Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The resection of tumors within the primary motor cortex is a constant challenge. Although tractography may help in preoperative planning, it has limited application. While it can give valuable information on subcortical fibers, it is less accurate in the cortical layer of the brain. A 38-year-old patient presented with paresis of the right hand and focal epileptic seizures due to a tumor in the left precentral gyrus. Transcranial magnetic stimulation was not applicable due to seizures, so microsurgical resection was performed with preoperative tractography and intraoperative direct electrical stimulation. A histopathological assessment revealed a diagnosis of glioblastoma. Postoperative magnetic resonance imaging (MRI) showed complete resection. The paresis dissolved completely during follow-up. Surgery within the precentral gyrus is of high risk and requires multimodal functional planning. If interpreted with vigilance and consciousness of the underlying physical premises, tractography can provide helpful information within its limitations, which is especially subcortically. However, it may also help in the identification of functional cortex columns of the brain in the presence of a tumor.

Animals learn from past experience to guide future behavior and improve survival. This ability relies in part on specific episodic memories of past events encoded by neuronal activity and stored by updated connectivity between neurons. The unique architecture and activity of the hippocampus and related cortical regions are crucial for supporting these episodic memories. Hippocampal models propose the need for a pattern separation function to disambiguate similar memories and a pattern completion function to recall the full breadth of an experience from a partial cue. Past work suggests that neuronal activity in the dentate gyrus (DG) of hippocampus contributes to memory-guided navigation and plays a role in pattern separation. We tested the role of specific DG neuronal ensembles (i.e. engrams) in supporting the pattern separation function and altering downstream neural activity and, ultimately, behavior. To that end, we used an activity-dependent labeling paradigm to identify and manipulate engram ensembles during navigational and contextual fear conditioning (CFC) tasks. The results of our first experiment revealed that the DG partially disambiguates specific maze trajectories while still exhibiting greater overlap than chance levels. These findings suggest that the DG contributes to memory-guided navigation by both pattern separation and completion. Our second experiment manipulated nonspecific memory-related DG populations to assess the functional role of these cells in task generalization across contexts and ongoing spatial working memory. Optogenetic activation of these ensembles disrupted performance accuracy and exhibited a time-dependent impairment effect suggesting a role of the DG in task generalization between contexts. The final experiments investigated the physiological ramifications of artificial memory ensemble reactivation during ongoing navigation behavior. We recorded local field potential (LFP) and single unit responses in mouse DG and CA1 during artificial reactivation of a DG-mediated CFC memory engram. Stimulation of the DG entrained LFP and individual cell spiking in a subpopulation of CA1 pyramidal cells. Their spatial information was disrupted by stimulation despite stable navigational representation before and after the manipulation. Further, the presence of stimulation could be reliably decoded by the firing rate of the network, suggesting that engram reactivation forced the CA1 to adopt a repeatable state, perhaps to support behavioral expression of memories. In summary, my dissertation work presents empirical and theoretical evidence for the role of the dentate gyrus as a single node of an extended separation/completion circuit distributed anatomically and temporally as a neural mechanism supporting episodic memory.

The main aim of this dissertation was to investigate the difference in neural language patternsrelated to language ability in healthy adults. The focus lies on unraveling the contributions of theright‐hemispheric homologues to Broca’s area in the inferior frontal gyrus (IFG) and Wernicke’s areain the posterior temporal and inferior parietal lobes. The functions of these regions are far from fullyunderstood at present. Two study populations consisting of healthy adults and a small group ofpeople with generalized epilepsy were investigated. Individual performance scores in tests oflanguage ability were correlated with brain activation obtained with functional magnetic resonanceimaging during semantic and word fluency tasks. Performance‐dependent differences were expectedin the left‐hemispheric Broca’s and Wernicke’s area and in their right‐hemispheric counterparts. PAPER I revealed a shift in laterality towards right‐hemispheric IFG and posterior temporal lobeactivation, related to high semantic performance. The whole‐brain analysis results of PAPER IIrevealed numerous candidate regions for language ability modulation. PAPER II also confirmed thefinding of PAPER I, by showing several performance‐dependent regions in the right‐hemispheric IFGand the posterior temporal lobe. In PAPER III, a new study population of healthy adults was tested.Again, the right posterior temporal lobe was related to high semantic performance. A decrease in lefthemisphericIFG activation could be linked to high word fluency ability. In addition, task difficultywas modulated. Increased task complexity showed to correlate positively with bilateral IFGactivation. Lastly, PAPER IV investigated anti‐correlated regions. These regions are commonly knownas the default mode network (DMN) and are normally suppressed during cognitive tasks. It wasfound that people with generalized epilepsy had an inadequate suppression of regions in the DMN,and showed poorer performance in a complex language test. The results point to neural adaptabilityin the IFG and temporal lobe. Decreased left‐lateralization of the IFG and increased rightlateralizationof the posterior temporal lobe are proposed as characteristics of individuals with highlanguage ability.

Following traumatic brain injury (TBI), the hippocampus is particularly vulnerable to damage, and BDNF, an endogenous neurotrophin that activates the TrkB receptor, has been shown to play a key role in the brain’s neuroprotective response. Activation of the TrkB signaling pathway by BDNF in the CNS promotes cell survival and aids in cell growth. However, due to its inability to cross the blood brain barrier (BBB), the therapeutic advantages of BDNF treatment following TBI are limited. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid that mimics the effects of BDNF, is a potent TrkB receptor agonist, and can successfully cross the BBB. Our lab has previously demonstrated that administration of 7,8-DHF post-TBI results in improved cognitive functional recovery, increased neuronal survival, and reduced lesion volume. The current study examined the effects of 7,8-DHF on neurogenesis and neuronal migration in the dentate gyrus following TBI. In this study, adult male Sprague-Dawley rats were subjected to moderate controlled cortical impact injury (CCI) or sham surgery. Injured animals received 5 daily single doses of 7,8-DHF treatment (i.p) or vehicle starting either 60 mins after injury or 2 days after injury. BrdU was administered in 3 doses at 2 days post-injury for animals sacrificed at day 15, and single daily doses at days 1-7 post-injury for animals sacrificed at day 28 to label cell proliferation. Animals were sacrificed at 15 days or 28 days post-injury to examine cell proliferation, generation of new neurons, and differentiation of newly generated cells using proliferation marker Ki67, immature neuronal marker DCX, and BrdU double-labeling with markers for mature neurons (NeuN), astrocytes (GFAP) and microglia (Iba1). We found that administration of 5 doses (5mg/kg) of 7,8-DHF beginning two days post-injury had the strongest effect on neurogenesis and migration, but did not have a significant prolonged effect on cell proliferation at 15 days post-injury. We also found that 7,8-DHF treatment given early or 2 days post-TBI did not affect the neuronal differentiation in the granule cell layer. However, a higher percentage of BrdU/GFAP+ and BrdU/IBa1+ cells were found in the hilus regions in 7,8-DHF treated animals, suggesting newly generated cells in this region are mostly glial cell types. Our results suggest that 7,8-DHF has neurotrophic-like therapeutic effects following injury, and due to increased neurogenesis (compared to injured animals treated with vehicle), may effectively contribute to greater cell survival long-term. Additionally, potential long-term survival coupled with increased outward migration from the subgranular zone may result in increased integration of newly formed neurons into existing hippocampal circuitry, further contributing to cognitive recovery.

Introdução: A esclerose mesial temporal é causa frequente das síndromes epilépticas focais. A ressecação cirúrgica das estruturas mesiais temporais é a melhor opção para seu tratamento. Objetivo: Apresentar uma técnica operatória para tratar a epilepsia temporal e os resultados da intervenção Casuística e Métodos: Estudo prospectivo envolvendo 120 doentes operados por um único neurocirurgião e em uma única instituição de saúde de 2006 a 2012 com a aplicação da técnica de amígdalo-hipocampectomia transtemporal com acesso mínimo (key-hole). Cinquenta e cinco por cento dos doentes era do sexo masculino. A cirurgia foi realizada à direita em 85% dos doentes. Resultados: As primeiras 70 cirurgias duraram, em média, 2,51 horas e as últimas 50 cirurgias 1,62 horas. Ocorreram complicações em 3,3% dos doentes operados. Cinco por cento dos doentes apresentou atrofia discreta do músculo temporal. De acordo com a Escala de Engel, no segundo ano do período pós-operatório, 71% dos doentes foram classificados como Classe I, 21%, como Classe II, e 6%, como Classe III. Conclusão: A técnica descrita é viável, reprodutível, segura e proporciona resultados satisfatórios / Introduction: Temporal mesial sclerosis is a frequent cause of focal epilepsy. Surgical resection of the mesial temporal structures considered an effective method for its treatment. Objective: To describe a new operative technique for treatment of temporal epilepsy and the results of the procedure. Methods: prospective case-series in a single institution, by the same surgeon, from 2006 to 2012 envolving 120 patients underwent a minimally invasive keyhole transtemporal amygdalohippocampectomy. 55% of the patients were male and the operation was performed at the right side in 85% of them. Results: The first 70 surgeries had a mean surgical time of 2.51 hours, and the last 50 surgeries 1.62 hours. The morbidity rate was 3.3%. Mild temporal muscle atrophy was observed in 5% of the patients. At the second year follow-up 71% of the patients were classified according the Engel Outcome Scale as, Class I, 21%, as Class II and 6% as Class III. Conclusion: This new technique is feasible and reproducible and the clinical results were satisfactory

INTRODUÇÃO: O teste de fluência verbal fonológica é uma tarefa neuropsicológica amplamente utilizada em estudos de neuroimagem funcional que analisam os circuitos neurais relevantes para a produção de linguagem. A maioria dos estudos que utilizam a RMf para analisar as áreas cerebrais de maior ativação durante a tarefa de fluência verbal é realizado na língua inglesa. Embora estudos anteriores tenham demonstrado que dependendo da língua falada possa ocorrer diferença de desempenho na tarefa de fluência verbal, ainda não está claro se esta diferença leva a mudanças do padrão de ativação cerebral. Há indícios na literatura que a ativação cerebral regional durante a tarefa de fluência verbal pode variar com o aumento de dificuldade da tarefa, sendo o cíngulo anterior a área cerebral que parece estar envolvida no processo de adaptação ao grau de dificuldade da tarefa. Estudos com sujeitos saudáveis demonstram também a influência de variáveis demográficas, como idade, escolaridade, gênero e classificação socioeconômica no desempenho na produção de palavras, com alguns estudos reportando maior ativação cortical nos homens em comparação às mulheres. OBJETIVOS: Avaliar os efeitos da variação do grau de dificuldade da tarefa de fluência verbal utilizando a técnica de ressonância magnética funcional. Analisar se há correlação entre os dados demográficos e o desempenho na tarefa de fluência verbal. Comparar o padrão de ativação cerebral entre os gêneros. MÉTODOS: Foram incluídos 21 voluntários saudáveis (12 homens), destros e falantes do português do Brasil como primeira língua. Foram colhidos dados sociodemográficos, neuropsicológicos e de desempenho dos voluntários. Comparamos os achados adquiridos através da técnica de ressonância magnética funcional durante a produção de palavras iniciadas com letras classificadas anteriormente como fáceis e difíceis para produzir palavras na língua portuguesa. As imagens foram adquiridas em aparelho de ressonância magnética de 1,5 T através de uma sequência de aquisição de imagens compressed epi que permite aos sujeitos produzirem as palavras apenas durante o período de silêncio do equipamento. As imagens foram analisadas através do software XBAM para os grupos e para a análise de correlação comportamental. RESULTADOS: A tarefa de fluência verbal engajou circuitos cerebrais incluindo córtex frontal medial e inferior esquerdo, putamen e tálamo (p<0,001). O aumento de dificuldade da tarefa de fluência verbal fonológica na língua portuguesa mostrou-se associado a uma diferença significativa de ativação apenas em uma região cerebral, o cerebelo (maior ativação durante a tarefa realizada com letras mais fáceis). Houve correlações significativas entre o desempenho na tarefa de fluência verbal fonológica na língua portuguesa e o grau de ativação do cíngulo anterior quando foram usadas letras difíceis para produção de palavras, mas não com letras fáceis. Não houve correlação significativa entre os dados demográficos (idade, escolaridade, gênero e classificação socioeconômica) e o desempenho durante a produção de palavras iniciadas com letras fáceis e com letras difíceis. Observamos maior ativação de cíngulo posterior e giro lingual nas mulheres em comparação aos homens durante a produção de palavras iniciadas com letras difíceis e interação positiva entre os gêneros e os graus de dificuldade na região de cíngulo anterior, demonstrando maior ativação do cíngulo anterior nos homens durante a produção de palavras iniciadas com letras difíceis. CONCLUSÃO: Apesar das diferenças lingüísticas, o padrão de ativação cerebral encontrado no nosso estudo foi consistente com o padrão verificado em outras línguas, com recrutamento de múltiplas áreas cerebrais durante a produção de palavras. Na língua portuguesa, assim como na língua inglesa, há indícios de que o aumento de dificuldade da tarefa está associado com maior engajamento de cíngulo anterior. Houve diferenças entre os gêneros em termos do engajamento de áreas cerebrais consideradas críticas para o desempenho na tarefa de fluência verbal fonológica, particularmente no cíngulo anterior / INTRODUCTION: Phonological verbal fluency is a neuropsychological test used in numerous functional neuroimaging studies to allow the assessment of the neural circuits relevant to language production. The majority of studies that use functional magnetic resonance imaging (fMRI) to analyze the cerebral areas with greater activation during the verbal fluency task have been carried out in English. Although there is evidence that the verbal fluency performance varies as a function of the spoken language, it is unclear if this difference is associated with differences in cerebral activation patterns. Added to that, there is neuroimaging evidence that patterns of regional cerebral activation during VF task may vary with task demand. In particular, the anterior cingulate cortex seems critical to the adaptation process to the level of difficult. Studies of healthy individuals have demonstrated the influence of demographic variables, such as age, level of education, gender and socio-economic status, on word production performance, and some authors have shown greater cortical activation in men than in women. OBJECTIVES: To use the fMRI technique to evaluate the effect of varying levels of difficult of verbal fluency task on the brain activation patterns in healthy subjects. To analyze whether there is a significant correlation between demographic variables and verbal fluency performance. To compare cerebral activation patterns between genders. METHODS: We recruited 21 (12 men) right-handed healthy volunteers, having Portuguese as their first language. Demographic, neuropsychological and behavioral data were collected. We compared fMRI data acquired during production of words beginning with letters classified as easy or hard for word production in Portuguese. Images were acquired in 1,5 T magnet through a clustered image acquisition sequence that allowed overt verbal responses to be made in the absence of scanner noise. Data were analyzed through XBAM software on group basis and for behavioral correlation. RESULTS: The phonological verbal fluency task engaged a network including the left inferior and middle frontal cortices, putamen and thalamus (p<0.001). The hard condition was associated with greater anterior cingulate activation than the easy condition when associated with the performance, as previously demonstrated in studies carried out with English speaking subjects. Increased phonological verbal fluency task demand in Portuguese was associated with activation differences in only one brain region, namely the cerebellum (in the direction of greater activation during performance of the task with easy letters). There were significant correlations between phonological verbal fluency task performance in Portuguese and the intensity of anterior cingulate activation, when hard letters to produce words were used (but not with easy letters). There were no significant correlations between demographic variables and the performance during production of words beginning with easy or difficult letters. There was greater activation of the posterior cingulate cortex during the production of words beginning with the difficult letters in women than in men. There was also a significantly positive interaction between gender and level of difficult in anterior cingulate cortex, with men showing greater activation of this brain region during the word production beginning with difficult letters relative to women. CONCLUSIONS: Despite grammatical differences, the patterns of cortical activations observed in our study were in accordance with fMRI studies of phonological verbal fluency task carried out in other languages, with recruitment of a set of distributed cerebral areas during the word production. There is evidence that increased task demand is associated with greater engagement of the anterior cingulate cortex in Portuguese, similarly to the patterns previously observed in English. There were gender differences in regard to the engagement of brain regions seen as critical to verbal fluency performance, particularly in the anterior cingulate cortex

Every year over 2.5 million traumatic brain injuries (TBI) occur and are the leading cause of death and disability among adolescents. There are no approved treatments for TBI. Survivors suffer from persistent cognitive impairment due to posttraumatic tissue damage and disruption of neural networks which significantly detract from their quality of life. Posttraumatic cognitive impairment depends in part on the brain's limited ability to repair or replace damaged cells. Immature neurons in the hippocampus dentate gyrus, a brain region required for learning and memory, are particularly vulnerable to TBI. Insulin-like growth factor-1 (IGF1) is a potential therapeutic for TBI because it is a potent neurotrophic factor capable of mediating neuroprotection, neuro-repair, and neurogenesis. We hypothesized that conditional IGF1 overexpression in the mouse hippocampus following experimental controlled cortical impact injury (CCI) would enhance posttraumatic neurogenesis chronically. To this end, conditional astrocyte-specific IGF1 overexpressing mice (IGFtg) and wild-type (WT) mice received CCI or sham injury. The proliferation marker BrdU was used to label neurons born the first week after injury. Six weeks after injury, when surviving posttrauma-born neurons would be fully developed, we counted proliferated cells (BrdU+) and the subset expressing a mature neuronal marker (NeuN+/BrdU+) in the hippocampus. We also assessed cognitive performance during radial arm water-maze reversal (RAWM-R) testing, a neurogenesis-sensitive assay. IGF1 promoted end-stage maturity and decreased mis-migration of neurons born after trauma. These effects coincide with IGF1 induced improvements in performance on neurogenesis sensitive cognition following TBI. Mammalian target of rapamycin (mTOR), an early signaling molecule downstream of IGF1, has been identified as a potential target for TBI interventions because of its regulatory role in neuronal plasticity and neurogenesis. However, recent studies have also reported maladaptive plasticity and recovery associated with posttraumatic mTOR activation. It is imperative to elucidate the mechanism of action of IGF1 during pre-clinical evaluations. We hypothesized that IGF1 mediates posttraumatic neurogenic effects through IGF1 induction of mTOR activation. We injured cohorts of IGFtg and WT mice and harvested their brains for immunohistochemistry to assess IGF1 overexpression effects on posttraumatic mTOR activation at 1, 3, and 10 days post-injury (dpi). We found that IGF1 upregulated mTOR activation following TBI in a region-specific manner at 1 and 3dpi. To determine if IGF1 regulated differentiation and arborization through the mTOR pathway, injured WT and IGFtg mice received daily i.p. injections of rapamycin (10mg/kg), the inhibitor of mTOR, or its vehicle for 7 days. Vehicle and rapamycin administration began 3dpi, after the cells dividing at the peak of posttraumatic proliferation were labeled with BrdU. IGF1 enhancement of posttraumatic neurogenesis was not dependent on mTOR activation. In summary, IGF1 directs newborn neuron localization, promotes end-stage maturation, and chronically improves cognition. IGF1 can stimulate posttraumatic neurogenesis and plasticity independent of mTOR activation. These data suggest that IGF1 can stimulate neuron replacement following trauma-induced hippocampal neuron loss and cognitive improvement. Further studies should investigate IGF1 and mTOR inhibition as a combination therapy for neurorehabilitation.

Goal-directed behavior is based on representations of contingencies between a certain situation (S), a certain (re)action (R) and a certain outcome (O). These S-R-O representations enable flexible response selection in different situations according to the currently pursued goal. Importantly however, the successful formation of such representations is a necessary but not sufficient precondition for goal-directed behavior which additionally requires the actual usage of the contingency information for action control. The present fMRI study aimed at identifying the neural basis of each of these two aspects: representing vs. explicitly using experienced S-R-O contingencies. To this end, we created three experimental conditions: S-R-O contingency present and used for outcome-based response selection, S-R-O contingency present but not used, and S-R-O contingency absent. The comparison between conditions with and without S-R-O contingency revealed that the angular gyrus is relevant for representing S-R-O contingencies. The explicit usage of learnt S-R-O representations in turn was associated with increased functional coupling between angular gyrus and several subcortical (hippocampus, caudate head), prefrontal (lateral orbitofrontal cortex (OFC), rostrolateral prefrontal cortex (RLPFC)) and cerebellar areas, which we suggest represent different explicit and implicit processes of goal-directed action control. Hence, we ascribe a central role to the angular gyrus in associating actions to their sensory outcomes which is used to guide behavior through coupling of the angular gyrus with multiple areas related to different aspects of action control.

Only 200 years ago, virtually nothing was known about the biological workings of the mind. Today, there is a deep (though far from complete) understanding of the cellular and molecular mechanisms underlying the encoding of memory, arguably the most fundamental aspect of a cognitive being. In this thesis, I describe experiments that help complete this understanding and identify the very first molecules underlying curiosity. By using an inducible rtTA2-M2 double transgenic system to selectively overexpress the calcium sensor Ncs1 in the adult murine dentate gyrus, I created an animal with facilitated long-term potentiation, enhanced rapid acquisition of spatial memory and greater curiosity. These phenotypes are reversed by direct infusion of a small membrane-permeant interfering peptide designed to block complex formation between NCS-1 and Dopamine type-2 receptors (D2 receptors). Pharmacological antagonism of D2 receptors also attenuates plasticity in wild-type mice and direct antagonism of D2 receptors in the dentate of cannulized wild-type mice prevents spatial memory formation. Conversely, application of a dominant negative NCS-1 peptide reduces synaptic transmission in the dentate gyrus and impairs spatial fear learning. Far less understood than the mechanisms governing learning and memory, are the mechanisms used by the brain to generate curiosity. Strikingly, Ncs1 overexpressing mice also demonstrate increased exploratory behaviours in a variety of novel, non-fearful environments. But they do not explore novel fearful environments any more than their littermate controls. I argue that the specificity of this phenotype represents an effect on curiosity, thereby identifying NCS-1 and D2 receptors as the first known regulators of this primordial mental state. I propose that the generation of curiosity is a fundamental feature of the nervous system and is upstream of learning and cognition. As such, molecular cascades involved in curiosity likely also play roles in mental illnesses. To investigate this theory, I generated an NCS-1 point mutant mouse line. NCS-1P144S/P144S mice show endophenotypes of schizophrenia and depression, supporting the link between curiosity and mental illness. I integrate my findings with the current literature and propose a means to investigate the role of NCS-1 in humans with mental illnesses.