Doctor of Philosophy, Case Western Reserve University, 2022, Molecular Medicine

Epilepsy is the third most common neurological disorder worldwide and includes a clinically heterogeneous spectrum of disorders. Various genetic etiologies have been reported for rare forms of epilepsy, including severe monogenic epilepsies caused by de novo variants and lesional focal epilepsies caused by brain-specific somatic variants. In this work, we investigate the epidemiological and etiological landscape of these two individually rare forms of genetic epilepsies. This knowledge is critical to the development of precision medicine approaches for rare epilepsies. First, we applied novel data-based approaches to generate epidemiological estimates for these two rare forms of genetic epilepsies. For monogenic epilepsy disorders caused by de novo variants, we employed a genetics-based approach to generate gene-specific incidence estimates by adjusting a statistical model for de novo mutation. For lesional focal epilepsies, we combined epidemiological data from a systematic literature review with histopathological findings from surgical patients to generate subtype-specific incidence and prevalence estimates for epileptic brain lesions such as hippocampal sclerosis (HS), low-grade epilepsy-associated brain tumors (LEAT), and malformations of cortical development (MCD). Lastly, we characterize the somatic genetic landscape of these brain lesion categories through deep whole-exome sequencing and whole-genome genotyping of 474 surgically-resected brain lesions. Here, we detect somatic variants in twelve established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the etiology of LEAT (BRAF) and MCD (SLC35A2 and MTOR). We also identify novel candidate genes: PTPN11 and NF1 for LEAT and NRAS for MCD and reveal a role for large somatic copy number variants in the etiology of these lesions. In summary, our findings bring the clinical management of rare genetic epilepsies multiple steps closer to the goal of precision medicine f (open full item for complete abstract)

Committee: Dennis Lal (Advisor); John Barnard (Committee Chair); Imad Najm (Committee Member); Ignacio Fernandez Mata (Committee Member); Jonathan Smith (Committee Member) Subjects: Bioinformatics; Biology; Epidemiology; Genetics

Doctor of Philosophy, Case Western Reserve University, 2013, Epidemiology and Biostatistics

Background: People with uncontrolled epilepsy use considerable health care resources and have high risk of mortality. Epilepsy surgery is a highly effective treatment in stopping seizures for these otherwise intractable patients, however, utilization is low and there are disparities in access to this procedure. Objectives: 1.) investigate disparities in access to specialized epilepsy care considering both patient and community factors, with particular focus on the impact of insurance; 2.) describe the demographics, costs, and utilization among people with epilepsy on Medicaid; and 3.) compare surgery versus medical treatment for Medicaid patients with uncontrolled epilepsy on utilization, cost, attrition, and mortality outcomes. Study Data: California State Inpatient Database, State Ambulatory Surgery Database, State Emergency Department Database, Area Resource File, Ohio Medicaid claims data, and Ohio death certificate data. Methods: Utilization of video-EEG monitoring and epilepsy surgery were used to indicate access to specialized care. Hierarchical logistic regression modeled the impact of individual and county-level factors as barriers to access. Medicaid claims and enrollment data were used to describe the epilepsy population and their health care resource utilization. To compare the effectiveness of surgery, we used optimal pairwise matching with a time-dependent propensity score and inverse-probability of treatment weighting to control for selection bias, and repeated measures linear regression to estimate the effect of surgery on all outcomes. Results: The Medicaid-insured and uninsured had reduced access to specialized epilepsy care, while proximity to an epilepsy center was positively associated with access. Black race, males, older age also had lower access. Health care costs and utilization were highest among Medicaid-enrollees with uncontrolled seizures. Utilization of epilepsy surgery was low. Surgery lead to lower overall health care co (open full item for complete abstract)

Committee: Siran Koroukian (Committee Chair); Mendel Singer (Committee Member); Thomas Love (Committee Member); Kaiboriboon Kitti (Committee Member) Subjects: Biostatistics; Epidemiology; Health Sciences; Surgery

DNP, Otterbein University, 2022, Nursing

Long-term video-electroencephalography (EEG) monitoring in the epilepsy monitoring unit (EMU) is an elective procedure and generally safe. Clinical experts determined the EMU protocols at a level-4 comprehensive epilepsy center were not followed correctly. The project is a retrospective chart audit incorporating Ray's Bureaucratic Caring theoretical framework with Donabedian's conceptual model. The project objective is to evaluate if safety measures protocols are implemented appropriately in the EMU and determine whether a need exists for quality improvements. The project reviewed patients admitted to the EMU from September 2021 through November 2021 who developed a generalized tonic clonic (GTCs) seizure with electrographic epileptiform correlation. Data abstractors collected seizure safety indicators from eleven patients with fifteen GTCs. Of the fifteen GTCs, the seizure safety efficiency indicator revealed an average GTC was 92.7 seconds, and the time to responder response was 43.6 seconds. The GTC management and seizure precaution indicators showed (53%) had suction set up, (60%) suction initiated, (67%) vital signs recognized, (53%) no one called out vital signs, (40%) vital signs obtained, (60%) variation of a neurological assessment, (13%) of patients turned on their side, and (80%) had no objects to cause injury. Other indicators include (93%) had four side-rails up, (100%) no one called out bed in the low position, (13%) had continuous pulse oximetry, and (80%) had IV access and continuous telemetry. Interventions to stop seizure indicators include (67%) no one called out Ativan administration, (60%) no one called out notifying physician. During the postictal stage, (87%) variation of a neurological assessment, (73%) variation of vital signs, and (80%) postictal suctioning occurred. Medication change indicator revealed (80%) of antileptic drugs (AEDs) stopped and (20%) on AEDs. Of the fifteen GTCs, two GTCs, no one responded. The pr (open full item for complete abstract)

Committee: Joy Shoemaker (Advisor); Amy Hotler (Committee Member); Angela Parsons (Committee Member) Subjects: Health; Health Care; Health Education; Health Sciences; Medicine; Neurology; Neurosciences; Nursing

Master of Sciences, Case Western Reserve University, 2019, Biomedical Engineering

Low-frequency audio-visual stimulation has been shown to effectively reduce seizures in two animal models of medically refractory epilepsy. As such, low-frequency sensory stimulation (LFSS) may result in decreased epileptogenic activity in patients with MRE. A clinical trial was used to study the effect of LFSS in 6 patients with MRE. Each patient received both LFSS and control stimulation from a non-invasive audio-visual device for 20 minutes. Spike rates were then compared between stimulation, pre-stim, and post-stim periods. Globally, LFSS increased spike rates compared to baseline (116.126% increase, p = 0.005). For analysis of spikes originating from leads within the hypothesized epileptogenic zone, LFSS decreased spike rates compared to baseline (-41.567%, p < 0.001) and controls stimulation did not (-28.365%, p = 0.089). Therefore, LFSS decreases spike frequency in the EZ, indicating likely therapeutic effects with longer stimulation times, a study of which is needed in order to draw definitive conclusions.

Committee: Dominique Durand Ph.D. (Advisor); Colin Drummond Ph.D. (Committee Member); Richard Burgess M.D. Ph.D. (Committee Member); Dileep Nair M.D. (Advisor); Jorge Gonzalez-Martinez M.D. Ph.D. (Committee Co-Chair) Subjects: Biomedical Engineering; Biomedical Research; Engineering; Health Care; Medicine; Neurology; Neurosciences; Surgery

PhD, University of Cincinnati, 2018, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

Approximately 50 million people worldwide live with epilepsy and making this disease one of the most common neurological diseases worldwide. About 0.6 – 2 % of children aged 0-17 years have active epilepsy. Childhood epilepsy affects children at different ages and in many different ways; some seizures in childhood are not associated with a definite cause. The most common type of idiopathic focal epilepsy syndrome is Childhood Epilepsy with Centrotemporal Spikes (CECTS). CECTS is age-dependent and self-limited. CECTS was previously considered a `benign' epilepsy, because of the excellent seizure prognosis. However, there are increasing reports that children with CECTS exhibit various cognitive and behavioral problems. Recently, quantitative structural MRI analyses have shown that there is atypical cortical morphology in CECTS compared to typically developing children. However, the findings are often contradictory, which may be due to heterogenous study populations. Therefore, the aim of this study was to compare cortical thickness between drug-naive new onset CECTS patients and typically developing children, with careful inclusion criteria to promote homogeneity within groups and careful matching between. We also investigated the correlation with Processing Speed Index (PSI), which was significantly different between groups, and frequency of centrotemporal spikes (CTS) within regions of interest (ROIs). We did not find any cortical thickness differences between groups based on the whole brain analysis. We found a significant interaction between PSI and group in cortical thickness within the ROIs. There were positive correlations with PSI and cortical thickness in typically developing children, but no or negative correlation in CECTS. In addition, cortical thickness in right pars opercularis was thinner with higher frequency of right –sided CTS. These findings indicate that children with CECTS have atypical cortical features which may underlie poorer processing speed (open full item for complete abstract)

Committee: Steve Danzer Ph.D. (Committee Chair); Mekibib Altaye Ph.D. (Committee Member); Christina Gross Ph.D. (Committee Member); Darren Kadis Ph.D. (Committee Member); Jeffrey Tenney M.D. (Committee Member); Jennifer Vannest Ph.D. (Committee Member) Subjects: Neurology

Doctor of Philosophy, Case Western Reserve University, 2014, Physiology and Biophysics

Mesial temporal lobe epilepsy (MTLE) is the most common and medically refractory form of epilepsy. As an alternative to surgical resection, MTLE has been treated with vagal nerve stimulation and deep brain electrical stimulation (DBS) of gray matter with limited success. Stimulation of a white matter tract connecting the hippocampi could maximize treatment efficacy and extent. We tested low-frequency electrical stimulation (LFS) of a novel target that enables simultaneous targeting of bilateral hippocampi: the ventral hippocampal commissure (VHC) with a novel in-vitro slice preparation containing bilateral hippocampi connected by the VHC. The goals of this study are: (i) To understand the role of hippocampal interplay in seizure propagation and reduction by commissural fiber tract stimulation, (ii) To develop and test a novel DBS paradigm for hippocampal seizure reduction, and (iii) To test the role of long-lasting hyperpolarization in mediating the anti-epileptic effects of LFS. The third objective is divided into two parts as follows: (a) Pharmacologically assess whether GABAB receptors are necessary for seizure reduction by LFS and (b) Pharmacologically assess whether the sAHP is necessary for seizure reduction by LFS. To achieve these aims, LFS is applied to the VHC as electrophysiological techniques are combined with signal processing to estimate several metrics of epilepsy. Bilateral epileptiform activity in this preparation is highly correlated between hippocampi. Application of LFS to the VHC reduces seizures in bilateral hiipocampi during and after stimulation in an amplitude and frequency dependent manner. Importantly, enhanced post-stimulation 1-Hz spiking correlates with long-lasting seizure reduction and both are heightened by targeting bilateral hippocampi via the VHC. Understanding the mechanisms of seizure reduction by LFS is important for minimizing side effects of this potential therapy and maximizing efficacy. This study shows dep (open full item for complete abstract)

Committee: Dominique Durand (Advisor); Corey Smith (Committee Chair); George Dubyak (Committee Member); Thomas Nosek (Committee Member); Christopher Ford (Committee Member); Ruth Siegel (Committee Member); Imad Najm (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Biophysics; Neurology; Neurosciences

PhD, University of Cincinnati, 2009, Arts and Sciences : Psychology

The classic receptive (temporal lobe)/generative (frontal lobe) dissociation of language function may be inadequate in characterizing language function in epilepsy. The relative impact of temporal versus frontal lobe epileptogenic foci on language function is also unknown. Individuals with mesial temporal lobe epilepsy (MTLE), have higher rates of psychopathology relative to the general and other chronically ill populations, as well as structural hippocampal abnormalities associated independently with the MTLE syndrome and the effects of high levels of emotional distress. Therefore, cognitive dysfunction may result from some combination of the intrinsic epileptogenic lesion or damage associated with chronic high levels of emotional distress, or both. The present study evaluted the diagnostic utility of the Boston Naming Test, phonemic paraphasic error production on the BNT, Controlled Oral Word Association Task, Animal Naming, and Token Test in terms of their ability to predict frontal lob epilepsy (FLE), left MTLE, or right MTLE focus, as well as the potentially moderating effects of perceived emotional distress. Seventy-seven individuals with MTLE (43 left and 34 right) and 30 individuals with FLE were included. Binary logistic regression models evaluated the predictive ability of each language measure to differentiate diagnostic group. Main effect and interaction terms for scales D and Pt on the MMPI-2 were added to each model to assess the possible moderating effects of perceived emotional distress. The results did not explicitly support a receptive/generative dichotomy, but rather a continuum of language function with some tasks more or less reliant on receptive and generative language components. Left MTLE and FLE patients performed equally poorly on all language measures, while right MTLE patient performance was largely unimpaired. Performance was moderated by perceived emotional distress; however, depression and anxiety were found to differentially modera (open full item for complete abstract)

Committee: Bruce Schefft PhD (Committee Chair); Steven Howe PhD (Committee Member); Michael Privitera MD (Committee Member); Christine Hovantiz PhD (Committee Member) Subjects: Psychology

PhD, University of Cincinnati, 2007, Arts and Sciences : Psychology

The purpose of this study was to determine significant predictors of seizure and cognitive outcome following surgery for epilepsy. Participants included 41 patients who had undergone anterior temporal lobectomy (ATL) with pre- and post-surgical neuropsychological data. Seizure-related characteristics and cognitive functioning were determined from medical records and from evaluations using multiple measures of cognitive functioning (e.g., intelligence, memory, and language). Logistic regression analyses were conducted to examine predictors of seizure control. Hierarchical multiple regression analyses were employed to evaluate predictors of overall cognitive functioning using a conglomerate score. Results of the current study suggest that patients who develop seizures at a later age and demonstrate higher pre-surgical overall intelligence and lower nonverbal memory skills were more likely to be seizure free following ATL. Further, surgery in the hemisphere contralateral to language functioning and higher pre-surgical intelligence scores were predictive of better cognitive outcome post surgery. Identifying pre-surgical factors related to surgical outcome is important for counseling patients about the potential risks and benefits of surgery.

Committee: Dr. Bruce Schefft (Advisor) Subjects: Psychology, Clinical

Doctor of Philosophy, The Ohio State University, 2007, Biomedical Engineering

A multi-paradigm approach integrating three novel computational paradigms: wavelet transforms, chaos theory, and artificial neural networks is developed for EEG-based epilepsy diagnosis and seizure detection. This research challenges the assumption that the EEG represents the dynamics of the entire brain as a unified system. It is postulated that the sub-bands yield more accurate information about constituent neuronal activities underlying the EEG. Consequently, certain changes in EEGs not evident in the original full-spectrum EEG may be amplified when each sub-band is analyzed separately. A novel wavelet-chaos methodology is presented for analysis of EEGs and delta, theta, alpha, beta, and gamma sub-bands of EEGs for detection of seizure and epilepsy. The methodology is applied to three different groups of EEGs: healthy subjects, epileptic subjects during a seizure-free interval (interictal), and epileptic subjects during a seizure (ictal). Two potential markers of abnormality quantifying the non-linear chaotic EEG dynamics are discovered: the correlation dimension and largest Lyapunov exponent. A novel wavelet-chaos-neural network methodology is developed for EEG classification. Along with the aforementioned two parameters, the standard deviation (quantifying the signal variance) is employed for EEG representation. It was discovered that a particular mixed-band feature space consisting of nine parameters and LMBPNN result in the highest classification accuracy (96.7%). To increase the robustness of classification, a novel principal component analysis-enhanced cosine radial basis function neural network classifier is developed. The rearrangement of the input space along the principal components of the data improves the classification accuracy of the cosine radial basis function neural network employed in the second stage significantly. The new classifier is as accurate as LMBPNN and is twice as robust. Next, biologically realistic artificial neural networks are dev (open full item for complete abstract)

Committee: Hojjat Adeli (Advisor) Subjects:

Master of Sciences (Engineering), Case Western Reserve University, 2024, Biomedical Engineering

Beyond seizures themselves, individuals with epilepsy commonly grapple with cognitive comorbidities, with memory impairment being most prominent. Despite ongoing investigative efforts surrounding the origins of memory issues in epilepsy, a noteworthy factor identified is the prevalence of interictal epileptiform discharges (IEDs). These discharges primarily manifest in critical brain regions such as the cortex and hippocampus, and they can also propagate nonsynaptically. Human intra-cortical studies and in-vivo rodent experiments consistently underscore a strong connection between IED prevalence and memory impairment. Nevertheless, the cellular and physiological mechanisms remain obscured, in part due to the predominant reliance on behavioral markers in existing studies. To address this gap, this in-vitro mouse model study investigates the hypothesis that IEDs induce a downregulation and depression of synapses within the hippocampus. Using 4-Aminopyridine to induce epileptiform activity, changes in the excitatory evoked postsynaptic potentials (EPSPs) are gauged as measured from the CA1 stratum radiatum as evoked by single pulse stimulation of the Schaffer collaterals. The observed changes in EPSP are used to determine long-term depression or potentiation. The findings demonstrate a significant correlation between 4-AP-induced IEDs and synaptic depression over time with an average decrease of 82.31 ± 5.42% in EPSP slope after the generation of IEDs. Furthermore, a retrospective analysis reveals that lower spiking IED frequencies are correlated with a more pronounced downregulation of synapses. This in-vitro exploration seeks to directly assess the impact of IEDs on synaptic plasticity and to provide a basic model for memory. This study can contribute to the currently underexplored area of research targeting IEDs as a potential therapy for memory dysfunction, a condition too often endured in epilepsy

Committee: Dominique Durand (Advisor); Masashi Tabuchi (Committee Member); Chia-Chu Chiang (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Electrical Engineering; Neurobiology; Neurosciences

PhD, University of Cincinnati, 2024, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

Epilepsy affects over 50 million patients worldwide, and one-third of those patients are resistant to current therapeutic options. The development of acquired epilepsy typically begins with a brain insult such as status epilepticus (SE), traumatic brain injury, genetic mutation, or infection. Following such insults, patients enter what is known as the “latent period” of the disease. During the latent period, the brain is changing but patients do not exhibit spontaneous recurrent seizures (SRSs). The latent period ends when a patient first experiences an SRS, at which point the disease has progressed to epilepsy. Epileptogenesis is the process by which a healthy brain becomes prone to SRSs, and it occurs during initial insult as well as throughout the latent period and chronic disease. While the majority of available treatment options aim to reduce SRSs in patients with chronic epilepsy, research has increasingly sought to define and inhibit epileptogenic changes. Successful anti-epileptogenic intervention has the potential to prevent or delay the onset of chronic epilepsy following brain insult and/or prevent continued brain alterations in patients who have already developed chronic epilepsy. The work in this thesis aimed to clarify the molecular mechanisms underlying epileptogenesis. Chapters 2 and 3 discuss the role of microRNAs (miRNAs) in epileptogenesis, and Chapter 4 discusses the role of Ras-MAPK signaling in epileptogenesis. MiRNAs are short, non-coding RNA sequences that regulate post-transcriptional gene expression via translational suppression or degradation of target messenger RNAs (mRNAs). Although many miRNAs have been implicated in epilepsy development, this thesis primarily discusses the role of miR-324-5p. Previous work in our lab showed an anti-convulsant and anti-epileptic effect of miR-324-5p inhibition when administered before brain insult or in chronic epilepsy. Using the intrahippocampal kainic acid model in mice, we tested (open full item for complete abstract)

Committee: Mark Baccei Ph.D. (Committee Chair); Christina Gross Ph.D. (Committee Member); Katrina Peariso M.D. Ph (Committee Member); Anil Jegga DVM MRe (Committee Member); Steve Danzer Ph.D. (Committee Member) Subjects: Neurology

Doctor of Philosophy, Case Western Reserve University, 2024, Genetics

Epilepsy is a neurological disorder characterized by repeated seizures. It affects 1% of the US population. Despite the recent progress in antiepileptic drug discovery and development, approximately 30% of the patients do not respond to current therapies. A major pitfall of the current antiepileptic drug discovery pipeline is current animal seizure models. The most widely used animal models are mechanically or chemically induced models, and they fail to recapitulate drug-resistant seizures, which are largely genetic epilepsies. Induced pluripotent stem cells (iPSCs) are promising alternative preclinical epilepsy models. iPSCs preserve the genetic information of epilepsy patients and can be an unlimited source of neuronal cell types of interest. Many studies have shown that iPSC disease models successfully reproduce epilepsy phenotypes. Herein, we successfully leveraged stem cell reprogramming technologies and CRISPR/Cas9 gene editing tools to generate iPSCs models of three drug-resistant epilepsies with monogenic cause: Early infantile epileptic encephalopathy, subtype 76 (EIEE-76), Microcephaly, Epilepsy, Diabetes Syndrome (MEDS), and GRIN2A-related epilepsy. Using these models, we uncovered pathophysiological mechanisms underlying the epilepsy phenotype of these rare genetic epilepsies that were previously unknown. We demonstrated EIEE-76 patient variant of ACTL6B dysregulates genes essential for neuronal development and that EIEE-76 patient-derived neurons demonstrated elevated electrophysiological activity than control, consistent with the patient phenotype. Also, we elucidated MEDS patient-derived neural progenitor cells (NPCs) have defects in secretory protein trafficking. Impaired protein trafficking during neurogenesis resulted in abnormal neuronal differentiation and electrophysiologically less active neuronal population. Next, we took a step further and developed a disease-relevant, high-throughput, phenotypic screen platform to identify potential an (open full item for complete abstract)

Committee: Ashleigh Schaffer (Advisor); Yan Li (Committee Member); Drew Adams (Committee Chair); Anthony Wynshaw-Boris (Committee Member); Andrew Pieper (Committee Member) Subjects: Genetics

Doctor of Philosophy, Case Western Reserve University, 2023, Biomedical Engineering

Neural signals are primarily transmitted from one neuron to another through chemical and electrical synapses. We have studied another mechanism through which groups of orderly arranged neurons can communicate with other groups by endogenous electric fields independent of synaptic transmission. Large electric fields have been well documented particularly in epilepsy characterized by highly synchronized activity. We hypothesized that this electric field associated with the epileptic event can be used to control the generation and propagation of the spikes and seizures. In this study, induced epileptic activity was induced by 4-Aminopyridine in hippocampal and cortical slices as well as in the hippocampus in in-vivo experiments. Two recording electrodes were used to record the activity in the slices. Four recording electrodes along the longitudinal axis was used for these acute in-vivo experiments. Two recording electrodes and two stimulating electrodes were used for controlling the electric field using an extracellular voltage clamp. Induced activity propagated by electric field coupling across a physical cut in hippocampal and cortical slices. Theta waves, epileptic interictal spikes, and seizure like events also propagated across a physical cut or transection in the hippocampus in in-vivo experiments at a speed about 0.1 m/s characteristic of electric field coupling mediated propagation. The interictal spikes when analyzed for parameters differentiating spikes that make through the cut to the electrodes on the other side of the transection showed that sharp high amplitude spikes have a higher probability of propagating than smaller wider spikes. The feedback system using the extracellular voltage clamp suppressed 100% of the spikes and seizures induced. Electric fields play an important role in the generation and propagation of epileptic events even through a transection in the tissue. We have successfully used the endogenous field to control the induction (open full item for complete abstract)

Committee: Dominique Durand (Advisor) Subjects: Biomedical Engineering; Biomedical Research; Engineering; Neurosciences

PhD, University of Cincinnati, 2023, Engineering and Applied Science: Biomedical Engineering

Epilepsy is a neurological disease that causes recurrent, spontaneous seizures, which can lead people to experience ephemeral neurological and physiological impairments and disrupt day-to-day living. One of the most enervating facets of epilepsy is the unpredictability of seizures. Most people reside in fear, stress, and anxiety of not knowing when a seizure might occur, which in turn can serve as a major disability and cause people to encounter difficulties engaging in daily activities. For decades, many seizure prediction studies have concentrated on utilizing long term electroencephalography (EEG) data from continuous scalp or intracranial EEG electrode monitoring. While these studies have shown positive results for seizure predictive capabilities, continuous EEG electrode monitoring can be invasive, uncomfortable, and pose some potential risk for patient with epilepsy. Thus, seizure prediction remains a significant challenge within epilepsy-based research. In efforts to advance seizure prediction, this dissertation work applies both quantitative and machine learning methods to overcome these challenges. In examining patient-specific seizure diaries that consist of possible seizure predictive factors (e.g., measurements of mood, stress, and circadian patterns), the first method focuses on using generalized linear modeling, specifically logistic regression, to predict subsequent seizures within a 24-hour timeframe. Following, predictive factors were used to generate quantitative biomarkers that associated with seizure occurrences and were analyzed via diagnostic tests. The second method focused on using a machine learning technique, specifically decision trees, to showcase how possible predictive factors are associated with seizure outcome. Additionally, certain factors were categorized into groups based on frequently they appeared in patients' decision trees. The significance of these seizure predictive factors was also identified. This dissertation (open full item for complete abstract)

Committee: Marepalli Rao Ph.D. (Committee Chair); Ishita Basu Ph.D. (Committee Member); Michael Privitera M.D. (Committee Member); Matthew McCullough Ph.D. (Committee Member); Jason Heikenfeld Ph.D. (Committee Member) Subjects: Biomedical Engineering

Master of Engineering, Case Western Reserve University, 2023, Biomedical Engineering

Epilepsy is the second most burdensome disease worldwide. Despite multiple advancements, a significant fraction of patients cannot attain freedom from epilepsy through current treatments such as anti-epileptic drugs (AED) or deep brain stimulation (DBS). However, low-frequency stimulation (LFS) has shown promising results in-vitro and acute in-vivo studies as an alternative treatment modality. One limitation of chronic experiments for LFS is the lack of a well-established focal cortical seizure model. The stability of recurrent focal seizures generated by the Iron Chloride model was examined in this study. We investigated the number of seizures and percent time per day seizing for animals (N=5) after intraoperative intracortical injection of iron chloride for 14 days. Additionally, we investigated the capability of seizures generated to propagate to the contralateral cortex and hippocampus. Recorded seizures in our chronic study had a mean duration of 31±7.9 seconds, a mean peak-to-peak voltage of 2.5±1.5 mV, and an average peak frequency of 22.8±5 Hz (N=3370 seizure events). On average, animals showed a stable baseline of 50 seizures per day. Recording on the 8th day post-injection yielded a stable baseline of seizures for thirteen days. We observed 402 seizures (N=364) propagating to the contralateral cortex and 91 seizures to the hippocampus. The mean delay was 4±8 msec for the contralateral cortical and 1±1 msec for the hippocampal propagation. The Iron Chloride model provides a good alternative to genetically available models for the generation of focal cortical seizures.

Committee: Dominique Durand PhD (Committee Chair); Chaitali Ghosh PhD (Committee Member); Paul Marasco PhD (Committee Member); Kenneth Laurita PhD (Committee Member) Subjects: Biology; Biomedical Engineering; Biomedical Research; Medicine; Neurobiology; Neurology; Neurosciences

PhD, University of Cincinnati, 2022, Engineering and Applied Science: Electrical Engineering

Accurate functional mapping with intracranial electrodes is essential for preserving cognitive function during resective neurosurgery. However, conventional mapping techniques still frequently result in postoperative cognitive deficits. This research presents novel signal and neuroimage processing methods for 3D localization of electrodes and functional mapping of a visual naming task using stereotactic EEG recordings. These methods were found to outperform state-of-the-art general purpose time series classifiers and conventional clinical techniques. Insights gained from this work were then extended to propose a data-driven spatiotemporal cognitive model of visual naming.

Committee: Ravindra Arya M.D. D.M. (Committee Member); Gowtham Atluri Ph.D. (Committee Member); Ali Minai Ph.D. (Committee Member); H. Howard Fan Ph.D. (Committee Member); Katherine Bouley M.D. (Committee Member) Subjects: Neurology

PhD, University of Cincinnati, 2022, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary

Epilepsy is defined by the occurrence of recurrent and unprovoked seizures. Currently, little is known about the pathological changes that occur during epileptogenesis, the process by which a healthy brain becomes epileptic. As a result, research that adds to our understanding of the mechanistic changes in epilepsy is crucial to developing novel therapeutic options. The accumulation of improperly integrated adult hippocampal dentate granule cells (DGCs) is thought to have a role in temporal lobe epilepsy (TLE). DGCs regulate excitatory signaling in the hippocampus and undergo neuroplastic alterations during epileptogenesis. However, the mechanism that causes these abnormal alterations is unclear. Recently, the mechanistic target of rapamycin (mTOR) signaling pathway has emerged as a promising new target to combat epileptogenesis. The mTOR pathway regulates neuronal growth and synaptic strength by integrating a wide range of cellular processes through mTORC1 and mTORC2. Raptor (regulatory-associated protein of mTOR) and Rictor (rapamycin-insensitive companion of mTOR) are critical proteins that activate mTORC1 and mTORC2, respectively. Studies indicate pharmacological inhibition of mTOR with the mTOR antagonist rapamycin is anti-epileptogenic in rodent TLE models and reduces seizure incidence in patients with genetic hyperactivation of mTOR. These data support the concept that mTOR has a role in the development of acquired epilepsy, especially since mTOR hyperactivation is widespread in animal models and human TLE patients, and rapamycin can inhibit several TLE-related pathological alterations in DGCs. However, because rapamycin is administered systemically, it is unknown where the drug acts to produce its positive effects. Rapamycin could act directly on hyperexcitable neurons in the epileptic focus, it could work on other targets in the brain or even operate in the periphery. Our guiding hypothesis is that rapamycin has disease-modifying effects by blocking (open full item for complete abstract)

Committee: Christina Gross Ph.D. (Committee Member); Mark Baccei Ph.D. (Committee Member); Jeffrey Tenney M.D. Ph.D. (Committee Member); Kim Seroogy Ph.D. (Committee Member); Steve Danzer Ph.D. (Committee Member) Subjects: Neurosciences

Master of Science in Biomedical Sciences (MSBS), University of Toledo, 2022, Biomedical Sciences (Bioinformatics and Proteomics/Genomics)

Temporal Lobe Epilepsy (TLE) is one of the most common neurological disorders and is characterized by recurrent and spontaneous seizures. Although TLE genetic and electrophysiological markers such as gamma oscillations are well characterized, alterations in the interactions between neurons predisposing a cortical region to seizures are not fully understood. To study these non-linear interactions, we incorporated RNA expression changes into a microcircuit computer model of the hippocampus, an area strongly implicated in TLE. Cellular deconvolution of bulk RNAseq data with single-cell transcriptomic data from the hippocampi of pilocarpine-induced temporal lobe epilepsy mice revealed three distinct cell clusters characterized as pyramidal (PYR) cells, oriens-lacunosum moleculare (OLM) interneurons, and parvalbumin-positive (PV) interneurons. We used the differential expression (log fold change) of genes coding for the Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA), N-methyl-D-aspartate (NMDA), and Gamma-aminobutyric acid type A (GABAA) receptor subunits in the control and epileptic conditions for each cell cluster to guide scaling of receptor density iv in the model. The model was composed of 800 PYR, 200 PV and 200 OLM neurons. PYR cells of the model activate PV, OLM, and other pyramidal cells via NMDA and AMPA receptors; in return, the PV and OLM interneurons inhibit PYR cells by acting on their GABAA receptors. Guided by the RNA expression data, we ran simulations where we increased the density of PYR AMPAR, OLM NMDAR, PV AMPAR, and PV GABAAR scaling. PYR GABAAR subunits were both upregulated and downregulated and thus, both changes were implemented when running simulations. Our simulations showed two dynamical changes with the RNA sequence changes. The first is the expected increased seizure susceptibility, reflected as increased gamma power. That pattern took place with pyramidal AMPAR/GABAAR upscaling. The second pattern was a surprising reduc (open full item for complete abstract)

Committee: Robert Mccullumsmith (Advisor); Rammohan Shukla (Committee Co-Chair); Mohamed Sherif (Committee Member); Bruce Bamber (Committee Member); Imran Ali (Committee Member) Subjects: Bioinformatics; Biophysics; Neurosciences

MS, University of Cincinnati, 2022, Medicine: Genetic Counseling

Aicardi syndrome is a rare disorder historically defined by a classic diagnostic triad of manifestations – agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms – and characterized by a range of neurodevelopmental and systemic complications. To add to existing knowledge of the spectrum of clinical presentation, we conducted a detailed medical record review of 17 patients with Aicardi syndrome. Patients with a clinical diagnosis of Aicardi syndrome that presented between January 2002 through March 2021 were included in the cohort. Specific details of clinical presentation were collected to describe intracranial anomalies, seizure severity, non-neurological complications, and neurodevelopmental outcomes. All available fetal imaging was reviewed. Spearman correlation coefficients were derived for three scores calculated for intracranial anomalies, seizure severity, and non-neurologic complications. Correlations with mortality and neurodevelopmental outcomes were analyzed for each score. The most common intracranial anomalies identified on postnatal magnetic resonance imaging (MRI) were agenesis / dysgenesis of the corpus collosum (15/15), heterotopias (14/15), and polymicrogyria (10/15). Posterior fossa anomalies (5/15), interhemispheric cysts (5/15), and basal ganglia anomalies (2/15) were present in lower proportions. Fetal MRI findings from 7 patients included agenesis of the corpus callosum (ACC, 6/7), heterotopia (4/7), ventriculomegaly (4/7), sulcation anomalies (2/7), and arachnoid cysts (2/7). All patients had seizures in their lifetime. In long term follow up, 1 patient experienced more than 10 daily seizures, 6 patients had 1-9 daily seizures, 4 patients had weekly seizures, and 4 patients had no or occasional seizures. Two patients did not have seizure frequency data available. An average of 5.1 antiepileptic drugs (AEDs) were tried over course of the lifetime, and 20 unique AEDs were tried among all members of the cohort. Of the seven (open full item for complete abstract)

Committee: Melanie Myers Ph.D. (Committee Member); Paul Horn Ph.D. (Committee Member); Beatrix Wong M.S. (Committee Member); Charulata Venkatesan (Committee Member); Christine Spaeth M.S. C.G.C. (Committee Member) Subjects: Surgery

MS, University of Cincinnati, 2022, Engineering and Applied Science: Biomedical Engineering

The objective of the current study is to investigate brain alterations in patients with localization-related epilepsy (LRE) compared to healthy controls using different brain activity measures including regional homogeneity (ReHo); functional connectivity density mapping (FCDM) with global (gFCD) and lobal (lFCD); amplitude of low-frequency fluctuations (ALFF) and fractional amplitude of low-frequency fluctuations (fALFF), based on resting-state fMRI data. ReHo, gFCD and lFCD, ALFF and fALFF were used to examine the alterations in the brain from 19 LRE patients and 19 healthy controls, by using the whole brain resting-state fMRI (rs-fMRI) data. For each method, a two sampled t-test was conducted; and all results were corrected for family wise error for group analysis. The LRE patients were placed into subgroups based on whether the seizure onset falls into the limbic regions. The two-samples t-test was conducted to investigate the brain alterations in the limbic LRE patients versus the healthy controls, the non-limbic LRE patients versus the healthy controls, and between these two epileptic patient groups. The current findings demonstrated ReHo, gFCD, lFCD, ALFF, and fALFF alterations in the LRE patients compared to healthy subjects during resting state. For both group analysis and for subgroup limbic analysis, we obtained specific brain regions with significantly altered ReHo, lFCD, ALFF, and fALFF values. The targeted brain regions with significant alterations might be contributing to the overall lower synchronization and more impaired functional activity in the processing of motor pathways, visual information, and emotional functions. The targeted brain regions were also in the salience network and the default mode network (DMN), as well as part of the language area, sensorimotor regions, and those associated with the posterior attention system. We also (open full item for complete abstract)

Committee: Jing-Huei Lee Ph.D. (Committee Member); Marepalli Rao Ph.D. (Committee Member); Zackary Cleveland Ph.D. (Committee Member) Subjects: Biomedical Research