Saudi Cultural Missions Theses & Dissertations
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Item Restricted THE NEUROPHYSIOLGY OF SELECTIVE ATTENTION IN HUMAN SUBCORTICAL MOTOR NUCLEI(University of Toronto, 2025) Alanazi, Frhan; William, HutchisonSelective attention and working memory are fundamental cognitive processes traditionally attributed to cortical regions. Emerging evidence suggests that subcortical motor nuclei, such as the thalamus and basal ganglia, also play crucial roles in these functions, but the mechanism is still unclear. This thesis aimed to examine the neurophysiological mechanisms of selective attention and working memory in subcortical motor nuclei through intraoperative single-unit and local field potential (LFP) recordings in humans. In the first study, neuronal activity was recorded from the ventral intermediate nucleus (Vim) and ventral oral anterior/posterior nuclei of the motor thalamus in 25 patients with parkinsonian and non-parkinsonian tremors during an auditory oddball task. Results showed a significant decrease in neuronal firing rates and in beta-band (13–35 Hz) oscillations to the deviant tones, indicating the involvement of Vim in auditory selective attention. Parkinson’s disease (PD) patients off medication exhibited increased beta power but reduced modulation to attended tones, suggesting dopamine's role in modulating thalamic beta oscillations for selective attention. The second study focused on the centromedian nucleus (CM) of the thalamus in 11 epilepsy patients performing a similar auditory attention task. CM neurons demonstrated selective, multiphasic firing and beta/low gamma (13–45 Hz) modulations to deviant tones in 81% of neurons tested. These findings highlight the CM's participation in cognitive function, supporting its role under top-down control and implicating beta and gamma oscillatory activities in cognitive processing. The third study investigated neuronal activity in the subthalamic nucleus (STN) and Vim during a visual 1-back task in 16 patients with PD or essential tremor. Both nuclei exhibited selective firing rate changes and beta desynchronization in response to target stimuli. Vim beta desynchronization occurred earlier than in the STN, even preceding the stimulus, suggesting a role in stimulus prediction. Collectively, these studies provide evidence that subcortical motor nuclei are actively involved in selective attention and working memory and have significant implications for understanding the neural circuitry underlying cognitive functions and the pathophysiology of neurological disorders like Parkinson’s disease and epilepsy. Furthermore, they offer potential insights for developing deep brain stimulation therapies targeting cognitive symptoms associated with these conditions.14 0Item Restricted DEEP LEARNING-ASSISTED EPILEPSY DETECTION AND PREDICTION(Florida Atlantic University, 2024) Saem Aldahr, Raghdah; Ilyas, MohammadEpilepsy is a multifaceted neurological disorder characterized by superfluous and recurrent seizure activity. Electroencephalogram (EEG) signals are indispensable tools for epilepsy diagnosis that reflect real-time insights of brain activity. Recently, epilepsy researchers have increasingly utilized Deep Learning (DL) architectures for early and timely diagnosis. This research focuses on resolving the challenges, such as data diversity, scarcity, limited labels, and privacy, by proposing potential contributions for epilepsy detection, prediction, and forecasting tasks without impacting the accuracy of the outcome. The proposed design of diversity-enhanced data augmentation initially averts data scarcity and inter-patient variability constraints for multiclass epilepsy detection. The potential features are extracted using a graph theory-based approach by analyzing the inherently dynamic characteristics of augmented EEG data. It utilizes a novel temporal weight fluctuation method to recognize the drastic temporal fluctuations and data patterns realized in EEG signals. Designing the Siamese neural network-based few-shot learning strategy offers a robust framework for multiclass epilepsy detection. Subsequently, Federated Learning (FL) architecture enables epileptic seizure prediction and enhances the generalization capability by utilizing numerous seizure patterns across diversified and globally distributed epileptic patients. By capturing the potential patterns, the hybrid model design potentially offers superior prediction accuracy by integrating a spiking encoder with graph convolutional neural networks. The preictal probability of each local model then aggregates the weights of the local medical centers with the global FL. Furthermore, applying the adaptive neuro-fuzzy inference system ensures a patient-specific preictal probability by combining the local model with patientspecific clinical features. Finally, epileptic seizure forecasting utilizes Self-Supervised Learning (SSL) capabilities to overcome the limitations of annotated EEG data. This selfsupervised transfer learning improves the training efficiency in massively arriving EEG data streams. The dual-feature embedding enhances the learning ability while a lightweight prediction utilizes the embeddings from the pretext task for epilepsy forecasting in the downstream task. The performance testing on the benchmark datasets reveals the accuracy of epilepsy detection, prediction, and forecasting by addressing the limitations of the existing approaches for effective patient management. The research outcomes ultimately enable real-time, transparent, and personalized solutions to ensure commitment towards the quality of life.21 0Item Restricted Seizure Control and Developmental Outcomes After Epilepsy Surgery in Infants(University College London, 2024) Alanazi, Samar; Eltze, ChristinBackground: Managing epilepsy in infants is challenging, even with antiseizure medications, and is associated with developmental delays. This study evaluated epilepsy surgery in infants, focusing on seizure control, developmental outcomes, and quality of life. Method: We conducted a retrospective analysis of infants who underwent epilepsy surgery ≤12 months of age at Great Ormond Street Hospital between January 2007 and October 2023. Data included neuroimaging, cognitive, language, and quality of life assessments. Seizure outcomes were classified using the Engel system. Results: Thirty-eight patients (22 female) were included. The median age at onset was 6 weeks. Patients had structural abnormalities, including hemimegalencephaly (n=12, 31.6%) and focal cortical dysplasia (n=10, 26.3%). Surgery was performed at a median age of 6.5 months (IQR=4 months) and included hemispherotomy (47.4%), lesionectomy/lobectomy (31.5%), and multilobar disconnection (18.4%). Six patients (15%) required a second surgery. After a median follow-up of 4 years (IQR=6 years), 23 patients (60.5%) achieved seizure freedom, and 21 patients (55.3%) discontinued antiseizure medications. Hemiplegia was the most common motor impairment both pre- and post-surgery. Paired pre- and post surgery cognitive data were available for 21 patients, with 53% maintaining and 21% showing improvement in cognitive trajectories. Paired language data were available for 16 patients, with 34% maintaining and 13% showing improvement in language trajectories. Patients achieving seizure freedom exhibited more favourable language trajectories. Post-surgery quality of life data for 13 patients (34.2%) showed scores below normative levels. Conclusion: Epilepsy surgery significantly reduces seizures, but developmental outcomes vary, highlighting the need for ongoing evaluation.14 0Item Restricted THE IMPACT OF O-GLCNAC SIGNALING ON DNA HYDROXYMETHYLATION IN TEMPORAL LOBE EPILEPSY(the University of Alabama at Birmingham, 2024) Bahabry, Rudhab; Lubin, FarahTemporal Lobe Epilepsy (TLE) is the most prevalent form of focal epilepsy and the most treatment-resistant type. This condition is characterized by recurrent, unprovoked seizures typically originating in the hippocampus. Epigenetic modifications such as DNAme changes have been implicated in brain functions such as synaptic plasticity, learning and, memory, and cognition. The oxidation of DNA 5-methylcytosine (5-mC) and its oxidized form, 5-hydroxymethylcytosine (5-hmC) catalyzed by Ten- Eleven Translocation (TET) family of dioxygenases and linked to epilepsy's hyperexcitable state. Post‐translational modifications (PTMs) of proteins, such as O- GlcNAcylation, facilitate cells' immediate responses to intracellular or extracellular environmental stimuli by modifying the functions of targeted proteins. Recent evidence suggests a significant interaction between O-GlcNAc transferase (OGT) and TET enzymes, affecting TET activity and chromatin structure, thus influencing gene expression. This dissertation hypothesized that decreased TET1 O-GlcNAcylation in the epileptic hippocampus contributes to pathological hyperexcitability via decreased 5-hmC levels in a TLE rat model. We found a significant reduction in 5-hmC levels in the hippocampi of both human TLE patients and kainic acid-induced TLE rats, without affecting 5-mC levels. hydroxyMethylated DNA immunoprecipitation sequencing (hMeDIP-Seq) analysis indicated a notable loss of 5-hmC in intergenic regions of the epileptic hippocampus, with identified pathways related to GABA signaling and ion transport. In-vivo manipulating hippocampal Tet1/5-hmC levels showed direct implications on seizure susceptibility and resilience. Furthermore, a co-immunoprecipitation (co-IP) assay was utilized to investigate the interactions between TET1 and OGT within the hippocampus of epileptic tissues, revealing a decrease in their interaction compared to the controls. Additionally, we further identified the presence of a TET1-OGT complex by Western blot assays, emphasizing the presence of physical interaction between these proteins. Moreover, we aimed at detecting protein O-GlcNAcylation levels through the use of sWGA assay demonstrating a significant reduction in the O-GlcNAcylation of TET1 in epileptic animals, to the point where it was nearly undetectable when compared to control animals. Finally, using Thiamet-G treatment, we were able to increase O-GlcNAcylation and global 5-hydroxymethylcytosine in our epileptic animals, restoring the levels to levels similar to the control. These results elucidate the significant role of TET1 levels and O-GlcNAcylation in epilepsy, establishing a foundational link between PTMs and epigenetic regulation in the disorder and suggesting the potential of targeting O-GlcNAcylation pathways as a novel therapeutic strategy for epilepsy.6 0Item Restricted The Role of HBP1 and Wnt signaling in Genetic and Idiopathis Epilepsy(2023-04-06) Alrubiaan, Sumaiah; Yee, AmyEpilepsy is one of the most prevalent neurological diseases which results from abnormal neuronal firing, leading to the development of spontaneous recurrent seizures. Despite the development of multiple anti-epileptic medications in the last decade, about one third of the patients eventually develop resistant to anti-epileptic drugs. One of the most important reasons behind the drug resistance is the inability to identify a clear mechanistic pathway to be targeted for treatment. Existing pharmaceutical treatments function primarily to reduce hyper-excitability thus providing only symptomatic control. Identifying alternative mechanistic targets for anti-epileptic treatment to prevent the progression of chronic epilepsy has been the main research focus recently. The Yee lab has shown that the Wnt/β-catenin pathway is aberrantly activated in both acute and chronic epilepsy, driving a metabolic reprogramming of aerobic glycolysis (Warburg-like metabolism) resulting in elevated mTOR signaling. Key to these changes was phosphorylation-dependent inhibition of Pyruvate Dehydrogenase (PDH) by the Wnt target gene PDK4. One of the known inhibitors of Wnt signaling, HMG box protein 1 (HBP1), was shown to decline in the epileptogenic period, suggesting a mechanism for Wnt activation in epileptogenesis. As a test of this mechanism, HBP1 knockout mice had elevated Wnt signaling in the hippocampus and recapitulated the metabolic reprogramming to aerobic glycolysis (Warburg-like metabolism) and elevated mTOR signaling. In-depth analysis of gene and protein expression, bioinformatics and confocal microscopy suggested additional changes. Among these, we observed a reduction in multiple GABA receptors and increased glutamate receptor expression along with altered glutamate transport. These results were consistent with a remarkably altered susceptibility to seizure induction along with occasional spontaneous seizures in HBP1-/- mice. Accompanying the seizure phenotype we observed gliosis, which is consistent with seizure and the altered signaling and metabolic alterations. Collectively, these data provide evidence that HBP1 alterations/Wnt signaling may determine the threshold of acquired seizure susceptibility. Consistent with the mouse results, several genome-wide studies suggest a disruption of Wnt/β-catenin in epilepsy patients. Moreover, multiple case reports were published highlighting deletions within the genomic region of the HBP1 and its possible correlation with neurological diseases including autism, intellectual disability and epilepsy. Human genetic sequencing data were obtained from 1600 patients and family members in the Epi4K database yielded 8 HBP1 variants and a near-significant association with Lennox-Gastault epilepsy tied to a specific variant (R375P). Mutagenesis experiments to evaluate the functional impact of these variants on HBP1 protein function demonstrated that R375P was disruptive, resulting in HBP1R375P failing to repress Wnt activity. These data suggest that loss of HBP1 function through deletion or mutation results in susceptibility to epilepsy.26 0