Impact du genre et du modèle sur les mécanismes d’épileptogénèse dans le cerveau immature

Les modèles kainate et pentylènetétrazole représentent deux modèles d’épilepsie du lobe temporal dont les conséquences à long terme sont différentes. Le premier est un modèle classique d’épileptogénèse avec crises récurrentes spontanées tandis que le second se limite aux crises aigües. Nous avons d’abord caractérisé les différents changements survenant dans les circuits excitateurs et inhibiteurs de l’hippocampe adulte de rats ayant subi des crises à l’âge immature. Ensuite, ayant observé dans le modèle fébrile une différence du pronostic lié au genre, nous avons voulu savoir si cette différence était aussi présente dans des modèles utilisant des neurotoxines. L’étude électrophysiologique a démontré que les rats KA et PTZ, mâles comme femelles, présentaient une hyperactivité des récepteurs NMDA au niveau des cellules pyramidales du CA1, CA3 et DG. Les modifications anatomiques sous-tendant cette hyperexcitabilité ont été étudiées et les résultats ont montré une perte sélective des interneurones GABAergiques contenant la parvalbumine dans les couches O/A du CA1 des mâles KA et PTZ. Chez les femelles, seul le DG était légèrement affecté pour les PTZ tandis que les KA présentaient, en plus du DG, des pertes importantes au niveau de la couche O/A. Les évaluations cognitives ont démontré que seuls les rats PTZ accusaient un déficit spatial puisque les rats KA présentaient un apprentissage comparable aux rats normaux. Cependant, encore une fois, cette différence n’était présente que chez les mâles. Ainsi, nos résultats confirment qu’il y a des différences liées au genre dans les conséquences des convulsions lorsqu’elles surviennent chez l’animal immature.

Rôle des récepteurs glutamatergiques dans l'activité épileptiforme des interneurones inhibiteurs de l'hippocampe

Les patients atteints d'épilepsie du lobe temporal (TLE) ainsi que les rats injectés à l'acide kaïnique (KA) exhibent des patrons pathophysiologiques similaires de crises, de sclérose de l'hippocampe et de perte de certains types neuronaux. Parmi les cellules atteintes dans le modèle KA du TLE on retrouve certains interneurones inhibiteurs du CA1. En effet, certains interneurones des couches oriens et alveus (O/A-IN) meurent suite à une injection de KA chez le rat, contrairement aux interneurones à la bordure des couches radiatum et lacunosum/moleculare (R/LM-IN) de la même région. Bien que cette perte soit empêchée par des antagonistes des récepteurs glutamatergiques métabotropes de groupe I (mGluR1/5), la cause de cette perte sélective des O/A-INs reste à être précisée. Au cours des travaux de cette thèse, nous avons effectué des enregistrements de patch-clamp en configuration cellule-entière en modes courant- et voltage-imposé couplés à l'imagerie calcique pour étudier les causes de la vulnérabilité sélective des O/A-INs dans ce modèle. Dans un premier temps, nous avons évalué les effets d'une application aiguë de KA sur les propriétés membranaires et calciques pour voir s'il y avait des différences entre les O/A-INs et R/LM-INs qui pourraient expliquer la vulnérabilité. Nos résultats montrent que les dépolarisations et variations de résistance d'entrée ainsi que les augmentations de calcium intracellulaire, dépendantes principalement des récepteurs -amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA), sont similaires entre les deux types d'interneurones suite à des applications aigües de KA. Ceci indique que l'effet aigu du KA sur les interneurones ne serait pas la cause de la vulnérabilité des O/A-INs. Dans un second temps nous avons comparé l'implication des sous-types de récepteurs mGluR1 et 5 dans l'activité épileptiforme des deux types d'interneurones évoquée dans un modèle de tranche désinhibée. Dans ce cas, nos données montrent un rôle important des mGluR1 et 5 activés synaptiquement lors des décharges épileptiformes et ce, de manière spécifique aux O/A-INs. Les courants synaptiques sous-tendant ces décharges impliquent des récepteurs ionotropes et métabotropes du glutamate. En présence d'antagonistes des récepteurs ionotropes glutamatergiques, les courants synaptiques sont biphasiques et formés de composantes rapide et lente. Les récepteurs mGluR1 et 5 sont différemment impliqués dans ces composantes: les mGluR5 étant impliqués dans les composantes rapide et lente, et les mGluR1 que dans la composante lente. Ces résultats indiquent que les mGluR1 et 5 contribuent différemment à l'activité épileptiforme, et spécifiquement dans les O/A-INs, et pourraient donc être impliqués dans la vulnérabilité sélective de ces interneurones dans le modèle KA.

Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis.

Induction of cyclooxygenase-2 (COX-2) has been described in a wide range of neurological diseases including animal models of epilepsy. The present study was undertaken to assess COX-2 expression in hippocampal biopsies from patients with therapy-refractive temporal lobe epilepsy (TLE). For this purpose, hippocampal CA1 subfield was dissected from epileptic patients with (n=5) or without (n=2) hippocampal sclerosis (HS). COX-2 expression was investigated using immunohistochemistry and semi-quantitative RT-PCR. COX-2 immunoreactivity in TLE patient material in the absence of HS was restricted to a few neurons of the hippocampus. In the presence of HS, on the other hand, a significant induction of astrocytic COX-2 immunoreactivity associated with a concomitant increase in the steady-state level of COX-2 mRNA was observed in the CA1 subfield. These findings suggest that induction of astrocytic COX-2 is implicated in the pathogenesis of HS in TLE and is consistent with the previous findings of increased concentrations of prostaglandins in the cerebrospinal fluid of these patients.

Localisation des aires cérébrales impliquées dans le rappel de mots : validation d’un protocole d’imagerie optique

Jusqu'à récemment, les patients souffrant d'épilepsie réfractaire aux traitements médicamenteux étaient destinés à un avenir incertain. Le recours à la chirurgie comme traitement alternatif offre l'espoir de mener un jour une vie normale. Pour déterminer si un patient peut bénéficier d’une intervention chirurgicale, une évaluation complète est cruciale. Les méthodes d’évaluation préchirurgicale ont connu des progrès importants au cours des dernières décennies avec le perfectionnement des techniques d’imagerie cérébrale. Parmi ces techniques, la spectroscopie proche infrarouge (SPIR), aussi connue sous le nom d’imagerie optique, présente de nombreux avantages (coût, mobilité du participant, résolution spatiale et temporelle, etc.). L’objectif principal de cette étude est de développer un protocole d'évaluation préchirurgicale de la mémoire. Une tâche de mémoire verbale incluant l’encodage, le rappel immédiat et le rappel différé de listes de mots a été administrée à dix adultes sains lors d’un enregistrement en imagerie optique. Les résultats obtenus suggèrent l’activation bilatérale des aires préfrontales antérieures et dorsolatérales ainsi que des aires temporales antérieures et moyennes. Les aires préfrontales et temporales antérieures semblent modulées par les différents processus mnésiques et la position du rappel dans le temps. La première fois qu’une liste est rappelée, l’activité hémodynamique est plus élevée que lors des rappels subséquents, et ce, davantage dans l’hémisphère gauche que dans l’hémisphère droit. Cette étude constitue la première étape dans le processus de validation du protocole à des fins cliniques auprès de patients épileptiques.

El perfil criminal del asesino en serie colombiano desde la perspectiva psicodinámica. Una revisión de literatura

El objetivo de la presente investigación consiste en describir las características de un asesino en serie colombiano desde la perspectiva psicodinámica. En este sentido, el abordaje teórico realizado en este trabajo se compone inicialmente de una concepción de asesinos en serie, posteriormente se hace una revisión acerca de las bases biológicas y los factores sociales del homicida serial, igualmente, se explican tres teorías psicodinámicas a trabajar (Sigmund Freud y Erick Erickson). Finalmente, se hace mención dentro de la investigación a la comparación casuística de los asesinos en serie, teniendo en cuenta a cuatro asesinos en serie mediante el abordaje psicodinámico. Por otra parte, a nivel metodológico, el tipo de estudio realizado es descriptivo con un corte cualitativo y un diseño no experimental, basado en la revisión de fuentes bibliográficas. Como producto se pretende hacer una aproximación al perfil correspondiente de la personalidad de un asesino en serie colombiano mediante las teorías psicodinámicas.

Autobiographical memory and the self in a case of transient epileptic amnesia

Transient epileptic amnesia (TEA) is characterized by deficits in autobiographical memory (AM). One of the functions of AM is to maintain the self, suggesting that the self may undergo changes as a result of memory loss in temporal lobe epilepsy. To examine this, we used a modification of a task used to assess the relationship between self and memory (the IAM task) in a single case, E.B. Despite complaints of AM loss, E.B. had no difficulty in producing a range of self-images (e.g., I am a husband) and collections of self-defining AMs in support of these statements. E.B. produced fewer episodic memories at times of self-formation, but this did not seem to impact on the maintenance of self. The results support recent work suggesting the self may be maintained in the absence of episodic memory. The application of tasks such as that used here will further elucidate AM impairment in temporal lobe epilepsy. (C) 2011 Elsevier Inc. All rights reserved.

The anterior temporal lobes support residual comprehension in Wernicke’s aphasia

Wernicke’s aphasia occurs following a stroke to classical language comprehension regions in the left temporoparietal cortex. Consequently, auditory-verbal comprehension is significantly impaired in Wernicke’s aphasia but the capacity to comprehend visually presented materials (written words and pictures) is partially spared. This study used fMRI to investigate the neural basis of written word and picture semantic processing in Wernicke’s aphasia, with the wider aim of examining how the semantic system is altered following damage to the classical comprehension regions. Twelve participants with Wernicke’s aphasia and twelve control participants performed semantic animate-inanimate judgements and a visual height judgement baseline task. Whole brain and ROI analysis in Wernicke’s aphasia and control participants found that semantic judgements were underpinned by activation in the ventral and anterior temporal lobes bilaterally. The Wernicke’s aphasia group displayed an “over-activation” in comparison to control participants, indicating that anterior temporal lobe regions become increasingly influential following reduction in posterior semantic resources. Semantic processing of written words in Wernicke’s aphasia was additionally supported by recruitment of the right anterior superior temporal lobe, a region previously associated with recovery from auditory-verbal comprehension impairments. Overall, the results concord with models which indicate that the anterior temporal lobes are crucial for multimodal semantic processing and that these regions may be accessed without support from classic posterior comprehension regions.

Short- and long-term anxiogenic effects induced by a single injection of subconvulsant doses of pilocarpine in rats: investigation of the putative role of hippocampal pathways

Behavioral consequences of convulsive episodes are well documented, but less attention was paid to changes that occur in response to subconvulsant doses of drugs. We investigated short- and long-term effects of a single systemic injection of a subconvulsant dose of pilocarpine on the behavior of rats as evaluated in the elevated plus maze. Pilocarpine induced an anxiogenic-like profile 24 h later, and this effect persisted for up to 3 months (% of time spent on open arms at 24 h, control = 35.47 +/- 3.23; pilocarpine 150 = 8.2 +/- 2.6; 3 months, control = 31.9 +/- 5.5; pilocarpine 150 = 9.3 +/- 4.9). Temporary inactivation of fimbria-fornix with lidocaine 4% promoted an anxiolytic-like effect per se, suggesting a tonic control of this pathway on the modulation of anxiety-related behaviors. Lidocaine also reduced the anxiogenic-like profile of animals tested 1 month after pilocarpine treatment (% of time spent on open arms, saline + phosphate-buffered saline (PBS) = 31.7 + 3.7; saline + lidocaine = 54.4 + 4.7; pilocarpine + PBS = 10.3 + 4.1; pilocarpine + lidocaine = 40.1 + 9.1). To determine whether the anxiogenic-like effect was mediated by septal region or by direct hippocampal projections to the diencephalon, the neural transmission of post-commissural fornix was blocked, and a similar reduction in the anxiogenic-like effect of pilocarpine was observed. Our findings suggest that a single systemic injection of pilocarpine may induce long-lasting anxiogenic-like behavior in rats, an effect that appears to be mediated, in part, through a direct path from hippocampus to medial hypothalamic sites involved in fear responses.

Interferindo com oscilações de alta frequência no hipocampo epiléptico: consequências para as crises espontâneas

Conselho Nacional de Desenvolvimento Científico e Tecnológico

The antiepileptic activity of JSTX-3 is mediated by N-methyl-D-aspartate receptors in human hippocampal neurons

We analyzed the effect of the acylpolyaminetoxin JSTX-3 on the epileptogenic discharges induced by perfusion of human hippocampal slices with artificial cerebrospinal fluid lacking Mg2+ or N-methyl-D-aspartate. Hippocampi were surgically removed from patients with refractory medial temporal lobe epilepsy, sliced in the surgical room and taken to the laboratory immersed in normal artificial cerebrospinal fluid. Epileptiform activity was induced by perfusion with Mg2+-free artificial cerebrospinal fluid or by iontophoretically applied N-methyl-D-aspartate and intracellular and field recordings of CAI neurons were performed. The ictal-like discharges induced by Mg2+-free artificial cerebrospinal fluid and N-methyl-D-aspartate were blocked by incubation with JSTX-3. This effect was similar to that obtained with the N-methyl-D-aspartate receptor antagonist DL(-)2-amino-5 phosphonovaleric acid. Our findings suggest that in human hippocampal neurons, the antiepileptic effect of JSTX-3 is mediated by its action on N-methyl-D-aspartate receptor.

Microsurgical Anatomy of the Optic Radiation and Related Fibers in 3-Dimensional Images

BACKGROUND: The fiber dissection technique provides unique 3-dimensional anatomic knowledge of the white matter. OBJECTIVE: To examine the optic radiation anatomy and its important relationship with the temporal stem and to discuss its findings in relation to the approaches to temporal lobe lesions. METHODS: We studied 40 cerebral hemispheres of 20 brains that had been fixed in formalin solution for 40 days. After removal of the arachnoid membrane, the hemispheres were frozen, and the Klingler technique was used for dissection under magnification. Stereoscopic 3-dimensional images of the dissection were obtained for illustration. RESULTS: The optic radiations are located deep within the superior and middle temporal gyri, always above the inferior temporal sulcus. The mean distance between the cortical surface and the lateral edge of the optic radiation was 21 mm. Its fibers are divided into 3 bundles after their origin. The mean distance between the anterior tip of the temporal horn and the Meyer loop was 4.5 mm, between the temporal pole and the anterior border of the Meyer loop was 28.4 mm, and between the limen insulae and the Meyer loop was 10.7 mm. The mean distance between the lateral geniculate body and the lateral margin of the central bundle of the optic radiation was 17.4 mm. CONCLUSION: The white matter fiber dissection reveals the tridimensional intrinsic architecture of the brain, and its knowledge regarding the temporal lobe is particularly important for the neurosurgeon, mostly because of the complexity of the optic radiation and related fibers.

Consequences of pilocarpine-induced status epilepticus in immunodeficient mice

Systemic injection of pilocarpine in rodents induces status epilepticus (SE) and reproduces the main characteristics of temporal lobe epilepsy (TLE). Different mechanisms are activated by SE contributing to cell death and immune system activation. We used BALB/c nude mice, a mutant that is severely immunocompromised, to characterize seizure pattern, neurochemical changes, cell death and c-Fos activation secondarily to pilocarpine-induced SE. The behavioral seizures were less severe in BALB/c nude than in BALB/c wild type mice. However, nude mice presented more tonic clonic episodes and higher mortality rate during SE. The c-Fos expression was most prominent in the caudate-putamen, CA3 (p < 0.05), dentate gyrus, entorhinal cortex (p < 0.001), basolateral nucleus of amygdala (p < 0.01) and piriform cortex (p < 0.05) of BALB/c nude mice than of BALB/c. Besides, nude mice subjected to SE presented high number of Fluorojade-B (FJB) stained cells in the piriform cortex, amygdala (p < 0.05) and hilus (p < 0.05) in comparison with BALB/c mice. A significant increase in the level of glutamate and GABA was found in the hippocampus and cortex of BALB/c mice presenting SE in comparison to controls. However, the level of glutamate was higher in the brains of BALB nude mice than in the brains of BALB/c wild type mice, while the levels of GABA were unchanged. These results indicate that the brains of immunodeficient nude mice are more vulnerable to the deleterious effects of pilocarpine-induced SE as they present intense activation, increased glutamate levels and more cell death. Published by Elsevier B.V.

Morphological Alterations in Newly Born Dentate Gyrus Granule Cells That Emerge after Status Epilepticus Contribute to Make Them Less Excitable

Computer simulations of external current stimulations of dentate gyrus granule cells of rats with Status Epilepticus induced by pilocarpine and control rats were used to evaluate whether morphological differences alone between these cells have an impact on their electrophysiological behavior. The cell models were constructed using morphological information from tridimensional reconstructions with Neurolucida software. To evaluate the effect of morphology differences alone, ion channel conductances, densities and distributions over the dendritic trees of dentate gyrus granule cells were the same for all models. External simulated currents were injected in randomly chosen dendrites belonging to one of three different areas of dentate gyrus granule cell molecular layer: inner molecular layer, medial molecular layer and outer molecular layer. Somatic membrane potentials were recorded to determine firing frequencies and inter-spike intervals. The results show that morphologically altered granule cells from pilocarpine-induced epileptic rats are less excitable than control cells, especially when they are stimulated in the inner molecular layer, which is the target area for mossy fibers that sprout after pilocarpine-induced cell degeneration. This suggests that morphological alterations may act as a protective mechanism to allow dentate gyrus granule cells to cope with the increase of stimulation caused by mossy fiber sprouting.

A critical and descriptive approach to interictal behavior with the Neurobehavior Inventory (NBI)

Purpose: The purpose of this study was to test the psychometric properties of the Neurobehavior Inventory (NBI) in a group of temporal lobe epilepsy (TLE) patients from a tertiary care center, correlating its scores with the presence of psychiatric symptoms. Methods: Clinical and sociodemographic data from ninety-six TLE outpatients were collected, and a neuropsychiatric evaluation was performed with the following instruments: Mini-Mental State Examination (MMSE), structured psychiatric interview (MINI-PLUS), Neurobehavior Inventory (NBI), and Hamilton Depression Rating Scale (HAM-D). Results: Some traits evaluated by the NBI showed adequate internal consistency (mean inter-item correlation between 0.2 and 0.4) and were frequent, such as religiosity (74%) and repetitiveness (60.4%). Principal component analysis showed three factors, named here as emotions (Factor 1), hyposexuality (Factor 2), and unusual ideas (Factor 3). Depressive symptoms on HAM-D showed a strong association with emotions and hyposexuality factors. When patients with left TLE and right TLE were compared, the former exhibited more sadness (p=0.017), and the latter, a greater tendency toward sense of personal destiny (p=0.028). Conclusion: Depression influences NBI scoring, mainly emotionality and hyposexuality traits. Neurobehavior Inventory subscales can be better interpreted with an appropriate evaluation of comorbid mood and anxiety disorders. Compromise in left temporal mesial structures is associated with increased tendency toward sad affect, whereas right temporal pathology is associated with increased beliefs in personal destiny. (C) 2012 Elsevier Inc. All rights reserved.