Le trouble obsessionnel-compulsif (TOC) est un trouble anxieux fréquent et invalidant. Pour un grand nombre de patients, il existe une résistance aux thérapeutiques actuellement disponibles, soulignant toute l'importance de mieux préciser la physiopathologie du TOC. Le principal objectif de cette thèse est d’étudier les altérations anatomiques et fonctionnelles des voies thalamo-corticales intéressant le cortex orbitofrontal (COF) et le cortex cingulaire antérieur (CCA) dans le TOC. Pour cela, nous avons utilisé plusieurs outils complémentaires permettant d’appréhender cette problématique sous différents angles méthodologiques.Concernant les altérations anatomiques associées au TOC, nous avons rapporté les données de méta-analyses des études de neuro-imagerie volumétrique et morphométrique ainsi que les résultats d'une étude originale d'imagerie volumétrique. Une diminution du volume orbitofrontal, une augmentation du volume thalamique et une relation entre ces modifications de volumes ont été observées chez les patients avec TOC comparativement aux témoins. Les modifications de densité de matière grise concernaient le COF et le putamen dans le sens d'une augmentation et les cortex pariétal et préfrontal dorsolatéral dans le sens d'une diminution dans le TOC.Concernant les altérations fonctionnelles associées au TOC, nous avons détaillé un travail de méta-analyse des études d'imagerie fonctionnelle, un travail expérimental chez le primate basé sur des manipulations pharmacologiques intra-cérébrales, puis un travail expérimental chez l'homme reposant sur le développement d'une tâche comportementale originale couplée à l'imagerie fonctionnelle. Dans notre méta-analyse, nous avons décrit la participation fonctionnelle de régions comme le COF, le thalamus et le striatum lorsque des symptômes obsessionnels et compulsifs étaient provoqués chez des patients. Chez le primate subhumain, nous avons montré qu'une hyperactivation du noyau ventral-antérieur, par levée de l'inhibition GABAergique, entraînait l'apparition de comportements pseudo-compulsifs. Ensuite, à l'aide d'une tâche originale qui mettait les sujets en situation de vérifier, nous avons mis en évidence que les dysfonctions orbitofrontales associées au doute lors de la prise de décision n'étaient pas modulées ni par les informations contextuelles (signaux d'erreur), ni par la réponse comportementale chez les patients avec TOC comparativement à des sujets témoins.Enfin, la superposition des cartes morphométriques et fonctionnelles a trouvé une relation entre les altérations anatomiques et fonctionnelles au sein du COF. Nos résultats soulignent toute l'importance des voies thalamo-orbitofrontales dans la physiopathologie du TOC. / Obsessive-compulsive disorder (OCD) is a frequent and disabling anxiety disorder. Available treatments are effective for most patients but impairing residual symptoms and treatment resistance are common in OCD patients. Therefore, a better understanding of OCD pathophysiology is essential for further improvement of therapeutic strategies. The main goal of my thesis was to assess the anatomical and funtional thalamocortical alterations associated with OCD. Concerning the anatomical thalamocortical alterations associated with OCD, we conducted two meta-analyses of anatomical neuroimaging studies and an original volumetric neuroimaging study. We reported a smaller thalamic volume and a greater orbitofrontal volume, but also an inverse relationship between the volume changes in OCD patients compared with healthy subjects. Furthermore, we showed that gray matter density within the orbitofrontal cortex and the putamen were enhanced in OCD. Concerning the functional thalamocortical alterations associated with OCD, we reported data coming from a meta-analysis of functional neuroimaging studies, an experimental study in subhuman primates using local brain pharmacological manipulations and an event-related neuroimaging study in OCD patients. In our meta-analysis, we showed that the orbitofrontal cortex, the thalamus and the striatum were involved in the mediation of OCD symptoms. In subhuman primates, the pharmacologically induced overactivity within the ventralanterior thalamic nucleus leaded to the emergence of compulsive-like behaviors. Then, in our neuroimaging study, we found that doubt-related orbitofrontal dysfunctions were not modulated by neither error signals nor compulsive-like behaviors in OCD patients, compared with healthy subjects. Finally, we described by using meta-analytic data that anatomical and functional brain alterations overlap with the lateral orbitofrontal cortex in OCD. In conclusion, our results suggest that the thalamo-orbitofrontal network may play a primary role in the genesis and mediation of OCD symptoms.

Can the brain register the emotional valence of brief exposures of complex natural stimuli under conditions of forward and backward masking, and under conditions of attentional competition between foveal and peripheral stimuli? To address this question, three experiments were conducted. The first, a behavioural experiment, measured subjective valence of response (pleasant vs unpleasant) to test the perception of the valence of natural images in brief, masked exposures in a forward and backward masking paradigm. Images were chosen from the International Affective Picture System (IAPS) series. After correction for response bias, responses to the majority of target stimuli were concordant with the IAPS ratings at better than chance, even when the presence of the target was undetected. Using functional magnetic resonance imaging (fMRI), the effects of IAPS valence and stimulus category were objectively measured on nine regions of interest (ROIs) using the same strict temporal restrictions in a similar masking design. Evidence of affective processing close to or below conscious threshold was apparent in some of the ROIs. To further this line of enquiry, a second fMRI experiment mapping the same ROIs and using the same stimuli were presented in a foveal (‘attended’) peripheral (‘to-be-ignored’) paradigm (small image superimposed in the centre of a large image of the same category, but opposite valence) to investigate spatial parameters and limitations of attention. Results are interpreted as showing both valence and category specific effects of ‘to-be-ignored’ images in the periphery. These results are discussed in light of theories of the limitations of attentional capacity and the speed in which we process natural images, providing new evidence of the breadth of variety in the types of affective visual stimuli we are able to process close to the threshold of conscious perception.

As teorias mais influentes acerca do funcionamento do córtex pré-frontal (PFC) tomam essa estrutura como um córtex de associação e de integração de informações oriundas de outras estruturas nervosas. Isso implicaria na participação direta do PFC nos processos de memória operacional e em processo atencionais. Estudos hodológicos e neurofisiológicos sugerem, que o córtex orbitofrontal (OFC) seria responsável pela integração de informações de caráter sensorial, motivacional e afetivo, enquanto o córtex pré-frontal ventromedial (vmPFC) seria diretamente ligado ao OFC, tendo um papel crucial na codificação de estímulos emocionais oriundos da amígdala. Nesse contexto, é aceito que a integração das informações feita por essas estruturas seja essencial para o processo de tomada de decisões, uma vez que esse comportamento necessita de uma avaliação do ambiente em termos de comparações de situações novas a experiências prévias armazenadas na memória, assim como um balanço entre custos, benefícios e cálculo de possíveis valores da recompensa. Para testar essas hipóteses, ratos com danos seletivos no vmPFC foram submetidos testes de avaliação de ansiedade e medo condicionado no paradigma de teste e reteste no labirinto em cruz elevado (LCE), assim como a testes de memória de referência espacial e memória operacional no labirinto aquático de Morris. Outro grupo de animais teve matrizes de multi-eletrodos implantadas no OFC para a avaliação da atividade neuronal dessa estrutura em um teste envolvendo tomada de decisões, no qual devem escolher entre ganhar 1 pellet de chocolate imediatamente ou 4 pellets envolvendo atrasos variados. No teste no LCE, animais com lesão no vmPFC diferem dos animais controle por apresentarem uma diminuição do tempo de avaliação de risco sem apresentar alterações nos parâmetros que aferem memória, atividade locomotora e ansiedade. No teste de memória de referência espacial após treinamento extensivo de busca pela plataforma em um mesmo local no labirinto aquático, animais com lesão persistem no local quando se retira a plataforma (probe test). Já no teste de memória operacional, no qual a localização da plataforma é alterada diariamente, esses animais não diferem do grupo controle. Na tarefa envolvendo tomada de decisões, observou-se uma atividade eletrofisiológica de neurônios do OFC relacionada ao momento crítico no qual o animal deve realizar uma escolha. Em conjunto, esses resultados mostram que o vmPFC está relacionado à flexibilidade comportamental e tomada de decisões, possivelmente em conjunto com o OFC, cuja atividade neuronal sugere uma participação nos processos de tomada de decisões e de elaboração de estratégias / The most influential theories on the function of the prefrontal cortex (PFC) suggest that this structure is an association cortex, responsible for integration of information received from other parts of the brain. This would implicate in direct participation of the PFC in working memory and attentional processes. Given this context, hodological and neurophysiological studies suggest that the orbitofrontal cortex (OFC) would be responsible for the integration of sensory, motivational and affective aspects, while the ventromedial prefrontal cortex (vmPFC), which is directly connected to the OFC, would have a key role in encoding emotional stimuli from the amygdala. It is well accepted that the processing of these aspects of information is crucial for decision-making processes, given the fact that this expression of behavior requires an evaluation of the environment in terms of comparing novel situation to previous experiences, as well as processing the balance between costs, outcomes and reward values. In order to test these hypotheses, rats with selective lesions to the vmPFC were subjected to the elevated plus maze (EPM) to evaluate anxiety and conditioned fear in the test retest paradigm. Animal were also tested in a spatial reference memory and a working memory tasks in the Morris water maze. Another group of rats had multi-electrode arrays chronically implanted in the OFC for the evaluation of the neuronal activity during a decision-making task, in which the animals had to choose between a small reward of one chocolate pellet immediately and a large reward of four chocolate pellets after varying delays. The results of the EPM show that animals with lesion to the vmPFC differ from control animals by showing diminished time evaluating risk in the second exposure to the EPM, without damage to locomotor activity, memory and anxiety levels. In the reference spatial memory task in the water maze, after extensive training searching for the hidden platform in the same location, lesioned animals persisted searching for the platform in that particular location after it was removed (probe test). However, in the working memory task, in which the platform is presented in a different location each day, lesioned animals did not differ from control animals. In the decision-making task, differential electrophysiological activity in OFC neurons was observed, particularly in the moment of the task in which the animal was required to perform the choice between rewards. Together, these results suggest that the vmPFC is related to behavioral flexibility and decision-making, possibly acting together with the OFC, which neuronal activity suggests participation in decision-making processes

Les Troubles Obsessionnels et Compulsifs (TOC) sont un trouble mental sévère et fréquemment résistant. La physiopathologie du trouble se caractérise par des anomalies au sein des boucle cortico-striato-thalamo-cortical entrainant une hyper-activité du cortex orbito-frontal, du cortex cingulaire antérieur, du putamen. Au cours des dernières années, des anomalies structurales et fonctionnelles du cervelet ont de plus été mise en évidence dans les TOC venant compléter le modèle existant.Nous avons mise au point un protocole de traitement par tDCS ciblant le cortex orbito-frontal gauche et le cervelet droit pour les TOC résistants. Dans une première étude, nous avons étudié la faisabilité de ce protocole de traitement dans une étude ouverte. Cette étude a mis en évidence une réduction significative des symptômes dans une population de patient à haut niveau de résistance. Dans une deuxième étude, nous avons évaluer l’effet de ce traitement dans un protocole randomisé, contrôlé et parallèle contre placebo. Cette étude n’a pas confirmé l’efficacité de ce protocole de traitement. Dans cette même population, nous avons au cours du protocole mesuré les paramètres d’excitabilité corticale au niveau du cortex moteur par stimulation magnétique transrânienne. Nous avons ainsi mis en évidence que la tDCS provoquait une augmentation significative des processus d’inhibition (Short Interval Cortical Inhibition : SICI ) et une diminution non significative des processus de facilitation (Intra Cortical Facilitation : ICF). L’étude des effets cliniques et électro-physiologiques de cette approche thérapeutique novatrice dans les TOC résistants n’a pas permis de confirmer son intérêt clinique malgré un impact de ce protocole sur les modifications de l’excitabilité corticale inhérentes aux troubles. Ces données ont été mise en relation avec la littérature afin de proposer des perspectives d’évolution dans l’utilisation de la tDCS dans les TOC résistants / Obsessive-compulsive disorder (OCD) is a severe mental illness. OCD symptoms are often resistant to available treatments. Neurobiological models of OCD are based on an imbalance between the direct (excitatory) and indirect (inhibitory) pathway within this cortico-striato-thalamo-cortical loops, which causes hyperactivation in the orbito-frontal cortex, the cingular anterior cortex, the putamen. More recently, the role of cerebellum in the OCD physiopathology has been brought to light by studies showing structural and functional abnormalities. We proposed to use tDCS as a therapeutic tool for resistant OCD by targeting the hyperactive left orbito-frontal cortex with cathodal tDCS (assumed to decrease cortical excitability) coupled with anodal cerebellar tDCS. In a first study, we studied the feasibility of this treatment protocol in an open-trial. This study found a significant reduction in symptoms in a population with a high level of resistance. In a second study, we evaluated the effect of this treatment in a randomized-controlled trial. This study did not confirm the effectiveness of this intervention. We have assessed motor cortex cortical excitability parameters by transcranial magnetic stimulation. We thus demonstrated that the tDCS caused a significant increase of inhibition processes (Short Interval Cortical Inhibition: SICI) and a nonsignificant decrease in the facilitation processes (Intra Cortical Facilitation (ICF)). In addition, clinical improvement assessed by Clinical Global Impression at the end of the follow-up period (3 months) was positively correlated with SICI at baseline.tDCS with the cathode placed over the left OFC combined with the anode placed over the right cerebellum decreased hyper-excitability in the motor cortex but was not significantly effective in SSRI- resistant OCD patients. These works were discussed in light of the available literature to create future prospect in the field of tDCS treatment for OCD resistant patients

Drug-specific reward and associated effects on neural signaling are often studied between subjects, where one group self-administers drug and a separate group self-administers a natural reinforcer. However, exposure to drugs of abuse can cause long-term neural adaptations that can affect how an organism responds to drug reward, natural reward, and their reward-associated stimuli. Thus, to isolate drug-specific effects it is important to use models that expose the same organism to all of the aforementioned. Multiple schedules provide a means of dissociating the rewarding effects of a drug from the rewarding effects of food within a single animal. Further, drug users do not take drugs in isolation; rather, they are often faced with several concurrently available commodities (e.g. monetary goods, social relationships). Thus, using choice measures to assess the relative subjective value of drug reinforcers in both humans and animals promotes a translational understanding of mechanisms that govern drug-associated decision-making. Thus, in order to gain a more translational view of the neurobehavioral mechanisms that underlie drug-associated behavior, in the first study, glutamate was measured in the nucleus accumbens core (NAcC) and prefrontal cortex (PrL) in freely-moving rats as they behaved in a cocaine-food multiple schedule procedure. In the second study, oxygen dynamics were measured in the orbitofrontal cortex (OFC) of freely-moving rats as they behaved in a cocaine/food choice procedure. The results from the first study showed that, in the NAc and PrL, there was an increase in glutamate release when animals earned cocaine. Further, the number of glutamate peaks that occurred per cocaine lever press and per cocaine reinforcer was increased compared to food. In the second study, OFC oxygen dynamics were positively correlated with cocaine/food choice and generally tracked preference. Further, OFC oxygen dynamics were greater to cocaine related events. Taken together, these results showed the feasibility of combining electrochemical measurements with complex drug-related behavioral procedures. These results also highlight the importance of the PrL, NAcC, and OFC in the valuation of drug and non-drug commodities. Overall, these results add to our understanding of the neurobehavioral mechanisms that guide drug-associated behavior and create more precise experimental avenues to research potential treatments.

As teorias mais influentes acerca do funcionamento do córtex pré-frontal (PFC) tomam essa estrutura como um córtex de associação e de integração de informações oriundas de outras estruturas nervosas. Isso implicaria na participação direta do PFC nos processos de memória operacional e em processo atencionais. Estudos hodológicos e neurofisiológicos sugerem, que o córtex orbitofrontal (OFC) seria responsável pela integração de informações de caráter sensorial, motivacional e afetivo, enquanto o córtex pré-frontal ventromedial (vmPFC) seria diretamente ligado ao OFC, tendo um papel crucial na codificação de estímulos emocionais oriundos da amígdala. Nesse contexto, é aceito que a integração das informações feita por essas estruturas seja essencial para o processo de tomada de decisões, uma vez que esse comportamento necessita de uma avaliação do ambiente em termos de comparações de situações novas a experiências prévias armazenadas na memória, assim como um balanço entre custos, benefícios e cálculo de possíveis valores da recompensa. Para testar essas hipóteses, ratos com danos seletivos no vmPFC foram submetidos testes de avaliação de ansiedade e medo condicionado no paradigma de teste e reteste no labirinto em cruz elevado (LCE), assim como a testes de memória de referência espacial e memória operacional no labirinto aquático de Morris. Outro grupo de animais teve matrizes de multi-eletrodos implantadas no OFC para a avaliação da atividade neuronal dessa estrutura em um teste envolvendo tomada de decisões, no qual devem escolher entre ganhar 1 pellet de chocolate imediatamente ou 4 pellets envolvendo atrasos variados. No teste no LCE, animais com lesão no vmPFC diferem dos animais controle por apresentarem uma diminuição do tempo de avaliação de risco sem apresentar alterações nos parâmetros que aferem memória, atividade locomotora e ansiedade. No teste de memória de referência espacial após treinamento extensivo de busca pela plataforma em um mesmo local no labirinto aquático, animais com lesão persistem no local quando se retira a plataforma (probe test). Já no teste de memória operacional, no qual a localização da plataforma é alterada diariamente, esses animais não diferem do grupo controle. Na tarefa envolvendo tomada de decisões, observou-se uma atividade eletrofisiológica de neurônios do OFC relacionada ao momento crítico no qual o animal deve realizar uma escolha. Em conjunto, esses resultados mostram que o vmPFC está relacionado à flexibilidade comportamental e tomada de decisões, possivelmente em conjunto com o OFC, cuja atividade neuronal sugere uma participação nos processos de tomada de decisões e de elaboração de estratégias / The most influential theories on the function of the prefrontal cortex (PFC) suggest that this structure is an association cortex, responsible for integration of information received from other parts of the brain. This would implicate in direct participation of the PFC in working memory and attentional processes. Given this context, hodological and neurophysiological studies suggest that the orbitofrontal cortex (OFC) would be responsible for the integration of sensory, motivational and affective aspects, while the ventromedial prefrontal cortex (vmPFC), which is directly connected to the OFC, would have a key role in encoding emotional stimuli from the amygdala. It is well accepted that the processing of these aspects of information is crucial for decision-making processes, given the fact that this expression of behavior requires an evaluation of the environment in terms of comparing novel situation to previous experiences, as well as processing the balance between costs, outcomes and reward values. In order to test these hypotheses, rats with selective lesions to the vmPFC were subjected to the elevated plus maze (EPM) to evaluate anxiety and conditioned fear in the test retest paradigm. Animal were also tested in a spatial reference memory and a working memory tasks in the Morris water maze. Another group of rats had multi-electrode arrays chronically implanted in the OFC for the evaluation of the neuronal activity during a decision-making task, in which the animals had to choose between a small reward of one chocolate pellet immediately and a large reward of four chocolate pellets after varying delays. The results of the EPM show that animals with lesion to the vmPFC differ from control animals by showing diminished time evaluating risk in the second exposure to the EPM, without damage to locomotor activity, memory and anxiety levels. In the reference spatial memory task in the water maze, after extensive training searching for the hidden platform in the same location, lesioned animals persisted searching for the platform in that particular location after it was removed (probe test). However, in the working memory task, in which the platform is presented in a different location each day, lesioned animals did not differ from control animals. In the decision-making task, differential electrophysiological activity in OFC neurons was observed, particularly in the moment of the task in which the animal was required to perform the choice between rewards. Together, these results suggest that the vmPFC is related to behavioral flexibility and decision-making, possibly acting together with the OFC, which neuronal activity suggests participation in decision-making processes

No description available.

Odorous sensations are based on trigeminal and olfactory perceptions. Both trigeminal and olfactory stimuli generate overlapping as well as distinctive activations in the olfactory cortex including the piriform cortex. Orbitofrontal cortex (OFC), an integrative center for all senses, is directly activated in the presence of olfactory stimulations. In contrast, the thalamus, a very important midbrain structure, is not directly activated in the presence of odors, but rather acts as a relay for portions of olfactory information between primary olfactory cortex and higher-order processing centers. The aims of the study were (1) to examine the number of streamlines between the piriform cortex and the OFC and also between the piriform cortex and the thalamus and (2) to explore potential correlations between these streamlines and trigeminal and olfactory chemosensory perceptions. Thirty-eight healthy subjects were recruited for the study and underwent diffusion MRI using a 3T MRI scanner with 67 diffusion directions. ROIs were adapted from two studies looking into olfaction in terms of functional and structural properties of the olfactory system. The “waytotal number” was used which corresponds to number of streamlines between two regions of interests. We found the number of streamlines between the piriform cortex and the thalamus to be higher in the left hemisphere, whereas the number of streamlines between the piriform cortex and the OFC were higher in the right hemisphere. We also found streamlines between the piriform cortex and the thalamus to be positively correlated with the intensity of irritating (trigeminal) odors. On the other hand, streamlines between the piriform cortex and the OFC were correlated with the threshold scores for these trigeminal odors. This is the first studying the correlations between streamlines and olfactory scores using tractography. Results suggest that different chemosensory stimuli are processed through different networks in the chemosensory system involving the thalamus.

People suffering from congenital anosmia show normal brain architecture although they do not have functional sense of smell. Some studies in this regard point to the changes in secondary olfactory cortex, orbitofrontal cortex (OFC), in terms of gray matter volume increase. However, diffusion tensor imaging has not been explored so far. We included 13 congenital anosmia subjects together with 15 controls and looked into various diffusion parameters like FA. Increased FA in bilateral OFC confirms the earlier studies reporting increased gray matter thickness. However, it is quite difficult to interpret FA in terms of gray matter volume. Increased FA has been seen with recovery after traumatic brain injury. Such changes in OFC point to the plastic nature of the brain.

No description available.