Biomedical Physiology and Kinesiology - Theses, Dissertations, and other Required Graduate Degree Essays

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Cardiovascular autonomic control after spinal cord injury: Comprehensive investigations into classification and care

Author: 
File(s): 
Date created: 
2020-04-26
Supervisor(s): 
Victoria Claydon
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) Ph.D.
Abstract: 

Over 86,000 Canadians live with the consequences of a spinal cord injury (SCI). Injury to spinal autonomic pathways can lead to profound cardiovascular autonomic dysfunction. Key areas of concern identified by individuals living with SCI relate to continence and cardiovascular dysfunction. Conditions that result from autonomic dysfunction, such as autonomic dysreflexia (sudden extreme hypertension) are of particular concern. This thesis examined the cardiovascular autonomic consequences of SCI and their relationship to bowel care, the most potent stimulus for dysreflexia, and a key factor that negatively impacts quality of life after SCI. To assess cardiovascular autonomic control, first a quantitative marker of autonomic dysfunction following SCI had to be identified. In Aim 1 (Chapter 3), cardiovascular dysfunction during, and beyond, the first year of injury (n=63) was assessed using a novel quantitative non-invasive marker of cardiovascular autonomic control. From here, a randomized double-blind placebo-controlled crossover clinical trial to determine the effect of topical afferent blockade (lidocaine) on dysreflexia severity during bowel care was conducted (n=13). Aim 2 (Chapter 4) provides evidence that, contrary to current clinical guidelines, topical lidocaine prolongs bowel care, worsens dysreflexia, and increases cardiovascular symptoms. Despite bowel care concerns, past research shows that individuals do not change bowel care practices, highlighting knowledge translation gaps concerning evidence-based bowel management strategies. To address this, in Aim 3 (Chapter 5), semi-structured interviews (n=13) were used to examine the barriers and facilitators to changing bowel care. The largest influences on changing bowel care and potentially relevant intervention options were identified. Finally, during dysreflexia profound sympathetic stimulation may increase risk for cardiac arrhythmia. Aim 4 (Chapter 6) evaluated susceptibility to arrhythmia in a rodent-model of SCI, the impact of the sympathomimetic drug dobutamine on arrhythmia risk, and the potential mitigating effect of exercise training. SCI increased susceptibility to cardiac arrhythmia, with dobutamine further increasing susceptibility in high-level SCI. Exercise training ameliorated markers of arrhythmia risk during dobutamine. The research conducted in this thesis uses a translational and patient-orientated approach to bridge the gap between physiological understanding and meaningful improvement in the clinical setting for individuals living with cardiovascular and continence implications of SCI.

Document type: 
Thesis

Task-phase fMRI in detection of improvements in working memory post-interventions for carotid stenosis and early Alzheimer’s disease

Author: 
File(s): 
Date created: 
2021-09-24
Supervisor(s): 
Sam Doesburg
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.
Abstract: 

Working memory allows for coordination of complex goal-driven behavior. Decline of working memory is linked to severe cognitive disabilities and is an important feature of both severe carotid stenosis and Alzheimer's disease. Functional Magnetic Resonance Imaging (fMRI) can help detect functional brain changes for the evaluation of the impact of standard clinical interventions for both diagnoses. This thesis used fMRI, coupled with cognitive tasks to investigate possible working memory improvements post-standard clinical interventions for both conditions. The study observed post-intervention improvements in task-phase fMRI brain activation patterns together with improvements in task performance. Meanwhile, patients demonstrated complex response patterns associated with disease expression and other individual variability, which were considered with results interpretation. This thesis showed that working memory improvements were possible following standard clinical treatments for both conditions. It also supports for tailoring interventions based on patient peculiarities to maximize treatment effectiveness.

Document type: 
Thesis

Investigating metabolic dysfunction and arrhythmogenesis in an early-onset atrial fibrillation patient cohort

Author: 
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Date created: 
2021-04-23
Supervisor(s): 
Glen Tibbits
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.
Abstract: 

Despite the prevalence of atrial fibrillation (AF) and the burden it places on health care systems, there remains much that is unknown regarding heritable factors influencing its development and progression. In this study, I investigated whole-exome sequencing (WES) data from a cohort of patients presenting with early-onset AF to explore the role that metabolic dysfunction might play in contributing to disease onset. I curated a metabolism-related gene panel and, following in silico prediction of variant pathogenicity, performed gene-level burden testing using reference data from the Genome Aggregation Database (gnomAD) and the human mitochondrial genome database MITOMAP. I further explored genes associating with AF in the UK Biobank data set, and discovered associations with several AF comorbidities including diabetes, hypertension, and stroke.

Document type: 
Thesis

The effects of muscle tissue mass on contractile performance

Author: 
File(s): 
Date created: 
2021-07-14
Supervisor(s): 
James Wakeling
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) Ph.D.
Abstract: 

Skeletal muscles are the motors that drive human and animal locomotion. Yet despite their fundamental importance, our understanding of whole muscle behaviour is relatively limited due to practical and ethical considerations that hinder accurate in vivo measures. To estimate the behaviour of whole muscles, measures of single fibres or fibre bundles are often extrapolated to larger sizes without considering the consequences of the greater muscle mass. The goal of this thesis was to determine the effects of muscle mass on the contractile performance of whole skeletal muscles. In my first study, I developed a novel modelling framework to test different Hill-type model formulations under a range of cyclic contractile conditions. I then used this framework in my second study to examine the effects of distributed muscle mass on mass-specific mechanical work per cycle during cyclic contractions. I found that when the mass-enhanced muscle model was geometrically scaled from the size of a fibre bundle up to a whole human plantarflexor muscle, the mass-specific work per cycle decreased. In my third study, I examined the effects of muscle mass on the contractile behaviour of in situ rat plantaris muscle to validate the mass-enhanced Hill-type muscle model in my second study. In the fourth study of my thesis, I simulated cyclic contractions of a 3D continuum muscle model that accounts for tissue mass across a range of muscle sizes. I additionally compared the effects of greater muscle mass on tissue accelerations of the 3D muscle model to that of the in situ rat plantaris muscle from my third study to qualitatively validate the model simulations. I found that increasing the mass of the 3D muscle increased its volume-specific kinetic energy and was associated with lower mass-specific mechanical work per cycle. In my fifth study, I examined the effects of muscle mass on the metabolic cost and efficiency of muscle during cyclic contractions and how tendons of different stiffnesses alter these relationships. I found that larger muscles with greater mass are less efficient, primarily due to lower mass-specific mechanical work, and that the work and efficiency penalty of larger muscles can be offset to a certain extent by a tendon of optimal stiffness. Taken together, the results of these studies highlight that muscle mass is an important determinant of whole skeletal muscle behaviour.

Document type: 
Thesis

Molecular fingerprinting of VNUT-containing compartments in Neuro-2a cells

Author: 
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Date created: 
2021-09-17
Supervisor(s): 
Damon Poburko
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.
Abstract: 

Vesicular ATP release is involved in regulating biological processes like nociception, blood glucose, and vascular tone. ATP-containing vesicles are filled by the vesicular nucleotide transporter (VNUT) and are molecularly distinct from catecholaminergic vesicles of sympathetic neurons. This work sought to identify the molecular fingerprint of VNUT-containing vesicles. Fluorescence microscopy in Neuro-2a, HeLa, and HEK293 cells showed VNUT being widely dispersed throughout the cells with a perinuclear enrichment. VNUT failed to colocalize with known markers of synaptic vesicles, lysosomes, dense cored vesicles, and catecholaminergic vesicles. Bioinformatic analyses of mammalian VNUT C-terminus identified a unique KDEL-like HEDL motif, as well as a lack of classic synaptic vesicle-targeting dileucine-like and tyrosine-based motifs. This work suggests that VNUT likely resides primarily in the Golgi-ER complex, a previously unconsidered location for what is thought to be a vesicle-associated translocase.

Document type: 
Thesis

Examining the effects of activator compounds on hERG cardiac potassium channel protective currents conducted in response to premature stimulations

Author: 
File(s): 
Date created: 
2020-08-05
Supervisor(s): 
Tom Claydon
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.
Abstract: 

The human ether-a-go-go-related gene (hERG) encodes the rapid delayed rectifier cardiac potassium channel. Vital for repolarization of the myocardium and termination of the cardiac action potential, loss of function in hERG K+ channels can result in Long QT Syndrome Type II (LQTS2). Additionally, hERG channels have been shown to mediate robust repolarizing currents in response to premature depolarizations, reflective of channels remaining in the open state into the refractory period. Thought to be protective against afterdepolarizations, loss of function in this regard may leave individuals susceptible to arrhythmia. Recently, several small molecule activators of hERG have been discovered. The effects of these compounds on the protective currents mediated by hERG channels have yet to be studied. The work presented in this thesis examines the effects of both Type I and II hERG channel activators on protective currents mediated by hERG channels, in the context of an inherited mutation.

Document type: 
Thesis

Thermodynamic characterization of hypertrophic cardiomyopathy associated troponin C mutations

Author: 
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Date created: 
2019-07-15
Supervisor(s): 
Glen Tibbits
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) Ph.D.
Abstract: 

Hypertrophic Cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young adults under the age of 35; a devastating disease that is not yet well understood. To date, greater than 1000 HCM-associated mutations have been found in genes that encode mostly sarcomeric proteins. Familial Hypertrophic Cardiomyopathy (FHC) is the heritable form of HCM. The overlying phenotype of FHC is thought to be derived from an increase in calcium (Ca2+) sensitivity of contraction and impaired relaxation of the myocardium. Dilated Cardiomyopathy (DCM) associated mutations are thought to have the opposite functional effect. This study focuses on cardiac troponin C (cTnC) a component of the cardiac troponin complex where binding of Ca2+ acts as the regulatory switch, leading to a series of conformational changes that culminate in muscle contraction. This project explores Ca2+ binding by focusing on the proximal-most unit of the contractile apparatus. The interaction of Ca2+ with the regulatory domain of cTnC is studied through isothermal titration calorimetry in conjunction with Molecular Dynamics simulations to understand structural and functional changes in the N-terminal region of cTnC. Initially, we established a workflow by exploring the functional consequences of sequence variations in coordinating Ca2+ binding and the genetic control of paralog expression in response to environmental temperature change in zebrafish. We then focused on a series of FHC-associated mutations (A8V, L29Q, A31S, and C84Y), as well as an engineered Ca2+ sensitizing mutation (L48Q), and a DCM-associated mutation (Q50R). The effects of temperature in modulating the Ca2+-cTnC interaction was also studied in these mutants. We further explored the role of cellularly abundant magnesium (Mg2+) which also interacts with cTnC and may modulate the Ca2+ coordinating capabilities of this contractile protein. Lastly, the role of Mg2+ binding to the mutants of interest, under normal cellular condition and in energy depleted states was explored to better understand the etiology of FHC and provide biomedical and physiological insight into potential treatments for this disease.

Document type: 
Thesis

When motor control hangs in the balance: Sensorimotor learning during balance-challenging conditions

Author: 
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Date created: 
2021-03-10
Supervisor(s): 
Daniel S. Marigold
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) Ph.D.
Abstract: 

Maintaining balance while moving is fundamental for safe and successful motor performance. However, this aspect of daily movement is often overlooked in experimental paradigms that assess adaptation during constrained and/or isolated tasks. Consequently, we cannot easily extrapolate the results from these studies to naturalistic motor behaviours. The goal of this thesis is to determine how the necessity to maintain balance during unconstrained movement affects sensorimotor learning. For my first study, I assessed how challenging balance during adaptation affects generalization of learning. Four groups of participants adapted to a new visuomotor mapping induced by prism lenses while performing either a standing-based reaching or walking task, with or without a manipulation that challenged balance. To assess generalization, participants performed a single trial of each of the other group’s tasks without the prisms. I found that both the reaching and walking balance-challenged groups showed greater generalization to their equivalent, non-adapted task compared to the balance-unchallenged groups. I also found that challenging balance modulated generalization across the reaching and walking tasks. For my second study, I tested how challenging balance affected motor memory retention. To do this, the same four groups of participants returned to the lab and repeated their adaptation protocol one week later. I found that only the walking groups demonstrated faster relearning (or savings) during re-exposure to the prisms. Crucially, I found that challenging balance significantly enhanced savings during walking. In my third study, I determined how a stability consequence associated with movement errors affected sensorimotor learning. Two groups of participants adapted to a new visuomotor mapping while performing a precision walking task either with or without the possibility of experiencing a slip perturbation when making errors. I assessed generalization of learning across two visually guided walking tasks and motor memory consolidation. To assess consolidation, I introduced an opposite direction visuomotor mapping following adaptation and evaluated relearning one week later. I found that the experiencing a physical consequence when making errors enhanced generalization and motor memory consolidation. Overall, this thesis provides a novel perspective on how the necessity for balance control contributes to sensorimotor learning, which has intriguing implications for the development of rehabilitation interventions.

Document type: 
Thesis

Examining the potential for information and communication technology to support patients with cardiovascular disease

Author: 
File(s): 
Date created: 
2020-12-01
Supervisor(s): 
Scott Lear
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) Ph.D.
Abstract: 

The overall goal of this work was to investigate the potential of information and communication technology (ICT) to support patients with cardiovascular disease (CVD). There were two specific aims: (1) to determine access to and willingness to use technology for health-related information in patients with CVD; and (2) to develop and pilot test a text-messaging intervention to support patients with acute coronary syndrome (ACS) following discharge from the hospital. The first aim was done with a cross-sectional survey (n=169). ICT ownership was common, as 98% of participants owned at least one ICT device. Computers were the most commonly owned device (88%), the device most commonly used for health information (74% of computer owners), and the device participants had the most interest in using for health information (72% of computer owners). Participants with lower incomes and education levels were less interested in receiving health information on at least one of their devices. The second aim was done with a mixed-methods, assessor-blinded, pilot randomized controlled trial (n=76). An advisory committee composed of patients, researchers, and clinicians developed 48 one-way text messages to send over 60 days to patients with ACS. There were no statistically significant differences between the intervention and usual care groups for self-management domains, medication adherence, health-related quality of life, self-efficacy, and healthcare resource use except for one self-efficacy domain. The study protocol was feasible, except recruitment took longer than anticipated. Ninety-three percent reported they were satisfied with the text messages. In the semi-structured interviews, many participants reported the program made them feel normal, perceived the program to be a source of social support, reinforced they were on the right track, and reminded them of their condition. However, some participants felt they did not need the messages, wished for a more tailored experience, or did not change their behaviours as a result. Learnings from the pilot study should be addressed prior to proceeding to a larger trial. Overall, these two studies indicate that ICT can be acceptable to patients with CVD. Further work needs to be done to determine how to best use ICT to support patients.

Document type: 
Thesis

Inhibition of voltage-dependent sodium currents by cannabidiol

File(s): 
Date created: 
2020-09-29
Supervisor(s): 
Peter Ruben
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) Ph.D.
Abstract: 

Voltage-gated sodium channels initiate action potentials in excitable tissues. Altering these channels’ function can lead to many pathophysiological conditions. The family of voltage-gated sodium channel genes encodes 10 proteins (including Nav2.1) distributed throughout the central and peripheral nervous systems, cardiac and skeletal muscles. The SCN4A gene encodes the Nav1.4 channel, which is primarily responsible for depolarization of the skeletal muscle fibers. Many mutations in SCN4A are found and associated with the myotonic syndromes and periodic paralyses. These conditions are both considered gain-of-function and can be severely life-limiting with respect to performing everyday tasks. From a broader standpoint, hyperexcitability presents as a significant problem in other tissues besides skeletal muscles. Gain-of-function in sodium channels has been linked to a wide-range of pathophysiological conditions such as inherited erythromelalgia, epilepsy, and arrhythmias. Treating these types of pathologies requires an in-depth understanding of their underlying mechanisms. One way to gain this understanding is to investigate physiological triggers. There is also a dire need for novel ways of reducing the hyperexcitability associated with mutant sodium channels. One promising compound is the non-psychotropic component of the Cannabis sativa plant, cannabidiol. This compound has recently been shown to modulate some of the neuronal sodium channels. Although cannabidiol has shown efficacy in clinical trials, the underlying mechanism of action remains unknown. Sodium channels could be among the molecular targets for cannabidiol.In my doctoral research: 1) I studied how a single missense mutation, P1158S, in Nav1.4 causes various degrees of gain-of-function (myotonia and periodic paralysis) by using pH changes to probe P1158S gating modifications; 2) I studied the inhibitory effects of cannabidiol on voltage-dependent sodium currents; 3) I investigated the mechanism through which cannabidiol imparts inhibition. Overall, these data reveal novel insights into sodium channel hyperexcitability and pharmacologically targeting of this hyperexcitability using cannabidiol.

Document type: 
Thesis