evident in the dementia group, indicating that they may be more protected against Lewy pathology than the nuclei of the thalamus. Our findings confirm previous histological, animal and lesion studies and provide a reliable estimate of cortical degeneration in PD that can be applied non-invasively and in vivo. A longitudinal study is needed to monitor the progression of cognitive decline in PD but we have provided the basis for further investigation into the predictive validity of thalamic degeneration for cognitive dysfunction. In the future, the microstructural changes of the thalamus could be used as biomarkers for the identification of individuals with a higher risk for dementia development and for the longitudinal monitoring of any interventions into cognitive decline.

Prostate cancer is the most common malignancy afflicting Canadian men in 2011. Physicians use digital rectal exams (DRE), blood tests for prostate specific antigen (PSA) and transrectal ultrasound (TRUS)-guided biopsies for the initial diagnosis of prostate cancer. None of these tests detail the spatial extent of prostate cancer - information critical for using new therapies that can target cancerous prostate. With an MRI technique called proton magnetic resonance spectroscopic imaging (1H-MRSI), biochemical analysis of the entire prostate can be done without the need for biopsy, providing detailed information beyond the non-specific changes in hardness felt by an experienced urologist in a DRE, the presence of PSA in blood, or the “blind-guidance” of TRUS-guided biopsy. A hindrance to acquiring high quality 1H-MRSI data comes from signal originating from fatty tissue surrounding prostate that tends to mask or distort signal from within the prostate, thus reducing the overall clinical usefulness of 1H-MRSI data. This thesis has three major areas of focus: 1) The development of an optimized 1H-MRSI technique, called conformal voxel magnetic resonance spectroscopy (CV-MRS), to deal the with removal of unwanted lipid contaminating artifacts at short and long echo times. 2) An in vivo human study to test the CV-MRS technique, including healthy volunteers and cancer patients scheduled for radical prostatectomy or radiation therapy. 3) A study to determine the efficacy of using the 1H-MRSI data for optimized radiation treatment planning using modern delivery techniques like intensity modulated radiation treatment. Data collected from the study using the optimized CV-MRS method show significantly reduced lipid contamination resulting in high quality spectra throughout the prostate. Combining the CV-MRS technique with spectral-spatial excitation further reduced lipid contamination and opened up the possibility of detecting metabolites with short T2 relaxation times. Results from the in vivo study were verified with post-histopathological data. Lastly, 1H-MRSI data was incorporated into the radiation treatment planning software and used to asses tumour control by escalating the radiation to prostate lesions that were identified by 1H-MRSI. In summary, this thesis demonstrates the clinical feasibility of using advanced spectroscopic imaging techniques for improved diagnosis and treatment of prostate cancer.

This dissertation is comprised of four studies investigating the hypothesis that adults and children who stutter differ from their same-age fluent peers in the neuroanatomy and neurophysiology underlying auditory speech processing. It has been consistently reported that adults who stutter demonstrate unique functional neural activation patterns during speech production, including reduced auditory activation, relative to nonstutterers. The extent to which these functional differences are accompanied by abnormal morphology of the brain in stutterers is unclear. The first study in this dissertation examined the neuroanatomical differences in speech-related cortex between adults who do and do not stutter using magnetic resonance imaging and voxel-based morphometry analyses. Adults who stutter were found to have localized grey matter volume increases in auditory and motor speech related cortex. The second study extended this line of research to children who stutter, who were found to have localized grey matter volume decreases in motor speech related cortex. Together, these studies suggest an abnormal trajectory of regional grey matter development in motor speech cortex of people who stutter. The last two studies investigated the mechanism underlying the repeated findings of reduced auditory activation during speech in people who stutter in more detail. Magnetoencephalography was used to investigate the hypothesis that people who stutter have increased speech induced suppression of early evoked auditory responses. Adults and children who stutter demonstrated typical levels of speech induced suppression relative to fluent peers. However, adults and children who stutter showed differences from peers in the timing of cortical auditory responses. Taken together, the studies demonstrate structural and functional abnormalities in brain regions related to auditory processing and point to the possibility that people who stutter have difficulty forming the neural representations of speech sounds necessary for fluent speech production.

Doctor of Philosophy (PhD) / Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide, and which typically has a devastating effect on the lives of its sufferers. The characteristic symptoms of the disease include hallucinations, delusions, disorganized thought and reduced emotional expression. While many of the early theories of schizophrenia focused on its psychosocial foundations, more recent theories have focused on the neurobiological underpinnings of the disease. This thesis has four primary aims: 1) to use magnetic resonance imaging (MRI) to identify the structural brain abnormalities present in patients suffering from their first episode of schizophrenia (FES), 2) to elucidate whether these abnormalities were static or progressive over the first 2-3 years of patients’ illness, 3) to identify the relationship between these neuroanatomical abnormalities and patients’ clinical profile, and 4) to identify the normative relationship between longitudinal changes in neuroanatomy and electrophysiology in healthy participants, and to compare this to the relationship observed between these two indices in patients with FES. The aim of Chapter 2 was to use MRI to identify the neuroanatomical changes that occur over adolescence in healthy participants, and to identify the normative relationship between the neuroanatomical changes and electrophysiological changes associated with healthy periadolescent brain maturation. MRI and electroencephalographic (EEG) scans were acquired from 138 healthy participants between the ages of 10 and 30 years. The MRI scans were segmented into grey matter (GM) and white matter (WM) images, before being parcellated into the frontal, temporal, parietal and occipital lobes. Absolute EEG power was calculated for the slow-wave, alpha and beta frequency bands, for the corresponding cortical regions. The age-related changes in regional tissue volumes and regional EEG power were inferred with a regression model. The results indicated that the healthy participants experienced accelerated GM loss, EEG power loss and WM gain in the frontal and parietal lobes between the ages of 10 and 20 years, which decelerated between the ages of 20 and 30 years. A linear relationship was also observed between the maturational changes in regional GM volumes and EEG power in the frontal and parietal lobes. These results indicate that the periadolescent period is a time of great structural and electrophysiological change in the healthy human brain. The aim of Chapter 3 was to identify the GM abnormalities present in patients with FES, both at the time of their first presentation to mental health services (baseline), and over the first 2-3 years of their illness (follow-up). MRI scans were acquired from 41 patients with FES at baseline, and 47 matched healthy control subjects. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. The analysis technique of voxel-based morphometry (VBM) was used in conjunction with the Statistical Parametric Mapping (SPM) software package in order to identify the regions of GM difference between the groups at baseline. The related analysis technique of tensor-based morphometry (TBM) was used to identify subjects’ longitudinal GM change over the follow-up interval. Relative to the healthy controls, the FES patients were observed to exhibit widespread GM reductions in the frontal, parietal and temporal cortices and cerebellum at baseline, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES patients lost considerably more GM over the follow-up interval than the controls, particularly in the parietal and temporal cortices. These results indicate that patients with FES exhibit significant structural brain abnormalities very early in the course of their illness, and that these abnormalities progress over the first few years of their illness. Chapter 4 employed the same methodology to investigate the white matter abnormalities exhibited by the FES subjects relative to the controls, both at baseline and over the follow-up interval. Compared to controls, the FES patients exhibited volumetric WM deficits in the frontal and temporal lobes at baseline, as well as volumetric increases at the fronto-parietal junction bilaterally. Furthermore, the FES patients lost considerably more WM over the follow-up interval than did the controls in the middle and inferior temporal cortex bilaterally. While there is substantial evidence indicating that abnormalities in the maturational processes of myelination play a significant role in the development of WM abnormalities in FES, the observed longitudinal reductions in WM were consistent with the death of a select population of temporal lobe neurons over the follow-up interval. The aim of Chapter 5 was to investigate the clinical correlates of the GM abnormalities exhibited by the FES patients at baseline. The volumes of four distinct cerebral regions where 31 patients with FES exhibited reduced GM volumes relative to 30 matched controls were calculated and correlated with patients’ scores on three primary symptom dimensions: Disorganization, Reality Distortion and Psychomotor Poverty. The results indicated that the greater the degree of atrophy exhibited by the FES patients in three of these four ‘regions-of-reduction’, the less severe their degree of Reality Distortion. These results suggest that an excessive amount of GM atrophy may in fact preclude the formation of hallucinations or highly systematized delusions in patients with FES. The aim of Chapter 6 was to identify the relationship between the longitudinal changes in brain structure and brain electrophysiology exhibited by 19 FES patients over the first 2-3 years of their illness, and to compare it to the normative relationship between the two indices reported in Chapter 2. The methodology employed for the parcellation of the MRI and EEG data was identical to Chapter 2. The results indicated that, in contrast to the healthy controls, the longitudinal reduction in GM volume exhibited by the FES patients was not associated with a corresponding reduction in EEG power in any brain lobe. In contrast, EEG power was observed to be maintained or even to increase over the follow-up interval in these patients. These results were consistent with the FES patients experiencing an abnormal elevation of neural synchrony. Such an abnormality in neural synchrony could potentially form the basis of the dysfunctional neural connectivity that has been widely proposed to underlie the functional deficits present in patients with schizophrenia. The primary aim of Chapter 7 was to assimilate the findings from the preceding empirical chapters with the theoretical framework provided in the literature, into an integrated and testable model of schizophrenia. The model emphasized dysfunctions in brain maturation, specifically in the normative processes of synaptic ‘pruning’ and axonal myelination, as playing a key role in the development of disintegrated neural activity and the subsequent onset of schizophrenic symptoms. The model concluded with the novel proposal that disintegrated neural activity arises from abnormal elevations in the synchrony of synaptic activity in patients with first-episode schizophrenia.

Marching Cubes is a rendering technique that has many advantages for a lot of areas. It is a technique for representing scalar fields as a three-dimensional mesh. It is used for geographical applications as well as scientific ones, mainly in the medical industry to visually render medical data of the human body. But it's also an interesting technique to explore for the usage in computer games or other real-time applications since it can create some really interesting rendering. The main focus in this paper is to present a novel hybrid solution using marching cubes and heightmaps to render terrain; moreover, to find if it’s suitable for real-time applications. The paper will follow a theoretical approach as well as an implementational one on the hybrid solution. The results across several tests for different scenarios show that the hybrid solution works well for today's real-time applications using a modern graphics card and CPU (Central Processing Unit).

Circadian Rhythms (CR) are driven by a biological clock called as suprachiasmaticnucleus (SCN), located in a brain region called the hypothalamus. These rhythms are very much necessary in maintaining the sleep and wake cycle at appropriate times in a day. As a starting step towards non-invasive investigation of CR, aim is to study changes in the physiological processes of two Regions of Interest (ROI), the hypothalamus and the visual cortex. This was studied using a functional Magnetic Resonance Imaging (fMRI) technique to investigate for any changes or differences in the Blood Oxygen Level Dependent (BOLD)signals extracted from the ROI during a visual stimulation. We acquired and processed fMRI data to extract BOLD signals from ROI and the extracted signals are again further used to study the correlation with the experimental ON-OFF design paradigm. The extracted BOLD signals varied a lot between the two specified brain regions within the same subject and between three types of fMRI data. These variations were found in terms of number of activated voxels and also Signal to Noise ratio(SNR) level present in the signals. The number of activated voxels and SNR werehigh in visual cortex whereas low number of activated voxels and low SNR were found in hypothalamus. The correlation between BOLD responses from primaryvisual cortex were shown as positive with the experimental stimulation whereas BOLD responses extracted from hypothalamus have shown a negative correlation in time with the experimental stimulation. As a start up of the project, these BOLD responses can provide references for a future use in research studies, especially to further study about change in phase of the BOLD signal extracted exactly from the SCN. These phase responses can then be used to study physiological processing in subjects affected by sleep disorders.

I have in my thesis produced a start of a multiplayer, voxel, strategy sandbox game with advanced AI. The world is made out of voxels in the form of blocks that both the players and other units can affect and change. In a world where every block follows the laws of physics for both fluids and physics. The game is designed for several players that fights for controll over land and resources. / Jag har i mitt examensarbete producerat en början av ett flerspelar, voxel, strategi och sandlådespel med avancerad AI. Världen är uppbyggd av voxlar i form av block som både spelaren och andra enheter har möjlighet att påverka och förändra. En värld där varje block följer fysiska lagar för både vätska och fysik. Spelet är designat för flera spelare som strider om områden och resurser med hjälp av sina AI kontrollerade bybor.