Medicine and Health Sciences Commons^™

Combining Repetitive Transcranial Magnetic Stimulation (Rtms) With Corticosteroid Joint Injections (Cji) For The Treatment Of Chronic Axial Pain (Cap): A Pilot Double-Blinded Randomized-Controlled Trial, Anike A. Alarape Ms

Electronic Thesis and Dissertation Repository

Chronic axial pain (CAP) is a debilitating condition impacting millions globally, with traditional treatments providing only short-term relief. This pilot study explored the primary outcomes of feasibility, tolerability, and safety, as well as the secondary outcomes of pain intensity, disability, quality of life, and patients’ perceived response to the combined intervention of repetitive transcranial magnetic stimulation (rTMS) and corticosteroid joint injections (CJI) as a novel approach to address CAP. Sixteen participants from St. Joseph’s Healthcare Pain Clinic were randomized (1:1) to receive 11 active or sham rTMS sessions over 12 weeks, with follow-up until week 24 or their next CJI, …

Differential Effects Of Cannabis Vapour Constituents On Brain Connectivity: Exploring The Long-Term Effects Of Adolescent Exposure, Pedro Marinho

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Cannabis use is common in adolescence and there is evidence for sex differences regarding the long-term effect of cannabis use. We aimed to investigate how exposure to 3 types of cannabis vapour in adolescent rats impacts brain development using magnetic resonance imaging. Male and female Sprague Dawley rats were divided into four groups and exposed to high-CBD, high-THC, balanced CBD + THC, or air at post-natal days 28-42 using a vaporizer. In adulthood, rats underwent diffusion and functional MRI. Results indicated sex-dependent differences in the long-term effects of cannabis exposure in the adult brain. In male rats, we found a …

Exploring The Effect Of Combining Repetitive Transcranial Magnetic Stimulation With Functional Electrical Stimulation Cycling On Lower Extremity Function Following Incomplete Spinal Cord Injury, Fereshteh Ghahremani

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Spinal cord injury (SCI) is a neurological condition that disrupts lower extremity function, limiting mobility and independence. This dissertation explores the feasibility, acceptability, and safety of combining repetitive transcranial magnetic stimulation (rTMS) with functional electrical stimulation (FES) cycling to improve lower extremity function following motor incomplete SCI (iSCI). This study is a case series pilot study in which participants with iSCI underwent a combined protocol of rTMS and FES cycling for six weeks. The results demonstrate the preliminary feasibility, participant acceptability, and safety of combining rTMS and FES cycling. While results varied between participants, one participant showed improvements in walking …

Investigating Synergistic Effects Of Mild Traumatic Brain Injury And Reduced Cholinergic Tone On Attentional Deficits And Alzheimer's-Like Pathology In Haβ And Htau Mice, Elizabeth M. Teasell

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Mild traumatic brain injury (mTBI) increases the risk of Alzheimer’s disease. The early cholinergic decline in Alzheimer’s disease and cholinergic damage observed after TBI suggest a distinct role of this neural system in vulnerability to Alzheimer’s disease following TBI. This thesis evaluated the role of repetitive mTBI and cholinergic dysfunction in the development of cognitive deficits, specifically attentional deficits, and Alzheimer’s-related pathology in mice expressing humanized amyloid-beta and tau and a vesicular acetylcholine transporter knockdown to induce a mild cholinergic deficit. Using the rodent continuous performance test, it was shown that repetitive mTBI in the presence of an already vulnerable …

Cognitive Changes In Early Untreated Parkinson's Disease, Kunj Patel

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Cognitive impairment is the most common non-motor symptom in Parkinson’s disease (PD), affecting up to one-third of early-stage patients. However, the cognitive profile in early PD remains unclear due to the use of heterogenous samples of disease severity, small sample sizes, and the inclusion of medication effects. This study aims to characterize cognitive deficits in early PD using a large, drug-naive sample. This study examined performance on the Montreal Cognitive Assessment and the Hopkins Verbal Learning Test from the Parkinson’s Progression Markers Initiative dataset (n= 643 patients with PD; n= 240 healthy controls). Patients were restricted to …

Quantifying Resting-State Functional Connectivity In Critically Brain-Injured Patients: A Graph-Theoretical Approach With Fnirs, Ira Gupta

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Assessment of consciousness in behaviourally unresponsive patients with critical brain injuries continues to be a challenge. There remains a need for robust tools that can accurately characterize preserved cortical function and predict patient outcomes. In the present study, functional near-infrared spectroscopy is employed in conjunction with graph theory and machine learning to quantify resting-state functional connectivity in 16 acutely brain-injured patients and 23 healthy controls. Results revealed significant channel-level differences between the groups for three graph metrics, including degree, clustering coefficient, and local efficiency. Further investigation using machine learning algorithms revealed that these metrics can be used to distinguish between …

Validation Of A Virtual Auditory Space, And Its Use To Investigate How Pitch And Spatial Cues Contribute To Perceptual Segregation Of Auditory Streams, Nima Zargarnezhad

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The human auditory system can decompose complex sound mixtures into distinct perceptual auditory objects through a process (or processes) known as Auditory Scene Analysis. Pitch and spatial cues are among the sound attributes known to influence sequential streaming (Plack 2018). In this project, the fidelity of a virtual acoustic space (the Audio Dome) in reproducing precisely located sound sources with a 9^th-order ambisonics algorithm was validated. The estimated horizontal Minimum Audible Angles aligned with previously reported values (Mills 1958) homogeneously across the space, and a robust low-frequency presentation was identified. Then, the Audio Dome was utilized to test …

Lbnp Reduces Cerebral Perfusion But Does Not Impact Executive Function, James Van Riesen

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A growing body of literature has demonstrated that a single bout of aerobic exercise and/or hypercapnic manipulations increase cerebral blood flow (CBF) and are linked to a transient (i.e.,min) post-intervention executive function (EF) benefit. However, there are no direct studies examining whether a transient decrease in CBF elicits a post-intervention EF decrement. Accordingly, my thesis employed 10-min single bout manipulations of -30 mmHg and -50 mmHg lower-body negative pressure (LBNP) to determine whether a transient reduction in CBF impacts EF. LBNP was applied as it renders sub-atmospheric pressure to the lower limbs and redistributes blood from the upper to lower …

The Adaptor Protein P66shc Governs Central Nervous System Cell Metabolism And Resistance To Aβ Toxicity, Asad Lone

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Alzheimer’s disease (AD), a progressive and irreversible neurodegenerative disorder, and is the leading cause of dementia worldwide. It has been posited that AD is caused by the gradual deposition of toxic amyloid-b (Ab) plaques in the brain- that cause oxidative stress and eventually leads to neuronal death and synaptic loss. However, multiple therapies that either interfere with the production, or enhance the removal of Ab from the brain, have ultimately failed to slow or prevent AD. With the ever-increasing burden of AD worldwide, there exists an urgent need for novel therapeutic targets. The adult human brain is an energy demanding …

Investigating The Effects Of Infantile Hydrocephalus On Visuomotor Integration: A Study Utilizing Behavioural And Neuroimaging Analyses, Derya Adil

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This thesis describes studies which explore the impact of infantile hydrocephalus on the posterior cortex, specifically focusing on the parietal and occipital lobes. Using resting-state functional MRI, the functional connectivity within the visuomotor integration network was investigated and connectivity was traced through the corpus callosum. We hypothesized that children with hydrocephalus would demonstrate altered functional connectivity compared to typically developing controls. Our findings revealed that patients had reduced functional connectivity in visuomotor pathways, particularly the inferior frontal occipital fasciculus, superior longitudinal fasciculus, and the frontal aslant tract, with notable impact on the left and right fusiform gyrus and precuneus. We …

Sex Differences In Mood And Anxiety-Related Outcomes In Response To Adolescent Nicotine Exposure, Tsun Hay Jason Ng

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Nicotine dependence is causally linked to increased risk of mood/anxiety disorders in later life. Females are reported to experience a higher prevalence of anxiety/depressive disorders and challenges in smoking cessation therapies, suggesting a potential sex-specific response to nicotine exposure and mood/anxiety disorder risk. However, pre-clinical evidence of sex-specific responses to adolescent nicotine exposure is unclear. Thus, to determine any sex differences in anxiety/depressive-related outcomes, adolescent male and female Sprague Dawley rats received nicotine (0.4 mg/kg; 3x daily) or saline injections for 10 consecutive days, followed by behavioural testing, in-vivo electrophysiology and Western Blot analyses. Our results revealed that adolescent nicotine …

The Combined Effects Of Physical Exercise And Cognitive Training On Gait Speed And Primary Motor Cortex Metabolism In Individuals With Mild Cognitive Impairment: A 1h-Mrs Analysis, Jack Thomas Emsey Elkas

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Mild cognitive impairment (MCI) is a transitional stage before dementia. Altered gait in MCI has been associated with progression to dementia. Using magnetic resonance spectroscopy, a relationship between primary motor cortex (M1) neurochemistry and dual task gait speed has been reported in MCI. Interventional research suggests exercise, cognitive training, and vitamin D supplementation may benefit MCI, yet the combined effect of these treatments on gait speed and M1 metabolism is unknown. Participants with MCI (N=75) were assigned to one of five intervention arms and dual task cost on gait speed and M1 metabolism was assessed before and five months after …

Neuropsychological Outcomes After Cardiac Surgery: A Pilot Feasibility Study, Sydni G. Paleczny

Electronic Thesis and Dissertation Repository

Approximately half of patients who have cardiac surgery will experience deficits in attention, memory, and thinking speed after their operation. Given that heart surgery is one of the most common medical procedures in Canada, it is necessary to better understand the natural history of cognitive impairment after such surgery. Yet, there is no globally accepted method for measuring cognitive function in patients who undergo heart surgery. To address this, we assessed whether it was feasible to use a web-based approach to measure cognition in heart surgery patients before and after their operation. Findings showed that remote administration of cognitive testing …

Shedding Light On Hearing In Coma: Investigating The Applicability Of Functional Near-Infrared Spectroscopy For Assessing Auditory Function And Aiding Prognosis In Patients With Acute Disorders Of Consciousness, Reza Moulavi Ardakani

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There is a critical need for a bedside neuroimaging tool to aid in the prediction of functional recovery outcomes for patients with acute disorders of consciousness (DoC) in the early days following severe brain injury. Current neurobehavioral examinations and prognosis tools have limitations in predicting good outcomes, leading to potential mistreatment or premature withdrawal of life support. Functional near-infrared spectroscopy (fNIRS) is a viable candidate for such purposes due to its portability and cost-effectiveness. Auditory processing, viewed as a multi-level and multifaceted brain function, could provide a sensitive and specific marker of residual cognitive function in unresponsive patients. This study …

Longitudinal Dynamics Of Cerebrospinal Fluid Aꞵ, Ptau And Strem2 Reveal Predictive Preclinical Trajectories Of Alzheimer’S Pathology, Bahaaldin Helal

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Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with limited early-stage treatment options. There is an urgent and unmet need for accurate biomarkers which can identify patients at risk for AD before cognitive symptoms emerge. Here I compared the performance of two analytical methods, univariate and multivariate classification, for identifying cognitively normal (CN) and mild cognitive impairment (MCI) patients based on their cerebrospinal fluid (CSF) biomarkers of Aβ42, pTau-181, sTREM2. Post-hoc analyses were then employed to assess patient progression in each of the SNF clusters. I found that SNF identified subgroups within the CN and MCI cohorts, based solely on …

Monitoring Intraventricular Hemorrhage In Preterm Infants, Lilian Mn Kebaya

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Germinal Matrix-Intraventricular hemorrhage (GMH-IVH) remains a significant cause of adverse neurodevelopmental outcomes in preterm infants. Current management options for GMH-IVH rely on serial 2-dimensional cranial ultrasound (2D cUS) ventricular measurements and clinical signs. A need exists for reliable biomarkers to aid in the early detection of posthemorrhagic ventricular dilatation (PHVD) and cerebral palsy (CP). We incorporated 3-dimensional cranial US (3D cUS) and functional infrared spectroscopy (fNIRS) to monitor ventricle volumes (VV) and spontaneous functional connectivity (sFC) in preterm infants with GMH-IVH. Infants with severe GMH-IVH who underwent cerebrospinal fluid diversion showed larger VV, which correlated with decreased sFC. Our findings …

Data-Driven Neuroanatomical Subtypes In Various Stages Of Schizophrenia: Linking Cortical Thickness, Glutamate, And Language Functioning, Liangbing Liang

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The considerable variation in the spatial distribution of cortical thickness changes has been used to parse heterogeneity in schizophrenia. We aimed to recover a ‘cortical impoverishment’ subgroup with widespread cortical thinning. We applied hierarchical cluster analysis to cortical thickness data of three datasets in different stages of psychosis and studied the cognitive, functional, neurochemical, language and symptom profiles of the observed subgroups. Our consensus-based clustering procedure consistently produced a subgroup characterized by significantly lower cortical thickness. This ‘cortical impoverishment’ subgroup was associated with a higher symptom burden in a clinically stable sample and higher glutamate levels with language impairments in …

Postexercise Executive Function Benefits And Cerebral Blood Flow: In The Lab And At Home, Benjamin Tari

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A single bout of aerobic exercise improves executive function; however, the mechanism, or mechanisms, supporting this improvement remain unclear. One candidate mechanism is an exercise-mediated increase in cerebral blood flow (CBF) that enhances the efficiency of executive-related frontoparietal networks. To evaluate the link between exercise, CBF and executive function, three separate experiments were conducted. In the first study, separate 10-min sessions of moderate-to-heavy-intensity aerobic exercise, and a hypercapnic environment (i.e., 5% CO₂) were implemented. The hypercapnic condition was included because it increases CBF independent of the metabolic demands of exercise. The second study investigated whether exercise intensity-specific changes …

Validation Of Arterial Spin Labeling For Longitudinal Monitoring And Differential Diagnosis Of Frontotemporal Dementia, Tracy Ssali

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Frontotemporal dementia (FTD) is a devastating neurodegenerative disease characterized by a rapid decline in behavioural, language, and motor abilities. Advances in the understanding of FTD genetics and pathophysiology, and the subsequent development of novel disease modifying treatments have highlighted the need for tools to assess their efficacy. While structural magnetic resonance imaging (MRI) and functional imaging with ¹⁸F-flurodeoxyglucose (FDG) positron emission tomography (PET) are used for clinical diagnosis, structural changes are subtle at the early stages and PET imaging is expensive and access limited. Given the coupling of cerebral blood flow (CBF) to energy metabolism, an attractive alternative is …

Describing Functional Brain Connectivity's Role In The Relationship Of Multimodal Interventions To Improve Cognitive And Physical Function In Vulnerable (Frailty & Mild Cognitive Impairment) Older Adults., Nicholas (Nick) W. Bray

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Aging is associated with declining cognitive and physical function. The decline accelerates in older adults diagnosed with mild cognitive impairment (MCI), a pre-dementia state, and frailty, a state of decreased physiological reserve. Previous work shows that frailty modifies the relationship between dementia pathology and clinical symptoms. Functional brain network connectivity (FBNC) refers to brain areas that are anatomically separate but temporally related in their neural signaling; it is believed to enable the completion of complex cognitive and physical functions. FBNC is considered a sensitive biomarker for monitoring the progression of dementia syndromes and investigating the efficacy of interventional strategies. Therefore, …

Protein Misfolding Toxicity And Inclusion Formation In Cellular Models Of Neurodegeneration, Sonja E. Di Gregorio

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Protein misfolding characterizes most neurodegenerative diseases. Protein misfolding is the conversion of specific proteins from their normal, often soluble, and native three-dimensional conformation into an aberrant, often insoluble, non-functional conformation. Protein inclusions and aggregates are among the major pathological hallmarks of protein misfolding associated with many neurodegenerative diseases. Yet, the role of aggregates and inclusions is not clearly defined and heavily debated. This study utilizes powerful genetic approaches in yeast and verification in mammalian neuronal cell lines to address the misfolding and toxicity of three proteins, the Rho Guanine Nucleotide Exchange Factor (RGNEF), Matrin3, which are involved in amyotrophic lateral …

Evaluating Anesthetic Protocols For Non-Human Primate Functional Neuroimaging, Megha Verma

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Functional magnetic resonance imaging (fMRI) is a non-invasive technique that can be used to measure a proxy of neural activity in vivo with high spatial specificity. One subject can be followed for a long period of time to assess changes in functional brain organization. However, fMRI is extremely sensitive to motion. The challenges of training non-human primates to reduce motion in an MRI scanner motivate the study of anesthesia which is commonly used to substitute for this training. In this thesis, I compare three different commonly used anesthetic protocols: isoflurane, propofol-fentanyl in combination, and fentanyl alone, to test which of …

The Impact Of Levodopa Administration On Learning From Short-Term And Long-Term Action Consequences: A Paradigm Validation., Masood Rezaei

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Behavioral and neuroimaging studies have identified two valuation systems in the human brain for controlling behavior known as model-free (MF) and model-based (MB). MF is based on immediate evaluation and MB is based on long-term evaluation of the outcome of our decisions. Previous studies suggest that dopamine baseline activity may play an important role in the balance between the two systems and determine how they compete or interact in controlling our actions. The overarching aims of this study is to investigate the impact of levodopa administration on learning from immediate and long-term action consequences, and to dissociate the role of …

Examining Brain Connectivity And Reading Ability In Children, Alexandra M. Cross

Electronic Thesis and Dissertation Repository

In this thesis, I investigated the relationship between functional and structural connectivity and reading ability in children. Prior research has tended to use single word reading measures or composite measures, however this is problematic as reading is a complex skill relying on multiple subskills, such as decoding efficiency, sight word reading efficiency, reading comprehension, and rapid automatized naming. As a result, the multi-faceted relationship between brain connectivity and reading ability is not well understood. I aimed to address this issue by considering multiple reading subskills while examining the neural substrates of reading. In Chapter 2, I examined how individual differences …

Assessment Of Intrinsic Hand Neuromuscular Physiology, Philemon Tsang

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Alterations to the peripheral nervous system and neuromuscular physiology may impact hand function in a typical or clinical population, such as individuals with ulnar neuropathy. The mechanisms that influence these positive and negative changes are still not well understood. The three studies within my thesis aim to validate the reliability of decomposition-based quantitative electromyography (DQEMG) measurements and explore the changes in intrinsic hand neuromuscular physiology in a typical aging population and individuals recovering from a surgical intervention for severe ulnar neuropathy.

The purpose of the first study was to determine the test-retest reliability of near-fibre (NF) jiggle, a measure of …

High Frequency Oscillations Are Phase-Amplitude Coupled In Stress Induced Seizures Following Traumatic Brain Injury, Paul Jung

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Traumatic Brain Injury (TBI) often leads to the development of epilepsy, especially with the occurrence of stressful events. Stressors increase the levels of corticotropin-releasing factor (CRF) in the amygdala, which can be damaged by the secondary effects of TBI. It is hypothesized that the activity of CRF receptor type 1 (CRFR₁) in the amygdala is altered post-TBI and supports the generation of epileptiform waves, namely high-frequency oscillations (HFOs). Sprague-Dawley rats were given a moderate TBI and in vivo recordings of the amygdala were taken during the administration of an acute tail pinch stressor. The stressor increased broadband activity …

Comorbid Metabolic Syndrome And Prodromal Alzheimer's Disease In A Rat Model, Nadezda Ivanova

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Metabolic syndrome (MetS), the development of which is associated with high-caloric Western diet intake, represents a risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and appears to contribute to AD progression when MetS and AD are comorbid. The interaction between AD and MetS might be through white matter inflammation, since white matter abnormalities and inflammation are important early events in the etiopathogenesis of both diseases. In these investigations, the effect of a high-caloric diet (HCD), to induce metabolic disturbances, on white matter neuroinflammation and cognitive function was investigated in a transgenic (TG) rat model of prodromal AD …

The Role Of Atf4 In Amyloid-Beta-Induced Neuronal Death., Gillian Petroff

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Alzheimer’s disease (AD) is partially characterized by excessive accumulation of amyloid-b (Ab) in the brain. Ab oligomers have greater toxicity than Ab fibrils and induce neuronal stress. The Integrated Stress Response (ISR) is activated in response to cellular stress and increases expression of activating transcription factor 4 (ATF4) and its target genes. Prolonged activation has been shown to induce aberrant cell death, and increased markers of the ISR have been found in the brains of AD patients. However, the exact mechanism of amyloid-b-induced death is largely unknown. We aimed to determine if Ab-induced neuronal death occurs through ATF4-mediated upregulation of …

Effects Of A Unilateral Injection Of Botulinum Neurotoxin Subtype-A In The Subthalamic Nucleus Of A Parkinsonian Rat Model, Olga Khazov

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Dopaminergic degeneration in Parkinson’s disease (PD) leads to altered functional activity within the basal ganglia (BG) circuitry, including hyperactivity of the subthalamic nucleus (STN). Treatments restoring the BG functional circuitry often result in improvements in parkinsonian symptoms in patients and animal models. A recent study from our laboratory identified that infusing botulinum toxin (BoNT-A) into the internal globus pallidus provided a transient restoration of motor asymmetry and goal-directed locomotion in a rat model of PD. We hypothesized that infusions of BoNT-A into the STN in a parkinsonian rat model will improve motor asymmetry and locomotor abnormalities. Infusions of BoNT-A into …

Connectomic Analysis Of Substantia Nigra Pars Compacta And Ventral Tegmental Area Projections To The Striatum And Cortex, Nicholas Handfield-Jones

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We investigated the connectivity of dopamine (DA) neurons emerging from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) and targeting the dorsal striatum (DS), ventral striatum (VS), and prefrontal cortex (PFC). We used diffusion magnetic resonance imaging (dMRI) probabilistic tractography on human connectome project MRI data. We found that unlike conventional descriptions of DA pathways (i.e., nigrostriatal, mesolimbic, mesocortical), connectivity from both SNc and VTA each targeted DS, VS, and PFC. We also found that from the DS, VS, and PFC, a greater proportion of connections targeted the SNc as compared to the VTA. These findings suggest …