Autism and associated gene mutations can be studied with genetic mouse models. Magnetic Resonance Imaging (MRI) of these animal models quantifies the impact of genetics on brain morphology. Using MRI, three genetic mouse models of autism were imaged: Neuroligin 3 R451C knock-in, Methyl-CpG binding protein-2 308-truncation and Integrin β-3 knock-out. Morphological differences were identified using a newly developed MRI mouse cerebellum atlas. The results show all three genes to alter cerebellar anatomy. Each studied gene affected a unique set of cerebellar structures. I hypothesize that the results and known behavioural phenotypes of the models are linked, with anatomy contributing to specific behaviours. In the future work section, a surface-based analysis method is presented to investigate the variance in cerebellum foliation across disease models and inbred strains. This work shows that autism risk-genes alter distinct regions of the cerebellum.

Autism and associated gene mutations can be studied with genetic mouse models. Magnetic Resonance Imaging (MRI) of these animal models quantifies the impact of genetics on brain morphology. Using MRI, three genetic mouse models of autism were imaged: Neuroligin 3 R451C knock-in, Methyl-CpG binding protein-2 308-truncation and Integrin β-3 knock-out. Morphological differences were identified using a newly developed MRI mouse cerebellum atlas. The results show all three genes to alter cerebellar anatomy. Each studied gene affected a unique set of cerebellar structures. I hypothesize that the results and known behavioural phenotypes of the models are linked, with anatomy contributing to specific behaviours. In the future work section, a surface-based analysis method is presented to investigate the variance in cerebellum foliation across disease models and inbred strains. This work shows that autism risk-genes alter distinct regions of the cerebellum.

Individuals with mild cognitive impairment (MCI) show variable impairment in autobiographical memory function, source memory function and reduced integrity in the brain’s default mode network (DMN). There is overlap between the DMN, such as the medial posterior cortical hub, and brain regions that are active when participants recall autobiographical memories. To assess the association between autobiographical memory and the DMN, 14 MCI and eleven age and education-matched healthy control participants were assessed using the autobiographical memory interview (AMI) and underwent resting state fMRI scans. The same participants underwent a test of source memory which assessed both recognition and source memory. The MCI group showed significantly increased semantic as well episodic memory impairments using the AMI, evident across the lifespan for episodic memory but not for childhood semantic memory. Significantly poorer DMN connectivity, using a goodness of fit index (GOF) of the DMN template, was evident in the MCI group. MCI participants showed poorer performance on both recognition and source memory relative to HC participants. A modest association between AMI semantic memory (r=0.4) scores, but not episodic memory scores (r=0.09), and DMN connectivity was found in these participants. For future study the predictive value of MR imaging in the DMN of MCI participants should be explored.

This dissertation describes the development, implementation, validation, optimization, and application, of a noninvasive and quantitative method for measuring cerebral blood volume changes with functional magnetic resonance imaging (fMRI) for mapping of neural activity changes. Since its inception over twenty years ago, the field of fMRI has grown in usage, sophistication, range of applications, and impact. Nevertheless it has yet to exploit its full potential regarding, spatiotemporal resolution, signal specificity, and quantifiability of hemodynamic changes. By utilization of a new MR pulse sequence, new concepts of radio frequency pulses, and high magnetic fields (7 T), a novel fMRI method named SS-SI VASO is presented here that overcomes sensitivity limitations of other noninvasive quantitative imaging methods. In order to validate that its signal represents changes in cerebral blood volume without other contaminations, SS-SI VASO is implemented in animal models for a close comparison with established, but invasive methods. A good agreement of blood volume sensitivity has been found with the new method compared to the established ones. After its validation, the SS-SI VASO method and its unprecedented sensitivity was used to localize and quantify hemodynamic changes in applications where conventional oxygenation based fMRI methods are limited. (A) SS-SI VASO was used to investigate biophysical aspects of actively controlled arteries and passive balloon-like veins during activity induced hemodynamic changes. (B) SS-SI VASO was used to provide insights whether the interplay of neural activity and resultant vascular response are the same for tasks that increase neural activity compared to tasks that suppress neural activity. (C) SS-SI VASO was used to calibrate conventional oxygenation based fMRI to quantify local changes in oxygen metabolism. (D) The high sensitivity of SS-SI VASO was further used to obtain sub-millimeter resolutions and estimate activity changes between cortical layers. This enables to address questions not only where the brain is activated but also how and whereby this activity is evoked. The implementation and application of this new SS-SI VASO fMRI method is a major step forward for the field of imaging neuroscience; it demonstrates that the current limitations of fMRI can be even overcome with respect to quantifiability, spatial specificity and distinguishing between vascular and neuronal phenomena.

The overall aim of the present thesis was to study post-resuscitation care of cardiac arrest (CA) patients treated with target temperature management 33°C with a focus on evaluation of two prognostic tools: variations in cerebral venous saturation and acute magnetic resonance imaging (MRI) findings on the brain post-CA. An additional aim was to investigate patients’ neurological outcome and relatives’ experiences 6 months after the event. Paper I describes the cerebral oxygen saturation of blood obtained from a jugular bulb (SjvO2) catheter The results showed that patients with poor outcome tended to have higher SjvO2values,but this difference was only significant at 96 and108 hours post-CA. The main findings of Paper II were that patients with good outcome displayed a pathological pattern mainly in the frontal and parietal lobes on MRI of the brain. Patients with poor outcome had an extensive pathological pattern in several brain regions. Furthermore, very low apparent diffusion coefficient (ADC) values were associated with poor outcome regardless of brain region. Paper III investigated physical and cognitive function over time, between one month and 6 months post-CA, as well as d life satisfaction at 6 months. The results showed that impairment in physical and cognitive function is common in CA survivors but tends to decrease over time. Despite a severe illness, which has impaired the physical and cognitive functions, satisfaction with life as a whole was reported by 70% of CA survivors. In Paper IV, relatives described their experiences 6 months after a significant others CA. The analysis resulted in three themes reflecting relatives’ everyday life 6 months after the event: Difficulties managing a changed life situation, Feeling like I come second and Feeling new hope for the future. In conclusion, the results of the present thesis have increased our understanding of the two prognostic tools that were investigated; they have generated new and revealed aspects that should be taken into account during prognostication and assessing neurological outcome of this group of patients. The thesis has also shown that the healthcare needs to improve its routines for follow-ups and information provision to both patients and their relatives.

Diffuse liver disease is a growing problem and a major cause of death worldwide. In the final stages the treatment often involves liver resection or transplant and in deciding what course of action is to be taken it is crucial to have a correct assessment of the function of the liver. The current “gold standard” for this assessment is to take a liver biopsy which has a number of disadvantages. As an alternative, a method involving magnetic resonance imaging and mechanistic modeling of the liver has been developed at Linköping University. One of the obstacles for this method to overcome in order to reach clinical implementation is the speed of the parameter estimation. In this project the methodology of metamodeling is tested as a possible solution to this speed problem. Metamodeling involve making models of models using extensive model simulations and mathematical tools. With the use of regression methods, clustering algorithms, and optimization, different methods for parameter estimation have been evaluated. The results show that several, but not all, of the parameters could be accurately estimated using metamodeling and that metamodeling could be a highly useful tool when modeling biological systems. With further development, metamodeling could bring this non-invasive method for estimation of liver function a major step closer to application in the clinic.

Many disorders are associated with regional brain volumes. The analysis of these volumes from MR images often requires sequential processing steps such as localization and delineation. It is common to perform volumetric normalization using intracranial volume (ICV, the total volume inside the cranial cavity) when comparing regional brain volumes, since head size varies considerably between individuals. Multiple methods for estimating ICV and procedures for volume normalization exist. A method for interhemispheric surface localization and extraction, using both intensity and symmetry information and without time consuming pre-processing, was developed. Evaluations of hemisphere division accuracy as well as suitability as a pre-processing step for interhemispheric structure localization were made. The performance of the method was comparable to that of methods focusing on either of these tasks, making it suited for use in many different studies. Automated ICV estimations from Freesurfer and SPM were evaluated using 399 reference segmentations. Both methods overestimated ICV and estimations using Freesurfer contained errors associated with skull-size. Estimations from SPM contained errors associated with gender and atrophy. An experiment showed that the choice of method can affect study results. Manual ICV estimation is very time consuming, but can be performed using only a subset of voxels in an image to increase speed and decrease manual labor. Segmenting every nth slice and stereology were evaluated in terms of required manual labor and estimation error, using the previously created ICV references. An illustration showing how much manual labor is required for a given estimation error using different combinations of n and stereology grid spacing was presented. Finally, different procedures for ICV normalization of regional brain volumes when investigating gender related volume differences were theoretically explained and evaluated using both simulated and real data. Resulting volume differences were seen to depend on the procedure used. A suggested workflow for procedure selection was presented. Methodological contributions that can aid the analysis of the human brain have been presented. The performed studies also contribute to the understanding of important methodological considerations for regional brain volume analysis.

Femoro-Acetabular Impingement (FAI) is a hip joint disease which affects and impairs the range of hip motion during performing activities of daily living, jogging, walking, or climbing stairs due to the bony abnormalities of the joint. Ballet dancers and athletes (e.g. gymnasts and hockey players) put their hips at the risk of FAI by extremely moving the hip mainly by excessively rotating the joint. In this research, we introduce a visualization system which helps surgeons to analyze the range of hip motions as well as to have a better communication with patients. These goals are achieved by presenting three dimensional (3D) visualizations of motion envelope by examining the maximum possible rotation of the digital hip bones. Our computer simulation system estimates, analyzes and visualizes the maximum hip range of motion (ROM) for the constructed 3D bone models that are extracted from Magnetic Resonance Images (MRI) after segmenting the bones. These tasks are accomplished by first calculating Hip Joint Center (HJC) which is center of rotation of femoral head on the 3D segmented MRI models followed by simulating hip motions with examining impingement between the femur and the acetabulum using our collision detection system. In our collision detection system, surfaces of femoral head and acetabulum bones are sampled in the spherical coordinates based on rasterization and interpolation. Then, the distance between the femoral head and acetabulum are computed to prevent impingement between them. The maximum motion degree of femur bone within depression of acetabulum in every direction during the digital simulation shows the ROMs of the inputted MRI of the hip joint. Six primary plane motions (flexion/extension, abduction/adduction and internal/external rotation) as well as various combinations of these motions (maximum rotation of the hip between every two rotational movements) and successive movements (maximum rotational movement of the hip per another rotational movement) are simulated and analyzed along with 3D visualization of estimated range of these motions. Generally, the ROM differs by some factors such as age, gender, ethnicity, and geographic location. For instance, newborns up to age two have considerably greater motion in hip flexion and hip abduction than adults. Our system by 3D visualization of motion envelope will provide a platform to understand quicker and better the effect of bony morphology of the hip joint on the possible ROM. We also examine the long-standing question about moving center of rotation related to ROM. We found out the ROM becomes bigger especially when the center moves outward to the direction of acetabulum axis. This thesis does not consider the effect of muscle and other surrounding connective tissue on the hip ROM since they can be altered significantly by physical training to show the potential of maximum ROM. For example a ballerina has a bigger ROM leading a bigger motion envelope compared with non-dancers. Hence we visualize the range of joint motions and their envelopes that are obtained from the osseous anatomy of the hip joint. The osseous anatomy of the joint is the most fundamental and permanent factor of ROM which indicates the maximum motion that the joint can achieve if the muscle and other connective tissues are perfectly trained.

Covert stroke (CS) comprises lesions in the brain often associated by risk factors such as a diet high in fat, salt, cholesterol and sugar (HFSCS). Developing a rodent model for CS incorporating these characteristics is useful for developing and testing interventions. The purpose of this thesis was to determine if magnetic resonance (MR) can detect brain abnormalities to confirm this model will have the desired anatomical effects. Ex vivo MR showed brain abnormalities for rats with the induced lesions and fed the HFSCS diet. Spectra acquired on the fixed livers had an average percent area under the fat peak relative to the water peak of (20±4)% for HFSCS and (2±2)% for control. In vivo MR images had significant differences between surgeries to induce the lesions (p=0.04). These results show that applying MR identified abnormalities in the rat model and therefore is important in the development of this CS rodent model.

A series of lanthanide complexes, {[CpCo(P=O(OR)2)3]2Ln(H2O)x}+Cl- (Ln = Nd, Eu, Tb, Yb; R = Et, Ph), (Kläui)2Ln, were prepared. The related complex {[CpCo(P=O(OPh)2)3]2Yb}+ [CoCl3(THF)]- was crystallographically characterized and the cation in this case was confirmed to be 6-coordinate and solvent free. To determine the Kläui complexes potential as magnetic resonance (MR) imaging agents, ligand exchange rates between the d0- and d60-isotopomers of the Kläui lanthanide complexes were determined in acetonitrile by electrospray mass spectrometry. The ligand exchange rate was found to increase by almost 4-orders of magnitude from the smallest (Yb) to largest ion (Nd) in acetonitrile. Additionally, the ligand exchange rate increased rapidly for the Tb complex with increasing water concentration. Changing the phosphite substituent had no significant impact on the rate of ligand exchange for R = Ph relative to R = Et. Modification to the phosphite substituents to decrease ligand exchange was unsuccessful indicating that these ligands were not suitable as MR imaging agents. Oxazoline based ligands are known to complex lanthanide ions, however, most of these complexes undergo rapid ligand exchange when not in water solution. Several novel oxazoline based ligands with increased chelation to stop ligand exchange were designed. During the course of their synthesis it was discovered that these ligands were too unstable to be used in vivo and this ligand set was abandoned for a more stable alternative. A series of ligands based on a calix[4]arene scaffold were developed. Through modifications to the upper rim of the calix[4]arene scaffold a mono, di, and tri substituted catechol calix[4]arene were designed. After the mono-catechol tri-sulfonated calix[4]arene was found to decompose in solution the catechol substituent was determined to be too reactive for use as a contrast agent. An upper rim tetra substituted iminodiacetic acid calix[4]arene was synthesized. Upon addition of the lanthanide a coordination polymer was likely forming. Using a dye displacement assay it was found that this ligand was not able to out-compete the dye for metal chelation and would not be suitable for MR use. Using established Suzuki chemistry, DO3A functionality was incorporated onto a tri-sulfonated calix[4]arene scaffold. Using a dye displacement assay it was found that the stability constant KML of this complex was similar to DO3A at pH 8.35. At pH 3.99 it was found that no displacement occurred, most likely due to intramolecular hydrogen bonding. / Graduate / 0488 / kjallen@uvic.ca