INTRODUÇÃO: Epilepsia do lobo temporal (ELTM) é a forma mais comum de epilepsia parcial, ocorrendo em cerca de 40% dos pacientes. Na ELTM as crises epilépticas podem ter origem na região cortical, o que é menos comum, porém ocorrem frequentemente em estruturas mesiais do lobo temporal, representadas basicamente pelo hipocampo e/ou amígdala. Com intuito de incluir novas possibilidades de tratamento e diagnóstico, torna-se necessário uma maior compreensão das bases moleculares da ELMT. Dentro desta perspectiva, um dos grandes desafios para a Neurociências na atualidade é o desenvolvimento de biomarcadores que facilitem o diagnóstico e prognóstico para a epilepsia. Recentemente, com o desenvolvimento de algumas pesquisas e novas técnicas no campo da biologia molecular demonstram que microRNAs circulantes no sangue são biomarcadores sensíveis e específicos para várias doenças, incluindo doenças neurológicas, podendo ser obtido de forma não invasiva, representando assim um método de eficiente detecção e custo baixo. OBJETIVOS: Analisar o perfil de expressão dos microRNAs miR-629-3p, miR-1202, miR1225-5p na amígdala, hipocampo e sangue de pacientes submetidos a cirurgia para tratamento da epilepsia do lobo temporal mesial refratários ao tratamento medicamentoso e investigar se os mesmos podem auxiliar como biomarcadores de diagnóstico e prognóstico para a epilepsia. PACIENTES E MÉTODOS: Foram utilizadas amostras de amígdalas, hipocampos e sangue de 20 pacientes com ELTM, sendo 10 com boa evolução pós-operatória (Engel I) e 10 com evolução pós-operatória insatisfatória (Engel III e IV), e para controle foram utilizados 10 amostras de amígdalas e 10 de hipocampos de necrópsias, assim como 10 amostras de sangue de indivíduos saudáveis. A análise de expressão dos miRNAs foi feita utilizando a técnica de RQPCR. RESULTADOS e CONCLUSÕES: Os miRNAs miR-629-3p, miR-1202 e miR- 1225-5p apresentaram-se hiperexpressos no sangue de pacientes com ELTM, podendo sugerir um possível papel de biomarcadores auxiliando no diagnóstico da ELTM. Os miRNAs-629-3p, 1202 e 1225-5p apresentaram aumento nos níveis de expressão sanguíneos progressivos entre os grupos controle, Engel I e Engel III e IV respectivamente, apresentando também possível potencial de biomarcadores no prognóstico cirúrgico entre Engel I e Engel III e IV. / INTRODUCTION: Epilepsy of the temporal lobe is the most common form of partial epilepsy, occurring in about 40% of patients. In TLE epileptic seizures may originate in the cortical region, which is less common. However they occur more frequently in temporal lobe mesial structures, represented primarily by the hippocampus and / or amygdala. A greater understanding of the epilepsy molecular basis is necessary when aiming to implement new treatments possibilities. Within this field of study, one of the major challenges for neuroscience today is the development of biomarkers that facilitate the diagnosis and prognosis for epilepsy. Recently, with the development of some researches and new techniques in the field of molecular biology, it demonstrate that microRNAs circulating in the blood are sensitive and specific biomarkers for various diseases, including neurological diseases and they can be obtained noninvasively, thus representing a low cost method of efficient detection. OBJECTIVES: To analyze the expression profile of miR-629-3p, miR-1202, miR1225-5p microRNAs in the amygdala, hippocampus and blood of patients operated to treat the mesial temporal lobe epilepsy refractory to drug treatment and investigate whether they can be used as biomarkers for epilepsy diagnosis and prognosis. PATIENTS AND METHODS: Amygdala, hippocampus and blood samples of 20 patients with MTLE were used; 10 with good postoperative outcome (Engel I) and 10 with poor postoperative outcome (Engel III and IV), and for the control group 10 amygdalas and 10 hippocampus of necropsy, as well as, 10 samples blood from healthy individuals. The analysisof the expression of miRNAs was performed using RQ-PCR. RESULTS AND CONCLUSION: MiRNAs miR-629-3P, miR-1202 and miR- 1225-5P were hyper-expressed in the blood of patients with MTLE, and may suggest a possible role of biomarkers in the diagnosis of MTLE. miR-629-3p, miR-1202 and miR-1225-5p were progressively expressed in the blood of patients in the control, Engel I and Engel III and IV groups respectively, representing also potential biomarkers for surgical prognosis between Engel I and Engel III and IV.

Introdução: O Padrão Alternante Cíclico (“CAP”, do inglês - Cyclic Alternating Pattern) é um ritmo fisiológico do sono NREM, que corresponde aos períodos de ativação cíclica expressos por eventos fásicos do sono. O aumento na expressão de taxa do CAP tem sido considerado uma medida de instabilidade e fragmentação do sono. O CAP representa uma condição favorável para a ocorrência de descargas interictais e/ou ictais. A modulação do CAP em pacientes com Epilepsia do Lobo Temporal (ELT) não está bem definida. Objetivos: Analisar a expressão do CAP em pacientes com ELT e comparar com o grupo de controle. Selecionar o grupo de pacientes sem distúrbios do sono que possam influenciar a organização do sono. Métodos: Foi realizado estudo transversal com grupo de controle de comparação. A seleção foi pareada em sexo e idade entre pacientes com ELT e o grupo de controle, obedecendo aos critérios de inclusão e exclusão. Os parâmetros do sono e CAP foram analisados em 13 pacientes com ELT (6 do sexo masculino e 7 do sexo feminino; idade média: 33,8 ± 8,5 anos) e 13 indivíduos sadios (8 do sexo masculino e 5 do sexo feminino; idade média: 26,1 ± 9,2 anos), os quais não apresentaram distúrbios do sono. A comparação dos dois grupos foi realizada através do “teste t” de Student e confirmada pelo “teste U” de Mann-Whitney. Resultados: Os pacientes com ELT apresentaram aumento na taxa de CAP (44,02 ± 5,23 % versus 31,83 ± 3 %; p<0,001) e maior duração do tempo de CAP (133,77 ± 15,56 min. versus 99,38 ± 9,6 min.; p<0,001) em relação aos indivíduos sadios. Não houve diferença na média da duração da fase A (9,27 ± 1,15 seg. versus 8,7 ± 0,61 seg.; p<0,131), e a média da duração da fase B não atingiu diferença significativa (22,92 ± 1,71 seg. versus 21,54 ± 1,78 seg.; p<0,054) entre os dois grupos. A comparação dos parâmetros de sono e de CAP dentro de cada grupo, mostrou não haver diferença entre os gêneros. A análise estatística dos parâmetros do sono em pacientes com ELT evidenciou uma diferença significativa das seguintes variáveis: menor latência ao sono (5,8 ± 2,4 min. versus 14,2 ± 7,6 min.; p=0,002); aumento do número da troca de estágios com média de 91,1 ± 25,7 versus 68,2 ± 12,8; p=0,008; menor duração de estágio IV (30,8 ± 14,8 min. versus 51,4 ± 12,5 min.; p=0,001); maior percentual do estágio III (7,7 ± 2,8% versus 5,7 ± 1,7%; p=0,035); menor percentual do estágio IV (7,9 ± 4% versus 12,9 ± 3,3%; p=0,002) em pacientes com ELT, comparando com o grupo de controle. A análise dos despertares breves demonstrou em pacientes com ELT: maior número de despertares breves em sono (66,5 ± 20 versus 41,8 ± 9; p=0,001); maior número de despertares breves em sono NREM (52,9 ± 19,6 versus 31 ± 9,5; p=0,002); maior duração total de despertares breves em sono (549,1 ± 170,3 seg. versus 357,2 ± 88,5 seg.; p=0,002); maior duração total de despertares breves em sono NREM (436,8 ± 165,7 seg. versus 271,9 ± 95,2 seg.; p=0,006); aumento do índice de despertar breve em sono (10,2 ± 2,9 versus 6,3 ± 1,7; p=0,001); aumento do índice de despertar breve em sono NREM (10,3 ± 3,4 versus 6 ± 2; p=0,001). Não houve diferença significativa de número (13,6 ± 5,6 versus 10,8 ± 3,7; p=0,149), duração total (112,3 ± 48,3 seg. versus 85,3 ± 25,2 seg.; p=0,091) e índice de despertar breve (9,7 ± 3,8 versus 7,4 ± 2,4; p=0,075) em sono REM entre os dois grupos. Todos os pacientes comELT tiveram uma eficiência do sono normal e similar ao grupo de controle (90,4 ± 2,9 % versus 90,6 ± 2,9 %). Conclusões: Os pacientes com ELT apresentam aumento da taxa de CAP e da duração de tempo de CAP em relação ao grupo controle, demonstrando um aumento na instabilidade e fragmentação do sono. O aumento na expressão da taxa de CAP, alterações nos parâmetros de fragmentação e descontinuidade do sono, expressos pelo aumento de número, duração e índice de despertares breves em sono NREM e o número de mudanças de estágios, associados à eficiência normal do sono em nosso grupo de pacientes com ELT, podem sugerir que o CAP tem um papel na modulação do sono. A fragmentação e a instabilidade do sono em pacientes com ELT, provavelmente, ocorrem devido à própria epilepsia e podem refletir a interação do foco epiléptico com os sistemas responsáveis pela manutenção e estabilidade de sono. / Introduction: Cyclic Alternating Pattern (“CAP”) is a NREM sleep physiological rhythm corresponding to periods of cyclical activation expressed by phasic events of sleep. The increase in the CAP rate expression has been considered a measure for sleep instability and fragmentation. CAP offers a favorable condition for interictal and/or ictal discharges. The CAP modulation in patients with Temporal Lobe Epilepsy (TLE) is not well defined. Objectives: Analyze the CAP expression in patients with TLE comparing it with a control group. Select the group of patients without sleep disorders which may interfere with sleep organization. Methods: A transversal study was conducted with a comparing control group. The selection was paired on gender and age between patients with TLE and the control group, in accordance with inclusion and exclusion criteria. The sleep parameters and CAP were analyzed in 13 patients (6 males and 7 females; mean age: 33,8 ± 8,5 years) and 13 healthy individuals (8 males and 5 females; mean age: 26,1 ± 9,2 years) who did not present sleep disorders. The comparison of the two groups was made through Student’s t-test and was confirmed by the Mann-Whitney U test. Results: Patients with TLE showed an increase in the CAP rate (44,02 ± 5,23% versus 31,83 ± 3%; p<0,001) and CAP time was longer (133,77 ± 15,56 min. versus 99,38 ± 9,6 min.; p<0,001) as compared to healthy individuals. There was no difference in the duration average of stage A (9,27 ± 1,15 sec. versus 8,7 ± 0,61 sec.; p<0,131), and the duration average of stage B did not show a significant difference (22,92 ± 1,71 sec. versus 21,54 ± 1,78 sec.; p<0,054) between both groups. The comparison of sleep parameters and CAP within the group showed that there is no difference between the genders. The statistical analysis of sleep parameters in patients with TLE showed a significant difference in the following variables: lower sleep latency (5,8 ± 2,4 min. versus 14,2 ± 7,6 min.; p=0,002); increase in the number of stage shifts with an average of (91,1 ± 25,7 versus 68,2 ± 12,8; p=0,008); lower duration of the stage IV (30,8 ± 14,8 min. versus 51,4 ± 12,5 min.; p=0,001); higher percentage of the stage III (7,7 ± 2,8% versus 5,7 ± 1,7%; p=0,035); lower percentage of the stage IV (7,9 ± 4% versus 12,9 ± 3,3%; p=0,002) in patients with TLE as compared to the control group. The analysis of arousals in patients with TLE showed: a higher number of arousals during sleep (66,5 ± 20 versus 41,8 ± 9; p=0,001); a higher number of arousals during NREM sleep (52,9 ± 19,6 versus 31 ± 9,5; p=0,002); a longer total duration of arousals during sleep (549,1 ± 170,3 sec. versus 357,2 ± 88,5 sec.; p=0,002); a longer total duration of arousals during NREM sleep (436,8 ± 165,7 sec. versus 271,9 ± 95,2 sec.; p=0,006); an increase of arousal index during sleep (10,2 ± 2,9 versus 6,3 ± 1,7; p=0,001); an increase of arousal index during NREM sleep (10,3 ± 3,4 versus 6 ± 2; p=0,001). There was not a significant difference in number (13,6 ± 5,6 versus 10,8 ± 3,7; p=0,149), total duration (112,3 ± 48,3 sec. versus 85,3 ± 25,2 sec.; p=0,091) and arousal index (9,7 ± 3,8 versus 7,4 ± 2,4; p=0,075) during REM sleep between the two groups. All patients with TLE showed a sleep efficiency that is normal and similar to the control group (90,4 ± 2,9% versus 90,6 ± 2,9%).Conclusions: Patients with TLE showed an increase in CAP rate and a longer CAP duration in relation to the control group, demonstrating an increase in the instability and fragmentation of sleep. The increase in the CAP rate expression, alterations in the parameters of sleep fragmentation and discontinuity that as expressed by increase in the number, duration, arousal index during NREM sleep and number of stage shifts, associated with normal sleep efficiency in our group of patients with TLE may suggest that CAP may have influence in the modulation of sleep. Sleep fragmentation and instability in patients with TLE may occur probably due to epilepsy itself, reflecting the interaction of the epileptic foci with the systems responsible for the maintenance and stability of sleep.

A memória prospectiva (MP), função não avaliada em baterias neuropsicológicas tradicionalmente aplicadas em pacientes com epilepsia do lobo temporal secundária à esclerose de hipocampo (EMT), refere-se a um conjunto de habilidades cognitivas que permitem lembrar-se de uma intenção a desempenhar no futuro, no momento adequado. Estudos de neuroimagem associam os lobos frontais ao desempenho do componente prospectivo da MP (lembrar a intenção) e as estruturas mesiais temporais ao componente retrospectivo da MP (lembrar o conteúdo da atividade). Estudou-se a MP, com ênfase no componente prospectivo, em pacientes com EMT unilateral. Correlacionou-se o desempenho no teste de MP com o desempenho em testes neuropsicológicos tradicionalmente utilizados e escalas de auto-avaliação. Incluímos 26 pacientes com EMT à direita, 22 à esquerda e 26 controles sadios pareados por idade, sexo e escolaridade. Houve alteração do componente prospectivo da MP em ambos os grupos EMT (p<0,001) (efeito lesão), com pior resultado no grupo EMTE (p<0,05) (efeito lateralidade da lesão). O grupo EMTE também apresentou rebaixamento no componente retrospectivo da MP. A alteração do desempenho não pôde ser explicada por depressão, ansiedade, efeito das drogas antiepilépticas, número de crises ou duração da epilepsia. O desempenho de pacientes com EMTE no teste de MP correlacionou-se com o desempenho em testes de evocação tardia de material verbal e autopercepção de desempenho de memória, o que sugere substrato neurobiológico comum para as funções avaliadas por estes instrumentos. A bateria de MP demonstrou o efeito da lesão e da lateralidade da lesão para os erros de componente prospectivo, e o efeito da lateralidade da lesão para os erros de componente retrospectivo. Sugere-se que o papel de estruturas mesiais temporais, incluindo os hipocampos, sobre o componente prospectivo da MP deve ser considerado, especialmente em atividades de longo prazo. A inclusão da avaliação da MP em baterias neuropsicológicas para pacientes com EMT pode auxiliar o entendimento das dificuldades de memória que estes apresentam em seu cotidiano. / Prospective memory (PM) refers to a set of cognitive abilities that allow future performance of a present intention, at the appropriate time. It has not been evaluated in mesial temporal sclerosis (MTS). Functional neuroimaging studies indicate the role of the frontal lobes in the prospective component of PM (intention recall) and the role of mesial temporal structures in the retrospective component (content recall). We studied PM, with emphasis on the prospective component, in patients with unilateral MTS and correlated performance in PM testing with performance in traditional neuropsychological tests, as well as self evaluation scales. We evaluated PM in 26 right MTS and in 22 left MTS patients, as well as in 26 age-gender and education matched normal controls. The prospective component of PM was impaired in both patient groups (p<0.001) (lesion effect), worse in LMTS group (p< 0.05) (laterality effect). Left MTS also impacted on performance in the retrospective PM component. Impaired performance could not be explained by depression, anxiety, age at epilepsy onset, duration of epilepsy or an antiepileptic drug effect. Mesial temporal lobe structures play an important role in prospective PM processes, especially in tasks involving long delay intervals. Inclusion of PM tests in neuropsychological batteries used to evaluate patients with temporal lobe structures dysfunction may allow a better understanding of memory impairment in these patients, especially of the impact of PM impairment on daily living activities.

A avaliação neuropsicológica é instrumento auxiliar para lateralização em epilepsia temporal (ET). Desempenho comprometido em memória verbal (MV) e não verbal (MNV) sugeririam, respectivamente, disfunção no sistema de memória do hemisfério dominante e não dominante. Não há consenso sobre a capacidade lateralizatória da avaliação de memória em pacientes com epilepsia. Estudou-se o poder lateralizatório da avaliação neuropsicológica em testes de memória verbal e não verbal em ET secundária a esclerose mesial temporal (EMT) unilateral. Comparamos o desempenho em memória verbal (RAVLT e o Memória Lógica) e não verbal (RVDLT e a figura complexa de Rey) em 87 pacientes destros com EMT (44 direita, 43 esquerda) e 42 controles. Pacientes e controles tinham escolaridade>8 anos, QI>70, sem comorbidades. Pacientes com EMTE tiveram desempenho rebaixado comparado a controles e EMTD em evocação livre e tardia do RAVLT. EMTE e EMTD tiveram desempenho rebaixado em relação a controles em evocação livre e tardia em Memória Lógica. EMTD tiveram desempenho rebaixado em relação a controles em evocação tardia da figura complexa de Rey. Observou-se baixa prevalência de dificuldade em ambos tipos de memória em ambos os grupos. Quando considerado acometimento de específico de MV observou-se associação com EMTE, com baixa sensibilidade, médio valor preditivo positivo (VPP) e alta especificidade. Quando considerado acometimento específico de MNV observou-se associação com EMTD, com baixa sensibilidade e altos valor preditivo positivo (VPP) e especificidade. O poder lateralizatório da testagem neuropsicológica de memória em EMT é observado, em apenas uma parcela de pacientes com EMT unilateral / Neuropsychological testing is a standard tool in the evaluation of patients with epilepsy. It allows assessment of performance in various cognitive domains, and is used as a lateralizing tool for seizure focus localization. Poor performance in verbal memory (VM) test is believed to indicate a dominant hemisphere focus. Poor performance in nonverbal memory (NVM) tests would localize the focus to the nondominant hemisphere. There still is a paucity of evidence of the ability of neuropsychological testing to predict seizure focus lateralization. We studied the lateralizing ability of neuropsychological testing of VM and NVM in a sample of 87 right handed patients with epilepsy secondary to unilateral mesial sclerosis (MTS) (44 right R, 43 left - L) and 42 controls (C), with an IQ>70, eight or more years of schooling, without comorbidities. LMTS patients performed significantly worse than controls in free and delayed recall of RAVLT items. L and RMTS performed worse than controls in immediate and delayed recall of the Logical Memory stories. RMTS performed worse than controls in delayed recall of the Complex Rey Figure. Our findings showed a low prevalence of VM and NVM impairment in both groups, an association between specific VM deficit and LMTS, with fair PPV and good specificity, and low sensibility. Selective NVM impairment was associated with RMTS, with good PPV and specificity for RMTS, and low sensibility. The lateralizing power of neuropsychological testing is noted only in a minority of patients with specific selective patterns of VM and NVM impairment

Abstract Epilepsy is associated with changes in autonomic cardioregulatory function. Ictally, autonomic disturbances may be evident with significant changes in heart rate (HR), blood pressure (BP) and respiration. However, interictal dysfunction of autonomic cardiovascular system may be subtle and it may be recognized only by delicate tools designed for that purpose. The aim of this study was to evaluate the function of the cardiovascular autonomic regulatory system in patients with epilepsy. Cardiovascular reflex tests were performed on patients with partial or idiopathic generalized epilepsies. Special attention was paid to temporal lobe epilepsy (TLE). An association of refractory and well controlled TLE and hippocampal sclerosis with altered cardioregulation was evaluated by using cardiovascular reflex tests and an analysis of spectral and non-linear analysis of heart rate variation (HRV). Cardiovascular reflexes were altered both in patients with partial and idiopathic generalized epilepsies who had been treated for epilepsy with antiepileptic drugs (AEDs), whereas patients with newly, untreated epilepsy did not differ from the control subjects. Diminished cardiovascular reflexes also seemed to be associated with carbamazepine (CBZ) treatment. Various parameters of cardiovascular reflex tests and analysis of spectral and dynamic measures of HRV were diminished in patients with TLE compared to the control subejcts. These results indicate that epilepsy, especially TLE, is associated with interictal changes of autonomic cardioregulation. Although these changes seem to be evident in patients with severe form of TLE, patients with well controlled TLE and patients without hippocampal sclerosis also have altered autonomic cardioregulatory function. These results suggest that dysfunction of the cardioregulatory system is rather associated with functional than structural changes of the inner temporal lobe in patients with TLE.

Le kaïnate, est une puissante neurotoxine connue pour induire des convulsions qui rappellent celles trouvées chez les patients atteints d'épilepsie du lobe temporal (ELT). Cependant, le rôle des récepteurs kaïnate activés par le glutamate endogène dans l'ELT n'est pas encore connu. Chez les patients atteints d'ELT et dans les modèles animaux, le tissu neuronal subit une réorganisation majeure. Ce phénomène est particulièrement bien documenté dans le gyrus denté où les axones des cellules granulaires, bourgeonnent pour former un circuit récurrent excitateur aberrant. L'équipe a montré que ces synapses récurrentes moussues nouvellement formées sont aberrantes dans leurs modes de fonctionnement. En effet, en plus des synapses opérant via des récepteurs glutamatergiques de type AMPA présentes en conditions physiologiques, la moitié des synapses aberrantes fonctionnent via des récepteurs de type kaïnate. Les évènements générés par les récepteurs kaïnate ont une cinétique lente, leur permettant de s'intégrer dans une fenêtre temporelle anormalement étendue engendrant un taux de décharge soutenu et fortement rythmique des cellules du gyrus denté de rats épileptiques. L'objectif de mon travail de thèse a été d'étudier l'implication des récepteurs kaïnate dans les activités épileptiques de l'hippocampe. En utilisant différents modèles d'ELT nous avons pu observer que l'absence de ces récepteurs induit une forte diminution de la fréquence des activités épileptiformes dans le gyrus denté in vitro mais également in vivo. Cette étude démontre que les récepteurs kaïnate contenant la sous-unité GluK2 contribuent à la genèse des crises. / Kainate is a potent neurotoxin known to induce acute seizures. However, whether kainate receptors play any role in the pathophysiology of temporal lobe epilepsy (TLE) is not yet known. In animal models of chronic epilepsy, as in human TLE, the hippocampus displays major network reorganization. In particular, sprouting of hippocampal mossy fibers leads to the formation of powerful recurrent excitatory circuits among dentate granule cells, which partly accounts for the enhanced ability of the hippocampus to generate epileptiform activity in human patients and animal models of TLE. At the aberrant recurrent excitatory synapses, mossy fiber inputs impinging on dentate granule cells operate mostly via ectopic kainate receptors and drive synaptic events with abnormal long lasting kinetics not present in naïve conditions. The goal of this work was to explore the pathophysiological implications of kainate receptors in generation of recurrent seizure in TLE through the use of kainate receptors subunit deficient mice and selected pharmacological agents. In an animal model of TLE, we observed a strong reduction of both interictal and ictal activities in the dentate gyrus in vitro and in vivo, in mice lacking the GluK2 subunit, and through the application of a pharmacological agent inhibiting GluK2/GluK5 receptors. Therefore, we demonstrate that aberrant GluK2-containing kainate receptors contribute to chronic seizures in TLE, urging for the development of antiepileptic strategies targeting these receptors.

L'épilepsie est une maladie fréquente affectant 0,5 à 1% de la population générale. Elle est caractérisée par des crises récurrentes responsables d'un sévère handicap médical et psychosocial. Les causes de l'épilepsie sont multiples et peuvent être liées notamment à des lésions cérébrales anténatales ou acquises, des causes génétiques ou métaboliques. L'épilepsie du lobe temporal (ELT) est la forme la plus répandue chez l’adulte, le plus souvent associée à une sclérose de l'hippocampe et réfractaire aux traitements antiépileptiques. Si pendant longtemps l'ELT a été perçue comme une pathologie focale centrée sur l'hippocampe sclérosé, de nombreux travaux montrent que les atteintes associées à l'ELT s'étendent bien au-delà de l'hippocampe et du lobe temporal, suggérant une altération plus globale du réseau cérébral structurel impactant le fonctionnement du cerveau. Toutefois, ces atteintes sont encore mal connues. Le développement récent des séquences et du traitement de l’imagerie de diffusion permettent l’acquisition d’images anatomiques du cerveau et la modélisation des fibres de substance blanche. L’architecture du réseau cérébral peut alors être représentée mathématiquement par un graphe, appelé « connectome » structurel, définissant la force des liens structurels (fibres de substance blanche) entre différentes régions du cerveau.L’objectif principal de la thèse est d’identifier les altérations du réseau structurel liées à l’épilepsie, avec un intérêt particulier à l’ELT. L’objectif secondaire est de développer de nouvelles méthodes d’extraction du connectome structurel pour en améliorer la précision anatomique et mieux identifier et localiser les altérations du réseau structurel.Ainsi, dans un premier temps, nous établissons l’état de l’art des méthodes d’extraction et d’analyse du connectome structurel et discutons leurs limites. Nous présentons alors une nouvelle méthode d’extraction du connectome structurel haute-résolution couvrant l’ensemble du cortex et incluant certaines régions sous-corticales, baptisée « high-resolution structural connectome ». L’objectif est de définir un cadre d’analyse du connectome structurel avec une très bonne précision anatomique et de fournir les outils nécessaires pour des études individuelles ou de groupe en tenant compte des contraintes de temps de calcul et d’utilisation de la mémoire et du disque.Dans un deuxième temps, nous analysons le connectome structurel de patients ELT avec sclérose hippocampique latéralisée dans le but de mettre en évidence le réseau structurel pathologique et d’en distinguer les caractéristiques en fonction de la latéralité de la lésion. Nous validons la stabilité et la reproductibilité du connectome structurel haute-résolution sur des sujets sains. La démonstration de son intérêt clinique potentiel est apportée en observant des différences structurelles subtiles entre deux groupes de sujets sains et en identifiant les sous-structures du striatum. Enfin, notre méthode est appliquée dans un contexte clinique pour identifier les altérations de connectivité structurelle du complexe hippocampo-amygdalien, impliqué dans l’ELT, en lien avec la pathologie. Nos travaux ont ainsi permis d’identifier les altérations globales et diffuses du réseau structurel liées à l’ELT, et plus particulièrement ont mis en évidence des disparités importantes selon la latéralité de la pathologie. Nous avons également présenté une nouvelle méthode d’extraction du connectome structurel augmentant considérablement sa précision anatomique et défini les outils nécessaires à l’analyse haute-résolution du connectome structurel. L’intérêt de cette méthode a été démontré par le gain de précision anatomique obtenu pour l’étude de l’architecture cérébrale du sujet sain ou pour une meilleure identification de réseaux pathologiques, ouvrant ainsi de nombreuses perspectives sur la caractérisation de l’architecture cérébrale et son lien sur le fonctionnement du cerveau. / Epilepsy is a frequent disease affecting 0.5 to 1% of the general population, characterized by recurrent seizures responsible for severe medical and psychosocial handicaps. The causes of epilepsy may be antenatal or acquired brain lesions, genetic history or metabolic disorders. Temporal lobe epilepsy (TLE) is the most common medically intractable epilepsy in adults, often associated with hippocampal sclerosis. Although TLE has been perceived for a long time as a hippocampal disorder, many studies show that the disease actually affects brain regions beyond the hippocampus and temporal lobe suggesting diffuse alteration of the brain structural network. However, these alterations are still unknown. Recent advances in diffusion weighted imaging and processing allow for the acquisition of brain anatomical images and the modeling of white matter fibers. Brain network architecture can then be represented mathematically by means of a graph, called “structural connectome”, defining the strength of the structural links (white matter fibers) across brain regions.The purpose of this thesis is to identify structural network alterations associated with epilepsy, in particular TLE. The secondary objective is to develop new methods for extracting the structural connectome in order to increase the anatomical accuracy and better localize network alterations.Therefore, we first review the state of the art of the methods used for extracting and analyzing the structural connectome and establish their limitations. We then introduce a new method to extract the structural connectome with increased anatomical accuracy, which we called “high-resolution structural connectome”. The purpose is to provide a framework to analyze brain connectivity at high-resolution and to define the necessary tools for individual and group analysis, keeping in mind processing time and memory and disk usages.Then, we analyze the structural connectome of TLE patients with hippocampal sclerosis to reveal underlying pathological network, we also highlight pathological network discrepancies between left and right sided lesions. Inter- and intra-subject stability and repeatability of the high-resolution structural connectome are assessed with a cohort of healthy subjects. We demonstrate potential clinical interest by observing subtle structural differences between two groups of healthy subjects and by delineating the sub-fields of the striatum. Finally, our method is applied to the pathological case of TLE and aims at uncover structural connectivity alterations of the hippocampo-amygdalian complex, known to be involved in TLE.In conclusion, we extend our current knowledge on TLE by showing that this is a network disease involving widespread brain regions, whose pattern largely depends on lesion laterality. We also introduce a new method for extracting the structural connectome at high-resolution, considerably increasing the anatomical accuracy. The interest of this method is demonstrated on healthy subjects to better characterize the healthy brain and on the diseased brain to localize more precisely the brain regions associated with the pathology.

Les chansons lient naturellement des mélodies à des paroles. Elles représentent l’une des formes les plus utilisées de l’expression musicale. De façon intéressante, les chansons nécessitent l’intégration simultanée d’informations verbales (les paroles) et d’informations musicales (la mélodie) pour former une seule trace mnésique. Le lobe temporal médian a été identifié comme région clé pour la mémoire épisodique et en particulier pour le processus de binding, qui consiste en la liaison de plusieurs éléments d’un souvenir. Néanmoins, les mécanismes par lesquels le cerveau réalise la liaison entre paroles et mélodies dans la mémoire des chansons restent peu connus. L’objectif de cette thèse est de montrer le rôle du lobe temporal médian dans le processus de binding de paroles et mélodies pour la création d’un souvenir unifié d’une chanson. Premièrement, nous avons étudié les effets d’une sclérose unilatérale de l’hippocampe associée à une épilepsie du lobe temporal sur le processus de mémorisation des chansons en IRM fonctionnelle (étude 1). Les patients avec une sclérose de l’hippocampe gauche avaient un déficit d’adaptation aux paroles et de la représentation intégrée des chansons. Puis, nous avons étudié l’organisation fonctionnelle de la mémoire des chansons dans une étude d’IRM fonctionnelle chez des volontaires sains (étude 2). Les résultats ont montré l’implication de l’hippocampe dans le processus de binding en mémoire des chansons ainsi que l’implication d’autres structures comme le gyrus frontal inférieur, les ganglions de la base et le cervelet. Enfin, dans une dernière étude (étude 3), nous avons examine la mémoire des chansons et plus particulièrement la mémoire de l’association (binding) des paroles au contexte musical chez des patients ayant bénéficié d’une résection unilatérale du lobe temporal médian pour traiter une épilepsie pharmacorésistante. La mémoire des paroles ainsi que celle du contexte mélodique des chansons a été testé dans une tâche explicite de reconnaissance. Un fort déficit en reconnaissance de paroles a été constaté chez les patients avec une lésion temporale gauche, et à un moindre degré chez les patients avec une lésion temporale droite. Ce déficit a été corrélé avec des déficits de la mémoire verbale. L'étude 3 suggère, en outre, que les structures du lobe temporal médian peuvent être cruciales pour le codage de la liaison détaillée entre les paroles et leur contexte mélodique, tandis que les effets implicites d'une représentation intégrée de la chanson peuvent être épargnés après des lésions du lobe temporal médian. Pour conclure, ces trois études ont apporté de nouvelles données sur le rôle du lobe temporal médian dans le processus de binding dans le domaine musical. Ce travail a également permis d’identifier un vaste réseau de régions corticales et sous-corticales impliqué dans l’encodage de nouvelles chansons avant de discuter les implications théoriques et cliniques de ces recherches. / Songs naturally couple music with language, constituting one of the most broadly used forms of music expression. Interestingly, songs require the simultaneous and integrated process of verbal (lyrics) and musical (melody) information to form a single memory trace. The medial temporal lobe has been identified as the key region for the integration of features of an event in episodic memory, also called the binding function. Nevertheless, the mechanisms by which the brain binds lyrics and melodies in song memory remain poorly understood. The purpose of this thesis is to elucidate the role of the MTL on the binding of lyrics and melodies for the creation of a unified song memory trace. First, the effects of unilateral hippocampus sclerosis on song processing were investigated in an fMR-adaptation study (Study 1). Patients with left hippocampal sclerosis showed adaptation deficits in response to lyrics as well as to the integrated representation of songs. To further explore the relation of these results with the emergence of memory for songs, the functional architecture of song memory was examined in a subsequent memory fMRI study (Study 2). The results support the implication of the hippocampus in song binding. Furthermore, the role of other structures, including the Inferior Frontal Gyrus (IFG), the Basal Ganglia (BG) and cerebellum was highlighted and discussed. Finally, Study 2 was adapted to test binding in patients following a unilateral temporal lobe excision for the relief of intractable temporal lobe epilepsy behaviorally in Study 3. Memory for lyrics as well for their melodic context was tested in an explicit recognition task. A strong deficit in lyrics recognition was found in patients with a left temporal lesion, and to a smaller degree in patients with a right temporal lesion. This deficit was correlated with deficits in verbal memory. Evidence from Study 3 further suggests that MTL structures may be crucial for encoding the detailed binding of lyrics with their melodic context, whereas implicit effects of an integrated representation of the song may be spared after MTL lesions. Altogether the studies presented in this thesis provide novel evidence for the role of the medial temporal lobe structures in binding lyrics and melodies for song memory. The present thesis proposes a comprehensive network of cortical and subcortical regions cooperating to successfully encode new songs. Finally, theoretical and clinical implications of these findings are considered.

Orientadores: Fernando Cendes, Helder Tedeschi / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T12:19:50Z (GMT). No. of bitstreams: 1 Yasuda_ClarissaLin_D.pdf: 4778661 bytes, checksum: a54d6507d5d93d41eca45778bf444ea5 (MD5) Previous issue date: 2009 / Resumo: Objetivo: A cirurgia para pacientes com epilepsia de lobo temporal mesial refratária oferece um controle de crises para aproximadamente 70% dos pacientes. Neste estudo comparamos a eficácia entre o tratamento clínico e cirúrgico e investigamos a relação entre as alterações estruturais (atrofia de substância branca, SB e cinzenta, SC) nas imagens de ressonância magnética (RM) pré-operatórias e o resultado cirúrgico; bem como evidências estruturais de neuroplasticidade nas imagens de RM pós-operatórias. Métodos: Realizamos uma curva de sobrevivência de Kaplan-Meier para comparar a eficácia entre os dois tipos de tratamento, para o grupo clínico (85 pacientes, 30 mulheres) e grupo cirúrgico (46 pacientes, 16 mulheres). Avaliamos as imagens de RM através da técnica de Morfometria Baseada em Voxel com o software SPM2 (Statistical Parametric Mapping)/MATLAB 7.0, comparando pacientes com indivíduos normais através de um Teste-T. Para essa análise dividimos os pacientes operados em grupos de acordo com o controle de crises obtido. Para investigar as alterações plásticas pós-operatórias realizamos um teste-T pareado entre as imagens pré e pós-operatórias. Resultados: A análise de sobrevivência confirmou a superioridade do tratamento cirúrgico (84% de pacientes controlados) em longo razo em comparação ao tratamento medicamentoso (7% de pacientes controlados), p< 0,001. Os pacientes com melhor resultado cirúrgico apresentavam um padrão restrito de atrofia de SC em comparação aos pacientes com crises após a cirurgia. Apenas os pacientes controlados tiveram evidências de recuperação de SB e SC após a cirurgia. Conclusão: A cirurgia oferece um melhor controle de crises que o tratamento medicamentoso e a chance de recuperar áreas com atrofia de SB e SC. / Abstract: Objective: Surgery for refractory mesial temporal lobe epilepsy (MTLE) generally offers good seizure control for approximately 70% of patients. In this study we compared the efficacy between surgical and clinical treatments and investigated the relationship between pre-operative structural abnormalities (white matter and grey matter atrophy) and surgical outcome. We also investigated the structural evidences of brain plasticity on post-operative MRI scans. Methods: We performed Kaplan-Meier survival analysis to compare the efficacy between surgical and medical groups. Clinical group included 85 patients (30 women) and the surgical group included 46 patients (16 women). We applied Voxel Based Morphometry technique on SPM2 (Statistical Parametric Mapping)/MATLAB 7.0 and compared patients with normal individuals with T-Test. For this analysis we separated patients according to post-operative surgical control. In order to investigate plastic changes after surgery we performed paired T-Test between pre and postoperative MR scans. Results: Survival analysis confirmed the superiority of surgical treatment for long-term seizure control (seizure control in 84% of patients) compared to medical treatment (seizure control in 7% of patients), p<0.001. Patients with better seizure control presented a restricted pattern of Grey matter atrophy, compared to patients with poorer seizure control which presented a widespread pattern of Grey matter atrophy. Our analysis showed that only patients with good seizure control presented structural evidences of white matter and grey matter recovery after surgery. Conclusion: Surgical treatment offers better chances of seizure control for refractory MTLE as well as the opportunity of relative white matter and grey matter recovery. / Doutorado / Neurologia / Doutor em Ciências Médicas

Submitted by Rafael Santana (rafael.silvasantana@ufpe.br) on 2017-07-25T18:11:48Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) ufpe_mestrado_disseracao_Michel_Melo_2016.pdf: 869604 bytes, checksum: 4942c04024c59c9a4a1be9407c5ff92c (MD5) / Made available in DSpace on 2017-07-25T18:11:48Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) ufpe_mestrado_disseracao_Michel_Melo_2016.pdf: 869604 bytes, checksum: 4942c04024c59c9a4a1be9407c5ff92c (MD5) Previous issue date: 2016-03-04 / A Epilepsia do Lobo Temporal (ELT) é a forma mais refratária ao tratamento farmacológico. Esse tipo de epilepsia tem origem nas estruturas do lobo temporal, sendo o hipocampo uma das estruturas mais afetadas, apresentando diminuição do volume e, consequentemente, gliose, caracterizando a Esclerose Hipocampal (EH). É sabido que o hipocampo desenvolve importante papel no processo mnemônico, sendo o déficit de memória a alteração mais importante nesses pacientes. Neste contexto, o presente trabalho tem como objetivo investigar a relação do desempenho de memória nos pacientes com ELT com as subpartes da formação hipocampal. Trata-se de um estudo retrospectivo, transversal, analítico, utilizando imagens de ressonância magnética (IRM) e escores de testes neuropsicológicos de memória verbal e visual, obtidos a partir de um grupo de 60 pacientes atendidos no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, da Universidade de São Paulo, no período de 2008 a 2011. Para a obtenção dos volumes das subpartes da formação hipocampal das IRM, foi utilizado a segmentada automática pelo software FreeSurfer®, obtendo os volumes da cauda do hipocampo, pré-subículo, CA1, CA2/3, CA4/GD, subículo, fímbria e fissura hipocampal. Posteriormente, foram correlacionadas com variáveis clínicas e escores de memória. A análise das imagens revelou atrofia generalizada nas subpartes da formação hipocampal ipsilateral (EH), exceto da fissura hipocampal. Essa redução do volume interferiu diretamente no desempenho de memória verbal e visual, desses pacientes. Os pacientes com EH à direita apresentaram déficit significativos na memória visual. Já os pacientes com EH à esquerda, apresentaram déficit na memória verbal e na memória visual. Foi possível avaliar, também, que a atrofia na região CA1 está relacionada com a diminuição do desempenho de memória declarativa e que os danos no CA2/3 e CA4/GD estão envolvidos com baixo desempenho das memórias de longo prazo. Neste contexto, é possível concluir que o desempenho de memória depende de uma rede de integração integra e não só de regiões especializadas. Concluímos, também, que tanto a memória verbal, quando a memória visual, possui um hemisfério dominante, no entanto, o hemisfério não dominante, quando lesionado, também interfere do desempenho de memória. / The Temporal Lobe Epilepsy (TLE) is the most resistant form of epilepsy to pharmacology treatment. This epilepsy type has its origin on the temporal lobe, which the hippocampus is one of the most affected structures, presenting volume decreasing and gliosis, characterizing the Hippocampal Sclerosis (HE). It is known that the hippocampus has an important role in the mnemônnico process and the memory deficit is the most important change in these patients. So, this work aims to investigate the relationship between the memory development in the TLE patients and the hippocampal formation subparts. It is a retrospective study, transversal, analytic, using Magnetic Resonance Images (MRI) and verbal and visual memory neuropsychological tests scores obtained from a group of 60 (sixty) patients from the Hospital das Clínicas of the Ribeirão Preto Medical School, University de São Paulo between 2008 and 2011. To measure the hippocampal formation subparts volume of IRM, it was used the automatic segmented by the FreeSurfer® software, getting the volume of the hipocampo tail, presubículum, CA1, CA2/3, CA4/DG, subiculum, fímbria and hippocampal fissure, that had been correlated with clinical variables and memory scores. The image analysis revealed a general atrophy in the hippocampal formation subparts, except the hippocampal fissure. This volume reduction had directly interfered in the declarative memory performance, verbal and visual, of these patients. The Right HE patients, presented significant visual memory deficit. The Left EH patients presented both verbal and visual memory deficit. It was also possible to evaluate that CA1 region atrophy is related to the declarative memory performance decrease and the damage in the CA2/3 and CA4/DG are related to the low performance of the long term memories. In this way, we conclude that memory performance depends on a whole integration network and not only an specific region. We also conclude that both verbal and visual memory has a dominant hemisphere, eventhough damages to the non dominant hemisphere will also interfere in te memory performance.