Search

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231152001 for Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease by Julie Ottoy, Miracle Ozzoude, Katherine Zukotynski, Min Su Kang, Sabrina Adamo, Christopher Scott, Joel Ramirez, Walter Swardfager, Benjamin Lam, Aparna Bhan, Parisa Mojiri, Alex Kiss, Stephen Strother, Christian Bocti, Michael Borrie, Howard Chertkow, Richard Frayne, Robin Hsiung, Robert Jr Laforce, Michael D Noseworthy, Frank S Prato, Demetrios J Sahlas, Eric E Smith, Phillip H Kuo, Jordan A Chad, Ofer Pasternak, Vesna Sossi, Alexander Thiel, Jean-Paul Soucy, Jean-Claude Tardif, Sandra E Black, Maged Goubran in Journal of Cerebral Blood Flow & Metabolism

Background and Objectives To determine whether cognitive reserve attenuates the association of vascular brain injury with cognition. Methods Cross-sectional data were analyzed from 2 harmonized studies: the Canadian Alliance for Healthy Hearts and Healthy Minds (CAHHM) and the Prospective Urban and Rural Epidemiology (PURE) study. Markers of cognitive reserve were education, involvement in social activities, marital status, height, and leisure physical activity, which were combined into a composite score. Vascular brain injury was defined as nonlacunar brain infarcts or high white matter hyperintensity (WMH) burden on MRI. Cognition was assessed using the Montreal Cognitive Assessment Tool (MoCA) and the Digit Symbol Substitution Test (DSST). Results There were 10,916 participants age 35–81. Mean age was 58.8 years (range 35–81) and 55.8% were female. Education, moderate leisure physical activity, being in a marital partnership, being taller, and participating in social groups were each independently associated with higher cognition, as was the composite cognitive reserve score. Vascular brain injury was associated with lower cognition (β –0.35 [95% confidence interval [CI] –0.53 to −0.17] for MoCA and β −2.19 [95% CI −3.22 to −1.15] for DSST) but the association was not modified by the composite cognitive reserve variable (interaction p = 0.59 for MoCA and p = 0.72 for DSST). Conclusions Both vascular brain injury and markers of cognitive reserve are associated with cognition. However, the effects were independent such that the adverse effects of covert vascular brain injury were not attenuated by higher cognitive reserve. To improve cognitive brain health, interventions to both prevent cerebrovascular disease and promote positive lifestyles are needed.

Valerie Evans,1,2 Michael Behr,2,3 Anshika Gangwar,2 Michael D Noseworthy,4 Dinesh Kumbhare1– 3 1Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto, Ontario, Canada; 2University Health Network – Toronto Rehabilitation Institute, Toronto, Ontario, Canada; 3Department of Medicine, Division of Physical Medicine and Rehabilitation, University of Toronto, Toronto, Ontario, Canada; 4Department of Electrical and Computer Engineering, McMaster University, Hamilton, Ontario, CanadaCorrespondence: Dinesh KumbhareDepartment of Medicine and IBBME, University of Toronto, 550 University Ave, Suite 7-131, Toronto, ON, M5G 2A2, CanadaTel +1 416-597-3422 x 4612Email dinesh.kumbhare@uhn.caAbstract: The most common cause of chronic musculoskeletal pain is chronic myofascial pain syndrome (MPS). MPS often presents with increased muscle stiffness, and the myofascial trigger point (MTrP). Imaging modalities have been used to identify the MTrP, but their role in the detection and diagnosis of MPS remains unclear. The purpose of this review was to identify evidence in literature for the use of imaging in the role of classifying and explaining the physiology of MTrPs. Since few imaging techniques have been performed on MTrPs, we explored the imaging techniques that can effectively image complex skeletal muscle microstructure, and how they could be used. As part of a scoping review, we conducted a systematic search from three medical databases (CINAHL, EMBASE and MEDLINE) from year to year to analyze past MTrP imaging, as well as analyzing imaging techniques performed on the microstructure of muscle. Previously, ultrasound has been used to differentiate active, latent MTrPs, but these studies do not adequately address their underlying anatomical structure. MRI remains the standard method of imaging skeletal muscle. The existing MRI literature suggests that the DTI technique can quantify muscle injury, strain, and structure. However, theoretically, HARDI and DKI techniques seem to provide more information for complex structural areas, although these modalities have a disadvantage of longer scan times and have not been widely used on skeletal muscle. Our review suggests that DTI is the most effective imaging modality that has been used to define the microstructure of muscle and hence, could be optimal to image the MTrP. HARDI and DKI are techniques with theoretical potential for analysis of muscle, which may provide more detailed information representative of finer muscle structural features. Future research utilizing MRI techniques to image muscle are necessary to provide a more robust means of imaging skeletal muscle and the MTrP.Keywords: myofascial pain syndrome, MRI, trigger points, chronic pain, imaging

A mild traumatic brain injury (mTBI), commonly referred to as a concussion, is when the brain experiences an abrupt acceleration and/or deceleration that sends shock waves through the brain tissue, upsetting its structure and function. A mTBI is a heterogeneous condition with acute and chronic outcomes for patients. The chronic form of mTBI can lead to a wide range of neurological, behavioral, and cognitive symptoms. Critically, this injury is not defined by a simple process or pathophysiological event but rather biomechanical and neurological brain damage that can trigger highly complex physiological cascades. These further lead to a wide range of cellular, molecular, and functional changes that alter genes and associated metabolites. These changes, if specifically characterized, could be used to predict a patient’s outcome and recovery timeline. Recently, genetic studies showed that specific genotypes could increase an individual’s risk of more severe injury and impaired recovery following mTBI. Consequently, an improved understanding of gene alteration and genetic changes is necessary to develop personalized diagnostic approaches which can guide the design of novel treatments. The current study proposes utilizing bioinformatic tools, biological networks, and databases to identify potential genes and microRNAs associated with the mTBI in order to aid the early diagnosis of mTBI and track recovery for individual patients. With bioinformatic techniques, we were able to identify and compare genetic and epigenetic data associated with mTBI, as well as understand the various aspects of molecular changes after brain injury. Ultimately, we analyzed and cataloged the biological pathways and networks associated with this injury. A critical search of online bioinformatics databases was performed to determine interactions between mTBI-related genes, and relevant molecular processes. The major finding was that APOE, S100B, GFAP, BDNF, AQP4, COMT, MBP, UCHL1, DRD2, ASIC1, and CACNA1A genes were significantly associated with mTBI outcome. Those genes are primarily involved in different neurological tasks and neurological pathways such as neuron projection regeneration, regulation of neuronal synaptic plasticity, cognition, memory function, neuronal cell death and the dopaminergic pathway. This study predicted specific miRNAs linked to mTBI outcomes and candidate genes (hsa-miR-204-5p, hsa-miR-16-5p, hsa-miR-10a-5p, has-miR-218-5p, has-miR-34a-5p), and RNA-seq analysis on the GSE123336 data revealed that one miRNA found (hsa-miR-10a-5p) matched our predictions related to mTBI outcomes. Pathway analysis revealed that the predicted miRNA targets were mainly engaged in nervous system signaling, neuron projection and cell differentiation. These findings may contribute to developing diagnostic procedures and treatments for mTBI patients who are still experiencing symptoms, but validation of these genetic markers for mTBI assessment requires patient participation and correlation with advanced personalized MRI methods that show concussion related changes. Thesis Master of Applied Science (MASc) Traumatic brain injury (TBI) is a highly prevalent neurological injury affecting millions of individuals globally. Mild TBI (mTBI), sometimes called concussion, makes up over 85% of TBI cases. A mTBI is a heterogeneous condition with acute and chronic outcomes for patients and involves complex cascades of cellular and molecular events that can lead to functional changes in genes and associated metabolites. In recent genetic studies, it has been shown that certain genotypes are associated with a higher risk of experiencing a more serious injury and a slower recovery after mTBI. These genes can be utilized as crucial biomarkers to predict how long it will take for a person to recover from a concussion. The purpose of this study was to find potential biomarkers that could help in the early detection of mTBI and the monitoring of individual patients’ recovery. It was hypothesized that genes and miRNAs (and their associated proteins) involved in neuronal body, axonal and myelin integrity and regeneration would be identified as important markers of severity.

High contact sports put athletes at a higher risk of sustaining a concussion. This work focused on assessing regional brain health in aging, retired Canadian Football League (rCFL) players years to decades after retirement. Advanced, quantitative magnetic resonance imaging (MRI) techniques were implemented to identify and quantify microstructural brain white matter damage, cognitive functional signal characteristics (fractal dimension (FD) and amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF)), and cerebral blood flow (CBF) dysregulation. Due to the high reproducibility of diffusion tensor imaging (DTI) and resting state functional MRI (rsfMRI), a Z-scoring approach exploring outliers relative to a large normative dataset was implemented to examine each rCFL subject individually. However, arterial spin labelling (ASL) data is more sensitive to scanner inconsistencies, therefore a group-wise analysis was performed with the CBF and ASL spatial coefficient of variance (ASL sCoV) data. Minimal microstructural damage was detected in the rCFL subjects, but a substantial amount of functional and CBF abnormalities were present. The FD was significantly reduced in 48 of 91 regions-of-interest (ROIs) examined, and the four rCFL subjects with the highest number of abnormal ROIs all exhibited worse motor speed, social functioning and general health scores than the other rCFL subjects. Furthermore, the ALFF analysis identified the cerebellum, parietal lobe ROIs, and central sub-cortical ROIs to be consistently abnormal. Finally, the temporal occipital fusiform cortex, superior parietal gyrus, caudate nucleus, and the cerebellum were significantly abnormal bilaterally based on CBF and ASL sCoV values, which also correlated with worse physical functioning and elevated daily chronic pain. This work adds to the growing literature that brain changes are present later in life that may be related to concussions and repetitive sub-concussive head impacts sustained years earlier. Several consistently damaged ROIs also correlated with adverse clinical presentations to indicate areas of future research. Dissertation Doctor of Philosophy (PhD) Clinical concussion assessment has a limited ability to identify brain injury location and severity. Therefore, there is a need for more advanced diagnostic tools to provide meaningful, objective information to concussion patients and clinicians. The work presented in this thesis aimed to assess brain health using magnetic resonance imaging (MRI) techniques of retired professional football players with a complex history of concussions and repetitive sub-concussive impacts. Our research found concussion-related functional and cerebral blood flow brain abnormalities past that of normal aging, but minimal white matter damage, present in the retired athletes that also correlated with clinically testable health metrics such as motor speed, emotional well-being, and pain. Through personalized subject-specific analyses, this work provides further evidence of the effects of concussions later in life.

Sodium (23Na) plays a critical role in all organisms – it is crucial in cellular homeostasis, pH regulation and action potential propagation in muscle and neuronal fibres. Healthy cells have a low intracellular 23Na and high extracellular concentration, with the sodium-potassium pump maintaining this sodium gradient. In the human brain approximately 50% of its total energy consumption is occupied by maintenance of this gradient, demonstrating the pump’s importance in health. A failure of the sodium-potassium pump leads to cellular apoptosis and ultimately necrosis, with potentially disastrous results for neurological function. Magnetic resonance imaging (MRI) of 23Na is of great interest because of the ubiquity of sodium in cellular processes. However, it is hampered by many technical challenges. Among these are a low gyromagnetic ratio, short T2∗ relaxation times, and low concentrations all of which lead to long acquisitions in order to account for the poor inherent signal. In addition, 23Na MRI requires specialized hardware, non-standard pulse sequences and reconstruction methods in order to create images. These have all contributed to render clinical applications for 23Na MRI virtually non-existent, despite research indicating sodium’s role in various neurological disorders, including multiple sclerosis, Alzheimer’s, stroke, cancer, and traumatic brain injury. This work is motivated by a desire to use 23Na MRI in clinical settings. To that end, hardware and software methods were initially developed to process sodium images. In order to quantify the imaging system the point-spread function (PSF) and the related modulation transfer function (MTF) were calculated with the aid of a 3D-printed resolution phantom with different 23Na concentrations in gelatin. Two pulse sequences, density-adapted projection reconstruction (DA-3DPR) and Fermat looped orthogonally encoded trajectories (FLORET), with similar acquisition times were tested. Reconstructions were performed with the non-uniform fast Fourier transform. Results indicated a full-width, half-maximum (FWHM) value of 1.8 for DA-3DPR and 2.3 for FLORET. In a follow-up study, simulation experiments were added to various sodium phantom concentrations in 3% agar. The simulations indicated high potential variability in the MTF calculations depending on the methodology, while the phantom experiments found a FWHMs of 2.0 (DA-3DPR), and 2.5 (FLORET). Diffusion tensor imaging (DTI) is an MRI technique with wide adoption for the assessment of a variety of neurological disorders. Combining DTI with 23Na MRI could provide novel insight into brain pathology; however, a study with a healthy population is warranted before examinations with other populations. Fifteen subjects were scanned with DTI and sodium MRI, and the latter was used to derive voxel-wise tissue sodium concentration (TSC). Regional grey and white matter (WM) TSC was analyzed and compared to fractional anisotropy (FA) and cerebrospinal fluid (CSF) proximity. Results indicated that WM voxels proximal to CSF regions (i.e. corpus callosum) could have lower than expected FA values and higher measured TSC, with an inverse correlation between TSC and distance to CSF. This is likely the result of the broad PSF of 23Na MRI, as regions distal to CSF did not exhibit this phenomenon. This potentially represents a confounding effect when interpreting sodium concentrations, especially in regions proximal to the high 23Na content in CSF. Thesis Doctor of Philosophy (PhD)

Traditional 1H lung imaging using MRI faces numerous challenges and difficulties due to low proton density and air-tissue susceptibility artifacts. New imaging techniques using inhaled xenon gas can overcome these challenges at the cost of lower signal to noise ratio. The signal to noise ratio determines reconstructed image quality and is an essential parameter in ensuring reliable results in MR imaging. The traditional RF surface coils used in MR imaging exhibit an inhomogeneous field, leading to reduced image quality. For the last few decades, fractal-shaped antennas have been used to optimize the performance of antennas for radiofrequency systems. Although widely used in radiofrequency identification systems, mobile phones, and other applications, fractal designs have yet to be fully researched in the MRI application space. The use of fractal geometries for RF coils may prove to be fruitful and thus prompts an investiga- tion as the main goal of this thesis. Preliminary simulation results and experimental validation results show that RF coils created using the Gosper and pentaflake offer improved signal to noise ratio and exhibit a more homogeneous field than that of a traditional circular surface coil. Thesis Master of Applied Science (MASc)

Aerobic exercise is recognized for its many benefits to the cardiorespiratory system, as well as the brain. For this reason, aerobic exercise has been extensively investigated over the last decade to understand the mechanisms involved in its beneficial effects. However, the model of fitness-related neural plasticity remains incomplete. Purpose: The primary goal of this thesis was to investigate the effect of long-term aerobic exercise, in the form of cardiorespiratory fitness, on neurotransmission. In order to achieve this goal, methodological validation was required. The secondary goal was to investigate commonly assessed structural changes associated with exercise, to compare with previous literature. Materials and Methods: The first experiment involved phantom and human validation of measures of the neurotransmitter g-aminobutyric acid (GABA) using magnetic resonance spectroscopy (MRS). Following this objective, the second experiments recruited a total of thirty-five healthy post-menopausal women to investigate the effect of fitness on neurophysiological and structural measures. Transcranial magnetic stimulation (TMS) and MRS were used to evaluate GABA and glutamate (Glu) concentrations and receptor function in the primary motor cortex (M1). Magnetic resonance imaging (MRI) was used to assess cortical thickness (CT) and the microstructure of white matter (WM) tracts. Results: Regression analysis found that fitness improved the microstructure in pre-motor and sensory tracts, as well as the hippocampal cingulum in post-menopausal women. There was no effect of fitness on CT nor neurotransmission. This suggests cardiorespiratory fitness may preserve motor control and tactile acuity, as well as memory in post-menopausal women via improvements in WM microstructure. Conclusion: The results provided in this thesis can improve our understanding of how aerobic exercise and cardiorespiratory fitness achieve their benefits in order to create efficient training programs to prevent agerelated decline and improve prognosis of age-related disease. Thesis Master of Applied Science (MASc)

Phosphorus magnetic resonance spectroscopy and spectroscopic imaging (31P-MRS/MRSI) non-invasively provide very important information regarding energy metabolism as they can detect high energy metabolites and membrane phospholipids in vivo. They have repeatedly proven their utility in the study of healthy and disease conditions, as many disorders are related to imbalances in bioenergetic processes. However, they are not often used in a clinic setting as there are technical challenges that lead to very long acquisition times. To address this issue, the present work focused on the implementation of two fast phosphorus magnetic resonance spectroscopic imaging (31P-MRSI) pulse sequences. The first one, "fidEPSI" uses a flyback echo planar readout trajectory calculated in real time to achieve an acceleration factor up to x10. The second, "fidepsiCS" further accelerates the acquisition by combining the flyback EPSI readout with a compressed sensing (CS) sampling scheme. For this latter approach two different data reconstruction processes were compared. Both sequences were tested in phantoms as well as in skeletal muscle and brain tissues of healthy volunteers. The results showed feasibility of the flyback Echo Planar Spectroscopic Imaging (EPSI) to acquire good quality data in a fraction of the time when compared to traditional phase encoded MRSI. Furthermore, the compressed sensing approach was used in an exercise-recovery paradigm to evaluate skeletal muscle high energy phosphate dynamics, achieving a temporal resolution of 9 seconds. Additionally, the comparison of CS reconstruction algorithms suggested that a low-rank approach is more suitable for 31P-MRSI data, compared to traditional thresholding, due to the fact that it exploits the sparsity of the NMR signal as the least number of spectral peaks rather than the fewest amount of non-zero values. Overall, this thesis presents new accelerated methods for the acquisition of 31P-MRSI, and its use in the evaluation of energy metabolism. Thesis Doctor of Philosophy (PhD)

Radiation therapy has a significant role in the management of cancer patients. Computed tomography (CT) has been at the forefront of radiation therapy planning due to its widespread diagnostic use and its electron density information. Magnetic resonance (MR) imaging is another proven diagnostic modality, which can achieve superior soft tissue contrast and margin delineation, relative to CT. As such it has become a valuable tool for cancer diagnoses and staging. In this study, a centre-out radial acquisition using an off-resonance reception (co-RASOR) MR sequence, sensitive to magnetic field inhomogeneity, was applied to excite a broader frequency range of spins in the vicinity of metallic seeds. The resultant images display local hyperintensities around metallic markers. These images were then reconstructed with frequency offsets to rewind these hyperintensities to the geometric centre to obtain positive contrast. The contrast-to-noise ratio (CNR) was measured between a fiducial and its surrounding to compare Fourier and iterative reconstruction methods for undersampled co-RASOR. The motivation was to reduce the sequence acquisition time, while preserving sufficient CNR and resolution. For single slices, acquisition was 2.8 sec and multi-slice acquisition could acquire more than 50 slices in 73 sec, by reducing the acquired data by a factor of 8. This effectively encodes acquisition to 1.4 sec/slice. The noise present in undersampled images decreased significantly using iterative reconstruction methods, but a total variation based penalty better preserved the edges. Further extensions to the reconstruction method applied frequency-based filters that could isolate signals from different metallic compounds. The local hyperintensities rewind using opposite signed frequency offsets for diamagnetic and paramagnetic seeds. This allowed individual visualization of a low dose rate (LDR) brachytherapy seed and a gold fiducial marker. Phantom validation showed that each seed contains its maximal CNR in opposing frequency regions. The relative difference between global and local maxima in each frequency band ranged from 1.19 -- 3.73, and a single cut-off frequency was successfully applied for each acquisition plane. Image guidance systems rely on the position of these fiducial markers to compare daily setup images with CT and MR simulations. Phantom experiments and porcine tissue samples were used to assess the minimum separation of fiducials, geometric accuracy, and random errors associated with using the co-RASOR sequence. co-RASOR images were able to resolve fiducials separated by 0.5 - 1 cm, depending on image resolution. No systematic biases were observed by comparing co-RASOR to CT using rigid body registrations. The standard deviation of the systematic errors were \textless 0.5 mm between MR and CT registrations, and \textless 0.4 mm between MR scans without CT. These values are smaller than the current total systematic uncertainties, which should be limimed to

A magnetic resonance imaging (MRI) compatible near infrared spectrometer (NIRS) system was developed and evaluated for continuous-wave diffuse optical spectroscopy (DOS) and concurrent functional MRI measurements of human muscle. Phantom and in-vivo experiments using the system’s fiber bundle suggested that an isolation distance greater than 8 mm needs to exist between adjacent illumination-detection channels. Using single and probe-pair arrangements (inter-fiber separations of 80 µm and 5 mm, respectively), in-vivo DOS point-measurements (total=20 images) were performed on 1) the antecubital vein and a reference tissue area and 2) the lower leg at the medial (MG) and lateral gastrocnemius (LG) under isokinetic exercise. Mean spectral morphological differences and relative mean intensity changes at Hemoglobin key wavelengths were found, namely reduced mean pixel intensity (~30%) for the vessel-area and a signal change of ~1-4% between the rest and the recovery condition at both muscle locations for the single-probe configuration. Subsequent work is necessary to evaluate the oxygenation assessment capabilities of this system. Lastly, experiments were performed in which two volunteers had concurrent measurement of optical and blood oxygen level dependent (BOLD) MRI, before and following exercise. The same probe arrangement was used for DOS measurements for this experiment. The BOLD signal was studied for manually-derived ROIs. BOLD recovery curves corresponding to the LG followed routine temporal progression where immediate post-exercise signal is hypointense, followed with a sigmoidal-shaped recovery. A decrease ranging between ~0.1-20% was found in the normalized mean spectral signal (20 images) for recovery with reference to the rest condition at both muscle locations for single-probe measurements and for one probe-pair measurement (for 800,808 and 850 nm). The specific trend of the measured decrease in the mean spectral curves during recovery was not consistent among these trials. Future steps include repeatable phantom experiments, increased optical power delivery, enhanced skin contact and improved reflectance measurements Thesis Master of Applied Science (MASc)

Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) method that resolves structures by three-dimensional measurement of water movement, and has shown to benefit studies of anisotropic tissues such as brain and skeletal muscle. While many studies have used DTI to non-invasively study static tissue architecture, little attempt has been made to use this technique to temporally characterize muscle during post-exercise recovery. Thus, the goal of this work was to use DTI to study the timecourse of changes in skeletal muscle following exercise. The first study was performed to test stability of DTI eigenvectors (ε1 ε2 ε3), and to determine how time-expensive parameters such as increased number of diffusion directions (NDD) or signal averages (NSA) improve vector stability. The ε2 vector was found to have more directional variability than ε1, and showed less improvement than ε1 with increased NDD or NSA. Furthermore, decreasing directional variability of ε1 was correlated with increasing NDD, not NSA (p

Sodium (23Na) plays a pivotal role in cellular homeostasis throughout all life forms. In the human body it has a plethora of physiological functions including regulation of bodily fluids, muscle contraction, neuronal transmission, and connective tissue integrity. The 23Na nucleus can be visualized using magnetic resonance imaging (MRI) because it has spin 3/2 and is the 100% naturally abundant isotope of sodium. However, unlike hydrogen (1H), the nucleus of choice for MRI scanning, 23Na MR clinical applications are almost non-existent, even though it is the second most MR visible nucleus after 1H. This is primarily because 23Na requires its own customized hardware (i.e. radiofrequency RF coil) and software (i.e. pulse sequence/acquisition and image reconstruction techniques). Additionally, 23Na MR is challenging because of significantly lower signal-to-noise ratio (SNR), which translates to a requirement for lengthy scans and lower spatial resolution. Hence, development and optimization of 23Na MR acquisition techniques is an ongoing subject of research. In this dissertation development and optimization of approaches that exploit sodium as a biomarker for musculoskeletal health are described. Specifically, discussions of advanced 23Na MR techniques fall into two main categories: magnetic resonance imaging (MRI) and spectroscopy (MRS). The work first explored development of a MRI compatible electrical muscle stimulation (EMS) system that could be used as a consistent alternative to voluntary muscle contraction. A variety of MRI methods were used to confirm the similarity between stimulation and voluntary activation of muscles of the lower leg. In a follow- up study quantum filtered (QF) 23Na MRS was used to assess dynamic changes in skeletal muscle before, during and following voluntary exercise. Total (single quantum filtered, SQF) and bound intracellular sodium (triple quantum filtered, TQF) were measured in 9 healthy subjects with a 12s temporal resolution. Total sodium (SQF) significantly increased 4% (p < 0.01), while bound intracellular sodium content decreased 7% (p < 0.01) with exercise. Both returned to baseline following exercise; TQF after a few seconds and SQF after approximately 12 minutes (p < 0.05). In a preliminary study the MR-compatible EMS unit demonstrated similar QF 23Na MRS results. Sodium MR imaging, like typical 1H-MRI scanning, can be performed by rasterizing k-space. However, this approach is both temporally and SNR inefficient. There- fore newer optimized 23Na MRI pulse sequence approaches have been developed. The cost-benefit of extending the acquisition window length in terms of SNR gain and blurring in the in vivo 23Na MRI of the human knee was explored in 3 healthy subjects using a density adapted 3-dimensional projection reconstruction (DA-3DPR) sequence. Mean SNR doubled when the acquisition window was increased from 4 to 25ms. Concurrently, the FWHM, as a measure of cartilage blurring, increased by only 1±0mm across three different sections of articular cartilage. In a second imaging experiment, a pseudo-random 3D non-Cartesian k-space acquisition scheme for 23Na MRI was introduced. This scheme was highly effective in minimizing the aliasing artifacts leading to 9 times less number of shots required to cover k-space compared to a fully-sampled acquisition scheme. Hence, this resulted in a 9-fold reduction in scan time to cover k-space. Images of a resolution phantom and healthy human knee, with 3mm isotropic resolution (zero padded to 1mm isotropic resolution), were reconstructed using a non-uniform fast Fourier transform (NUFFT). Dissertation Doctor of Philosophy (PhD)

The rapid advancements in the field of machine learning and artificial intelligence has led to the emergence of technologies like the Brain Computer Interface (BCI), which has revolutionized rehabilitation protocols. However, given the neural basis of BCIs and the dependence of its performance on cognitive factors, BCIs may be used to characterize the functional capacity of the user. A resting state segment can also be considered for characterization of the functional network integrity, creating a two part framework that probes the functional networks and their cognitive manifestations. This thesis explores such a two part framework using a simultaneous EEG-fMRI setup on a healthy population. The BCI accuracies for all subjects increased over the course of the scan and is thought to be due to learning processes on the subject's part. Since such learning processes require cognitive faculties such as attention and working memory, these factors might modulate the BCI performance profile, making it a potential metric for the integrity of such cognitive factors. The resting state analysis identified four EEG Microstates that have been previously found to be associated with verbal, visual, saliency and attention reorientation tasks. The proportion of each microstate that composed the corresponding fMRI resting state networks (RSN) were identified, opening up the potential for predicting fMRI-based RSN information, from EEG microstates alone. The developed protocol can be used to diagnose potential conditions that negatively affect the functional capacity of the user by using the results from this study as healthy control data. This is the first known BCI based system for characterization of the user's functional integrity, opening up the possibility of using BCIs as a metric for diagnosing a neuropathology. Thesis Master of Applied Science (MASc)

Diagnosing diffuse liver disease first involves measurement of blood enzymes followed by biopsy. However, blood markers lack spatial and diagnostic specificity and biopsy is highly risky and variable. Although structural changes have been evaluated using diffusion weighted imaging (DWI), the technique is minimally quantitative. Quantitative MR diffusion approaches, such as intra-voxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) have been proposed to better characterize diseased liver. However, the so called pseudo-hepatic artefact due to cardiac motion, drastically affects DWI results. The overall goals of this thesis were thus to evaluate the pseudo-hepatic anisotropy artefact on the quality of diffusion tensor (DT) and IVIM metrics, and to identify potential solutions. Intra- and intersession DTI repeatability was evaluated in healthy human livers when varying the number of diffusion encoding gradients (NGD) and number of signal averages (NSA). Although no further advantage was observed with increasing NGD beyond 6 directions, increased NSA improved intra- and inter-session repeatability. The pseudo-hepatic artefact resulted in increased fractional anisotropy (FA) and tensor eigenvalues (λ1, λ2, λ3), most prominent in the left liver lobe during systole of the cardiac cycle. Without taking advantage of tensor directional information, increasing the acquired NGD slightly improved IVIM fit quality thus helping to minimize the pseudo-hepatic artefact. Combining IVIM and DTI resulted in FA values closer to the hypothesized value of 0.0, which, based on liver microstructure is most logical. Although both IVIM-DTI and DTI-IVIM exhibited similar fit R2 values, the latter failed more often, especially near major blood vessels. Thus, IVIM-DTI was concluded to be more robust and thus the better approach. Thesis Doctor of Philosophy (PhD)

Diffusion tensor (DT) and blood oxygen-level dependent (BOLD) imaging are two noninvasive magnetic resonance (MR) techniques that have been used to probe skeletal muscle microstructure and microvasculature, respectively. Over a series of four studies, the work in this thesis aimed at furthering our understanding of baseline DT metrics and BOLD signals in lower limb muscles (calf and foot) of healthy young subjects. Since postural changes have been shown to alter numerous quantities, including fluid volumes and muscle cross sectional area, DT indices and BOLD signal characteristics were examined in response to movement from upright to supine position. Reductions of 3.2-6.7% and 3.4-7.5% were measured in calf DT eigenvalues and apparent diffusion coefficient (ADC) in the various muscles, following 34 and 64 minutes of supine rest, respectively (P Establishment of baseline diffusion metrics in the foot region was feasible (chapter 6). Examination of foot DT indices in response to positional change showed that the metrics decreased from 2.7-4.6% following 34 minutes of supine rest (P Doctor of Philosophy (PhD)

This thesis presents a family of automatic elastic registration methods applicable to single and multimodal images of similar or dissimilar dimensions. These registration algorithms employ a generic dynamic linear elastic continuum mechanics model of the tissue deformation which is discretized using the finite element method. The dynamic deformation model provides spatial and temporal correlation between images acquired from different orientations at different times. First, a volumetric registration algorithm is presented which estimates the deformation field by balancing internal deformation forces of the elastic model against external forces derived from an intensity-based similarity measure between images. The registration is achieved by iteratively solving a reduced form of the dynamic deformation equations in response to image-derived nodal forces. A general approach for automatic deformable image registration is also presented in this thesis which deals with different registration problems within a unified framework irrespective of the image modality and dimension. Using the dynamic deformation model, the problem of deformable image registration is approached as a classical state estimation problem with various image similarity measures providing an observation model. With this formulation, single and multiple-modality, 3D-3D and 3D-2D image registration problems can all be treated within the same framework.The registration is achieved through a Kalman-like filtering process which incorporates information from the deformation model and an observation error computed from an intensity-based similarity measure. Correlation ratio, normalized correlation coefficient, mutual information, modality independent neighborhood descriptor and sum of squared differences between images are similarity/distance measures employed for single and multiple modality image registration in this thesis Doctor of Philosophy (PhD)

Chronic kidney disease (CKD) has an annual mortality rate of 22% and can cause secondary complications including hypertension, anemia, secondary hyperparathyroidism, and malnutrition. Currently, clinical diagnosis and evaluation of CKD involves blood and urine testing and biopsy. MRI is not currently used to image CKD, but there is an interest in developing MRI techniques to test kidney function. Usually, renal functional MRI refers to single images reflecting tissue oxygenation. Using time series information may offer additional information about changes in kidneys as a result of disease. In this thesis, blood oxygen level-dependent (BOLD) MRI and diffusion weighted imaging (DWI) were used to investigate the effects of breath holding and water loading on kidneys. First, BOLD MRI was used to measure effects of breath holding on BOLD signal intensity. DWI and fractal analysis were used to measure changes in diffusion, perfusion and microcirculation shortly after water loading. Breath holding results showed no effect on temporal BOLD signal intensity in young, healthy subjects. A significant decrease in signal intensity was measured in the kidney of a single subject with impaired renal function. Although the renal BOLD signal was found to have fractal characteristics, no changes were measured using this technique between pre- and post-water loading scans during the time period examined. Because the signal appears to behave fractally, this technique may be a good candidate for similar kidney function studies in the future. DWI also remained unchanged as a result of water loading during the post-water loading time period examined. Master of Applied Science (MASc)

Alzheimer’s disease (AD) is a degenerative disease with progressive deterioration of neural networks in the brain. Fractal dimension analysis (FD) of resting state blood oxygen level dependent (BOLD) signals acquired using functional magnetic resonance imaging (fMRI) allows us to quantify complex signalling in the brain and may offer a window into the network erosion. This novel approach can provide a sensitive tool to examine early stages of AD. As AD progresses, we expect to see a reduction in brain connectivity and signal complexity concurrent with biochemical changes (e.g. altered levels of N-acetyl aspartate (NAA), myoinositol (mI) and glutamate as measured using magnetic resonance spectroscopy, MRS), volumetric changes and abnormally high levels of brain iron. Over a series of 4 studies we examined the relationship of BOLD signal complexity and functional connectivity with documented MRI markers of pathology in AD (n=38) as compared to normal controls (NC) (n=16). AD subjects were in early stage of illness (mild to moderate impairment on the mini mental state exam, MMSE). We validated the temporal (short term (within minutes) and longer term (over a number of months)) consistency of FD measurement and choice of BOLD acquisition method (spiral vs. EPI), provided MRI sequence repeat time (TR) was kept constant. FD reduction (decrease in signal complexity) correlated with worsening pathological values on MRS (­NAA decrease and mI increase) and with a decrease in functional connectivity. This demonstrates that FD (signal complexity) reduces in proportion to AD severity. FD reduction is connected to functional connectivity measured through resting state network (RSN) analysis suggesting the reduction in FD relates to neuronal loss rather than altered vascularity. The narrow range of cognitive impairment (such as scores on the MMSE or the clinical dementia rating scale, CDR) likely precluded correlation between these measures and FD or RSN. Functional connectivity (RSN) was also reduced when brain iron levels were increased within certain network nodes (posterior cingulate cortex and lateral parietal cortex). Therefore iron deposition may play a role in network disruption of AD brains. The overall conclusion of this thesis is that signal complexity of BOLD fMRI signals, as measured with FD, may detect early pathology in the progression of AD. FD can detect neuronal changes in deep brain structures before volume loss in these structures and before significant changes in MRS markers were detectable between the AD and NC groups. An FD change mirrors disruptions in functional connectivity but detection is not limited to RSN nodes in the brain. This novel approach could further our understanding of AD and may be applied to other pathologies of the brain. Doctor of Philosophy (PhD)

Breast cancer is a serious health problem that severely affects the society. Science and engineering communities are looking to find more advanced and new cures to contain this deadly disease. There has been considerable success in increasing the efficacy of conventional imaging techniques for breast cancer detection such as mammography. However, the use of ionizing radiation, the incidence of patient discomfort and the low specificity are some of the negative aspects of mammography. Also, the chances to successfully cure breast cancer can increase manifold with early detection of the malignant tumors. Magnetic Resonance Imaging (MRI) is successful with its highly clear and detailed images, but it is considered too expensive for wide screening. Its low specificity is another disadvantage. Microwave imaging of the breast, which uses non-ionizing radiation, is avery active research area of recent times. It is hoped that once developed, it can override the negative aspects of the existing imaging modalities. The idea is to detect malignant lesions in the breast based on their electrical-property contrast with healthy breast tissues. The electrical properties of biological tissues in the microwave region are described by their complex permittivity. Previous studies claimed that malignant tumors have very high permittivity and high loss compared to the surrounding healthy tissue. It was assumed that the modality exploiting this contrast can easily detect sub-centimeter tumors. Hence, very simple models with high permittivity and loss tumor models embedded in low permittivity homogenous models were employed to show the detection capabilities of microwave imaging techniques. The examples were fairly amateurish and claimed unrealistic performance of the rather simplistic microwave imaging techniques. Recent studies have shown that the breast is not as simple an electromagnetic medium as was thought previously. It is a complex heterogeneous environment with high permittivity and high loss healthy tissues (such as glandular tissue) and low permittivity and low loss healthy tissues (such as fat). The internal tissue distribution and volume varies significantly from woman to woman. Thus, simple models made with hemispheres, cylinders, etc., filled with water or oil cannot mimic the reality of the breast in imaging experiments and simulations. This is why there is a considerable demand of representing breasts as realistic physical and numerical models. Physical models are required to experimentally verify the imaging scanning systems with antennas. The numerical models are required for electromagnetic (EM) simulations that are indispensable in designing and testing image reconstruction algorithms. The work in this thesis mainly deals with the construction and representation of breast models both in experiments and in simulations. This is impoliant work toward making microwave imaging a practical stand-alone detection system. Master of Applied Science (MASc)

Chemotherapy Induced Peripheral Neuropathy (CIPN) is known to impact negatively on patients' quality of life. It has been reported that these patients tend to have sensitivity thresholds to stimuli, such as pain and temperature, that are different from those of normal subjects. The effect of chemotherapeutic agents on the central nervous system (CNS) has been observed; however, most of the mechanisms involved are not exactly understood. A quantitative investigation into the temperature sensitivity changes in the spinal cords and brains of chemotherapy patients would provide important information in understanding the side effects of this treatment modality. In the first part of the project, the temperature perceptional changes in terms of brain activation patterns of the chemotherapy patients with CIPN are studied using brain function MRI. In the second part of the project, the structural changes of the brain and spinal cord of chemotherapy patients with CIPN are studied using diffusion tensor imaging (DTI). High b-value (b = 1500 s/mm2) and low b-value (b=650 s/mm2) settings will be use during the spinal cord DTI scans. Due to the sample size limitation, no comparison between healthy volunteers and CIPN patients can be done based on the existing temperature fMRI data. However, the developed temperature fMRI protocol shows good reliability in detecting temperature response. Based on the spinal cord DTI result using b = 1500 s/mm2, decrease in FA value has been observed. The corresponding FA values of CIPN patient and healthy volunteers are 0.28±0.10 and 0.41±0.02 , respectively. (t-test = 2.63 >2.447, p=0.05 level of significant) However, no significant difference is observed in other diffusion parameters. This results also suggests that application of high b-value setting is more suitable as it is better at detecting diffusion at microstructure. Thesis Doctor of Philosophy (PhD)