Centre for Neuroscience Studies Graduate Theses
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Item Investigating affective modulation of pain in the brainstem and spinal cord in healthy people and those with fibromyalgia using functional magnetic resonance imaging(2025-01-03) Algitami, Hannan; Neuroscience Studies; Stroman, PatrickPain is a multidimensional experience that involves both sensory and affective components. Because of this, understanding how affect influences pain perception can help us understand the experience of pain more comprehensively. Furthermore, investigating this influence can identify possible mechanisms of fibromyalgia (FM), a chronic pain condition which is often associated with symptoms of negative affect. FM is a debilitating condition that disproportionately affects women and affects multiple domains of well-being. Despite this, the exact physiological and neural mechanisms of FM are still unknown. The aim of this thesis was to investigate the neural signaling in the brainstem and spinal cord associated with negative affective modulation of pain in healthy people and in people with FM. This was done in two separate projects. The first project was a re-analysis of fMRI data from a previous affective modulation study done in healthy people using novel connectivity analysis methods. The results from this study suggested that people differ in the way that they respond to affective modulation of pain, in terms of pain ratings and connectivity. Building on the study done in healthy people, the second project investigated the effect of negative affective modulation of pain in FM compared to HC. The results of this study suggested that pain ratings in FM participants were not modulated by negative affect, which indicated that differences in connectivity between FM and HC were not a result of the induced negative affect. However, these results were gathered from a relatively small sample and may not have detected subtle effects of affective modulation of pain, if there were any. Nevertheless, the results from this study demonstrated that although FM is thought to be influenced strongly by affect, our results do not support this idea. Combining these results with those from the first study, we suggest that affective modulation of pain is not a strong effect, both in HC and FM.Item Investigation of Behavior and Molecular Biomarkers Associated with Neurological and Psychiatric Disorders(2024-12-23) Braga de Freitas, Guilherme; Neuroscience Studies; De Felice, Fernanda G.; Munoz, Douglas P.Cognitive decline (CD) is driven by a combination of molecular, environmental, and intrinsic factors within the pathophysiology of neurodegenerative and psychiatric disorders. The overlapping mechanisms among these diseases present significant challenges for modern medicine, requiring collaborative diagnostic efforts to investigate onset, assess severity, and monitor progression. This thesis aimed to identify behavioral and molecular markers associated with CD, uncover new pharmacological targets, and enhance the characterization of related neurodegenerative and psychiatric conditions. For this sake, two distinct behavioral assessment methods were employed: neuropsychological evaluations and video-based eye-tracking. Additionally, cerebrospinal fluid (CSF) markers were profiled to evaluate factors contributing to disease development. Chapters 2 and 3 evaluated CSF analytes concerning metabolic and psychiatric risk factors within an older Brazilian adult cohort. In a dataset containing 31 CSF analytes, potential CD-associated therapeutical targets were identified through embedded feature selection methods, highlighting the ratio of the anti-inflammatory mediator lipoxin A4 to the inflammatory mediator cysteinyl leukotriene as significant in CD and generalized anxiety disorder. These findings supported the role of neuroinflammation in disease development. Furthermore, it was found, somewhat unexpectedly, that obesity was negatively associated with CD, suggesting protective effects. Although CSF leptin changes were related to obesity, leptin did not directly impact CD, indicating that obesity’s influence on CD was not dependent on leptin. In this context, considering that sedentarism significantly contributed to CD in Brazil, Chapter 4 reviewed the neuroprotective mechanisms induced by physical exercise, demonstrating its potential to prevent and reduce CD progression. Moreover, pharmacological alternatives were explored for individuals unable to engage in physical activity due to mobility constraints. Recognizing that external factors such as viral infections could exacerbate inflammatory processes associated with CD, Chapter 5 assessed oculomotor behavior parameters in a previously hospitalized Brazilian COVID-19 cohort. By utilizing inhibitory control paradigms and video-based free viewing, impairments were observed in inhibitory control signals originating from the frontal cortex and basal ganglia to the superior colliculus. These results suggested that COVID-19-related inflammation had lasting neurological impacts. Collectively, these findings may guide the development of comprehensive diagnostic tools and therapeutic strategies aimed at mitigating the progression of neurodegenerative and psychiatric disorders.Item Robotic evaluation of sensorimotor and cognitive function following exposure to subconcussive impacts(2024-11-21) Hambly, Cameron Charles; Neuroscience Studies; Cook, Douglas JamesSubconcussive impacts, caused by direct or indirect head trauma without immediate symptoms, are increasingly recognized as a contributor to long-term neurological sequelae Individuals repeatedly exposed to such impacts, including military personnel and contact sport athletes, often report symptoms as their careers progress. However, monitoring neurological changes related to subconcussive impacts is challenging because few objective measures are currently available. Robotic technology, such as the Kinarm device, presents an opportunity to objectively quantify sensorimotor and cognitive function. Here, military snipers operating 0.50-caliber long-range rifles completed a visually guided reaching (VGR) and reverse visually guided reaching (RVGR) task using Kinarm. Assessments were completed before (n = 18) and after (n = 7) a one-day shooting intervention. While overall performance in snipers did not significantly differ from controls (n = 53) at either time point, snipers made more direction errors than controls during the initial VGR assessment. This difference may relate to an accumulation of subconcussive impacts incurred throughout military service. Additionally, both groups improved between assessments, primarily driven by a training effect observed in the first few trials. Further analysis of individual trials revealed that snipers displayed poorer feedback adjustment compared to controls. However, snipers were consistently faster, suggesting that their specialized skill set may compensate for exposure to subconcussive impacts. Overall, these findings show that Kinarm may be useful in identifying markers of exposure and recovery in traumatic brain injury, potentially in conjunction with neuroimaging to link changes in the brain with a functional outcome.Item History-Dependence in the Neural Basis of Free Choice Saccadic Behaviour(2024-10-07) Caie, Brandon; Neuroscience Studies; Blohm, GunnarChoices are formed by combining sensory information with expectations that are formed from past experience. Although progress has been made in our understanding of how these transformations occur in decision-making tasks, where outcomes are well-defined, much less is known about conditions where we are free to choose between alternatives with no objective distinction. The work in this PhD thesis combined behavioural analysis, modelling, computational theory, neuroimaging, and causal interventions to improve our understanding of how visual information is combined with expectations during free choice saccadic behaviour. We developed a saccadic choice task, wherein the asynchrony between visual stimuli was manipulated across trials such that we could elicit 'free choice' saccades. In the first paper, we combined fMRI-guided HD-tDCS with EEG recordings in human participants performing the free choice saccade task. By combining within-participant test-retesting with a state-of-the-art neuroimaging pipeline, we provided a comprehensive assessment of within and across participant variability in the effects of HD-tDCS on biasing saccadic choice through frontal eye field neural activity. We found that intra-individual variability across different sessions was a significant driver of reported effects -- the profile of the variability was such that it was unclear whether these reported differences were caused by differences in tDCS-dependent effects, or variability that arises from history-dependence in measurements typically treated as independent. In a second study, we approached the problem of history-dependence from a theoretical standpoint, asking how the assumptions we make about generative models of behaviour and neural data shape our expectations of null effects when making causal interventions on the system. In a final study, we consider saccadic choice behaviour in more detail using a combination of choice history analysis and a novel computational model. There, we found evidence that anticipatory dynamics are an important contributor to how sensory expectations are formed in saccadic choice, and that these dynamics invalidate some assumptions of the models used to explain choice behaviour as a stationary process. In combination, these studies provide an empirical assessment of sources of variability when intervening on saccadic free choice, as well as a theoretically grounded treatment of causes and consequences of history-dependence.Item Development of A Gene Therapy for Creatine Transporter Deficiency(2024-10-07) Webster, Troy; Neuroscience Studies; Walia, JagdeepCerebral creatine deficiency syndromes are a group of genetic disorders caused by the inability to synthesize or transport creatine, leading to a severe depletion of creatine in the brain. Creatine transporter deficiency is one of the three Cerebral creatine deficiency syndromes caused by loss of function mutations in the X-linked SLC6A8 gene. In the absence of creatine transporter cells are unable to uptake creatine, resulting in a depletion of creatine in multiple tissues, including the brain. Symptoms include intellectual disability, developmental delays, hyperactivity, and motor function deficits. As creatine is unable to cross cell membranes, supplementation is ineffective, and there are no currently available treatments. Here, we present the development of a gene therapy for creatine transporter deficiency using a self-complementary adeno-associated virus serotype-9 vector. We first attempted to replicate previously reported phenotypes in a mouse model of creatine transporter disorder to use as a measure of gene therapy efficacy. We were unable to replicate deficits in memory but were able to show increased hyperactivity and decreased brain creatine. In Chapter 4. We show that gene therapy is capable of restoring creatine in creatine transporter-deficient patient cells. Then, in a proof of concept, gene therapy following neonatal intracerebroventricular (ICV) administration increases brain and peripheral organ creatine in a dose-dependent fashion. Brain creatine was able to be elevated to supraphysiological levels in creatine transporter knockout mice, indicating that gene therapy holds the potential for complete restoration of the biochemical phenotype. As neonatal gene therapy is difficult to translate to the clinic, we next compared neonatal ICV delivery with intrathecal lumbar puncture (IT) delivery in adult mice, as IT is much more clinically relevant. Both routes were assessed at 13 and 24-week endpoints. ICV resulted in a greater increase in brain creatine than IT at both endpoints. However, IT administration still resulted in increases in brain creatine, improvement in body mass, and a reduction in hyperactivity. This shows the first evidence of a clinically feasible gene therapy in treating creatine transporter deficiency.