Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / Segundo a OrganizaÃÃo Mundial de SaÃde (OMS, 2011), a epilepsia à uma das mais comuns doenÃas neurolÃgicas graves, afetando mais de 50 milhÃes de pessoas em todo o mundo. A principal manifestaÃÃo clÃnica de algumas epilepsias à a convulsÃo. Esta pode ser estudada em modelos animais pelo uso de diferentes estÃmulos. O Pentilenotetrazol (PTZ) à um antagonista GABA que mimetiza crise de ausÃncia e convulsÃes do tipo tÃnico-clÃnica em humanos. A Estricnina bloqueia a resposta inibitÃria da glicina, que age atravÃs de um receptor que se assemelha ao receptor GABAA. A Pilocarpina (PILO) à um agonista colinÃrgico que mimetiza epilepsia do lobo temporal em humanos. O Eletrochoque (ECS) à um procedimento que consiste na induÃÃo de convulsÃes generalizadas pela passagem de corrente elÃtrica pelo cÃrebro. Alpinia zerumbet, da famÃlia zingiberacea à uma espÃcie conhecida no Brasil por colÃnia que vem mostrando importantes efeitos depressores no SNC jà estudados por nosso grupo de pesquisa. O presente trabalho tem como objetivo investigar os efeitos da administraÃÃo aguda e repetida do Ãleo essencial de Alpinia zerumbet (OEAZ) em modelos animais de convulsÃo em camundongos (machos) por via intraperitoneal nas doses de 100 e 200 mg/Kg. OEAZ em tratamento agudo no modelo de PTZ 85 mg/kg, apresentou efeito neuroprotetor, tanto em latÃncia de convulsÃo (LC) quanto em latÃncia de morte (LM), apenas na dose 100 mg/kg. Jà em modelo de ESTRIC, em tratamento agudo, as duas doses estudadas mostraram efeito anticonvulsivante. Em modelo de PILO agudo nenhuma das doses ofereceu qualquer efeito neuroprotetor. No ECS, observa-se efeito anticonvulsivante, com relaÃÃo à reduÃÃo no tempo de estiramento, em ambas as doses comparadas ao controle. No entanto, apÃs administraÃÃo repetida por cinco dias o OEAZ apresentou efeitos anticonvulsivantes em todos os parÃmetros analisados de todos os testes de induÃÃo de convulsÃo, prolongando LC e LM com relaÃÃo ao grupo controle, podendo esta aÃÃo estar diretamente ligada aos constituintes do Ãleo, como monoterpenos. / According to the World Health Organization (WHO, 2011), epilepsy is one of the most common serious neurological diseases, affecting over 50 million people worldwide. The main clinical manifestation of some epilepsy is seizures. Seizures can be studied in animal models by using different stimuli. The pentylenetetrazol (PTZ) is a GABA antagonist that mimics absence seizures and tonic-clonic seizure in humans. The Strychnine blocks the inhibitory response of glycine, which acts via a receptor which resembles the GABAA receptor. The Pilocarpine (PILO) is a cholinergic agonist that mimics temporal lobe epilepsy in humans. The Electroshock (ECS) is a procedure which consists in induces the generalized seizures by the passage of electric current through the brain. Alpinia zerumbet, family zingiberacea is a specie known in Brazil as colony, showing significant CNS depressant effects already studied by our research group. The present study aims to investigate the effects of acute and repeated administration of the essential oil of Alpinia zerumbet (OEAZ) in animal models of seizures in mice (males) intraperitoneally at doses of 100 and 200 mg / kg. OEAZ in the acute treatment model PTZ 85 mg / kg, showed neuroprotective effect both in seizure latency (LC) and in death latency (ML), only at dose 100 mg / kg. On the other hand, when using model ESTRIC in acute treatment, both doses studied showed anticonvulsant effect. In a model of acute PILO none of doses offered any neuroprotective effect. In ECS was observed anticonvulsant effect with respect to reducing the time of stretching, at both doses, compared to the control. However, after repeated administration for five days the OEAZ showed anticonvulsant effects in all parameters of all tests seizure-inducing studied, prolonging LC and LM when compared with the control group, this action may be directly related to the constituents of the oil, as monoterpenes.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A Pilocarpina à um agonista colinÃrgico caracterÃstico por induzir convulsÃes que evoluem para status epilÃpticus, similar à epilepsia do lobo temporal humana. Neste presente trabalho, nÃs avaliamos a possÃvel aÃÃo neuroprotetora da doxiciclina, uma tetraciclina de segunda geraÃÃo, nas convulsÃes induzidas pela pilocarpina em ratos Wistar machos, que receberam pilocarpina (300mg/kg i.p) presenÃa ou na ausÃncia de doxiciclina (25 à 100 mg/kg) administrada intraperitonealmente uma vez ao dia durante sete dias. ApÃs a injeÃÃo de pilocarpina, foram observados os sinais colinÃrgicos perifÃricos, as latÃncias de 1 convulsÃo e de morte. Foram determinadas as concentraÃÃes de aminoÃcidos no cÃrtex temporal atravÃs de cromatografia lÃquida de alta eficiÃncia HPLC, e a atividade do sistema antioxidante, catalase e as dosagens dos nÃveis de TBARS e nitrito. Os resultados mostraram que a doxiciclina nÃo alterou os sinais colinÃrgicos perifÃricos, contudo aumentou a latÃncia decorrida para a primeira convulsÃo (1.6 a 5 vezes), quando comparada ao grupo (P300). Resultados semelhantes foram demonstrados com a latÃncia de morte, que foi aumentada de 1.9 a 9.9 vezes. Observou - se que o prÃ-tratamento com doxiciclina 50 mg/kg foi capaz de reduzir em 25% os nÃveis de MDA, 64% os nÃveis de nitrito e 67.7% a atividade da catalase no cÃrtex temporal desses animais, demonstrando com clareza seu potencial antioxidante. Interessantemente, a doxiciclina diminuiu as concentraÃÃes de glutamato de 28 a 33%, e aumentou GABA em 112 e 91%, nas dose de 50 e 100mg/kg respectivamente nos animais administrados com P300, Na maior dose, a droga alterou os nÃveis de aspartato e taurina, diminuindo em 61% aspartato enquanto elevou os nÃveis de taurina em cerca de 34%. Surpreendentemente, somente a menor dose alterou os nÃveis de glicina, aumentendo a concentraÃÃo deste aminoÃcido em 132%. Em conclusÃo, mostramos que o inÃcio e a intensidade das convulsÃes induzidas pela pilocarpina foram significativamente reduzidos pela doxiciclina. Portanto, pelo menos em parte, este mecanismo de aÃÃo parece estar relacionado a uma diminuiÃÃo nos nÃveis de aminoÃcidos excitatÃrios e a um aumento nas concentraÃÃes de aminoÃcidos inibitÃrios no cÃrtex temporal desses animais. / Pilocarpine is known to induce convulsions leading to status epilepticus, similar to the temporal lobe epilepsy in humans. In the present work, we evaluated the possible protection affored by doxycyvline, a 2nd generation tetracycline, agaist pilocarpine- induced convulsions in male Wistar rats (P300mg/kg, i.p) in the absence and in the presence of doxicycline (25 to 100 mg/kg i.p.) daily for 7 days.After the pilocarpine injection, all groups were observed for cholinergic signs, latency to the first convulsion and latency to death. Besides, amino acid concentrations in temporal cÃrtices were determined by RP-HPLC, as well catalase activity and levels of TBARS and Nitrite. Results showed that doxycycline did not alter cholinergic signs but increased the latency time to the first convulsion (1.6 to 5 times increase), as compared to P300, and the highest effect was observed with the dose of 25 mg/kg. Similar results were demonstrated to death latency that increased from 1.9 to 9.9 times with doxyciclyne at the doses of 25, 50 and 100 mg/kg. In fact we showed that the pre-treatment with doxycycline decreased in 25% MDA levels, 64% nitrite levels and 67.7% catalase activity. Interestingly, doxycycline decreased glutamate concentrations in 28 and 33% and increased GABA in 112 and 91% at the doses of 50 and 100mg/kg respectively. At the higher dose the drug altered aspartate and taurine concentrations, decreased aspartate levels in 61%, while increasing taurine levels in 34%. Surprisingly, only the lower dose altered glycine levels, increasing its concentration by 132%. In conclusion, we showed that the onset and intensity of pilocarpine-induced seizures were significantly reduced by doxycycline. Furthermore, at least in part, its mechanism of action seems to be mediated by the decrease and increase of excitatory and inhibitory aminoacids, respectively. In addiction the doxycycline capacity to reduce the oxidative stress associated with the pilocarpine-induced may also play a role

Doctorat en Sciences psychologiques et de l'éducation / info:eu-repo/semantics/nonPublished

Abstract Increased prevalence of anticardiolipin antibodies (aCL) and antinuclear antibodies (ANA) and changes in serum immunoglobulin concentrations have been reported in patients with epilepsy. The purpose of this study was to determine the presence of aCL, ANA, anti-B2 glycoprotein I -antibodies (anti-B2-GPI), antimitochondrial antibodies (AMA), immunoglobulin A, G and M serum concentrations and the presence of IgA and IgG class antigliadin antibodies (AGAbA and AGAbG), transglutaminase antibodies (tTGAbA) and antiendomysial antibodies (EMA) in a cohort of 1386 adult patients treated for epilepsy in the Oulu University Central Hospital during the years 1996–7 and in a reference population obtained from the Population Register Centre and matched for age, gender and municipality of residence. The effects of co-morbidity, medications, age, gender and different epilepsy attributes on the occurrence of the immunological parameters studied as well as the possible interrelations of these parameters were studied. There was no difference in the presence of aCL or ANA between the patients and the reference subjects. In patients, aCL were associated with long duration of epilepsy and poor seizure control. Low IgA serum concentrations were more common in patients with epilepsy, particularly those using phenytoin. Unspecific AMA were more common among the epilepsy patients. The prevalence of coeliac disease (CD)-related antibodies was similar in patients with epilepsy and in the reference population. AGAbA were associated with primary generalised epilepsy. No significant interrelations between the immunological markers were found. These findings suggest that patients with epilepsy do not have an increased prevalence of autoantibodies as a result of their disease. Various factors such as genetic traits and epilepsy attributes may independently affect the presence of each individual immunological marker.

In North America, the last two decades saw continued increases in population multimorbidity across all age groups. This trend, which is expected to endure in the coming years, has been attributed in large part to population aging and unhealthy lifestyle choices. While the societal consequences of multimorbidity have focused primarily on the burden it imposes on the sustainability of health systems and the need to implement innovative ways to deliver care, latent costs, such as possible increases in motor-vehicle accidents (MVAs) have received relatively little attention. The principal objective of this thesis was to investigate the relationship between multimorbidity and MVAs. To complement current knowledge on the topic, we conducted observational studies based on information recorded in electronic health records (EHR). The hypothesis that increasing levels of multimorbidity would translate into increasing risk of MVA was tested in both a general population of health care recipients and in persons with epilepsy, a subgroup of individuals predisposed to comorbidities and MVAs. To gain a better understanding of morbidity ascertainment in EHR data, preliminary validation studies were performed to evaluate the performance of Elixhauser comorbidity measures for predicting hospital mortality in our data source. A systematic review of risk factors contributing to the onset and progression of epilepsy was also performed in hopes of identifying elements that would help improve the methodological design of the principal thesis study limited to persons with epilepsy. Study results confirmed the excellent performance of the Elixhauser comorbidity measures for predicting hospital mortality in the Cerner Health Facts data repository. In the general health care recipient population, a positive exposure-outcome relationship was observed between multimorbidity and MVA risk. This relationship was consistent in adults across the lifespan and more pronounced in women than in men. In persons with epilepsy, the observed exposure-outcome relationship between multimorbidity and MVAs did not reach statistical significance. However, comorbid depression was identified as a risk factor for MVAs. Given increasing rates of multimorbidity in the general population, the findings of this thesis strongly support the need for replication and better characterization of the disease combinations that drive increases in MVA risk. Future work on this topic should also include estimates of MVA risk attributable to multimorbidity; this would inform and gauge the relevance of novel driving policies targeting individuals diagnosed with specific health conditions.

The occurrence of spikes during an electroencephalogram is a basic feature of Benign Epilepsy of Childhood (BREC). In this thesis we analyze several problems related to the structure of such spikes. The currently used mathematical model describing the spike assumes that all the inter-spike variations are due to background activity. We show that non-negligible additional variability is present during the spike and propose a slightly richer model which takes such variability into account. In particular we conclude that background noise may not be used to assess the precision of the estimates of the signal. The technique of spike averaging is presently used to obtain more precise estimates of the signal. By comparing averaging with trimmed mean, median and the "lowess" smoother, we find no discrepancies indicating the presence of skewness or long tails in the underlying distribution of the data and conclude that spike averaging is an adequate method for estimating the deterministic part of the spike. Next, three automated procedures for the detection of the peak of the spike are compared to the existing method, which is based on a visual analysis of the EEG tracing. None of the alternative methods is found to be superior, but the methodology developed for this problem is rather general and could be applied to other similar comparisons. Finally we address the question of whether "atypical" BREC patients, who are characterized by having other neurological abnormalities besides seizures, have a spike structure different from that of the "typical" patients. The non parametric method of "classification trees" is discussed and then applied to find whether certain features of the spike can discriminate between typical and atypical patients. The location and amplitude of the spike are found to provide a satisfactory classification rule, suggesting that the two groups may be affected by different types of epilepsy. We have used, throughout the thesis, simple methods which do not require strong assumptions. In particular we have tried to avoid assumptions of normality and linearity and to rely mostly on non parametric methods. / Science, Faculty of / Statistics, Department of / Graduate

Temporal lobe epileptics often experience interictal (i.e., between-seizure) emotional disturbances such as fear and anxiety. Despite the problem that these disturbances present, little progress has been made in characterizing their nature and etiology because they are not amenable to experimental analysis in clinical populations. Accordingly, the general purpose of the experiments in this thesis was to demonstrate the potential of long-term amygdala kindling in rats as a model of the interictal hyperemotionality of temporal lobe epileptics. Seven experiments comprise this thesis. Experiments 1 and 2 established that longterm amygdala kindling (i.e., 100 stimulations) results in large and reliable increases in emotionality. In Experiment 1, the long-term amygdala-kindled rats displayed more resistance to capture from an open field and more open-arm activity on an elevated plus maze than did the sham-stimulated rats; in Experiment 2, the magnitude of this hyperemotionality was shown to be dependent on the number of amygdala stimulations that the rats received. Experiment 3 showed that kindling-induced hyperemotionality is enduring; the hyperemotionality present 1 day after the final stimulation did not decline significantly over the ensuing month although some amelioration of symptoms was observed. Experiment 4 established that kindling-induced hyperemotionality is not unique to amygdala stimulation. Although increases in emotionality were greatest in amygdalakindled rats, hippocampal-kindled, but not caudate-kindled, rats also displayed significant increases. Experiments 5 and 6 showed that kindling-induced hyperemotionality is fundamentally defensive in nature. In Experiment 5, amygdala-kindled rats displayed high levels of emotionality in an unfamiliar, but not in a familiar, situation; in Experiment 6, amygdala-kindled rats displayed more defensive, but less aggressive behaviour, in their interactions with other rats. Finally, Experiment 7 showed that 8-OH-DPAT binding to serotonin 5HT1A receptors is increased in the dentate gyrus of amygdala-kindled rats, but not in the amygdala, periaqueductal grey, perirhinal cortex, or CA1 or CA3 hippocampal subfields. Together, the results of these experiments establish the potential of long-term amygdala kindling as a useful animal model of interictal emotionality in temporal lobe epileptics. / Arts, Faculty of / Psychology, Department of / Graduate

INTRO: There is mounting evidence to suggest a causal link between mild traumatic brain injury (mTBI) and post traumatic epilepsy (PTE). Significant ranges in the methods and definitions of “mild” TBI, each with their own limitations, make drawing cohesive conclusions from the state of the literature difficult. However, this body of work attempts to compile the literature in order to better elucidate the relationship between these populations. Ultimately, I hope this source to be a useful reference for understanding the state of the research such that one can make critical considerations in the future design of methods to definitively improve the quality of work in this field. Meaningful improvements could radically improve the outcomes for the millions of people who suffer as a result of these injuries and their lasting implications. METHODS: PubMed searches used keywords: Traumatic Brain injury (mild), Epilepsy, Concussion, Loss of cortical inhibition, Post Traumatic Epilepsy. Combinations of terms including mTBI or PTE AND MRI, fMRI, DTI, MRS, Biomarkers, TMS, EEG, and pathology. RESULTS: Strong trends persist despite the limitation in consistency of terminology and methods. Relative risk scores between 1.5 and 2.2 percent have been established across multiple long-term studies across decades of research and millions of person years, a 2-3-fold change over the baseline incidence of epilepsy in the general population (0.7%; less than one in every 100). Preclinical studies in mice have recently shown progressive increased seizure susceptibility after repeated mTBI. Within the first three weeks after injury, Glutamate homeostasis is altered meaningfully. Increased neural excitability results as the balance between excitation and inhibition shifts in the brain. An increased Glu/GABA ratio has also been linked to dysfunction in GABAergic cell populations, including parvalbumin positive inhibitory interneurons (PVI). Oxidative stress, as measured by a decreased GSH/GSSG ratio, suggests a dysregulation in homeostatic processes than can outlive clinical symptoms. Animals also display a decreased latency to induced seizure by Pentelynetetrazole (PTZ) a potent GABA receptor antagonist. Six weeks after injury, these mice have been shown to display; decreased GABA driving an increased Glu/GABA ratio, decreased EEG gamma power, and prominent signs of gliosis involving both astrocytes and microglia. Clinical investigations into the biology of this injury, utilizing a wide range of techniques, point to a loss of cortical inhibitory tone, an early hallmark of PTE. TMS findings of both reduced resting motor threshold and a shorter cortical silent period suggest a loss of cortical inhibitory tone likely shifting the excitation/inhibition balance. Signs of microstructural damage and altered cell permeability point to a disruption in chemical gradients which leads to greater functional deficits, as the parameters for normal cell function are no longer maintained. Changes in function and metabolism have been shown to outlast many of the behavioral and acute clinical symptoms suggesting a slow development but long duration of this insidious process. CONCLUSION: Mechanisms that link mTBI to PTE include a loss of cortical inhibition, increased oxidative stress and gliosis which over time increases Glu/GABA ratio, in turn increasing the likelihood of developing epilepsy. Although the relationship between mTBI and PTE has been suggested before through epidemiological studies, there is now emerging biochemical evidence to better describe this connection. Due to the high incidence of mTBI, any small increase in risk to develop PTE pursuant to concussion will affect millions of lives. With this new evidence, treatments can be designed to halt the progression and alleviate symptoms for those afflicted. The investigation of the biological mechanisms that link concussion and epilepsy is a critical step in developing treatment strategies and prophylaxis that could prove to be crucial for so many.

In this dissertation, we discuss spatiotemporal patterns in the wake of traveling waves in a microelectrode array (MEA) recording of a human epileptic seizure. In chapter two, we describe a method for estimating the direction of planar waves found in the last third of the seizure. We categorize the different phenomena that occur during those waves when projected along a one-dimensional slice in the domain. In chapter three, we summarize known examples of patterns in the wake of traveling wave solutions to reaction-diffusion systems. A brief review of results regarding the spectral stability of traveling wave solutions to reaction-diffusion equations is provided in chapter four. We review the essential spectrum and absolute spectrum, and summarize results about glued front-and-back pulse solutions. Using a reaction-diffusion model with Morris-Lecar dynamics, we present numerical experiments on a one-dimensional domain that exhibit spatiotemporal patterns in the wake of traveling waves. These patterns are precipitated by “backfiring” waves emitted from the primary wave in the opposite direction of initial travel, and qualitatively reproduce many of the features found in the last third of the seizure. A review of the model is given in chapter five. and a description of the phenomena found over an exhaustive set in a relevant parameter space of the model is given in chapter six. We compute branches of solutions in the parameter plane using numerical continuation in chapter seven. We describe the different types of solutions found along these branches. We present results on a curve of solutions where two branches of homoclinic orbits to equilibria in the moving coordinate frame meet at a heteroclinic loop, or T-point. We analyze the linear stability of solutions along this branch and draw comparisons to a known model that exhibits backfiring behavior. In chapter eight, we discuss seizure behavior in two spatial dimensions and present numerical experiments of the Morris-Lecar model in two dimensions. We describe results from backfiring waves initiated by a single point source and by two point sources in a two-dimensional domain. We show examples of simulations generated by two point sources that mimic the patterns in the empirical data.