While it is known that acute and chronic stress can impact cognition, less is known about the immediate impacts of minor frustrations or positive experiences on subsequent behavior and cognition in primates. This study used a novel methodology to engineer both a positive and (slightly) frustrating experience, using the same apparatus, in 15 adult capuchin monkeys. Subjects were presented with a working memory task (DMTS) for 30 minutes after the experimental manipulations (or a control). As predicted, the frustrating task prior to testing resulted in a decrease in performance on the DMTS compared to performance after a positive experience or the control. Contrary to predictions, a positive experience did not facilitate performance to higher levels than the control condition. Manipulations also impacted several behaviors. Although there may be different results in different contexts, these results indicate that even mild negative experiences impact subsequent behavior and cognition in primates.

Cerebral blood flow dynamics is an essential component for preserving cerebral integrity. Cerebral blood flow abnormalities are often seen in patients with central nervous system pathologies such as epilepsy, migraine, Alzheimer's Disease, vascular dementia, stroke, and even HIV/AIDS. There is increasing clinical and experimental evidence implicating cerebral hypoperfusion during ageing. The determination of cerebral perfusion has therefore become an important objective in physiological, pathological, pharmacological, and clinical investigations. The knowledge of regional cerebral blood flow further provides useful diagnostic information and/or data for a better understanding of the complex clinical presentations in patients with neurological and psychiatric disorders. Several cerebrovasoactive drugs have found application in the clinical setting of cerebrovascular diseases such as migraine and dementia. Due to the similarities between humans and non-human primates with respect to their brains, both structurally and behaviourally, numerous studies have been conducted and several non-human primate models have been developed for physiological, pathological, pharmacological, and clinical studies, amongst others in Parkinson's disease and diabetes. The relatively large size of the Cape baboon Papio Ursinus with a weight of 27-30 kg for a large male, makes this primate especially suitable for in vivo brain studies using radiotracers and Single Photon Emission Computed Tomography (SPECT). The main aim of the current study was therefore to develop a suitable radiotracer (99m Tc-hexamethylpropylene amine oxime (HMPAO) or 99m Tc_ethyl_cysteinatedimer (ECD) or 123l-iodoamphetamine (IMP)) for adapted in vivo cerebral blood flow measurements in a non-human primate (Papio ursinus) as an investigative model. The model was to be validated and applied in various drug studies for the evaluation of pharmacological interventions. The study design made use of split-dose methodology, whereby the radiopharmaceutical (radiotracer) was administered twice during each study. The first administration was injected soon after the induction of the anaesthesia, and was followed by the first SPECT data acquisition. The second administration of the radioligand, a double dose of radioactivity with respect to the first radioligand injection, was done at a specific time during the study, which took into account the pharmacodynamics of the drug. A second SPECT data acquisition followed subsequently. The drugs that were included in the study were acetazolamide, a carbonic acid anhydrase inhibitor (often used in nuclear medicine to determine cerebral reserve); sumaptriptan, a 5-HT (serotonin) agonist used for treatment of migraine; sodium valproate (an anti-epileptic drug); nimodipine, a calcium channel blocker and nitro-glycerine, a vasodilator used for angina. Arterial blood pressures were recorded from a catheter in the femoral artery and heart rates were concurrently monitored. The split-dose method was successfully applied to develop a non-human primate cerebral blood flow model under anaesthesia. The model showed differences in cerebral perfusion of the different anaesthesia regimes. These anaesthesia data sets were suitable as control/baseline results for drug intervention studies. Acetazolamide evaluation through the split-dose method in the baboon confirmed the sensitivity of the model by presenting comparable perfusion. This result compared to those already familiar prompted the model to be applied in pharmacological intervention studies. Subsequent results of these investigations showed increases in perfusion for single drug nimodipine treatment (25%). However, nimodipine attenuated the increases in perfusion when administered in combination with acetazolamide. Sumatriptan was able to decrease and normalise the increased perfusion after long duration anaesthesia. Decreased cerebral blood flow was observed for combinations of nimodipine with sodium valproate suggesting drug-drug interaction with important clinical implications. Similar decreases were found also for sumatriptan and nitro-glycerine when administered in combination with nimodipine. Studies with the various tracers (99m Tc_HMPAO or 99m Tc_ECD or 123l_IMP) showed clear differences in the perfusion data, confirming variation in the biochemical performance of the tracers. These differences, if not taken into consideration, caution for inappropriate clinical conclusions and subsequent erroneous therapeutic decisions. Improvement of radiotracer efficacy was subsequently attempted through application of the cyclodextrine complexation approach. Although cyciodextrine technology did not markedly improve the brain disposition of the 99m Tc-ECD, protection of the tracer against degradation was demonstrated. This study encouraged further exploration of this method for protection of the tracer against chemical and metabolic degradation. The current study was aimed to develop and effectively apply a non-human primate model with nuclear medicine technology for cerebral blood flow determinations after pharmacological interventions. This was achieved through the split-dose method and dedicated computer programming, which yielded a successful model with the non-human primate under anaesthesia. The model was validated with the application of acetazolamide to confirm familiar cerebrovascular reserve results, indicating that the model is sensitive to CBF changes. The model was also effectively applied in several pharmacological intervention studies, whereby cerebropharmacodynamics of selected drugs were investigated and established. This unique model of a non-human primate, Papio ursinus for cerebral blood flow determinations has served pharmacological research successfully during the past 12 years and could do so in the future, with scope to investigate new frontiers with improved technologies. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.

Cerebral blood flow dynamics is an essential component for preserving cerebral integrity. Cerebral blood flow abnormalities are often seen in patients with central nervous system pathologies such as epilepsy, migraine, Alzheimer's Disease, vascular dementia, stroke, and even HIV/AIDS. There is increasing clinical and experimental evidence implicating cerebral hypoperfusion during ageing. The determination of cerebral perfusion has therefore become an important objective in physiological, pathological, pharmacological, and clinical investigations. The knowledge of regional cerebral blood flow further provides useful diagnostic information and/or data for a better understanding of the complex clinical presentations in patients with neurological and psychiatric disorders. Several cerebrovasoactive drugs have found application in the clinical setting of cerebrovascular diseases such as migraine and dementia. Due to the similarities between humans and non-human primates with respect to their brains, both structurally and behaviourally, numerous studies have been conducted and several non-human primate models have been developed for physiological, pathological, pharmacological, and clinical studies, amongst others in Parkinson's disease and diabetes. The relatively large size of the Cape baboon Papio Ursinus with a weight of 27-30 kg for a large male, makes this primate especially suitable for in vivo brain studies using radiotracers and Single Photon Emission Computed Tomography (SPECT). The main aim of the current study was therefore to develop a suitable radiotracer (99m Tc-hexamethylpropylene amine oxime (HMPAO) or 99m Tc_ethyl_cysteinatedimer (ECD) or 123l-iodoamphetamine (IMP)) for adapted in vivo cerebral blood flow measurements in a non-human primate (Papio ursinus) as an investigative model. The model was to be validated and applied in various drug studies for the evaluation of pharmacological interventions. The study design made use of split-dose methodology, whereby the radiopharmaceutical (radiotracer) was administered twice during each study. The first administration was injected soon after the induction of the anaesthesia, and was followed by the first SPECT data acquisition. The second administration of the radioligand, a double dose of radioactivity with respect to the first radioligand injection, was done at a specific time during the study, which took into account the pharmacodynamics of the drug. A second SPECT data acquisition followed subsequently. The drugs that were included in the study were acetazolamide, a carbonic acid anhydrase inhibitor (often used in nuclear medicine to determine cerebral reserve); sumaptriptan, a 5-HT (serotonin) agonist used for treatment of migraine; sodium valproate (an anti-epileptic drug); nimodipine, a calcium channel blocker and nitro-glycerine, a vasodilator used for angina. Arterial blood pressures were recorded from a catheter in the femoral artery and heart rates were concurrently monitored. The split-dose method was successfully applied to develop a non-human primate cerebral blood flow model under anaesthesia. The model showed differences in cerebral perfusion of the different anaesthesia regimes. These anaesthesia data sets were suitable as control/baseline results for drug intervention studies. Acetazolamide evaluation through the split-dose method in the baboon confirmed the sensitivity of the model by presenting comparable perfusion. This result compared to those already familiar prompted the model to be applied in pharmacological intervention studies. Subsequent results of these investigations showed increases in perfusion for single drug nimodipine treatment (25%). However, nimodipine attenuated the increases in perfusion when administered in combination with acetazolamide. Sumatriptan was able to decrease and normalise the increased perfusion after long duration anaesthesia. Decreased cerebral blood flow was observed for combinations of nimodipine with sodium valproate suggesting drug-drug interaction with important clinical implications. Similar decreases were found also for sumatriptan and nitro-glycerine when administered in combination with nimodipine. Studies with the various tracers (99m Tc_HMPAO or 99m Tc_ECD or 123l_IMP) showed clear differences in the perfusion data, confirming variation in the biochemical performance of the tracers. These differences, if not taken into consideration, caution for inappropriate clinical conclusions and subsequent erroneous therapeutic decisions. Improvement of radiotracer efficacy was subsequently attempted through application of the cyclodextrine complexation approach. Although cyciodextrine technology did not markedly improve the brain disposition of the 99m Tc-ECD, protection of the tracer against degradation was demonstrated. This study encouraged further exploration of this method for protection of the tracer against chemical and metabolic degradation. The current study was aimed to develop and effectively apply a non-human primate model with nuclear medicine technology for cerebral blood flow determinations after pharmacological interventions. This was achieved through the split-dose method and dedicated computer programming, which yielded a successful model with the non-human primate under anaesthesia. The model was validated with the application of acetazolamide to confirm familiar cerebrovascular reserve results, indicating that the model is sensitive to CBF changes. The model was also effectively applied in several pharmacological intervention studies, whereby cerebropharmacodynamics of selected drugs were investigated and established. This unique model of a non-human primate, Papio ursinus for cerebral blood flow determinations has served pharmacological research successfully during the past 12 years and could do so in the future, with scope to investigate new frontiers with improved technologies. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.

Chronic itch has a significant impact on quality of life for millions of patients worldwide, on a level comparable to that of chronic pain. Yet, although there are a host of effective drugs available for pain, there are no therapies that specifically target chronic itch. Current experimental approaches to investigate the pathogenesis of chronic pruritus and to test novel therapeutic agents are largely limited to rodent models. However, rodent models display significant dermatological, neurophysiological, and immunological differences from humans with chronic itch. The disadvantages of the current rodent paradigms call for the design of a valid primate model of chronic itch. For four years, we have monitored scratching behavior in a primate colony (n=35) of Cynomolgus macaques (Macaca fascicularis) suffering from idiopathic chronic itch. By comparing molecular and genetic analyses of the primates’ skin to their quantified scratching behavior, we attempted to characterize the underlying mechanisms of chronic itch in this model. Furthermore, the expression of itch-related proteins was examined in both the primate model and in humans with pruritic diseases. The first aim of the study was to characterize the underlying molecular and genetic basis of chronic itch in the primate model. We were able to distinguish specific peripheral targets related to pruritus by correlating the genetic and protein expression results to the primates’ scratching severity. In Aim 1a, RNA-sequencing was performed on skin biopsies from the primates to identify differentially expressed genes in pruritic, lichenified versus non-pruritic, non-lichenified skin. These results were then correlated to the quantified primate scratching behavior. This led to the identification of over 400 genes that were differentially expressed in the skin based on scratching intensity. Many of these differentially expressed transcripts were associated with sensory nerve fibers, keratinocytes, mast cells, or lymphocytes. Selected genes that were overexpressed and correlated to itch intensity were then targeted for immunohistochemical and proteomic analysis in Aim 1b. Immunohistochemical examination of the primate skin biopsies revealed that histamine levels were not elevated in primates that exhibited increased scratching behavior. However, mast cells containing tryptase were significantly increased in the skin of primates with severe scratching as compared to primates with mild scratching. The increased levels of gastrin-releasing peptide and substance P in lichenified skin were also found to be correlated to the primates’ scratching behavior. Of note, transient receptor potential channels V1, V3, and A1 were increased in the epidermis of primate skin, but the numbers of TRPV1+ and TRPA1+ nerve fibers were not significantly different between lichenified and non-lichenified skin. Transcriptome analysis of the opioid receptors and their ligands showed that primates with severe scratching behavior had a significant imbalance between the µ- and κ-opioid receptors and ligands. The µ-opioids had upregulated gene expression, while the κ-opioids were downregulated. In Aim 2, to further characterize this primate model of chronic itch, we compared immunohistochemical results from the primate studies to human findings. Lesional and non-lesional skin biopsies from patients with atopic dermatitis, psoriasis, and cutaneous T-cell lymphoma underwent immunohistochemical analysis in order to reveal the similarities and differences between the primate model and different types of chronic itch in humans. As in the primate model, substance P was found to be increased in the skin of lesional atopic and psoriasis skin. Additionally, similar to primate skin, human atopic and psoriatic skin had high levels of tryptase and its receptor in the epidermis. While IL-31 was only slightly elevated in primates, patients with cutaneous T-cell lymphoma or atopic dermatitis showed a significant correlation between itch severity and IL-31 levels. In conclusion, our primate model displayed expression patterns of many endogenous pruritogens and receptors that were similar to those of humans with atopic dermatitis or psoriasis. While the primate model did not completely mimic these specific pruritic diseases, the overlap of pruritic components suggests a commonality of signaling pathways across several different chronic itch states. The similarity of this primate model to human disease offers the combined advantages of experimental modeling and long-term behavioral follow-up. / Biomedical Sciences

No description available.

La vaccination est considérée comme l’un des plus grandes découvertes de l’histoire des maladies infectieuses, ayant permis le déclin et l’éradication de plusieurs pathogènes. Cependant, nous ignorons encore tous les mécanismes impliqués dans la protection contre les pathogènes. Cette méconnaissance est la cause de notre incapacité à formuler des nouveaux vaccins contre le VIH, la tuberculose, le paludisme et les pathogènes émergents. Récemment, on note des efforts pour induire une réponse cellulaire efficace après une vaccination, qui joue un rôle crucial dans la clairance des pathogènes.Cette thèse s’appuie sur un modèle de vaccin vivant atténue issu du virus de la vaccine : le MVA (Modified Vaccinia Ankara) et sur le modèle de primate non-humain. Nous avons caractérisé la réponse cellulaire après une immunisation intradermique suivant un schéma en prime-boost homologue, avec un boost à 2, suivi d’un boost à 9 mois. Le MVA a induit une infiltration massive de Lymphocytes T CD8 au niveau du site d’injection, 7 jours après l’immunisation. La réponse cellulaire systémique était modérée et ne reflétait pas l’amplitude de la réponse locale. Les injections du prime et du boost ont orienté la réponse cellulaire de façon différente, ce qui a mené à une importante induction de cellules T CD4 et CD8, persistantes, spécifiques de l’antigène et polyfonctionnelles après l’injection du boost à 9 mois.Cette étude souligne la différence entre les réponses systémiques et locales, démontrant l’importance de se focaliser sur la réponse tissulaire. Elle a également mis en lumière l’impact du schéma d’immunisation sur la qualité de la réponse cellulaire. / Vaccination has been considered as one of the greatest discoveries in the history of infectious diseases by allowing pathogens decline or eradication. However, we still ignore all the mechanism that lead to protection and therefore, fail to elaborate new vaccines against HIV, tuberculosis, malaria and emergent pathogens. Recently, efforts have been made to elicit effective cellular response after vaccination, which is crucial for pathogen clearance.This thesis relied on live-attenuated vaccine model derived from the vaccinia virus: the MVA (Modified Vaccinia Ankara) and a non-human primate model. We characterized the cellular immune response triggered by a homologous prime-boost intradermal injection of MVA, with a 2 months and 9 months boost. The MVA induced a massive infiltration of CD8 T cells at the injection site 7 days post immunization. In comparison, the systemic cellular response was mild and did not reflect the magnitude of the local response. The prime and boost injections elicited distinct orientation of the systemic and local T cells, which led to an important induction of a persistent, antigen-specific and polyfunctional CD8 and CD4 T cell responses after the 9 months boost.This work emphasizes the difference between local and systemic response, demonstrating the importance of the focus on tissue immunity. It also highlights the impact of the immunization schedule on the quality of the cellular response.

Die vorsätzliche Freisetzung von Variola Virus (VARV) und schwere Erkrankungen des Menschen durch zoonotische Affen- (MPXV) und Kuh- (CPXV) pocken Viren stellen nach wie vor eine Bedrohung für die Bevölkerung dar. Klassische Pockenimpfstoffe bergen die Gefahr einer schweren Erkrankung. Deshalb ist die Entwicklung neuer Impfstoffe und Therapeutika von entscheidender Bedeutung. Deren Wirksamkeit und Sicherheit muss zunächst in verschiedenen Tiermodellen bewiesen werden. Existierende Makakken-Primatenmodelle leiden unter sehr artifiziellen Bedingungen der letalen Krankheitsinduktion durch VARV oder MPXV. Aus diesem Grund wurde das Calpox Virus/Krallenaffen-modell etabliert, welches auf einem CPXV aus natürlich infizierten Neuweltaffen (Marmosets) basiert. Das neue Modell hat drei wesentliche Vorteile: Die Arbeit mit Calpox Virus kann unter Sicherheitsstufe 2 durchgeführt werden und ist folglich einfacher in der Handhabung. 2. Die intranasale (i.n.) Infektion von Marmosets (Krallenaffen; Callithrix jacchus) spiegelt den natürlichen Infektionsweg von VARV wieder. Infizierte Affen entwickelten Pocken ähnliche Symptome und verstarben innerhalb von 2-3 Tagen nach Auftreten erster Symptome. Hohe Viruslasten wurden im Blut, Speichel und allen untersuchten Organen nachgewiesen. 3. Die i.n. Titration des Calpox Virus ergab eine 50 % Affen-Infektions-Dosis (MID50) von 8.3x102 pfu. Diese ist um den Faktor 10000 niedriger als in anderen Pocken-Primatenmodellen. Neun bis zehn Wochen nach einer Immunisierung mit dem Lister-Elstree Impfstoff waren alle Krallenaffen gegen eine letale Dosis des Calpox Virus (10 MID50) geschützt. Damit konnte der Nutzen des Calpox Virus/Krallenaffen-modells für die Erforschung neuer Impfstoffe gezeigt werden. Das Calpox Virus/Krallenaffen-modell überwindet wesentliche Nachteile bestehender Primatenmodelle und ist somit ein geeignetes Model für die Evaluierung von neuen Impfstoffen, Impfstrategien und antiviralen Therapien. / The intentional re-introduction of Variola virus (VARV), the agents of smallpox, into the human population remains of concern today. Moreover, zoonotic infections with Cowpox (CPXV) and Monkeypox virus (MPXV) cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antivirals have to be demonstrated by different animal models. The existing primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously to induce a lethal infection in macaque monkeys. To overcome these drawbacks, the main objective of this study was to develop a primate model in which a smallpox-like disease could be induced by a CPXV virus designated calpox virus which was isolated from a lethal orthopox virus (OPV) outbreak in New World monkeys (marmosets). The new non-human primate model has three major advantages: 1. Working with calpox virus is less challenging and can be done under bio-safety-level two. 2. Mimicking the natural route of VARV infection, intranasally infected marmosets (Callithrix jacchus) reproducibly developed clinical symptoms of an OPV infection and died within two to three days after onset of the first symptoms. High viral loads of calpox virus were detected in blood, saliva and all analyzed organs. 3. Intranasal titration of the virus resulted in a 50 % monkey infectious dose (MID50) of 8.3x102 pfu, a lethal infectious dose 10,000 lower than those used in any other primate model. Moreover, we showed the aptitude of the primate model for the testing of new vaccines since nine to ten weeks after immunization with Vaccinia virus Lister-Elstree marmosets were completely protected against intranasal challenge with 10 MID50 of calpox virus. As the calpox virus/marmoset model overcomes major limitations of current primate models it is suitable to evaluate new vaccines, new vaccination strategies and antiviral therapies.

Les crises d'épilepsie proviennent d'une synchronisation pathologique de réseaux neuronaux du cortex. Les crises motrices, générées à partir du cortex moteur primaire, sont souvent pharmaco-résistantes. La résection neurochirurgicale du foyer épileptique est rarement l'option thérapeutique de choix au regard des risques de deficits moteurs potentiellement induits par la résection. Les ganglions de la base ont un rôle important dans la propagation des crises. Des enregistrements par micro-électrode réalisés dans une précédente étude ont montré que les activités des structures d'entrée des ganglions de la base telles que le Putamen, le noyau caudé et le noyau sous-thalamique (NST) sont fortement modifiées pendant des crises motrices. Le taux de décharge moyen des neurones du NST et du Putamen augmente et le pourcentage de neurones oscillants synchronisés avec l'EEG durant la période ictale est plus élevé durant les crises que pendant la période inter-ictale. Des études pilotes chez l'humain ont montré un effet bénéfique potentiel de la stimulation cérébrale profonde (SCP) chronique du NST pour traiter les crises motrices pharmaco-résistantes. Le but de notre étude est d'évaluer les effets thérapeutiques de la SCP des structures d'entrée des ganglions de la base. Nous avons dans un premier temps développé un modèle primate de crise d'épilepsie motrice focale stable et reproductible par injection intra-corticale de pénicilline. Nous avons ensuite caractérisé la pharmaco-résistance du modèle. Nous avons implanté stéréotactiquement des électrodes de SCP dans le NST et le Putamen. Le stimulateur a été placé sous la peau dans le dos de l'animal. Un protocole de stimulation à 130 Hz à un voltage inférieur à l'apparition d'effets secondaires a été réalisé dans le NST. Le stimulateur était mis en marche au moment de l'injection de la pénicilline. Un protocole de stimulation à 0 volt a été réalisé comme condition contrôle. Chaque primate étant son propre contrôle. L'apparition des crises, leur nombre et leur durée ont été comparés par période de 1 heure entre la condition stimulée et non stimulée. Chaque session expérimentale a été menée sur une durée de plus de six heures. Nous avons évalué l'effet préventif de la SCP à haute fréquence (130 Hz) du NST sur les crises motrices. Nous avons également étudié l'effet préventif de la SCP à basse fréquence (5-20 Hz) du Putamen sur ce même modèle. Enfin, sur un autre primate, nous avons étudié l'effet combiné de la SCP du NST à haute fréquence et du Putamen à basse fréquence sur les crises motrices. Résultats : Les effets de la SCP chronique du NST à haute fréquence ont été analysés à partir de 1572 crises apparues au cours de 30 sessions expérimentales chez 3 primates. Les effets de la SCP préventive du NST ont été évalués sur 454 crises motrices durant 10 sessions expérimentales chez un primate. L'effet de la SCP du Putamen à basse fréquence a été analysé sur 289 crises durant 14 sessions chez 2 primates. Enfin l'effet combiné de la SCP du NST et du Putamen a été évalué sur 477 crises durant 10 sessions. Les meilleurs résultats ont été obtenus par SCP chronique du NST. L'apparition de la première crise était significativement retardée lorsque le primate était stimulé. Le temps total passé en situation de crise motrice était diminué en moyenne d'environ 69 % (p ≤0.05) par rapport à la condition non-stimulé au regard de la diminution significative du nombre de crises particulièrement durant les 3 heures après le début de la stimulation. La durée de chaque crise était modérément réduite. Les modes de stimulation mono-polaire ou bi-polaire avaient une efficacité similaire. La SCP préventive du NST n'a pas eu d'effet supérieur à la stimulation chronique du NST. La SCP chronique du Putamen à basse fréquence avait un effet positif mais principalement durant les deux premières heures de stimulation. L'effet combiné de la SCP du NST et du Putamen était inférieur à la SCP chronique du NST ou du Putamen. / Epileptic seizures arise from pathological synchronization of neuronal ensemble.Seizures originating from primary motor cortex are often pharmacoresistant, and many times unsuitable for respective surgery because of location of epileptic focus in eloquent area. Basal ganglia play important role in seizure propagation. Micro electrode recordings performed during previous studies indicated that input structures of basal ganglia such as GPe, Putamen and Subthalamic nucleus (STN) are strongly modified during seizures. For example the mean firing rate of neurons of the STN and Putamen increased and the percentage of oscillatory neurons synchronized with the ictal EEG was higher during seizures as compared to interictal periods. Pilot studies in humans have shown the possible beneficial effect of chronic DBS applied to STN in treatment of pharmacoresistant motor seizures. Our study was aimed at studying the therapeutic effect of electrical stimulation of input structures of basal ganglia . We first developed a stable, predictable primate model of focal motor epilepsy by intracortical injection of penicillin and we documented it's pharmacoresistence. We then stereotactically implanted DBS electrodes in the STN and Putamen. The stimulator was embedded at the back of the animals. Subthreshold electrical stimulations at 130 Hz were applied to STN. Stimulator was turned ON when penicillin was injected. Sham stimulation at 0 volt was used as a control situation, each monkey being its own control. The time course, number and duration of seizures occurring in each epochs of 1 h were compared during ON and sham stimulation periods. Each experimental session lasted uptoo 6 hours,We also studied preventive high frequency stimulation of STN and subthershold low frequency stimulation of Putamen with 5 Hz and 20 Hz in the same model .Finally we studied combined effects of high frequency STN and low frequency Putamen stimulation in one monkey Results: Data was analysed from 1572 seizures in 30 experiments in three monkeys for chronic STN stimulation , 454 seizures in 10 experiments in one moneky during preventive STN stimulation ,289 seizures from 14 experiments in two monkeys during LFS putamen stimulation and 477 seizures from 10 sessions during combined STN and Putamen stimulation in one monkey The best results were observed during chronic STN stimulation The occurrence of first seizure was significantly delayed as compared to sham situation. Total time spent in focal seizures was significantly reduced by ≥69% on an average (p ≤0.05) after STN stimulation, due to a significant decrease in the number of seizures especially so during the first 3 hours after stimulation. The duration of individual seizures reduced moderately. Bipolar and monopolar stimulation modes were equally effective Preventive HFS STN (in one specimen) was not found to be superior to acute stimulation. LFS Putamen alone was effective but mainly in first two hours of stimulation .In a combined HFS STN and LFS Putamen stimulation the effect of stimulation in terms of seizure control was modest and poor compared to HFS STN alone or LFS Putamen alone. This study provides original data in primates showing the potential therapeutic effect of chronic HFS-STN DBS to treat focal motor seizures . A discussion explaining these results and comparison with STN DBS in human motor seizures as well as future translational perspective in human therapeutics is provided.

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第18186号 / 医科博第51号 / 新制||医科||4(附属図書館) / 31044 / 京都大学大学院医学研究科医科学専攻 / (主査)教授 小柳 義夫, 教授 松岡 雅雄, 教授 朝長 啓造 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Les avancées scientifiques sont de plus en plus dépendantes de l’évolution des technologies et des approches expérimentales. Dans la continuité des travaux initiés par Fagot, nous avons développé un nouveau dispositif expérimental permettant l’étude des capacités cognitives de singes vivant en groupes sociaux. Cet outil est automatisé, portable, muni d’un système d’apprentissage autonome, et il permet aux singes de réaliser plusieurs tâches cognitives en parallèle. Ce design expérimental nous a permis, pour la première fois, d’étudier l’évolution conjointe de différentes fonctions cognitives sur une échelle de temps réduite. Nos résultats révèlent un apprentissage des tâches rapide par les sujets qui présentent en outre des performances élevées et stables dans le temps. Ces travaux ouvrent ainsi des perspectives prometteuses à travers une utilisation de cet outil dans le cadre d’études i) sur les bases sous-jacentes à des processus cérébraux complexes, ii) sur les liens entre différentes fonctions cognitives, ou encore iii) pharmaceutiques, testant les l’effets de molécules sur une ou plusieurs fonctions cognitives simultanément. / Scientific advances are increasingly dependent on the evolution of both technologies and experimental approaches. Following on from Fagot's research, we developed a new experimental device to study cognitive abilities in nonhuman primates living in social groups. This tool is automated, portable, equipped with an autonomous self-learning system, and it allows the subjects to perform several complex cognitive tasks concurrently. This experimental design allowed us, for the first time, to study the co-evolution of different cognitive functions on a small time scale. Our results reveal the subjects learned the tasks rules rapidly and additionally they archieved high and stable performances over time. This developmental work thus opens up new investigation prospects in cognition for studies interested in i) the underlying bases of cerebral complex processes, ii) the links between several cognitive functions, or iii) testing the effects of drugs on one or more cognitive functions concurrently.