Thesis (M.Sc.)--York University, 2005. Graduate Programme in Kinesiology and Health Science. / Typescript. Includes bibliographical references (leaves 46-52). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url%5Fver=Z39.88-2004&res%5Fdat=xri:pqdiss &rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR11898

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Since the field-defining patient HM, consistent links have been made between a region of the brain called the hippocampus and memories that can be consciously declared - so called declarative memories. Declarative memories fall into two categories (1) episodic memories, memories that are highly detailed and re-experiential, and (2) semantic memories, fact-based memories for personal and public information but that have no sense of re-experiencing. It is believed that the intrinsic anatomy of the hippocampus supports episodic memory but not semantic memory. The hippocampus consists of five regions (cornu Ammonis, CA, 1-3, dentate gyrus, subiculum) with each purported to have a specific role in episodic memory acquisition and retrieval. However, controversy surrounds the temporal extent to which episodic memories rely on the hippocampus for retrieval: current consensus suggests the hippocampus supports these memories for five-10 years post-acquisition, but some suggest that it is required for retrieval across the lifetime. Voltage-gated potassium channel-complex antibody-mediated limbic encephalitis (VGKC-complex LE) is a recently described autoimmune disease that causes chronic hippocampal atrophy and mild amnesia on standardized neuropsychological assessment. Two subfields of the hippocampus - CA1 and CA3 - contain the antigenic targets of the disease but it is unknown if specific atrophy of these subfields underlies the hippocampal damage in humans. Here, the human hippocampal subfield volumes of VGKC-complex LE patients (n = 19, mean age: 64.0±2.55; range: 24-71) were investigated using ultra-high spatial resolution MRI at 7.0-Tesla. Assessment also included standardized neuropsychology to examine the impact of the pathology on hippocampal-dependent and -independent memory performance, as well as attention, language, executive function, and perception Declarative memory assessment measured semantic and episodic memory performance across the lifespan. Manual segmentation detected lesions to just CA3, with no volume loss noted elsewhere in the hippocampus or brain. Patients were impaired on hippocampal-dependent memory domains but not the hippocampal-independent and non-memory domains. Notably, episodic memory assessment revealed episodic amnesia across the lifetime except for their earliest memories. This counters the received convention that the hippocampus has a temporally limited role in episodic retrieval. Conversely, the performance of the VGKC-complex LE patients for semantic memory, including a new test developed herein, was comparable to controls across the lifespan. It was then shown that CA3 volume predicted episodic memory performance across the lifetime. Together, the results suggest that VGKC-complex LE provides a novel model of human hippocampal subfield pathology, with which to explore the roles of hippocampal subfields in episodic memory acquisition and retrieval.

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It has been reported previously that systemic administration of clonidine, an agonist of α-2 receptors for noradrenaline, significantly retards amygdaloid kindling, by delaying the emergence from partial seizure, Conversely, systemic administration of α-2 antagonists has been reported to facilitate amygdaloid kindling, The experiments I conducted attempted to discover whether α-2 adrenoceptors in the amygdala participated in these effects, I examined the effect of either systemic administration (i,p.) or intraamygdaloid infusions of a variety of noradrenergic drugs on the kindling of seizures with electrical stimulation of the amygdala, Rats received either low-frequency stimulation of the amygdala, to induce rapid kindling, or conventional high-frequency stimulation, Drugs and electrical stimulation were administered once every 48 hrs, I observed a significant retardation of kindling in rats receiving i,p. injections of clonidine (0.1 mg/kg) or unilateral infusions of clonidine in concentrations of [special characters omitted] to [special characters omitted] M, regardless of the stimulation frequency. The prophylactic effect was due to a delay in the progression out of partial seizure. I observed similar effects with infusions of xylazine, also an α-2 adrenoceptor agonist, The effect was specific to the amygdala/pyriform region, because infusions of clonidine dorsal lo the amygdala were without effect. Power spectral analysis of the AD from the stimulated and the contralateral amygdala during the initial occurrence of bilateral AD failed to reveal differences attributable to clonidine, Therefore, clonidine might retard kindling by modifying the propagation of AD from the stimulated amygdala to a midbrain or pontine brainstem area critical, for the expression of generalized seizures. Clonidine had no effect on established generalized seizures, suggesting that it was producing a genuine prophylactic effect against kindling. Unexpectedly, intraamygdaloid infusions of either idazoxan, yohimbine, or SK&F 104856, antagonists of α-2 receptors, failed to accelerate kindling. Simultaneous infusion of idazoxan blocked clonidine’s prophylactic effect, which suggests strongly that this effect was mediated at the α-2 adrenoceptor. Blockade of amygdaloid α-1 adrenoceptors with corynanthine failed to affect kindling. I conclude that the population of α-2 adrenoceptors in the amygdala/pyriform region contributes to the antiepileptogenic effect observed after systemic administration of clonidine and that the facilitation of kindling observed after systemic administration of α-2 antagonists reported previously may have been mediated by the blockade of a population of α -2 adrenoceptors in addition to, or outside of, the amygdala/pyriform region. / Graduate

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Orientadores: Jose Wilson Magalhães Bassani, Antonio Carlos Guimarães de Almeida / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e de Computação / Made available in DSpace on 2018-08-12T22:48:22Z (GMT). No. of bitstreams: 1 Azevedo_GersonFlorenceCarvalheirade_D.pdf: 2274193 bytes, checksum: 9c8a1fee0426b5335f1a55b9dfcdd33d (MD5) Previous issue date: 2009 / Resumo: Durante o burst epileptiforme e a depressão alastrante (DA), são observados um aumento da [K+]o (concentração extracelular de potássio) e uma diminuição da [Ca2+]o (concentração extracelular de cálcio), evidenciando a participação deste mecanismo não-sináptico nestes padrões oscilatórios anormais. Essas variações nas [K+]o e [Ca2+]o elevam a excitabilidade neuronal. No entanto, não está claro se a alta [K+]o é um fator primário na geração destas atividades neuronais ou se apenas desempenha um papel secundário neste processo. Para melhor compreender a dinâmica não-linear destes padrões, as condições experimentais de alta [K+]o e zero [Ca2+]o foram replicadas em um modelo ampliado de Golomb, referente à região CA1 da formação hipocampal. Importantes mecanismos regulatórios de concentração iônica, como a bomba Na+/K+, a difusão iônica e o sistema de buffer da glia, foram acrescentados ao modelo de Golomb. Dentro destas condições, foi possível simular atividades elétricas neuronais tipicamente apresentadas no burst epileptiforme em sua fase ictal. A DA foi iniciada pela interrupção da atividade da bomba Na+/K+. O bloqueio da bomba Na+/K+ por meio da hipóxia celular é uma manobra experimental para se obter a DA, conhecida também como depressão alastrante hipóxica - DAH. A teoria de bifurcação e o método fast-slow analysis foram utilizados para estudar a interferência do K+ extracelular na excitabilidade celular. Este estudo indicou que o sistema perde a sua estabilidade com o aumento da [K+]o, transitando para um elevado estado de excitabilidade. Este crescimento da [K+]o provoca bifurcações no comportamento dinâmico neuronal, que determinam transições entre diferentes estágios dessas atividades elétricas. No primeiro estágio, o aumento da [K+]o propicia a deflagração do burst epileptiforme e da DA via bifurcações sela-nó e de Hopf supercrítica, respectivamente. Ao longo da atividade neuronal, o nível de excitabilidade é mantido por meio de um crescimento contínuo da [K+]o, que deprime as correntes de K+ em um processo de realimentação positiva. Neste estágio, em relação ao burst epileptiforme, a amplitude e a freqüência dos disparos dos potenciais de ação são alteradas via bifurcação de Hopf supercrítica. No último estágio, com a depressão das correntes de K+, a bomba de Na+/K+ tem uma participação importante no término da atividade neuronal. O burst epileptiforme e a DA são finalizados por meio das bifurcações sela-órbita homoclínica e sela-nó, respectivamente. Portanto, este trabalho sugere que o K+ extracelular pode desempenhar um papel fundamental na dinâmica não-linear do burst epileptiforme e da sua transição para a DA. / Abstract: During the epileptiform burst and the spreading depression (SD), it is observed an increase of [K+]o (extracellular potassium concentration) and a decrease of [Ca2+]o (extracellular calcium concentration), pointing out the participation of this nonsynaptic mechanism in these abnormal oscillatory patterns. These ionic variations raise the neuronal excitability. However, whether the high [K+]o is a primary factor in the beginning of these neuronal activities or just plays a secondary role into this process is unclear. To better understand the nonlinear dynamics of these patterns, the experimental conditions of high [K+]o and zero [Ca2+]o were replicated in an extended Golomb model in which we added important regulatory mechanisms of ion concentration as Na+/K+ pump, ion diffusion and glial buffering. Within these conditions, it was possible to simulate epileptiform burst within the ictal phase. The SD was elicited by the interruption of the Na+/K+ pump activity. The blockage of Na+/K+ pump by cellular hypoxia is an experimental procedure to elicit SD, known as hypoxic spreading depression - HSD. The bifurcation theory and the method of fast-slow analysis were used to study the interference of extracellular K+ in the cellular excitability. This analysis indicates that the system loses its stability at a high [K+]o, transiting to an elevated state of neuronal excitability. This raise of [K+]o provokes bifurcations in the neuronal dynamic behavior, that determine transitions between different stages of these electrical activities. In the initial stage, the increase of [K+]o creates favorable conditions to trigger the epileptiform burst and the SD by saddle-node and supercritical Hopf bifurcations, respectively. During the neuronal activity, the level of excitability is maintained by a continuous growth of [K+]o that depresses K+ currents in a positive feedback way. At this stage, concerning epileptiform burst, the amplitude and frequency of action potentials are changed by supercritical Hopf bifurcation. At the last stage, with the depression of K+ currents, the Na+/K+ pump plays an important role in the end of neuronal activity. The epileptiform burst and SD activities terminate by saddle-homoclinic orbit and saddle-node bifurcations, respectively. Thus, this work suggests that [K+]o may play a fundamental role in the nonlinear dynamics of the epileptiform burst and the transition to SD. / Doutorado / Engenharia Biomedica / Doutor em Engenharia Elétrica