Medicine and Health Sciences Commons^™

Examining The Role Of Ganglioside Homeostasis In Neurodegeneration And Aging Using Maldi Imaging Mass Spectrometry, Sarah Caughlin

Electronic Thesis and Dissertation Repository

Gangliosides are a family of membrane lipids enriched in the central nervous system (CNS) that play an important role in cell signaling processes on the membrane. Alterations in the homeostatic distribution of the a-series family of gangliosides has been observed in both pre-clinical models and human patients with neurodegenerative diseases and injuries, such as Alzheimer’s disease (AD) and strokes. Ganglioside dysregulation has been implicated as an important mechanisms driving pathology in the aging brain, yet there is little information on where and when these lipid changes occur as well as the role of dysregulation during neurodegeneration. Matrix-Assisted Laser Desorption/Ionization (MALDI) …

Neuronal Correlates For Neuroendocrine Habituation To Repeated Stress, Sara Matovic

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One way that the body actively responds to an impending stressor is by increasing systemic glucocorticoids through the activation of the hypothalamic-pituitary-adrenal (HPA) axis. While it is essential for short-term adaptation to stress, the sustained activation of the HPA axis during chronic stress can be detrimental and is linked to stress-related psychiatric conditions such as anxiety and depression. Therefore, it is important that the HPA axis adapts, or habituates, during chronic stress to minimize the negative consequences. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) function to assimilate incoming information from the stress circuitry and …

Functional Magnetic Resonance Imaging As An Assessment Tool In Critically Ill Patients, Loretta Norton

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Little is known about whether residual cognitive function occurs in the earliest stages of brain injury. The overarching goal of the work presented in this dissertation was to elucidate the role of functional neuroimaging in assessing brain activity in critically ill patients. The overall objective was addressed in the following four empirical chapters: In Chapter 2, three versions of a hierarchically-designed auditory task were developed and their ability to detect various levels of auditory language processing was assessed in individual healthy participants. The same procedure was then applied in two acutely comatose patients. In Chapter 3, a hierarchical auditory task …

Age-Related Reductions Of Motor Unit Discharge Rates In The Human Hamstrings, Eric A. Kirk

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Neuromuscular age-related differences of human limb muscles have been widely described with the notable exception of the hamstring muscles. The purpose was to assess contractile function and spinal motor neuron output expressed as motor unit discharge rates in the hamstrings of 11 young (26 ± 4 y) and 10 old (80 ± 5 y) men. Maximal voluntary isometric contractions (MVC), stimulated contractile properties and motor unit discharge rates from sub-maximal to MVC were recorded from the lateral (biceps femoris) and medial (semimembranosus-semitendinosus) posterior thigh. In the old men, knee extension and flexion at MVC were lower (P < 0.05) and voluntary activation as assessed by the twitch interpolation technique was reduced (P < 0.05) compared with the young. Electrically evoked twitches were lower in amplitude and increased in duration of old hamstrings (P < 0.05) compared with the young. At sub-maximal to maximal contraction intensities the old had lower motor unit discharge rates as compared to the young (P < 0.001). At MVC, mean motor unit discharge rates in the biceps femoris and semimembranosus-semitendinosus of old hamstrings were 15.6 ± 6.4 and 15.3 ± 5.9 Hz, as compared to 26.1 ± 10.1 and 27.9 ±7.8 Hz in the young, respectively (P < 0.001). To date, the hamstrings show the greatest age-related reductions in motor unit discharge rates of any major limb muscle. These findings, in relation to motor unit discharge rates from other flexors and extensors support that in ageing, greater reductions are associated with limb flexor muscles.

A Non-Canonical Role For Choline Acetyltransferase In Chromatin Organization And The Response To Beta-Amyloid, Warren R. Winick-Ng

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The three-dimensional structure of chromatin is essential for context-dependent regulation of gene expression in post-mitotic neurons. Chromosomal rearrangements have been observed in the aging brain, and proteins involved in chromatin organization have altered expression and/or localization in Alzheimer’s disease (AD). A human- and primate-specific transcript of choline acetyltransferase produces an 82-kDa protein (82-kDa ChAT) that is localized to the nucleus of cholinergic neurons, but is found in the cytoplasm in individuals with mild cognitive impairment (MCI) and AD. The function of the 82-kDa ChAT protein is unknown, though recent evidence suggests it has a role in gene expression changes in …

Development Of Anatomical And Functional Magnetic Resonance Imaging Measures Of Alzheimer Disease, Samaneh Kazemifar

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Alzheimer disease is considered to be a progressive neurodegenerative condition, clinically characterized by cognitive dysfunction and memory impairments. Incorporating imaging biomarkers in the early diagnosis and monitoring of disease progression is increasingly important in the evaluation of novel treatments. The purpose of the work in this thesis was to develop and evaluate novel structural and functional biomarkers of disease to improve Alzheimer disease diagnosis and treatment monitoring. Our overarching hypothesis is that magnetic resonance imaging methods that sensitively measure brain structure and functional impairment have the potential to identify people with Alzheimer’s disease prior to the onset of cognitive decline. …

Is Online Motor Control Really Impaired In Parkinson's Disease?, Kate E. Merritt

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Patients with Parkinson’s disease (PD) are thought to be selectively impaired in consciously-mediated online automatic motor control, whereas the ability to perform subconscious online adjustments remains intact. This present study evaluates the hypothesis that the previously alleged deficits in online motor control in PD are not due to the consciousness of the correction, but rather are attributable to aspects of the prior experimental designs disproportionately penalizing patients for PD-related bradykinesia. Here, we implemented a modified traditional double-step paradigm to investigate consciously-mediated online motor control in PD, in a manner that would be unconfounded by disease-related bradykinesia. Further, we investigated the …

Characterization And Personalization Of Botulinum Toxin Type A Therapy For Upper Limb Tremor In Parkinson Disease And Essential Tremor Patients Using Multi-Sensor Kinematic Technology, Olivia Samotus

Electronic Thesis and Dissertation Repository

Tremor commonly affects the upper extremities in essential tremor (ET) and Parkinson disease (PD) patients where many experience functional disability and ultimately seek therapy. As ET and PD tremor features overlap and clinical assessment is challenging due to its highly complex nature, misdiagnosis is common resulting in unsuitable therapies and prognosis. Current treatment options for ET and PD tremor include pharmacotherapy, focal therapy with botulinum toxin type A (BoNT-A) injections, and surgical interventions which provide modest relief of tremor. However, such therapies are commonly associated with significant adverse events and lack long-term efficacy and tolerability. Hence lack of standardized, objective …

Serotonergic System And Gait: Dorsal Raphe Nucleus As A Control System For Gait, Nahal Farhani

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In advanced stages of Parkinson Disease (PD), gait and postural abnormalities emerge. These symptoms are not prominent at early stages of PD despite significant dopaminergic neuronal loss. Gait abnormalities are largely not responsive to levodopa. Therefore, other types of neurons might be responsible for gait abnormalities of the PD.

Since the reticulospinal tract (RET) is mainly implicated in the control of axial muscles, the degeneration of this pathway or populations of neurons controlling this pathway might be responsible for axial symptoms. However, there is limited data about the neurons controlling the RET. Our aim in this study is to delineate …

Analyzing A-Series Gangliosides In Neurons Following Exposure To Glutamate, Dae Hee Park

Electronic Thesis and Dissertation Repository

Neurons within different brain regions have varying levels of vulnerability to external stress and therefore respond differently to injury. A potential reason to explain this may lie within a key lipid class of the cell’s plasma membrane called gangliosides. These glycosphingolipid species have been shown to play various roles in the maintenance of neuronal viability. The purpose of this study is to use electrospray ionization mass spectrometry (ESI-MS) technique and immunohistochemistry to evaluate the temporal changes in the expression profiles of various ganglioside species during the course of neurodegeneration in rat primary cortical neurons exposed to glutamate toxicity. Primary embryonic …

Contribution Of The Dorsolateral Prefrontal Cortex To Attentional And Mnemonic Processes In Visual Search, Brandon Belbeck

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A key characteristic of selective visual attention is that it may be deployed on the basis of our knowledge or goals of the task at hand. Here, we used cryogenic deactivation to investigate the contribution of the dorsolateral PFC to cognitive flexibility and working memory, as well as their relation to the deployment of attention. Macaque monkeys performed visual search tasks requiring them to foveate a target in an array of stimuli. These included a feature search, a constant-target conjunction search, a variable-target search and variable-target with delay search task, with each being more cognitively demanding than the last. Bilateral …

Mechanisms Of Atf4-Mediated Neuronal Apoptosis, Patrick Swan

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Abstract to be provided

Exploring The Structural And Functional Organization Of The Dorsal Zone Of Auditory Cortex In Hearing And Deafness, Melanie A. Kok

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Recent neuroscientific research has focused on cortical plasticity, which refers to the ability of the cerebral cortex to adapt as a consequence of experience. Over the past decade, an increasing number of studies have convincingly shown that the brain can adapt to the loss or impairment of a sensory system, resulting in the expansion or heightened ability of the remaining senses. A particular region in cat auditory cortex, the dorsal zone (DZ), has been shown to mediate enhanced visual motion detection in deaf animals. The purpose of this thesis is to further our understanding of the structure and function of …

The Relationship Of Plantar Sensation With Standing Balance And Gait Post-Stroke, Stephen Parsons

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Gait and balance dysfunction after stroke limit independence and quality of life. Numerous contributing factors have been investigated but the role of sensation deficits has received little attention. This thesis investigated the relationship between plantar cutaneous sensation and 1) standing balance, 2) gait, and 3) use of vision to compensate for sensory loss with a secondary analysis of data from individuals with subacute stroke. Associations between standing balance, gait and sensation were investigated with Spearman correlations. Individuals classified as impaired or intact sensation were compared on gait and standing balance measures. This thesis found plantar sensation is related to standing …

Quantitative Mri Correlates Of Hippocampal And Neocortical Pathology In Intractable Temporal Lobe Epilepsy, Maged Goubran

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Intractable or drug-resistant epilepsy occurs in over 30% of epilepsy patients, with many of these patients undergoing surgical excision of the affected brain region to achieve seizure control. Advances in MRI have the potential to improve surgical treatment of epilepsy through improved identification and delineation of lesions. However, validation is currently needed to investigate histopathological correlates of these new imaging techniques. The purpose of this work is to investigate histopathological correlates of quantitative relaxometry and DTI from hippocampal and neocortical specimens of intractable TLE patients. To achieve this goal I developed and evaluated a pipeline for histology to in-vivo MRI …

Regulation Of Metabotropic Glutamate Receptor 5 Activity By Ca2+/Calmodulin-Dependent Protein Kinase Iiα, Fitore Raka

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The metabotropic glutamate receptor 5 (mGluR5) is a GPCR coupled to the heterotrimeric G protein Ga_q/11 and activates signaling pathways important for excitatory synaptic transmission. Emerging studies reveal that Amyloid b (Ab) acts as an extracellular scaffold for mGluR5. We have identified Ca²⁺/Calmodulin-dependent protein Kinase IIα (CAMKIIα) as an interacting protein of mGluR5. We hypothesize that CaMKIIα plays a role in mGluR5 signaling and Ab produces differential effects on the regulation of mGluR5 by CAMKIIα. We find that overexpression of CAMKIIα significantly impairs mGluR5-mediated ERK1/2 phosphorylation but does not effect inositol phosphate formation or Ca²⁺ release. …

Investigation Of Sox9 Ablation On Neuroplasticity And Recovery After Ischemic Stroke, Bethany Robin Lenore Bass

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Neuroplasticity is a key factor in post-stroke functional recovery. A chief inhibitor of post-stroke neuroplasticity is the expression of chondroitin sulfate proteoglycans (CSPGs). Recent research has shown that the transcription factor SOX9 is responsible for upregulating the expression of CSPGs in the injured central nervous system. Accordingly, CSPG levels are significantly lower in mice with the Sox9 gene conditionally knocked out. The purpose of this study was to determine how Sox9 ablation affects neuroplasticity and recovery after stroke. Behavioural test results revealed that Sox9 KO mice exhibited significantly improved functional recovery after stroke compared to controls. This correlated with increased …

The Antisaccade Task: Visual Distractors Elicit A Location-Independent Planning 'Cost', Jesse C. Desimone

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Prosaccades are rapid eye movements with direct stimulus and response relations and are designed to bring the fovea onto a target or area of interest. In contrast, antisaccades require the inhibition of a prosaccade and the evocation of a saccade to a target’s mirror-symmetrical location. Previous work has shown that a remote (i.e., midline, contralateral) – but not proximal (i.e., ipsilateral) – task-irrelevant distractor relative to a visual target delays prosaccade reaction times (RT) (i.e., remote distractor effect: RDE). To my knowledge, however, no work has examined whether antisaccade RTs are similarly influenced by a RDE. Accordingly, I sought to …

Task-Switching In Oculomotor Control: Systematic Investigations Of The Unidirectional Prosaccade Switch-Cost, Jeffrey Weiler

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An antisaccade requires suppressing a stimulus-driven prosaccade (i.e., response suppression) and remapping a target’s spatial location to its mirror-symmetrical position (i.e., vector inversion). Notably, my previous work demonstrated that the successful execution of an antisaccade selectively lengthens the reaction time (RT) of a subsequently completed prosaccade (i.e., the unidirectional prosaccade switch-cost; Weiler & Heath, 2012a; Weiler & Heath, 2012b). Thus, the objective of this dissertation was further investigate, and ultimately provide a mechanistic explanation for the unidirectional prosaccade switch-cost.

In Chapter Two, I demonstrate that the magnitude of the unidirectional prosaccade switch-cost is not dependent of the number of …

Deep Learning Via Stacked Sparse Autoencoders For Automated Voxel-Wise Brain Parcellation Based On Functional Connectivity, Céline Gravelines

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Functional brain parcellation – the delineation of brain regions based on functional connectivity – is an active research area lacking an ideal subject-specific solution independent of anatomical composition, manual feature engineering, or heavily labelled examples. Deep learning is a cutting-edge area of machine learning on the forefront of current artificial intelligence developments. Specifically, autoencoders are artificial neural networks which can be stacked to form hierarchical sparse deep models from which high-level features are compressed, organized, and extracted, without labelled training data, allowing for unsupervised learning. This thesis presents a novel application of stacked sparse autoencoders to the problem of parcellating …

Investigating The Effects Of Custom Made Orthotics On Brain Forms: A Pilot Study, Lindsay Carey

Electronic Thesis and Dissertation Repository

OBJECTIVES: To determine (1) the feasibility of this novel approach and technique of recording brain activity, wirelessly and continuously, during human gait, and (2) if custom made orthotics will alter the brain activity patterns recorded. METHODS: Gait trials were performed on 16 participants walking with and without orthotic devices in their shoes while simultaneously collecting EEG data through the Emotiv wireless neuroheadset. RESULTS: The Emotiv neuroheadset was capable of detecting changes in brain activity between the two gait trials. The differences in brain activity identified between conditions were not statistically significant. CONCLUSION: The findings suggest the Emotiv EEG device is …

The Effects Of Pre- And Postnatal Administration Of Propionic Acid And Lipopolysaccharide On The Behaviour Of Adolescent Male And Female Rats, Kelly A. Foley

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The gut microbiome plays an important role in immune functioning and neurodevelopment. Altered microbiome composition, leading to short chain fatty acid, and/or immune system dysfunction has been observed in children with autism spectrum disorders (ASD). This thesis describes the developmental influence of prenatal exposure to propionic acid (PPA), a metabolic fermentation product of enteric bacteria, or prenatal exposure to lipopolysaccharide (LPS), a bacterial mimetic and product of enteric bacteria, on a range of behaviours in male and female neonatal, adolescent and adult rats. Study one evaluated the effects of prenatal PPA and LPS, and postnatal PPA, on developmental milestones in …

Er Stress Coupled Pannexin Channel Activation Via Stim Proteins, Ankur Bodalia

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Many neurodegenerative diseases, including Alzheimer’s Disease, are associated with ER stress. It is suggested that plasma membrane channels contribute to the increased ionic influx and subsequent cell death in response to ER stress. Pannexin channels, which have been implicated in various pathophysiological conditions, are a suitable candidate for facilitating this response. However, mechanisms of pannexin channel activation are poorly defined. I investigated the potential regulation of pannexin activity by the ER stress sensor, STIM. It was hypothesized that pannexin channel activation during ER stress is contingent on the recruitment of STIM proteins. In neurons, pannexin activation was observed in response …

Secular Trends In Ischemic Stroke Subtypes, Chrysi Bogiatzi

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Background: With an aging population and an increasing prevalence of therapy for atherosclerosis, it might be expected that stroke subtypes would be changing over time. Limited information exists on the ischemic stroke subtypes in adults in Canada.

Methods: Patients referred to the Urgent TIA Clinic, in London, Ontario, between 2002-2012 were included. Secular trends were analyzed using Poisson regression with spline trend function. Ischemic stroke subtype classification was validated.

Results: 3,445 consecutive patients (mean age + SD 64.8 + 14.9) were included. Cardioembolic strokes/TIAs increased from 21% in 2002 to 56% in 2012, whereas all other ischemic stroke subtypes …

The Role Of Kisspeptin And Kndy Cells In The Reproductive Neuroendocrine System, Christina M. Merkley

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The gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus represent the final common output in the central control of reproduction. GnRH secretion is modulated indirectly by steroid feedback action of gonadal steroids on afferent interneurons. In recent years, the neuropeptide, kisspeptin, has emerged as a key mediator of steroid feedback onto GnRH neurons and the reproductive system. Kisspeptin neurons located in the preoptic area (POA) mediate estradiol (E2) positive feedback leading to the preovulatory surge, and kisspeptin cells in the arcuate nucleus (ARC) have been shown to mediate the negative feedback actions of E2 on pulsatile GnRH secretion. ARC kisspeptin neurons …

Magnetic Resonance Imaging Of Brain Tissue Abnormalities: Transverse Relaxation Time In Autism And Tourette Syndrome And Development Of A Novel Whole-Brain Myelin Mapping Technique, Yann Gagnon

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The transverse relaxation time (T2) is a fundamental parameter of magnetic resonance imaging sensitive to tissue microstructure and water content, thus offering a non-invasive approach to evaluate abnormalities of brain tissue in-vivo. Prevailing hypotheses of two childhood psychiatric disorders were tested using quantitative T2 imaging and automated region of interest (ROI) analyses. In autism, the under-connectivity theory, which proposes aberrant connectivity within white matter (WM) was assessed, finding T2 to be eleveted in the frontal and parietal lobes, while dividing whole brain data into neurodevelopmentally relevant WM ROIs found increased T2 in bridging and radiate WM. In Tourette syndrome, tissue …

Evaluation Of The Utility Of Decomposition-Enhanced Spike-Triggered Averaging Motor Unit Number Estimation As An Outcome Measure For The Study Of Amyotrophic Lateral Sclerosis, Colleen T. Ives

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OBJECTIVES: The objectives of this thesis were to review the use of outcome measures systematically across amyotrophic lateral sclerosis (ALS) clinical trials, and evaluate the utility of decomposition-enhanced spike-triggered averaging (DE-STA) motor unit number estimation (MUNE) as an outcome measure, with a particular focus on its application to the upper trapezius (UT).

METHODS: First, a systematic review quantified the frequency of use of outcome measures in ALS randomized controlled trials (Chapter 2). Next, the intra- and inter-rater reliability of DE-STA MUNE was evaluated in the UT of control subjects (Chapter 3), followed by the intra-rater reliability of the technique in …

Sexual Reward And Depression, Andrea R. Di Sebastiano

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Sexual behavior in male rats is a complex rewarding behavior and many neurotransmitters and neuropeptides play an important role in mediation of sexual performance, motivation and reward. The hypothalamic neuropeptide orexin has been shown play a key role in reward associated with food and drugs of abuse, but the role of this neuropeptide in control of sexual performance, motivation and reward is currently unclear. First, it was shown that orexin neurons in the hypothalamus are activated during sexual performance and reward. Next, using cell specific lesions of orexin neurons it was demonstrated that orexin is involved in arousal and anxiety, …

Frequency-Dependent Conduction Block In Demyelinating Focal Neuropathies, Brad V. Watson

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It is the objective of this thesis to demonstrate conduction block across regions of focal demyelination by utilizing a conventional electrophysiological technique used frequently in the diagnosis of peripheral nerve disease. Specifically, patients with moderate to severe carpal tunnel syndrome (CTS), but, with no evidence of conduction block via conventional motor nerve conduction study techniques, were assessed in the initial studies of this thesis for evidence of frequency-dependent conduction block (FDB) by way of high-frequency nerve stimulation (HFNS) applied across the region of entrapment. The final studies examined whether FDB could be demonstrated along the median motor fibers in mild …

Differential Effects Of Macaque Dorsolateral Prefrontal Deactivations During Uncued And Cued Role Conditions, Sabeeha Hussein

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Cognitive control enables us to guide our behaviour in an appropriate, context-dependent manner. This behavioral flexibility is probed by task-switching paradigms, which require working memory to maintain relevant rules and flexibility to switch between rules. The dorsolateral prefrontal cortex (DLPFC) has been implicated in rule maintenance by neuroimaging and electrophysiological studies. While these studies have identified a correlation between DLPFC activity and rule maintenance, deactivation studies allow us to establish a causal relationship. Here we have examined the effect of bilateral deactivation of areas 46 and 9/46d on rule maintenance, while a monkey (Macacca mulatta) performed blocks of …