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Chávez Wulsin, AynaraGlucocorticoid Mechanisms of Epileptogenesis and Comorbid Emotional Dysregulation
PhD, University of Cincinnati, 2017, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary
Dysregulation of the hypothalamo-pituitary-adrenocortical (HPA) axis is common in temporal lobe epilepsy. It is characterized by excess glucocorticoid signaling, a process that is similar to what is seen in a subset of patients with major depression. Although activation of the glucocorticoid receptor (GR) is essential for survival, exposure to excess glucocorticoids can lead to disruption of key neuronal circuits, particularly in the hippocampus. This disruption may compromise physiological and behavioral adaptations to stress. It is well documented that chronic exposure to excess corticosterone in rodents may be linked to the development of depressive and anxiety-like phenotypes. These effects can be blocked by treatment with GR antagonists. In addition to modulating behavior, glucocorticoids have been shown to exhibit pro-convulsant effects in several animal models of epilepsy. Thus hyperactivity of the HPA axis may be a common pathological mechanism that may help explain the high incidence of psychopathologies in epilepsy. The underlying mechanisms and long-term consequences of HPA axis hyperactivity in epilepsy are currently unknown. Exposure to elevated glucocorticoids may be particularly deleterious in epilepsy, as it may exacerbate hippocampal pathologies, increase brain excitability (pro-convulsant) and raise susceptibility for the development of depressive and anxiety-like phenotypes. These data support a role for GR in epileptogenesis. The studies presented in this dissertation aimed at testing our underlying hypothesis, that chronic hyper-activation of GR occurs early in the disease and contributes to the comorbid development of epilepsy and depression/anxiety-like phenotypes. In chapter 2, I used the pilocarpine induced status epilepticus (SE) mouse model of TLE to characterize changes in stress-regulatory circuitry and emotional behavior associated with TLE. These studies demonstrate that SE results in hypersecretion of baseline glucocorticoids. This elevation persists through the chronic period of epilepsy and is accompanied by increased glucocorticoid secretion in response to acute stress. Importantly, epilepsy generates profound impairments in the recruitment of forebrain circuits that are key in regulating stress inhibition and emotional reactivity. In chapter 3 I utilized the glucocorticoid antagonist RU486 to block glucocorticoid receptor signaling in the hours following SE. Glucocorticoid blockade successfully normalizes corticosterone secretion and reduces hippocampal pathologies associated with epileptogenesis, including reduction of mossy cell loss and decreased ectopic placement of post-SE generated cells. These findings support a role for GR in epileptogenesis. In chapter 4 we utilized a newly-develop glucocorticoid receptor modulator C108297 to test whether modulation rather than complete blockade has beneficial potential in epileptogenesis. Results from this study demonstrate a disease modifying effect of C108297 in the hippocampus and promising reduction in seizure severity. The studies conducted as a part of this dissertation research may prove critical for understanding mechanisms of epileptogensis, and suggest the potential of GR as a therapeutic target for the treatment of epilepsy and its comorbidities.

Committee:

Matia Solomon, Ph.D. (Committee Chair); Steve Danzer, Ph.D. (Committee Member); James Herman, Ph.D. (Committee Member); Louis Muglia, M.D. (Committee Member); Michael Privitera, M.D. (Committee Member)

Subjects:

Neurology

Keywords:

glucocorticoids;temporal lobe epilepsy;status epilepticus;C108297;Mifepristone;mice

Singh, Shatrunjai PQuantitative analysis on the origins of morphologically abnormal cells in temporal lobe epilepsy
PhD, University of Cincinnati, 2015, Medicine: Molecular and Developmental Biology
Epilepsy is a common and devastating neurological disease with no real preventive or cure. In most cases of acquired epilepsy, an initial precipitating injury to the brain is followed by a silent period which eventually culminates into the development of spontaneous, recurrent seizures. This interval between the primary insult and the first seizure is referred to as the latent period of epileptogenesis and is characterized by abnormal morphological and physiological changes in the hippocampus. In the studies described herein, I aim to elucidate changes in the different phases of epileptogenesis with the end goal of deciphering critical epileptogenic mechanisms. To study the initial stages of epileptogenesis, I employed the early kindling model. In this protocol, it is possible to administer a limited number of stimulations sufficient to produce a lifelong enhanced sensitivity to stimulus evoked seizures without associated spontaneous seizures. In these experiments, I characterized the morphology of GFP-expressing granule cells from Thy-1 GFP mice either one day or one month after the last evoked seizure. I observed several morphological changes at the one day time point, which all normalized to control levels at the one month time point. Interestingly, I did not observe the presence of basal dendrites, frequently observed in other models of epilepsy. These findings demonstrate that the early stages of kindling epileptogenesis produces transient morphological changes but not the dramatic pathological rearrangements of dentate granule cell structure seen in typical models associated with spontaneous seizures. To study epileptogenesis after the incidence of spontaneous, recurrent seizures, I used the pilocarpine model of epilepsy. Our lab has previously used this model to show that adult hippocampal neurogenesis is profoundly altered under epileptic conditions, leading to the production of morphologically abnormal dentate granule cells. Under epileptic conditions, these adult generated cells migrate to ectopic locations and develop misoriented basal dendrites. Although it has been established that these abnormal cells are newly-generated, it is not known whether they arise ubiquitously throughout the progenitor cell pool or are derived from a smaller number of bad actor progenitors. To explore this question, I describe clonal analysis experiments conducted in epileptic mice expressing the brainbow fluorescent protein reporter construct in dentate granule cell progenitors. Brain sections were rendered translucent so that entire hippocampi could be reconstructed and all fluorescently-labeled cells identified. The findings revealed that a small number of progenitors produced the majority of ectopic cells in epileptic mice, indicating that either the affected progenitors or their local micro-environments had become pathological. By contrast, granule cells with basal dendrites were equally distributed among clonal groups. These findings strongly predict that distinct mechanisms regulate different aspects of granule cell pathology in epilepsy. The experiments described here utilize different models of epilepsy and employ cutting edge technology to provide valuable insight into the process of epileptogenesis. The results and ideas presented here are intended to advance our knowledge of epilepsy and eventually lead to better antiepileptic therapies.

Committee:

Steve Danzer, Ph.D. (Committee Chair); Mark Baccei, Ph.D. (Committee Member); Kenneth Campbell, Ph.D. (Committee Member); Brian Gebelein, Ph.D. (Committee Member); Ronald Waclaw, Ph.D. (Committee Member)

Subjects:

Nanoscience

Keywords:

Temporal Lobe Epilepsy;Dentate Granule Cells;Clonal Analysis;Quantitative Analysis;Pilocarpine;Neural stem cells

Fiumedora, MarianneThe Contribution of Visuospatial Functioning to Verbal Paired Associate Learning in Temporal Lobe Epilepsy
MA, University of Cincinnati, 2018, Arts and Sciences: Psychology
It is well established that the mesial temporal lobes (MTL) mediate learning and memory. Further, the right and left temporal lobes contribute material-specific information. Specifically, (assuming typical, left language dominance) the left MTL is generally associated with learning and memory for verbal material, whereas the right MTL is generally associated with visuospatial learning and memory. Verbal paired associate (VPA) learning tasks are often used to assess left (language-dominant) mesial temporal lobe (MTL) functioning. However, because the stimuli in these tasks are often concrete nouns or other visualizable words, examinees have the opportunity to employ nonverbal strategies (e.g., imagery), which are known to be mediated by extratemporal regions within the right (language-nondominant) cerebral hemisphere. The current study examined the contribution of visuospatial skills to VPA learning in a clinical population with known MTL damage. It was hypothesized that 1) VPA learning would be more strongly related to visuospatial functioning as compared to other types of verbal memory (i.e., verbal list learning and story learning) and 2) the contribution of visuospatial functioning to VPA learning would persist beyond what is accounted for by other cognitive processes (i.e., verbal list learning and story learning, expressive language, nonverbal memory, and executive functioning). Data from 82 individuals with medically refractory temporal lobe epilepsy (TLE) were analyzed. Results indicated that scores on tests of visuospatial functioning were significantly and positively related to VPA learning (p < .001), but not to other tests of verbal memory (p > .30 for all analyses). Moreover, measures of visuospatial functioning correlated significantly more strongly with VPA than with the other verbal memory measures (p < .03), with the exception of one comparison that did not reach statistical significance. Hierarchical regression analyses indicated that performance on tests of visuospatial functioning was significantly and uniquely predictive of VPA learning, above and beyond the contribution of other tests of verbal memory and executive functioning (p < .05 for all analyses). Visuospatial functioning did not, however, account for significant additional variance after controlling the contribution of nonverbal memory or expressive language functioning (p > .05 for all analyses). The results of the current study suggest that, while VPA learning is highly correlated with verbal list learning and story learning, it also diverges from these other forms of verbal memory in the degree to which it is influenced by nonverbal abilities. In light of these findings, tests of VPA learning should be interpreted clinically in the context of other measures of both verbal memory and visuospatial functioning.

Committee:

Paula Shear, Ph.D. (Committee Chair); Quintino Mano, Ph.D. (Committee Member); Matia Solomon, Ph.D. (Committee Member)

Subjects:

Psychology

Keywords:

temporal lobe epilepsy;verbal paired associate learning;visuospatial functioning;neuropsychology

Rolle, Isaiah JThreshold for Hippocampal Dentate Granule Cell Mediated Epileptogenesis
PhD, University of Cincinnati, 2015, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary
Patients with temporal lobe epilepsy are treated with anticonvulsant drugs that neither prevent nor cure the disease. The development of true anti-epileptogenic therapies will require a better understanding of the molecular mechanisms of epileptogenesis. Animal and human studies of temporal lobe epilepsy have long implicated newly-born dentate granule cells (DGCs) as mediating many of these epileptogenic changes. Work from our lab described in this report demonstrates that phosphatase and tensin homolog (PTEN) deletion need only occur in up to 25% of hippocampal DGCs to produce a severe epilepsy syndrome in mice. This was the first direct evidence provided to show that abnormal DGCs can cause the disease. It is also conceivable that a certain threshold level of abnormal cells must be reached to provoke epileptogenesis; but after this threshold is passed, additional abnormal cells have no further impact. We hypothesize that the severity of epilepsy is dependent on the number of abnormal DGCs in these animals, and we predict, therefore, that modifying the model to produce fewer abnormal cells will mitigate the disease phenotype. The second chapter, previously published in Neuron, details the selective deletion of PTEN from hippocampal granule cells. The third chapter directly tests our guiding hypothesis, whether deletion from a smaller number of DGCs, roughly 5% or less, is sufficient to cause epilepsy. In the fourth chapter, we will describe initial experiments that test whether and when electroencephalogram (EEG) abnormalities can be reversed by ablating irregular DGCs. These studies will provide novel insights into 1) the role these neurons play in chronic epilepsy, and 2) whether we can identify a therapeutic window to interfere with disease progression.

Committee:

James Eliassen, Ph.D. (Committee Chair); Mark Baccei, Ph.D. (Committee Member); Kenneth Campbell, Ph.D. (Committee Member); Steve Danzer, Ph.D. (Committee Member); Darcy Krueger, M.D. Ph.D. (Committee Member)

Subjects:

Neurology

Keywords:

TEMPORAL LOBE EPILEPSY;HIPPOCAMPAL GRANULE CELLS;DENTATE GYRUS;PTEN;MTOR;HIPPOCAMPAL SEIZURES

Toprani, Sheela CMECHANISMS OF SEIZURE REDUCTION BY LOW FREQUENCY ELECTRICAL STIMULATION
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 depolarization blocking, LTD/LTP and GABAA are not involved in seizure reduction by LFS. Rather, decreased neuronal excitability by LFS-induction of long-lasting hyperpolarization (LLH) composed of (1) the GABAB slow inhibitory post-synaptic potential (IPSP) and (2) the slow afterhyperpolarization (sAHP) were found to be necessary for seizure reduction by LFS. These insights into the mechanisms of DBS, specifically LFS, promote safer implementation and optimization of this promising therapy.

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

Keywords:

epilepsy; mesial temporal lobe epilepsy; seizure reduction; deep brain stimulation; low frequency stimulation; GABA; GABAB; afterhyperpolarization; slow afterhyperpolarization

Ramirez, Maya J.Interictal Language Functioning and the Effects of Emotional Distress on Performance: A Comparison of Mesial Temporal Lobe and Frontal Lobe Epilepsy
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 moderate performance with both suppressive and faclitatory effects relative to seizure focus. Anxiety facilitated FLE patient performance on tasks more reliant on temporal lobe integrity, while depression tended to suppress language performance on measures for which impaired performance was intrinsic to the underlying epiltogenic lesion (e.g., BNT performance in left MTLE). Perceived emotional distress is an important treatment consideration in the management of intractable epilepsy patients.

Committee:

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

Subjects:

Psychology

Keywords:

Language; mesial temporal lobe epilepsy; frontal lobe epilepsy; emotional distress; visual naming; paraphasic error; fluency

Ghosh Dastidar, SamanwoyModels of EEG data mining and classification in temporal lobe epilepsy: wavelet-chaos-neural network methodology and spiking neural networks
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 developed to reach the next milestone in artificial intelligence. First, an efficient spiking neural network (SNN) model is presented using three training algorithms: SpikeProp, QuickProp, and RProp. Three measures of performance are investigated: number of convergence epochs, computational efficiency, and classification accuracy. Next, a new Multi-Spiking Neural Network (MuSpiNN) and supervised learning algorithm (Multi-SpikeProp) are developed. Finally, the models are applied to the epilepsy and seizure detection problems to achieve high classification accuracies.

Committee:

Hojjat Adeli (Advisor)

Keywords:

Temporal Lobe Epilepsy; Electroencephalogram (EEG); EEG Classification; Epilepsy Diagnosis; Seizure Detection; Wavelet Transform; Chaos Theory; Artificial Neural Networks; Spiking Neural Networks; Principal Component Analysis; Cosine Radial Basis Function