In the past few years, the study of electrical activity in the brain and its interactions with the body has become popular among researchers. One of the hottest topics related to brain activity is the epileptic seizure prediction. Currently, there are several techniques on how to predict a seizure; however, most of the techniques found in research papers are just mathematical models and not system implementations. The seizure prediction approach proposed in this thesis paper is achieved using the EMOTIV Epoc+ headset, MATLAB, and LabVIEW as the analog and digital signal processing devices. In addition, this thesis project incorporates the use of the Hilbert Huang transform (HHT) method to obtain intrinsic mode functions (IMF) and instantaneous frequency components of the transform. From the IMFs, features as variation coefficient (VC) and fluctuation indexes (FI) are extracted to feed a support vector machine that classifies the EEG data as pre-ictal and non-ictal EEGs. Outstanding patterns in non-ictal and pre-ictal are observed and demonstrated by significant differences between both types of EEG signals. In other words, a classification of EEG signals according to a category can be achieved proving that an epileptic seizure prediction technology has a future in engineering and biotechnology fields.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24282号 / 医博第4898号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 花川 隆, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

A antinocicepção é descrita como redução na capacidade de perceber a dor, sendo importante componente para o organismo, quando este está envolvido em situações de emergência. Muitos neurotransmissores e seus receptores estão envolvidos nas diversas formas de analgesia, como por exemplo, monoaminas, acetilcolina e opióides endógenos. A analgesia pós-ictal é uma das muitas formas de antinocicepção em que o recrutamento de cada um desses neurotransmissores é descrito. Algumas evidências mostram o envolvimento de estruturas mesencefálicas em processos antinociceptivos (GEBHART & TOLEIKIS, 1978; COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997; CASTILHO e col., 1999) O colículo inferior é a estrutura mesencefálica responsável pela origem e expressão de crises audiogênicas (MCCOWN e col, 1987). Estruturas como a substância cinzenta periaquedutal, camadas profundas do colículo superior e núcleo central do colículo inferior, têm sido implicadas em processos convulsivos (DE PAULIS e col., 1990; CARDOSO e col., 1994, MCCOWN e col., 1984). Recentes relatos demonstraram que a estimulação dessas estruturas, em cujo substrato neural há neurônios positivos para beta-endorfina e leu-encefalina (EICHENBERGER e col., 2002; OSAKI e col., 2003) pode gerar processos antinociceptivos (CASTILHO e col., 1999; GEBHART & TOLEIKIS, 1978), seja de natureza opióide (NICHOLS e col., 1989), seja de natureza monoaminérgica (COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997). Neste trabalho, foi realizado o estudo periférico para investigar o envolvimento, mais especificamente, dos receptores opióides µ1 na analgesia que segue as crises convulsivas evocadas pela administração de um antagonista de canais de Cl- ligados ao GABA, como é o caso do pentilenotetrazol, administrado por via intraperitoneal, após o pré-tratamento com o bloqueador opióide específico, o naloxonazine, administrado em diferentes doses. Assim também, estudou-se a participação do colículo inferior nesse processo de inibição de dor, mensurado pelo teste de retirada de cauda. O pré-tratamento com naloxonazine, administrado por via intraperitoneal por tempo prolongado (24h), mas não agudamente (10 min), antagonizou a antinocicepção evocada por convulsões tônico-clônicas. Microinjeções de naloxonazine realizadas nos núcleos central, cortical externo e cortical dorsal do colículo inferior antagonizaram a analgesia induzida por crises convulsivas tônico-clônicas, efeito que segue uma curva dose-resposta, bem como, causaram a redução do tempo do processo convulsivo induzido pelo bloqueio ionóforo de canais de cloro ligados ao GABA. Em vista disso, podemos sugerir o envolvimento de receptores µ1-opióides e das redes neurais do colículo inferior na elaboração da analgesia pós-ictal, e na modulação de crises convulsivas tônico-clônicas. / The post-ictal analgesia is an impressive kind of antinociception, in wich the involvement of many neural systems has been demonstrated. The inferior colliculus is a brainstem structure responsible for the origin and elaboration of convulsive responses (MCCOWN e col, 1987) in the presence of audiogenic stimulus or during the treatment of supralimiar administration of GABAergic antagonists. Mesencephalic structures such as the periaqueductal gray matter, the deep layers of the superior colliculus and the central nucleus of the inferior colliculus have been implicated in convulsive processes (DE PAULIS e col., 1990; CARDOSO e col., 1994, MCCOWN e col., 1984). The stimulation of these areas, in whose neural substrates there are beta-endorphin- and leu-enkephalin-positive neurons (EICHENBERGER e col., 2002; OSAKI e col., 2003) evokes antinociceptive processes (CASTILHO e col., 1999; GEBHART & TOLEIKIS, 1978), of either opioid (NICHOLS e col., 1989) or monoaminergic COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997) nature. The aim of the present work is to investigate the involvement of the µ1-opioid receptor-mediated system in the post-ictal analgesia. The antinociceptive responses were recorded by the tail-flick test, after the pre-treatment with the specific opioid antagonist naloxonazine, administrated either by peripheral (intraperitoneally) or central (into the inferior colliculus neural network) way, in different doses. The peripheral lon-lasting (24h) but not acute (10 min) pre-treatment with naloxonazine antagonized the analgesia evoked by tonic-clonic convulsions. Microinjections of naloxonazine in the central, dorsal cortical and external cortical nuclei of inferior colliculus antagonized the analgesia induced by tonic-clonic reactions, whose effect followed a dose-response curve. Also, microinjections of naloxonazine into the inferior colliculus decrease the time of convulsions reactions. These findings suggest the involvement of µ1-opiate receptors and the neural networks of the inferior colliculus in this antinociceptive phenomenon, and, in addition, the involvement of these receptors in the modulation of tonic-clonic convulsive reactions has been suggested. In conclusion, the endogenous opioid peptides-mediated system of the neural networks of the inferior colliculus is clearly implicated in the elaboration of the post-ictal antinociception and in the modulation of tonic-clonic convulsions. In theses processes, µ1-opioid receptors of the central nucleus, as well as of the cortical dorsal and cortical external nuclei of the inferior colliculus are crucially involved.

INTRODUÇÃO: A classificação recente das Crises Hipercinéticas (CH) proposta por Rheims et al. (2008) sugere dois padrões de CH, baseado na semiologia ictal (Tipos I e II): no Tipo I, a zona epileptogênica foi identificada na região ventral pré-frontal, enquanto que no Tipo II, na região mesial pré-motora. Estudos com SPECT ictal em pacientes com CH evidenciaram hiperperfusão nas regiões frontais e extrafrontais, incluindo ínsula e lobo temporal, além de áreas subcorticais, tais como cerebelo, tálamo, gânglios da base e tronco encefálico. OBJETIVO: Avaliar a rede neural ativada nas CH através do SPECT ictal, correlacionando-a aos dois subtipos de CH (Tipos I e II). MATERIAL E MÉTODOS: Uma amostra de 25 pacientes com idade entre 0 e 60 anos com CH que realizaram SPECT ictal foi submetida a análise do VEEG e das imagens do SPECT ictal a fim de determinar o tipo de CH e as áreas de hiperpefusão ativadas, bem como sua correlação. RESULTADOS: Nove pacientes (36%) tiveram CH do Tipo I, dez (40%), do Tipo II e seis (24%), do Tipo Misto. Não houve diferenças significativas entre os tipos de CH e a presença de semiologia ictal não hipercinética durante as crises, bem como o tempo de doença, frequência das crises, história familiar positiva e exame de neuroimagem anormal. A duração média do tempo de injeção do RF foi de 32,2 segundos. O SPECT demonstrou ativação difusa, com predomínio nas regiões subcorticais, temporal lateral, occipital mesial e frontal dorsolateral. Não houve correlação entre os diferentes tipos de CH e as áreas hiperperfundidas, exceto pela região occipital mesial, que foi significativamente maior no Tipo II. CONCLUSÃO: A classificação proposta por Rheims et al. (2008) é útil porém simplista, já que as CH abrangem uma fenomenologia complexa, não sendo possível classificar todos os pacientes em somente dois tipos (I e II). O SPECT ictal nesta amostra demonstrou a presença de hiperperfusão em diferentes áreas cerebrais, reforçando a hipótese de que uma rede neural ampla, que engloba as regiões frontais e possivelmente extrafrontais, incluindo áreas subcorticais, está envolvida na gênese destas crises. / BACKGROUND: The recent classification of hyperkinetic seizures (HS) proposed by Reims et al (2008) suggests two patterns of HS based on ictal symptomatology (Type I and II), whereas in Type I epileptogenic zone was identified in the ventromesial frontal córtex while in Type II, in the mesial premotor córtex. Ictal SPECT studies in patients with HS showed hyperperfusion in frontal and extrafrontal regions, including insula and temporal lobe, and subcortical areas, such as cerebellum, thalamus, basal ganglia and brain stem. OBJECTIVE: To evaluate the neural network activated in HS through the ictal SPECT and to correlate it to the two subtypes of HS (Type I and II). METHODS: We retrospective analyzed ictal signs and ictal SPECT data in 25 patients with HS aged between 0 and 60 years in order to determine the type of HS and the hyperperfused areas, as well as their correlation. RESULTS: Nine patients (36%) were classified as Type I, ten (40%) as Type II and 6 (24%) as a mixed type. There were no significant differences between the types of HS and the presence of non-hyperkinetic ictal semiology, as well as epilepsy duration, frequency of seizures, positive family history and abnormal neuroimage. The average injection duration time was 32.2 seconds. The ictal SPECT showed diffuse activation, predominantly in subcortical regions and the following areas: lateral temporal, mesial occipital and dorsolateral frontal cortex. There was no correlation between the different types of HS and the hyperperfused areas but the mesial occipital region that was significantly higher in Type II. CONCLUSION: The classification proposed by Rheims et al (2008) is useful but simplistic. Since the HS consists of a complex phenomenology, it is not possible to classify all patients in only two types (I and II). The ictal SPECT in this sample showed the presence of hyperperfusion in different brain areas, reinforcing the hypothesis that a broad neural network, which includes the frontal and possibly extrafrontal regions, including subcortical areas, are involved in the genesis of these seizures.

INTRODUÇÃO: A classificação recente das Crises Hipercinéticas (CH) proposta por Rheims et al. (2008) sugere dois padrões de CH, baseado na semiologia ictal (Tipos I e II): no Tipo I, a zona epileptogênica foi identificada na região ventral pré-frontal, enquanto que no Tipo II, na região mesial pré-motora. Estudos com SPECT ictal em pacientes com CH evidenciaram hiperperfusão nas regiões frontais e extrafrontais, incluindo ínsula e lobo temporal, além de áreas subcorticais, tais como cerebelo, tálamo, gânglios da base e tronco encefálico. OBJETIVO: Avaliar a rede neural ativada nas CH através do SPECT ictal, correlacionando-a aos dois subtipos de CH (Tipos I e II). MATERIAL E MÉTODOS: Uma amostra de 25 pacientes com idade entre 0 e 60 anos com CH que realizaram SPECT ictal foi submetida a análise do VEEG e das imagens do SPECT ictal a fim de determinar o tipo de CH e as áreas de hiperpefusão ativadas, bem como sua correlação. RESULTADOS: Nove pacientes (36%) tiveram CH do Tipo I, dez (40%), do Tipo II e seis (24%), do Tipo Misto. Não houve diferenças significativas entre os tipos de CH e a presença de semiologia ictal não hipercinética durante as crises, bem como o tempo de doença, frequência das crises, história familiar positiva e exame de neuroimagem anormal. A duração média do tempo de injeção do RF foi de 32,2 segundos. O SPECT demonstrou ativação difusa, com predomínio nas regiões subcorticais, temporal lateral, occipital mesial e frontal dorsolateral. Não houve correlação entre os diferentes tipos de CH e as áreas hiperperfundidas, exceto pela região occipital mesial, que foi significativamente maior no Tipo II. CONCLUSÃO: A classificação proposta por Rheims et al. (2008) é útil porém simplista, já que as CH abrangem uma fenomenologia complexa, não sendo possível classificar todos os pacientes em somente dois tipos (I e II). O SPECT ictal nesta amostra demonstrou a presença de hiperperfusão em diferentes áreas cerebrais, reforçando a hipótese de que uma rede neural ampla, que engloba as regiões frontais e possivelmente extrafrontais, incluindo áreas subcorticais, está envolvida na gênese destas crises. / BACKGROUND: The recent classification of hyperkinetic seizures (HS) proposed by Reims et al (2008) suggests two patterns of HS based on ictal symptomatology (Type I and II), whereas in Type I epileptogenic zone was identified in the ventromesial frontal córtex while in Type II, in the mesial premotor córtex. Ictal SPECT studies in patients with HS showed hyperperfusion in frontal and extrafrontal regions, including insula and temporal lobe, and subcortical areas, such as cerebellum, thalamus, basal ganglia and brain stem. OBJECTIVE: To evaluate the neural network activated in HS through the ictal SPECT and to correlate it to the two subtypes of HS (Type I and II). METHODS: We retrospective analyzed ictal signs and ictal SPECT data in 25 patients with HS aged between 0 and 60 years in order to determine the type of HS and the hyperperfused areas, as well as their correlation. RESULTS: Nine patients (36%) were classified as Type I, ten (40%) as Type II and 6 (24%) as a mixed type. There were no significant differences between the types of HS and the presence of non-hyperkinetic ictal semiology, as well as epilepsy duration, frequency of seizures, positive family history and abnormal neuroimage. The average injection duration time was 32.2 seconds. The ictal SPECT showed diffuse activation, predominantly in subcortical regions and the following areas: lateral temporal, mesial occipital and dorsolateral frontal cortex. There was no correlation between the different types of HS and the hyperperfused areas but the mesial occipital region that was significantly higher in Type II. CONCLUSION: The classification proposed by Rheims et al (2008) is useful but simplistic. Since the HS consists of a complex phenomenology, it is not possible to classify all patients in only two types (I and II). The ictal SPECT in this sample showed the presence of hyperperfusion in different brain areas, reinforcing the hypothesis that a broad neural network, which includes the frontal and possibly extrafrontal regions, including subcortical areas, are involved in the genesis of these seizures.

A antinocicepção é descrita como redução na capacidade de perceber a dor, sendo importante componente para o organismo, quando este está envolvido em situações de emergência. Muitos neurotransmissores e seus receptores estão envolvidos nas diversas formas de analgesia, como por exemplo, monoaminas, acetilcolina e opióides endógenos. A analgesia pós-ictal é uma das muitas formas de antinocicepção em que o recrutamento de cada um desses neurotransmissores é descrito. Algumas evidências mostram o envolvimento de estruturas mesencefálicas em processos antinociceptivos (GEBHART & TOLEIKIS, 1978; COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997; CASTILHO e col., 1999) O colículo inferior é a estrutura mesencefálica responsável pela origem e expressão de crises audiogênicas (MCCOWN e col, 1987). Estruturas como a substância cinzenta periaquedutal, camadas profundas do colículo superior e núcleo central do colículo inferior, têm sido implicadas em processos convulsivos (DE PAULIS e col., 1990; CARDOSO e col., 1994, MCCOWN e col., 1984). Recentes relatos demonstraram que a estimulação dessas estruturas, em cujo substrato neural há neurônios positivos para beta-endorfina e leu-encefalina (EICHENBERGER e col., 2002; OSAKI e col., 2003) pode gerar processos antinociceptivos (CASTILHO e col., 1999; GEBHART & TOLEIKIS, 1978), seja de natureza opióide (NICHOLS e col., 1989), seja de natureza monoaminérgica (COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997). Neste trabalho, foi realizado o estudo periférico para investigar o envolvimento, mais especificamente, dos receptores opióides µ1 na analgesia que segue as crises convulsivas evocadas pela administração de um antagonista de canais de Cl- ligados ao GABA, como é o caso do pentilenotetrazol, administrado por via intraperitoneal, após o pré-tratamento com o bloqueador opióide específico, o naloxonazine, administrado em diferentes doses. Assim também, estudou-se a participação do colículo inferior nesse processo de inibição de dor, mensurado pelo teste de retirada de cauda. O pré-tratamento com naloxonazine, administrado por via intraperitoneal por tempo prolongado (24h), mas não agudamente (10 min), antagonizou a antinocicepção evocada por convulsões tônico-clônicas. Microinjeções de naloxonazine realizadas nos núcleos central, cortical externo e cortical dorsal do colículo inferior antagonizaram a analgesia induzida por crises convulsivas tônico-clônicas, efeito que segue uma curva dose-resposta, bem como, causaram a redução do tempo do processo convulsivo induzido pelo bloqueio ionóforo de canais de cloro ligados ao GABA. Em vista disso, podemos sugerir o envolvimento de receptores µ1-opióides e das redes neurais do colículo inferior na elaboração da analgesia pós-ictal, e na modulação de crises convulsivas tônico-clônicas. / The post-ictal analgesia is an impressive kind of antinociception, in wich the involvement of many neural systems has been demonstrated. The inferior colliculus is a brainstem structure responsible for the origin and elaboration of convulsive responses (MCCOWN e col, 1987) in the presence of audiogenic stimulus or during the treatment of supralimiar administration of GABAergic antagonists. Mesencephalic structures such as the periaqueductal gray matter, the deep layers of the superior colliculus and the central nucleus of the inferior colliculus have been implicated in convulsive processes (DE PAULIS e col., 1990; CARDOSO e col., 1994, MCCOWN e col., 1984). The stimulation of these areas, in whose neural substrates there are beta-endorphin- and leu-enkephalin-positive neurons (EICHENBERGER e col., 2002; OSAKI e col., 2003) evokes antinociceptive processes (CASTILHO e col., 1999; GEBHART & TOLEIKIS, 1978), of either opioid (NICHOLS e col., 1989) or monoaminergic COIMBRA e col., 1992; COIMBRA & BRANDÃO, 1997) nature. The aim of the present work is to investigate the involvement of the µ1-opioid receptor-mediated system in the post-ictal analgesia. The antinociceptive responses were recorded by the tail-flick test, after the pre-treatment with the specific opioid antagonist naloxonazine, administrated either by peripheral (intraperitoneally) or central (into the inferior colliculus neural network) way, in different doses. The peripheral lon-lasting (24h) but not acute (10 min) pre-treatment with naloxonazine antagonized the analgesia evoked by tonic-clonic convulsions. Microinjections of naloxonazine in the central, dorsal cortical and external cortical nuclei of inferior colliculus antagonized the analgesia induced by tonic-clonic reactions, whose effect followed a dose-response curve. Also, microinjections of naloxonazine into the inferior colliculus decrease the time of convulsions reactions. These findings suggest the involvement of µ1-opiate receptors and the neural networks of the inferior colliculus in this antinociceptive phenomenon, and, in addition, the involvement of these receptors in the modulation of tonic-clonic convulsive reactions has been suggested. In conclusion, the endogenous opioid peptides-mediated system of the neural networks of the inferior colliculus is clearly implicated in the elaboration of the post-ictal antinociception and in the modulation of tonic-clonic convulsions. In theses processes, µ1-opioid receptors of the central nucleus, as well as of the cortical dorsal and cortical external nuclei of the inferior colliculus are crucially involved.

Understanding the factors shaping neuronal spiking is a central problem in neuroscience. Neurons may have complicated sensitivity and, often, are embedded in dynamic networks whose ongoing activity may influence their likelihood of spiking. One approach to characterizing neuronal spiking is the point process generalized linear model (GLM), which decomposes spike probability into explicit factors. This model represents a higher level of abstraction than biophysical models, such as Hodgkin-Huxley, but benefits from principled approaches for estimation and validation. Here we address how to infer factors affecting neuronal spiking in different types of neural systems. We first extend the point process GLM, most commonly used to analyze single neurons, to model population-level voltage discharges recorded during human seizures. Both GLMs and descriptive measures reveal rhythmic bursting and directional wave propagation. However, we show that GLM estimates account for covariance between these features in a way that pairwise measures do not. Failure to account for this covariance leads to confounded results. We interpret the GLM results to speculate the mechanisms of seizure and suggest new therapies. The second chapter highlights flexibility of the GLM. We use this single framework to analyze enhancement, a statistical phenomenon, in three distinct systems. Here we define the enhancement score, a simple measure of shared information between spike factors in a GLM. We demonstrate how to estimate the score, including confidence intervals, using simulated data. In real data, we find that enhancement occurs prominently during human seizure, while redundancy tends to occur in mouse auditory networks. We discuss implications for physiology, particularly during seizure. In the third part of this thesis, we apply point process modeling to spike trains recorded from single units in vitro under external stimulation. We re-parameterize models in a low-dimensional and physically interpretable way; namely, we represent their effects in principal component space. We show that this approach successfully separates the neurons observed in vitro into different classes consistent with their gene expression profiles. Taken together, this work contributes a statistical framework for analyzing neuronal spike trains and demonstrates how it can be applied to create new insights into clinical and experimental data sets.

Epilepsy is a disease affecting millions of people worldwide. Despite over 50 years of research, the mechanisms that generate and sustain ictal discharges, a key neural hallmark of seizures, remain unknown. While once thought to be caused by hypersynchronous neuronal firing, we now recognize that the activity underlying ictal discharges is much more complex. With the development of microelectrode arrays (MEAs) suitable for use in humans, it is possible to observe neural activity at fine spatiotemporal scales in human patients with epilepsy. However, the diversity of seizure characteristics and limited patient population has led to a number of conflicting observations and theories. The purpose of this work is to elucidate mechanisms underlying ictal discharges in humans by applying statistical analyses and computational modeling to MEA recordings from human patients with epilepsy. We approach this aim in two projects. In the first project, we unify two seemingly conflicting theories surrounding cortical sources of ictal discharges. According to the ictal wavefront theory, ictal discharges are seeded at an expanding narrow front of high neuronal firing that delineates the boundary between regions of cortex with compromised functionality, and surrounding territory where the seizure is observable in electrical recordings, but cortical function remains intact. A second theory posits that discharges are predominantly seeded from a stationary localized cortical source. The two theories are based on observations from MEA recordings of seizures in two different small cohorts of patients. In this project, we analyze and model the discharge propagation patterns in a combined dataset from both cohorts. We show that discharges are seeded at the ictal wavefront in addition to other–possibly stationary–locations. In the second project, we characterize spatiotemporal patterns in the secondary transients of complex ictal discharges. Electrographic recordings of ictal discharges often have complex waveforms. Existing analyses focus on the spatiotemporal dynamics of the first, high-amplitude transient. In this project, we establish that ictal discharges often comprise multiple transients separated by ≈60 ms. Surprisingly, and contrary to our initial hypothesis, we find that individual transients within a complex discharge may propagate with different speeds, suggesting that different mechanisms are involved in the propagation of different transients.

Tem sido estabelecido que microinjeções intraperitoneais (i.p) de Pentilenotetrazol, um antagonista não competitivo dos receptores GABAA, induzem crises convulsivas do tipo tônico-clônicas em animais de laboratório. Esse efeito convulsivante do PTZ ocorre devido ao bloqueio do fluxo de íons cloreto mediado pelo GABA. Adicionalmente, as crises convulsivas evocadas por PTZ em roedores são seguidas por antinocicepção. Tem sido sugerido que a estimulação elétrica do nervo vago pode reduzir as crises convulsivas e muitas das aferências do nervo vago ao núcleo do trato solitário (NTS) usam o glutamato como neurotransmissor. Há trabalhos mostrando que o NTS conectase ao núcleo reticular paragigantocelular (PGi), uma estrutura também responsável pela elaboração de pelo menos parte da antinocicepção pós-ictal, que o PGi projeta-se ao locus coeruleus, cuja estimulação também produz efeito anticonvulsivante e antinociceptivo.. Com intuito de investigar a participação do NTS nas crises convulsivas e na antinocicepção pós-ictal mediado por receptores glutamatérgicos locais do tipo NMDA e neurônios noradrenérgicos (NE) do LC, microinjeções de agonistas e antagonistas NMDA foram feitas no NTS, seguida da administração de PTZ por via i.p. Em adição foi investigado os efeitos da lesão neurotóxica do LC com administrações por via intratecal de DSP-4 , seguidas por microinjeções de NMDA no NTS sobre as crises convulsivas e antinocicepção pós-ictal induzidas por injeções de PTZ por via i.p. O bloqueio ionóforo de canais de cloreto ligado ao GABA causou crises convulsivas19 tônico-clônicas seguidas antinocicepção pós-ictal em todos os animais submetidos ao presente trabalho. Tanto as convulsões como a antinocicepção pós-ictal mostraram-se parcialmente dependentes da atividade de vias mediadas por aminoácidos excitatórios no núcleo do trato solitário, como da integridade do sistema noradrenérgico, pois o bloqueio de receptores de aminoácidos excitatórios do tipo NMDA no NTS e a administração intratecal de uma neurotoxina seletiva para neurônios noradrenérgicos alteraram a gravidade das crises tônico-clônicas e a intensidade da analgesia pós-ictal. Esses dados sugerem que o sistema glutamatérgico aferente ao NTS e tanto as vias noradrenérgicas ascendentes como descendentes do locus coeruleus são relevantes para o controle das atividades convulsivas e da antinocicepção pós-ictal. / Intraperitoneal injections of the non-competitive GABAA receptor antagonista pentylenetetrazole (PTZ) induce tonic-clonic seizures in laboratory animals. Tha convulsive effect of PTZ is due to GABA-mediated Cl- influx blockade. In addition, seizures caused by PTz in rodents are follwed by significant antinociception. The electrical stimulation of the vagus nerve is known to reduce seizures and several inputs from nervus vagus do the nucleus of the tractus solitarius (NTS) use glutamate as neurotransmitter. There are reports showing that the NTS is connected to the nucleus reticularis paragigantocellularis (PGi), a ventromedial medula oblongata structure also related to the elaboration of at least part of the post-ictal antinociception, and the PGi sends outputs to the locus coeruleus, whose stimulation also cause both anticonvulsant and antinociceptive effects. The goal of the present work was to investigate the involvement of the NTS in both seizures and post-ictal antinociception control mediated by NMDA receptors as well as the role played by noradrenergic neurons from locus coeruleus (LC). Either NMDA agonists or antagonists were microinjected in the NTS, followed by i.p. PTZ injections. In addition, it was investigated the effects of LC neurotoxic lesions with intrathecal injections of DSP-4, followed by NMDA receptor agonists microinjections in the NTS, on both tonic-clonic seizures and post-ictal antinociception elicited by peripheral administrations of PTZ. The ionophore blockade of GABA-mediated Cl- influx caused tonic-clonic seizures follwed by significant post21 ictal antinociception in all animals submitted to the present work. Both tonic-clonic seizures and the post-ictal antinociception were percially dependent of the neural activity of excitatory aminoacid-mediated neurotransmission in the NTS of seizing Wistar rats in addition to the integrity of noradrenergic system, since the NMDA receptors blockade in the NTS and the intra-thecal administration of DSP-4 . The neurotoxin selective to LC noradrenergic neurons modified the severity of tonic-clonic seizures and the intensity of post-ictal antinociception. These findings suggest that the glutamatergic inputs to the NTS, in addition to ascending and descending noradrenergic pathways from LC are critical to the control of both seizures and post-ictal antinociception.

Epilepsy is a serious neurological disorder characterized by recurrent unprovoked seizures due to abnormal or excessive neuronal activity in the brain. An estimated 50 million people around the world suffer from this condition, and it is classified as the second most serious neurological disease known to humanity, after stroke. With early and accurate detection of seizures, doctors can gain valuable time to administer medications and other such anti-seizure countermeasures to help reduce the damaging effects of this crippling disorder. The time-varying dynamics and high inter-individual variability make early prediction of a seizure state a challenging task. Many studies have shown that EEG signals do have valuable information that, if correctly analyzed, could help in the prediction of seizures in epileptic patients before their occurrence. Several mathematical transforms have been analyzed for its correlation with seizure onset prediction and a series of experiments were done to certify their strengths. New algorithms are presented to help clarify, monitor, and cross-validate the classification of EEG signals to predict the ictal (i.e. seizure) states, specifically the preictal, interictal, and postictal states in the brain. These new methods show promising results in detecting the presence of a preictal phase prior to the ictal state.