Centre for Neuroscience Studies Graduate Theses

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    Inhibitory Control of Chemistry Misconceptions
    (2024-09-11) Lawton, Will; Neuroscience Studies; Bongers, Amanda
    Misconceptions are a significant hindrance to students across all levels of learning. They are difficult to remedy, contributing to persistent errors and clashing with factual information. Research investigating the neural correlates of misconceptions suggests that cognitive control and inhibitory processes are important for overcoming these persistent errors and promoting conceptual change, something that is especially important to the suppression of scientific misconceptions. The current work was designed to expand these findings to include a prevalent but understudied misconception among chemistry learners involving the use of arrows. The first study, outlined in Chapter 3, focused on novice post-secondary chemistry students and their misconceptions about curved arrows in organic reaction mechanisms. Findings from this study quantitatively supported the existence of this specific misconception and informed the following study, described in Chapter 4. In the principal study, electroencephalography (EEG) and eye-tracking were used to study the neural correlates of this same misconception among chemistry experts. The replication of previous event-related potential (ERP) data as well as the novel use of eye-tracking and event-related spectral perturbation (ERSP) analysis led to a nuanced set of findings that suggest that measures of cognitive control and inhibition are active as experts process stimuli that adhere to their ingrained, misconceived ideas. Overall, the findings presented in this thesis support previous EEG work on scientific misconceptions and expand them into the field of chemistry education. Our work also contributes to the knowledge of cognitive control processes in learning, providing further support that inhibitory control is an important factor in expertise, allowing individuals to suppress incorrect information and access scientific knowledge.
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    DELIVERY OF A scAAV9.coGM2A FOR PHENOTYPIC CORRECTION OF GM2 GANGLIOSIDOSIS AB-VARIANT, IN THE NEWLY CHARACTERIZED GM2A/NEU3 DOUBLE KNOCKOUT MOUSE MODEL
    (2024-09-06) Cheng, Camilyn Schwey-Yi; Neuroscience Studies; Walia, Jagdeep
    AB-Variant GM2 gangliosidosis (ABGM2) is an autosomal recessive lysosomal lipid storage disorder characterized by an overaccumulation of GM2 gangliosides in neuronal lysosomes, ultimately resulting in neuronal cell death. This disorder arises due to a mutation in the GM2A gene, which encodes for GM2 Activator Protein (GM2AP), an essential cofactor in the hydrolysis of GM2 gangliosides. Overaccumulation of GM2 gangliosides and eventual neuronal cell death present as phenotypic symptoms of sensory, motor, and cognitive decline and ultimately result in a shortened lifespan. In its most severe and common infantile form, death can occur as early as 4 years of age. Currently, there are no curative treatments available for ABGM2. The delivery of a gene therapy using an Adeno-Associated Virus expressing a codon-optimized human GM2A transgene was proposed to treat ABGM2. Previous studies utilizing GM2A transgene administration in Gm2a-/- murine models showed reduction in GM2 ganglioside accumulation as well as widespread vector biodistribution to the central nervous system; however, this model does not accurately mirror the severe human form due to its normal lifespan. This has led to the creation and characterization of a Gm2a-/-/Neu3-/- murine model, which more closely parallels the symptoms and lifespan of the severe human form of ABGM2. The purpose of the present study was to investigate the dose-response relationship of intrathecal delivery of scAAV9.coGM2A (low 0.4e11vg/mouse, medium 0.8e11vg/mouse, or high 1.6e11vg/mouse) on GM2 ganglioside accumulation, behavioural parameters and mortality in the newly characterized Gm2a-/-/Neu3-/- murine model. Overall, the data suggests a dose response effect on GM2 ganglioside accumulation, with the high dose demonstrating the greatest reduction of 1.9-fold (p=0.0007, ***). Furthermore, all dosages produced improvements in behavioural parameters and significant improvement in survival of as high as 1.5-fold. These results contribute to the evidence for the potential clinical efficacy and safety of scAAV9.coGM2A in the treatment of ABGM2.
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    Impact of comorbid sleep disorders in patients with epilepsy on mortality risk
    (2024-09-04) Lazaj, Marion; Neuroscience Studies; Shukla, Garima
    Background: Pooled mortality is nearly three times higher in people with epilepsy (PWE), with epilepsy-related deaths, including sudden unexpected death in epilepsy (SUDEP), status epilepticus, and drowning, being more prevalent than other causes. Approximately 80% of SUDEP events occur during sleep, and sleep abnormalities are common in PWE, including disruptions in quality and architecture. Primary sleep disorders like sleep-disordered breathing and insomnia disorder are prevalent in both the general population and PWE. Currently, research is extensively exploring SUDEP risk evaluation and biomarkers, with limited studies investigating the connection between sleep and SUDEP/all-cause mortality risk in epilepsy. This study aims to assess the relationship between mortality risk in epilepsy and the diagnosis of primary sleep disorders. Methods: The study included consecutive patients with active epilepsy from a Canadian epilepsy clinic over a 4-year period. The database collected demographic, clinical, neurophysiological, and sleep information, along with accident and hospitalization records. Mortality risk was evaluated using the modified SUDEP-7 scale, and primary sleep disorder diagnoses were made by a qualified sleep physician based on ICSD-3 criteria. Patients were categorized into two groups: those without comorbid sleep disorders (Group 1) and those with sleep disorders (Group 2). Statistical analyses were conducted to compare mortality risk-related variables between the two groups. Results: The study enrolled 1506 PWE, with Group 1 (1130 patients) and Group 2 (376 patients). Both groups showed similar average epilepsy duration, epilepsy type distribution, and the percentage of PWE seizure-free for over a year. However, Group 2 exhibited a significantly higher proportion of PWE with high mortality risk, increased incidence of all-cause mortality, accidents, and poorer employment status. The most common sleep disorder in Group 2 was obstructive sleep apnea (54%), followed by insomnia disorder (29%) and restless legs syndrome (12%). Conclusion: Comorbid primary sleep disorders are associated with significantly higher SUDEP risk and all-cause mortality risk in epilepsy. PWE with these sleep disorders also face an elevated risk of accidents and unemployment. This study offers valuable insights for developing more accurate predictive models and tools for assessing mortality risk.
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    Robotic Assessment of Processing Speed and Longitudinal Cognitive Changes in Epilepsy
    Falah, Adam Mizied; Neuroscience Studies; Winston, Gavin
    Despite extensive research on cognition in epilepsy, processing speed (PS) impairments remain underexplored and often overlooked. Additionally, accelerated cognitive decline in epilepsy has been shown in multiple studies. Generally, traditional pen-and-paper neuropsychological assessments are used to determine cognitive status. However, these do not come without limitations. Therefore, this study aims to address these limitations and enhance the assessment of PS impairments and cognitive decline by using Kinarm Robotic Technology. The Symbol Digit Modalities Test (SDMT) is a commonly used traditional assessment for PS, recording only one parameter: the number of correct answers. Recently, a novel robotic version of SDMT has been developed on the Kinarm platform to improve assessment by recording multiple parameters. These parameters reflect both the speed and behavior of participants' during the test. The first part of this study focused on validating the robotic SDMT. To do this, we recruited 32 epilepsy patients and 30 controls. Both groups completed the two versions SDMT. Our results showed that patients had reduced performance on both versions of the SDMT compared to controls. Significant correlations were found between the two assessments in the number of correct selections (r = 0.79, p = 2.06e-14). Speed-based parameters of the Kinarm SDMT (e.g., mean time of correct selections) showed significant differences between patients and controls. Ratio-based parameters, which examine participants' behavior (e.g., ratio of time for correct vs. incorrect answers), did not show such differences. This indicates that PS is primarily impaired in epilepsy, not the participants’ strategy. Additionally, the Kinarm SDMT correlated with established PS assessments, including the Trail Making Test A, Grooved Pegboard Test, and the Coding subtest of the RBANS. In the second part of the study, cognitive decline was assessed after a ~3-year interval. Nine patients from a previous study were reassessed. Contrary to expectations, more cognitive improvements were observed. However, this finding was not considered conclusive due to study limitations. Overall, our findings highlight the presence of PS impairment in epilepsy and validate the use of robotics in PS assessment. Future studies with larger cohorts are needed to better understand the longitudinal cognitive trajectories in epilepsy.
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    Clinical Utility of Advanced Neuroimaging Techniques in the Presurgical Assessment of Patients with Epilepsy
    (2024-08-30) Ellsay, Andrea; Neuroscience Studies; Winston, Gavin
    For the 30% of people with focal epilepsy who are medically refractory, neurosurgery is a potential treatment option. However, identifying suitable candidates and localizing the epileptogenic zone remains a significant challenge. This study evaluates the clinical utility of three neuroimaging techniques in the pre-surgical assessment at the newly designated District Epilepsy Center, Kingston Health Sciences Center. Additionally, language lateralization indices (LI) are compared when processed start-to-finish using two popular open-source software packages, SPM12 and FSL, or preprocessed with fMRIPrep. Patients in the pre-surgical pathway were discussed in multidisciplinary team meetings (n=21). Exclusions included patients who had already undergone resections (n=5) and those deemed unsuitable for surgery (n=4). Patients meeting the criteria for surgical candidacy with inconclusive clinical data, such as a negative MRI or discordant data (n=12), were recruited for comprehensive MRI evaluation. This included high-resolution structural imaging for hippocampal/amygdala volumetry and lesion detection, and fMRI for language lateralization. The benefits of this additional data were documented in a follow-up questionnaire during the re-evaluation of the patients. Patients (n=12) and healthy controls (n=12) participated in two task-based fMRI paradigms: sentence completion and word generation. The analysis involved GLM and LI calculations for three regions of interest using tools specific to each software. 144 LIs were calculated for each of the four processing pipelines. Overlap of activations were assessed visually and with Dice coefficients (DC). Following assessment, all previously discussed surgery candidates were deemed suitable or could proceed to the next assessment step (n=12). The protocol identified previously unseen imaging abnormalities (n=4) or hippocampal asymmetry (n=2) and provided useful language laterality information (n=12). Visual assessment of overlap in the fMRI processing pipelines showed similar results, but DC ranged from 0.16-0.70. However, LI remained concordant in 531/576 (92%) of combinations. These findings demonstrate that these advanced neuroimaging modalities can be effectively integrated into clinical practice at a newly established epilepsy surgery center, providing valuable information to benefit patient care. Furthermore, all fMRI processing tools performed similarly for block design language fMRI data; software choice ultimately depends on factors such as usability and alignment with the standard practices of individual surgery centers.