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

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Gaze training to improve mobility problems caused by glaucoma-related visual deficits

Date created: 
2018-04-23
Abstract: 

People with glaucoma collide with objects and fall more frequently than normally sighted individuals. Glaucoma-related visual field loss disrupts appropriate gaze behaviour, which is necessary for foot placement and route selection through cluttered environments. Thus, we developed a gaze training intervention to modify gaze behaviour. We taught (2, 1-hr sessions) older adults with glaucoma (n = 10) appropriate scanning and task-specific gaze strategies. To assess its effectiveness, participants performed a precision walking and obstacle avoidance task before and one-week after training. After training, participants shifted their gaze away from targets later relative to stepping on them and decreased foot-placement error and error variability. In the obstacle avoidance task, participants made more fixations before walking, shifted their gaze away from obstacles earlier with respect to crossing them, and had fewer obstacle collisions. Our results suggest that gaze is modifiable in older adults with glaucoma, and that gaze training may improve mobility.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dan Marigold
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Brain vital signs: Auditory to visual translation

Date created: 
2018-04-20
Abstract: 

An objective measure is greatly needed to monitor the impacts of injury or disease on our brain health. In order to provide such a measure, the brain vital sign framework utilizes an established, non-invasive, and physiology-based technology, Electroencephalogram (EEG), along with a rapid auditory sequence used to elicit and assess specific markers of cognitive function (marked by event-related potentials (ERPs)). To date, applications for brain vital signs have included evaluation of cognitive function in healthy and patient populations. To expand the applications, this study aims to translate the established rapid auditory sequence to a visual based assessment. The objectives are to: 1) demonstrate the viability of visual brain vital signs assessment and 2) examine the differences between the two modalities. EEG data was collected in 30 healthy adults (33±14yrs) and analyzed at central electrodes. Similar to the interlaced auditory sequence, the visual sequence utilized an oddball paradigm (standard vs. deviant stimuli) to evoke a sensory (N100) and attention (P300) response, and a word pair paradigm (congruent vs. incongruent stimuli) to evoke a semantic language response (N400). Comparison of mean amplitudes between stimuli revealed the targeted ERPs were successfully evoked in the visual modality at a group-level as expected (N100: p < 0.001; P300: p < 0.0001; N400: p = 0.0105). Attention processing (P300) was found to be the most transferrable across modalities, with no group-level differences and correlated peak amplitudes (rho = 0.7, p =0.0001) across individuals. Auditory P300 latencies were shorter than visual (p < 0.0001) but normalization and correlation (r =0.5, p = 0.0033) implied a potential systematic difference across modalities. Reduced auditory N400 amplitudes compared to visual (p = 0.0061) paired with normalization and correlation across individuals (r = 0.6, p = 0.0012), also revealed potential systematic modality differences between reading and listening language comprehension. This study provides initial understanding of the relationship between the visual and auditory sequences, while importantly establishing a visual sequence within the brain vital signs framework as a potential translational tool to monitor brain health over the human lifespan in broader populations, such as those with hearing impairments, congenital or due to injury or aging.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Stephen Robinovitch
Ryan D'Arcy
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Physiological and pharmacological switches combine to uniquely modulate the most common cardiac sodium channel mutant, E1784K

Date created: 
2018-03-08
Abstract: 

The SCN5a gene encodes the cardiac voltage-gated sodium channel (NaV1.5) mainly expressed in cardiac muscle cells. The inward sodium current (INa) conducted by NaV1.5 triggers depolarization in the cardiac action potential. Mutations in SCN5a predominantly give rise to Long-QT syndrome 3 (LQT3), Brugada syndrome 1 (BrS1), and their overlapping phenotypes (mixed syndrome). The most common SCN5a mutation, expressed as E1784K in the NaV1.5 C-terminal domain (CTD), mainly displays LQT3 and sometimes mixed syndromes. E1784K causes mixed channel defects by decreasing the inward peak INa and increasing late INa, thought to underlie BrS1 and LQT3 pathogeneses, respectively. Very little is known, however, on how physiological and pharmacological switches modulate E1784K channel properties. These triggers may often govern phenotypes in SCN5a mutation carriers. The goal of my thesis is to study how exercise-related physiological triggers and pharmacological agents modulate E1784K ion channel properties. I used the whole-cell patch clamp technique to study elevated temperature, elevated cytosolic calcium, and their combined effects with ranolazine, on E1784K. Ranolazine is an antianginal drug with preferential selectivity for blocking late INa versus peak INa. My main results show that E1784K is uniquely altered by the triggers studied, compared to other NaV1.5 mutants: (1) Elevated temperature augments late INa in E1784K. (2) Elevated cytosolic calcium, which correlates with exercise-ameliorated LQT3, effectively blocks late INa in most NaV1.5 mutants. However, E1784K is resistant to the native calcium-induced block on late INa. (3) When temperature and cytosolic calcium are combined, they decrease ranolazine efficacy to suppress late INa in E1784K. The calcium-sensitivity in E1784K is clearly affected due to the mutant-induced instability in the CTD, which may cause a steric clash between the channel and ranolazine. To predict E1784K effects on arrhythmogenesis, I simulated a dynamic action potential model to account for the frequency-dependent elevations in cytosolic calcium. Alternans is observed at high heart rates in E1784K and is exacerbated by febrile temperatures and ranolazine. This work demonstrates the importance of personalized medicine since NaV1.5 mutants like E1784K display unique sensitivity to physiological triggers that potentially govern antiarrhythmic efficacy.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Peter Ruben
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

Physiological and anthropometric predictors of mountain ultra marathon performance

Date created: 
2017-12-13
Abstract: 

There is yet to be a resolution of the determinants of mountain ultra marathon (MUM) performance. The aim of this thesis was to contribute to resolving these determinants by measuring aerobic, anaerobic and anthropometric metrics and assessing their association to performance in a 50 km MUM race. It was hypothesized for MUM runners with high aerobic power that greater anaerobic capacity, greater lower limb girths, greater surface-area-to-mass, lower endomorphy and lower body fat percentage (BF%) would give better MUM performance. Thirty-four healthy participants volunteered for this study and were measured for their aerobic power, critical velocity (CV), anaerobic running capacity (D’), Wingate Anaerobic test (WAnT) power, and anthropometric variables. For these MUM runners with an aerobic capacity of 57.8±6.2 ml•min-1•kg-1 a greater CV predicted a faster finishing time in the MUM race (R2=0.75, p<0.001, n=12), while WAnT (r=-0.59, p<0.01, n=29) and mass-adjusted surface area (r=-0.35, p<0.05, n=34) was correlated to finishing time. Predictors of hill climb times included CV, body fat percentage and endomorphy (0.15

Document type: 
Thesis
File(s): 
Senior supervisor: 
Matthew White
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Proton modulation of residue E1784 and its regulation of fast inactivation

Date created: 
2017-12-14
Abstract: 

The cardiac voltage-gated sodium channel, NaV1.5, is responsible for the phase 0 depolarization of the ventricular cardiomyocyte action potential. NaV1.5 activates in response to depolarization, passes a transient inward sodium current, and then inactivates within milliseconds. Mutants in NaV1.5 that decrease the peak sodium transient cause Brugada syndrome and those that increase the fraction of channels that fail to inactivate cause long QT syndrome type 3 (LQT3). Some mutants both decrease the peak current and increase the non-inactivating current, leading to an overlapping phenotype of Brugada syndrome and LQT3. Of these mutants, E1784K in the proximal C-terminus is the most prevalent. The E1784K mutant alters channel opening, fast inactivation, and slow inactivation, but the exact mechanism by which it does so is unknown. Nor is it known why patients may experience normal heart function for many years before appearance of an arrhythmia. In these studies, the cut-open voltage-clamp technique is used to record NaV1.5 currents and voltage-sensor fluorescence from residue 1784 mutants expressed in Xenopus laevis oocytes. Experiments are conducted with extracellular pH between 7.4 and 4.0. Based on these data, a novel model of the voltage-gated sodium channel is constructed. The following data show that: (1) the E1784K mutant-dependent loss-of-function and gain-of-function effects are preferentially exacerbated by decreases in extracellular pH; (2) the E1784K mutant disrupts channel fast inactivation; (3) the mutant-dependent effects on channel conductance and the preferential effects of decreasing extracellular pH are due to altered channel fast inactivation; (4) non-inactivating sodium current is conferred by a positive charge at residue 1784. These data provide mechanistic insight into how a single mutant may cause multiple disease phenotypes, paving the way for future therapeutic research.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Peter Ruben
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

The beta-2 adrenergic receptor agonist fenoterol triggers arrhythmogenesis in isolated mouse ventricular cardiomyocytes.

Date created: 
2017-12-15
Abstract: 

Since the discovery of the role of Ca2+ in cardiac contractions, it has been clear that many cardiovascular disorders, specifically cardiac arrhythmias are due to irregularities in Ca2+ cycling. We hypothesize that fenoterol, a beta-2 adrenergic receptor agonist, is responsible for inducing abnormal Ca2+ release events that can lead to full cardiac arrhythmias. Ca2+ release events such as sparks, waves, and transients were studied using resonant confocal microscopy in isolated mouse ventricular cardiomyocytes with cumulative concentrations of fenoterol. Fenoterol application in clinically relevant doses can trigger potentially serious cardiac arrhythmias. The data showed that at low fenoterol concentrations, the frequency of Ca2+ sparks and waves were increased and caused Ca2+ oscillations during transients, all of which are indicators of arrhythmogenic Ca2+ activity, via the PKA-mediated pathway. At high concentrations, fenoterol lost its specificity and triggered beta-1AR, activating CaMKII, also resulting in more Ca2+ sparks and wave events and causing oscillations during field-stimulated elicited transients.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Glen Tibbits
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Using an activator of hERG (RPR-260245) in a model of acquired and inherited Long QT syndrome type 2

Author: 
Date created: 
2017-07-17
Abstract: 

The human ether-a-go-go related gene (hERG) channel is the molecular correlate of the rapid delayed rectifier current (IKr); its dysfunction causes Long QT syndrome type II (LQT II). RPR-260245 (RPR) is an activator of hERG that increases hERG current by slowing deactivation. Thus, it represents a potential treatment strategy for LQT. However, only few studies have addressed its impact on cardiac physiology. We used electrophysiology techniques in Xenopus Laevis oocytes and optical mapping in induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) to test the effects of RPR on hERG and on the cardiac action potential. We show that RPR has little effect on the cardiac AP in WT iPSC-CMs but demonstrate a partial rescue in our model of acquired LQT (aLQT) under dofetilide block and a partial rescue in our model of LQT II. Finally, RPR significantly increases protective hERG current, especially in instances of the R56Q mutation.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Glen Tibbits
Thomas Claydon
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Atypical Neuronal Oscillatory Synchrony of the Auditory Steady State Response in Down Syndrome

Author: 
Date created: 
2017-08-18
Abstract: 

The mechanisms by which the brain coordinates a constant flood of information to provide a unified perception of reality remains poorly understood. Mounting evidence suggests that information integration is closely related to oscillatory activity in the gamma frequency band. Individuals with Down Syndrome (DS) reportedly struggle with higher cognitive processes, but existing knowledge representing the neuronal oscillatory dynamics of the DS brain remains limited. Cortical circuit dysfunction can be probed by the examination of phase coherence of the Auditory Steady State Response (ASSR). Using a measure of phase coherence to assess oscillatory synchrony in the auditory cortices, results show evidence of reduced inter-hemispheric phase locking in the gamma band at the group level (N=12) for DS individuals (p < 0.01) compared to control participants. These findings indicate the DS brain does not integrate information as effectively as non-DS individuals do, contributing to a deeper understanding of the neurophysiological correlates of DS symptomology.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Sam Doesburg
Teresa Cheung
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

A pilot randomized controlled trial of exercise to improve walking energetics among older adults with mobility limitation: The HealthySteps Study

Date created: 
2017-07-11
Abstract: 

Mobility is a fundamental component of healthy aging; however, mobility limitation is a prevalent, energetically costly problem among older adults. We conducted a pilot randomized controlled trial to compare the effects of two, 12-week exercise interventions (timing and coordination, TC; aerobic walking, AW) to an active control (stretching and relaxation; SR) on outcomes related to mobility among community-dwelling older adults with mobility limitation (n=72). At 12 weeks, TC reduced mean energy cost of walking by 13-15% versus SR. Among those with high baseline cost, TC reduced mean energy cost by 20-26% versus SR. Reductions were maintained at 24-week follow-up. AW had no effect at 12 or 24 weeks. Fatigability, daily physical activity, endurance, physical function, and life-space mobility did not change with TC or AW versus SR at 12 or 24 weeks. In summary, 12 weeks of TC, but not AW, improved walking economy among older adults with mobility limitation.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dawn Mackey
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Mechanistic Insight into Human ether-a-go-go-related Gene (hERG) K+ Channel Activation and Deactivation gating

Author: 
Date created: 
2017-06-15
Abstract: 

hERG encodes the pore-forming α-subunit of the voltage-gated potassium channel that underlies the rapid delayed rectifier current, IKr, in the heart, which is essential for normal cardiac electrical activity and rhythm. Inherited mutations in, or pharmacological blockade of, hERG channels deplete the cardiac repolarization reserve, increasing the risk of life-threatening arrhythmias. The molecular bases of hERG gating events and drug binding are poorly understood. hERG channels display unique gating characteristics critical for their physiological function. They activate and deactivate slowly, yet inactivate and recover from inactivation rapidly. In addition, the promiscuous nature of drug interactions with hERG channels presents a therapeutic challenge for drug design and development. My thesis provides novel mechanistic and structural characterization of the unusual activation and deactivation gating processes of hERG. In my first study, I used a proline scan approach to define the activation gate region in hERG channels. Proximal substitutions (I655P-Q664P) impeded gate closure, trapping channels in the open state, while distal substitutions (R665P-Y667P) preserved normal gating, suggesting that Q664 marks the position of the activation gate in hERG. This is more than one helical turn lower than in related channels, which may allow for drug docking. Using two different approaches to measure voltage sensor gating in trapped open channels, I then demonstrated that slow activation is an intrinsic property of the voltage-sensing unit of hERG. In my second study, I showed that voltage-sensor stabilization slows hERG channel deactivation gating. I characterized the temporal sequence of events leading to voltage-sensor stabilization upon membrane depolarization. I showed that this occurs via two separable mechanisms, one derived from pore-gate-opening and the other from the voltage-sensing unit itself. In addition, I show that voltage sensor return in hERG channels is less energetically favourable than pore closure during repolarization and thus is what limits deactivation. Finally, I characterize the use of voltage clamp fluorimetry as a technique to track conformational rearrangements of the hERG voltage sensor associated with gating. These findings provide novel and in depth understanding regarding how hERG channels function and foundational knowledge relevant to finding targets for the treatment and management of cardiac arrhythmias.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Thomas Claydon
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.