Orientador: Sebastião Gobbi / Banca: Maria Elisa Pimentel Piemonte / Banca: Florindo Stella / Resumo: O objetivo do presente estudo foi analisar os efeitos de um programa de atividades físicas generalizadas e sistematizadas, especificamente delineado para parkinsonianos, sobre o nível de atividade física, comprometimento motor e capacidade funcional (flexibilidade, coordenação, força, agilidade, equilíbrio dinâmico, resistência aeróbia e habilidade de andar), em pessoas com Doença de Parkinson (DP). Participaram do estudo 22 idosos com DP, idade média de 66 anos e moradores do município de Rio Claro e região, que foram divididos em Grupo Treinamento (GT; n=11) e Grupo Controle (GC; n=11). Foram encontradas interações significativas (p,0,05) nas variáveis nível de atividade física, comprometimento motor e componentes de capacidade funcional, exceto coordenação motora manual, e resistência aeróbia/ habilidade de andar. Conclui-se que: a) o protocolo de treinamento utilizado é eficiente para aumentar nível de atividade física, melhorar a capacidade funcional e diminuir o comprometimento motor. Tais benefícios contrapõem-se aos efeitos deletérios do envelhecimento e da DP e, contrariamente a não participação agrava tais efeitos. Para amplificar os benefícios sugere-se: a) aumentar a freqüência das sessões com atividades de flexibilidade; b) incorporar mais atividades que demandem coordenação motora manual e; c) incorporar atividades de andar, seja num programa supervisionado ou como parte das ou relacionadas com AVD dos parkinsonianos / Abstract: The objective of this study was to analyze the effects of a physical activities program, designed for parkinsonians specifically, on the physical activity level, motor impairment and the functional capacity (flexibility, coordination, strength, agility, dynamic balance, endurance and walk ability) on older people with Parkinson's disease (PD). Twenty-two older people with PD, mean age of 66 yearold; living at Rio Claro city and region, who were assigned into Training Group (TG; n=11) and Control Group (CG; n=11). Significant statistical interactions were found on physical activity level, motor impairment level and the functional capacity components variables, with exception of manual motor coordination and aerobic endurance/walk hability. It was concluded that: a) the training protocol applied was efficient in order to increase physical activity level; to improve functional capacity and; to reduce motor impairment. Such benefits counteract the deleterious effects PD associated with aging and a non-attendance to the training worsens such effects, conversely. If its to amplify the benefits, it is suggested: a) to increase the frequency of the training sessions on flexibility; b) to incorporate more activities which demand manual motor coordination and; c) to add walking. Such improvements can be fostered, either as part of a supervised program or as part of daily living activities of the parkinsonians / Mestre

Orientador: Florindo Stella / Banca: Hanna Karen Antunes / Banca: Lilian Teresa Bucken Gobbi / Resumo: A doença de Parkinson (DP) é um processo neurodegenerativo crônico e progressivo que leva a um comprometimento físico refletindo os principais sinais e sintomas da DP. O comprometimento das funções motoras representa um comprometimento da execução das atividades da vida diária. O exercício físico (EF) tem um impacto positivo para os indivíduos com doenças neurodegenerativas, especificamente com DP. Dois estudos foram realizados. O estudo 1 teve como objetivo comparar a mobilidade funcional, distúrbios relatados do sono e os níveis séricos de homocisteína (Hcy) em pacientes com diferentes níveis de atividade física. 41 pacientes entre os estágios um a três da escala de estagiamento clínico de Hohen & Yahr foram distribuídos segundo a participação programas regulares de exercícios físicos. 17 pacientes eram sedentários e 18 mantinham uma prática regular de exercícios físicos. Os distúrbios relatados do sono foram avaliados por meio do Mini Questionário de Sono; as atividades instrumentais foram avaliadas por meio do questionário de Pfeffer; o estagiamento clínico da doença e a condição clínica dos pacientes foram mensurados, respectivamente, pela escala Hoehn e Yahr e pela Unified Parkinson's Disease Rating Scale - UPDRS. A escala de Schwab & England foi aplicada para medir o percentual de funcionalidade. O Mini-Exame do Estado Mental e Teste do Desenho do Relógio foram aplicados para avaliar o funcionamento cognitivo. Os níveis de Hcy foram medidos por meio de técnicas laboratoriais a partir de amostras de sangue. Para a análise dos dados foi realizada uma ANOVA one-way e um teste post hoc de Tuckey para verificar diferenças entre os grupos. A correlação de Pearson e análise de regressão múltipla foram usados para verificar a associação entre diversas variáveis, como a concentração sérica de Hcy... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Parkinson's disease (PD) is a chronic, progressive and neurodegenerative process. With progression of the disease, there are physical implicantions that reflects in physical symptoms. The motor impairment has a negative impact and compromise the execution of activities daily living. Physical exercise (PE) has a positive impact for individuals with neurodegenerative disabilities, specifically in PD. Two studies were conducted. The study 1 aimed to compare the functional mobility, sleep reported disorders and levels of homocysteine (Hcy) in PD patients with different levels of physical activity. Forty-one patients between stages one to three of Hohen & Yahr scale were distributed by participation in a program of regular physical exercises. 17 patients were sedentary and 18 had a regular practice of physical exercises. Sleep reported disorders were evaluated by Mini-Sleep Questionnaire; Instrumental activities were evaluated by Pfeffer Questionnaire; Clinical stages and motor condition of patients were respectively measured by the Hoehn and Yahr scale and by the Unified Parkinson's Disease Rating Scale - UPDRS. Schwab and England scale were applied to measure the daily functionality. The Mini-Mental State Examination (MMSE) and the Clock Drawing Test (CDT) were applied to evaluate the cognitive background. Levels of Hcy were measured by collection of blood and laboratorial techniques. The one-way ANOVA and Tuckey's post hoc was applied to verify differences between groups. Pearson correlation and stepwise multiple regression analysis were used to consider the association between several variables, as serum concentration of Hcy, motor condition, cognitive status, and L-dopa dosages. Patients who practice PE presented significant less sleep reported disturbances and lower levels of Hcy when compared... (Complete abstract click electronic access below) / Mestre

No description available.

Este trabalho teve como objetivo investigar as funções executivas (FE) e alterações do humor em pacientes com doença de Parkinson (DP). O primeiro estudo procurou apresentar uma revisão sistemática da literatura sobre o tema. No artigo seguinte, em um estudo empírico, comparou-se o desempenho das FE e alterações do humor em um grupo de pacientes com DP (N= 40) e um grupo controle (N= 30). O grupo clínico apresentou desempenho significativamente inferior em diversas medidas de avaliação cognitiva, especialmente no instrumento Behavioural Assessment of the Dysexecutive Syndrome (BADS), mas não para as variáveis ansiedade e depressão (p< 0,05). Os resultados demonstram que as alterações das FE e depressão são transtornos frequentes, mesmo em fases iniciais da DP. / This work aimed to investigate the executive functions (EF) and mood changes in patients with Parkinson's disease (PD). The first study sought to present a systematic review of the literature on the subject. In the second, in an empirical study, we compared the performance in EF and mood in a group of PD patients (N = 40) and a control group (N = 30). The clinical group had a significantly poorer performance on several measures of cognitive assessment, especially the BADS, but not for the variables anxiety and depression (p <0.05). The results show that changes in EF are frequent disorders, even in early stages of PD.

The biological basis of the clinical heterogeneity in Parkinson's Disease (PD) is unclear. It is likely to involve complex interactions between genetic and environmental factors and between a range of pathological processes, including protein homeostasis and immune system function. Microglial activation in the brain and peripheral innate immune changes are known to occur in PD. Recently genetic, animal and cellular studies have linked several innate immune related genes and proteins (e.g. HLADR, TREM2, TLR2, TLR4, caspase-1) to PD and provided evidence that they may have a role in PD pathogenesis. Alpha-synuclein is central to PD, with evidence from neuropathology, genetics and animal/cell models indicating that it plays a significant pathogenic role. There is developing evidence directly linking innate immune activity and alpha-synuclein pathology. For example, inflammation, particularly in response to microbial infection, is associated with increased alpha-synuclein accumulation in the periphery and activation of the innate immune inflammasome related caspase-1 leads to increased cleavage and aggregation of alpha-synuclein. Overall Hypothesis- "Parkinson's disease (PD) and its clinical heterogeneity are associated with systemic changes in innate immune and associated microbial factors and in alpha-synuclein". This was investigated from the perspective of an epidemiological study, a study of peripheral blood monocyte, innate immune/microbial markers and a cerebrospinal fluid (CSF) study in PD patients. *The epidemiological study, involved the longitudinal PICNICS cohort of 290 Idiopathic PD patients, and showed that the use of medication known to influence alpha-synuclein and immune function is associated with motor heterogeneity in PD. *The peripheral immune study involved 41 early PD patients and 41 age, gender and MAPT genotype matched paired controls, with the PD patients categorised into 2 groups based on the presence of previously identified clinical and genetic risk factors for the development of an early dementia (impaired semantic fluency, pentagon copying and MAPT H1/H1 haplotype). This study demonstrated that the phenotypic profile of peripheral monocytes and the level of serum alpha-synuclein and relevant innate immune and microbial markers do differ in early PD compared to controls and that there are differential changes in those patients at higher versus lower risk for early dementia. The systemic alpha-synuclein related changes appear to be present overall in PD patients compared to controls, while the more microbial/innate immune related changes appear to be more prominent in the dementia higher risk group. *The CSF study involved samples from 35 PD patients and has demonstrated evidence of relationships between neurodegeneration-linked CSF tau species and inflammatory cytokines, and between CSF alpha-synuclein and cognitive function, suggesting that these factors may be involved in PD heterogeneity within the central nervous system as well. Overall, these studies provide evidence that variations in alpha synuclein/ tau homeostasis and innate immune and microbial factors are related to PD and its clinical heterogeneity.

Bien que les symptômes moteurs soient prédominants chez les individus atteints de la maladie de Parkinson, les troubles cognitifs font aujourd'hui partie intégrante du spectre symptomatique de la maladie. Depuis peu, des troubles du langage ont été rapportés. Cette étude s'inscrit dans ce contexte et a pour objectif d'explorer l'influence de facteurs cognitivo-linguistiques sur la motricité des patients parkinsoniens. Pour cela, nous avons comparé trois tâches mettant en jeu trois types de motricités différentes chez quatre groupes de sujets : des sujets sains jeunes et âgés ; des patients parkinsoniens avec médication et d'autres patients parkinsoniens sans médication. Ces trois tâches avaient comme caractéristique principale de comparer des mots et des pseudo-mots. La 1ère tâche était une tâche de décision lexicale, la 2ème une tâche de réponse verbale et la 3ème une tâche d'écriture. Dans les 3 tâches, les stimuli étaient vus ou dictés. Nos résultats confirment que les patients parkinsoniens sans médication sont plus lents à réagir que les contrôles âgés. Néanmoins, ce ralentissement ne résulte pas de l'akinésie classiquement décrite. Ces patients parkinsoniens sans médication présentent en effet un trouble auditif majeur et un ralentissement cognitif dans les situations qui nécessitent un traitement lexical. Enfin, ces mêmes patients ont des difficultés à inhiber des processus automatiques qui viennent interférer et ralentir l'exécution de leur tâche motrice. Ces déficits semblent s'estomper sous traitement. Notre étude met ainsi en évidence l'existence de déficits cognitifs qui retardent l'initiation de la réponse motrice des patients parkinsoniens sans médication. / Even though the dominant symptom of Parkinson's disease (PD) is motor impairment, cognitive impairment is currently also considered an important symptom. Recently, language impairment has been reported in PD as well. The present study follows up on recent advances in PD research, and aims to explore the influence of cognitive-linguistic factors on motor control in PD. To this end, we compared three tasks, each of which relies on a different type of motor control. We tested four groups of participants: healthy young participants, healthy elderly participants, PD patients on medication, and PD patients off medication. In all three tasks, the primary comparison was between responses to words and pseudo-words, which were presented visually or auditorily. The first task was a lexical decision task, the second a verbal response task, and the third was a handwriting task. Our results show, in line with previous studies, that off-medication PD patients respond more slowly than healthy control participants. However, this slow-down does not result from akinesia, a well known symptom of PD. Instead, off-medication PD patients show auditory impairment and cognitive slowing in situations that require lexical processing. Moreover, these patients have an additional deficit in inhibiting automatic (lexical) processes, which interfere with the motor task. All of these deficits seem to be reduced by medication. Therefore, our study shows clear evidence for cognitive deficits in PD. These cognitive deficits slow the initiation of a motor response in off-medication PD patients.

La maladie de Parkinson (MP) est marquée par la présence d'une inflammation, pouvant être bénéfique ou délétère à la neurodégénérescence dopaminergique (DAgique). Nous avons adressé la nature des interactions pathologiques entre neurones DAgiques, cellules gliales et leucocytes infiltrant, nécessaire à la mise en place de cette inflammation. Dans un modèle MPTP murin de la MP, les objectifs de ma thèse ont été 1) d'identifier des signaux inflammatoires neuronaux et gliaux, par une approche transcriptomique associée à de la microdissection laser et 2) de déterminer leurs rôles dans la neuroinflammation ainsi que leurs effets sur la perte DAgique. Nous avons retenu parmi les candidats identifiés: les axes CXCL16-CXCR6 et CCL2-CCR2. Nous reportons dans le modèle MPTP, une expression microgliale de CXCL16 ainsi qu'une infiltration de population lymphocytaire CXCR6. Bien que la déplétion de CXCR6 permette de réduire cette infiltration, aucun effet n'est observé sur la perte DAgique. Nous décrivons une infiltration de monocyte CCR2 en concomitance avec une expression astrocytaire précoce de CCL2 dans le modèle MPTP murin, ainsi qu'une expression plus prolongée de CCL2 chez le primate non-humain MPTP, suggérant une relevance de l'axe CCL2-CCR2 dans la MP. En effet nous montrons que des souris surexprimant CCL2, intoxiquées au MPTP, ont non seulement une augmentation accrue de l'infiltrat monocytaire CCR2, mais également de la lésion DAgique. De manière inattendue, nous montrons que la neurotoxicité accrue observée chez des souris CX3CR1-/- MPTP passe indirectement par la voie CCL2-CCR2. Ainsi, nos données supportent l'hypothèse d'une neurotoxicité des monocytes CCR2 dans la MP. / Parkinson's disease (PD) presents signs of neuroinflammation, which can be beneficial or deleterious for dopaminergic (DA) neurodegeneration. We have analyzed the characteristics of such pathological interactions between DA neurons, glial cells and infiltrating immune cells. Using the neurotoxic MPTP mouse model of PD and focusing on chemokines, my thesis objectives were: 1) to identify using laser-microdissection and RNA profiling, the neuronal and glial inflammatory signals in the affected Substantia Nigra (SN) and 2) to assess the role of promising identified chemokine candidates during DA neurodegeneration. We have focused on the lymphocytic CXCL16-CXCR6 and the monocytic CCL2-CCR2 axes. We have found early microglial CXCL16 induction and parallel SN infiltration of CXCR6 lymphocyte subpopulations. CXCR6-deletion reduced infiltration of specific lymphocyte subpopulations, but did not affect the known deleterious infiltration of CD4 T-lymphocytes. For the CCL2-CCR2 axis, we found evidence for limited SN infiltration of CCR2 monocytes, which was preceded by transient astrocytic CCL2 induction in MPTP mice, but a prolonged CCL2 induction in MPTP monkeys, suggesting a potential relevance for human PD. While CCR2-gene deletion did not affect loss of DA neurons, astrocytic CCL2 overexpression increased MPTP induced DA neural loss, revealing the principally neurotoxic nature of infiltrating CCR2 monocytes in a PD-like environment. Unexpectedly, we also found that the known increased DA loss in CX3CR1-KO mice was mediated indirectly via over-induction of the CCL2-CCR2 axis. Combined, our results suggest a potential deleterious role of the CCL2-CCR2 axis in actual human PD.

L’intégration sensori motrice (ISM) est le processus par lequel les afférences sensitives sont intégrées par le système nerveux central et utilisées pour assister l’exécution des programmes moteurs. Plusieurs données suggèrent que celle-ci est anormale dans la maladie de Parkinson et serait impliquée dans la pathophysiologie de l’akinésie. En effet, la discrimination cutanée, l’acuité tactile spatiale, la kinesthésie ont été décrites déficientes dans cette maladie. Sa sensibilité aux traitements dopaminergiques est controversée. L’objectif de notre travail a été de tacher de mettre en évidence cette ISM anormale dans la maladie de Parkinson grâce à 2 techniques neurophysiologiques. Il s’agissait pour la 1e de la synchronisation liée à l’évènement des rythmes bêta (SLE bêta) qui permet d’étudier la désactivation corticale à la fin d’un mouvement actif mais aussi l’intégration corticale des afférences somesthésiques notamment lors des mouvements passifs et de la stimulation électrique des nerfs périphériques. La 2nde était l’étude de la modulation de l’excitabilité du cortex moteur primaire (évalué par la stimulation magnétique transcrânienne (TMS)) par des afférences somesthésiques générées par la stimulation électrique du nerf médian. Le but était de mettre en évidence des anomalies dans la modulation de l’excitabilité du cortex moteur primaire dans les intervalles inhibiteurs courts et longs (SAI et LAI) et/ou facilitateur (AIF). L’effet des traitements dopaminergiques a été évalué dans les deux cas par un enregistrement des patients après un sevrage thérapeutique. De nombreux protocoles de stimulation magnétique transcrânienne répétitive du cortex moteur que ce soit à basse ou haute fréquence, ont montré une efficacité sur l’akinésie. Il semblerait que les séances à fréquence plus rapides soient plus efficaces. Nous avons testé une nouvelle technique excitatrice à haute fréquence dite theta burst intermittente (ITBS) en regard du cortex moteur primaire chez des patients parkinsoniens et évalué l’effet sur l’akinésie. Nous avons par ailleurs étudié l’effet de cette stimulation sur l’ISM évaluée en conditionnant la TMS par une stimulation électrique du nerf médian. Notre 1e partie de l’étude a mis en évidence un effondrement de la SLE bêta dans la maladie de Parkinson après un mouvement actif, passif et une stimulation électrique du nerf médian. La levodopa a amélioré seulement la SLE bêta lors du mouvement actif. Nous avons pu ainsi confirmer l’atteinte de la SLE bêta active dans la maladie de Parkinson en lien avec un déficit de désactivation corticale en fin de mouvement mais aussi mettre en évidence une atteinte de la SLE bêta sensitive témoin d’un déficit du traitement cortical des afférences proprioceptives. La SLE bêta active a été améliorée par la levodopa alors que la SLE sensitive n’a pas été modifiée ce qui montre la dopa sensibilité de la désactivation corticale et le caractère non dopa sensible de l'ISM. Notre 2e partie n’a pas mis en évidence de différence significative dans la modulation de l’excitabilité du cortex moteur primaire par la stimulation électrique du nerf médian entre des patients parkinsoniens en début de maladie ni à un stade plus avancé par rapport à des témoins appariés par l’âge. En revanche la prise de levodopa a été associée à une aggravation de la LAI ce qui suggère aussi l’absence d’amélioration de l’ISM dans la maladie de Parkinson voire son aggravation par le traitement dopaminergique. Nous avons par contre montré que la modulation de l’excitabilité du cortex moteur primaire déclinait avec le vieillissement normal pour ce qui concerne les intervalles longs inhibiteurs (LAI) et facilitateurs (AIF) grâce à une comparaison d’une population de sujets contrôles jeunes et âgés sains. La session unique d’ITBS appliquée sur le cortex moteur primaire des patients parkinsoniens a permis d’améliorer transitoirement l’akinésie et la rigidité du membre supérieur controlatéral. [...] / Sensori motor integration (SMI) is the process whereby sensory inputs are integrated by the central nervous system and used for assisting motor program execution. Further data suggest that SMI is deficient in Parkinson's disease and might be implied in pathophysiology of akinesia. Indeed, two point skin discrimination, precision in tactile spatial acuity, kinaesthesia have been described deficient in Parkinson's disease. Dopaminergic treatment effects in sensory processing are controversial. The aim of our study was to investigate SMI in Parkinson's disease by using two neurophysiological techniques. The first one was the event related synchronization of beta rhythms (ERS beta) which reflects neural deactivation of the motor network at the end of active movement and also somesthesic afferences processing after passive movement or electric nerve stimulation. The second technique was the modulation of primary motor cortex excitability (investigated by trans cranial magnetic stimulation (TMS)) by somesthesic afferences generated by median nerve electric stimulation. This electric nerve stimulation consisted in inhibitory short or long interstimulation intervals (respectively SAI and LAI) and also facilitatory interval (AIF). Dopaminergic treatment effect was investigated in both techniques by recording patients after treatment withdrawal. Many protocols of repetitive transcranial stimulation over the primary motor cortex have been shown to be effective to reduce akinesia in Parkinson’s disease. High frequencies of stimulation seem to be more effective. We aimed at studying if a new excitatory protocol of high frequency called intermittent theta-burst (iTBS) over the primary motor cortex also affects akinesia and SMI investigated by conditioning TMS by median nerve stimulation. The first part of our study showed a decrease in ERS beta in Parkinson disease after an active movement, a passive movement and en electric median nerve stimulation. We have confirmed that the active ERS beta is deficient in Parkinson's disease and is associated to a deficient motor cortex deactivation at the end of the movement. Furthermore, we showed that sensory ERS beta is deficient, reflecting that cortical processing of sensory afferences is also deficient. Levodopa enhanced active but not sensory beta ERS. This suggests the dopa sensitivity of motor cortex deactivation and the absence of dopasensitivity of cortical processing of somesthesic afferences generated by movement.The second part failed to show a significant difference between parkinsonian patients and age matched controls in the modulation of primary motor cortex by median nerve stimulation. In patients with Parkinson's disease, levodopa worsened LAI. This suggests that SMI in Parkinson disease is not dopa sensitive and is even worsened by treatment. In control subjects, the modulation of primary motor cortex excitability by sensory afferences declined with normal aging because LAI and AIF decreased in old compared to young controls.The unique session of iTBS over primary motor cortex in parkinsonian patients improved akinesia and rigidity of contralateral upper limb. This improvement was higher in patients under their usual dopaminergic treatment than in de novo patients or after treatment withdrawal. AIF was clearly enhanced but only in patients under usual dopaminergic treatment suggesting that iTBS over primary motor cortex has improved akinesia in patients treated by levodopa via an improvement of SMI.

Les ganglions de la base (GB) sont principalement connus pour leurs fonctions motrices, mais présentent également des fonctions non motrices. Sans surprise, il a été montré qu’ils sont impliqués dans des troubles moteurs tels que la maladie de Parkinson ou les dystonies. Des études récentes suggèrent que les GB jouent également un rôle prépondérant dans des maladies “non-motrices” telles que l’épilepsie d’absence , qui est une épilepsie généralisée non convulsive. Dans l’ensemble de ces dysfonctions des GB, les symptômes sont accompagnés de différents patrons oscillants d’activité neuronale souvent synchronisés entre les différents noyaux des GB, le cortex et d’autres aires cérébrales. Comment les GB peuvent-ils favoriser ou soutenir ces différentes activitées oscillantes?Des expériences récentes ont montré le rôle clé joué par les GB dans l’épilepsie d’absence et remettent en question le point de vue traditionnel selon lequel les circuits thalamo-corticaux sont responsables des crises d’absence. Nous proposons une nouvelle théorie selon laquelle les rétroactions opérées par les GB sur l’activité corticale rend le réseau bistable et entraîne les patrons d’activité oscillante qui apparaîssent pendant les crises. Notre théorie est compatible avec l’ensemble des résultats expérimentaux connus et elle prédit qu’un input excitateur transitoire sur le cortex peut terminer prématurément les crises d’absence. Nous présentons ici des résultats préliminaires en accord avec cette prédiction.De multiples fréquences des oscillations d’activité sont observées dans la maladie de Parkinson au sein des GB, telles que les fréquences correspondant aux tremblement des membres ou encore les oscillations béta. Nous montrons que notre model peut générer des oscillations à différentes échelles temporelles qui coïncident avec les fréquences des oscillations dans la maladie de Parkinson. Notre théorie peut rendre compte des oscillations observées dans la maladie de Parkinson et dans l’epilépsie d’absence dans un cadre théorique unifié et suggère deux scénarios pour expliquer les multiples fréquences des oscillations d’activité, à la fois pathologiques et fonctionnelles. / The Basal Ganglia (BG) are thought to be involved primarily in motor but also in non-motor functions. Unsurprisingly, the BG are shown to be involved in motor dysfunctions such as Parkinson's disease or dystonia. More recent studies suggest the key role of the BG in "non-motor" diseases such as absence epilepsy which is a generalized non-convulsive epilepsy. In these diseases, symptoms accompany various oscillatory patterns of neural activity often synchronized across the BG, cortex and other brain areas. How can the BG support these different kinds of oscillatory patterns?Recent experiments have highlighted the key role of the BG in absence seizures and question the traditional view in which thalamocortical circuits underlie absence seizures. We propose a novel theory according to which the feedbacks of cortical activity through BG make this network bistable and drive the oscillatory patterns of activity occurring during the seizures. Our theory is compatible with virtually all known experimental results and it predicts that well-timed transient excitatory inputs to the cortex advance the termination of absence seizures. We report preliminary experimental results consistent with this prediction.Multiple oscillatory frequencies are observed in Parkinsonian BG such as the frequencies of the limb tremor and the beta oscillations. We show that our model can generate oscillations with multiple timescales which resemble Parkinsonian oscillations. Our theory can model the oscillations in Parkinson's disease and absence epilepsy in a unified framework and points to two scenarios to explain multiple frequencies of pathological and functional oscillations.

L'analyse protéomique du tissu cérébral pathologique dans la maladie de Parkinson (MP) est un enjeu majeur à l'identification des causes moléculaires de la dégénérescence en vue de développer des thérapies curatives. Jusqu'à présent, les études chez l'humain se sont limitées à l'analyse du cerveau post-mortem, trop souvent représentatif d'un stade très avancé de la maladie et potentiellement altéré par différents facteurs. Dans ce travail, nous avons exploité l'accès temporaire au cerveau parkinsonien durant l'implantation d'électrodes de stimulation, pour obtenir une information moléculaire du tissu cérébral, in vivo et à un stade moins avancé de la maladie. Afin d'optimiser notre stratégie, nous avons ensuite développé un outil dédié à la capture tissulaire dont l'efficacité et le caractère non lésionnel ont été validés in vivo chez le primate. Ce travail permet d'envisager l'analyse protéomique du cerveau parkinsonien « vivant » afin d'identifier les causes moléculaires de la MP. En revanche, cette approche tissulaire n'est pas envisageable pour un diagnostic en routine clinique. Aussi, de nombreux groupes s'intéressent à l'analyse protéomique du LCR en vue d'identifier des marqueurs diagnostiques. Dans cette optique, nous avons mis au point une stratégie, basée sur l'utilisation de nanoparticules (NPs) fonctionnalisées qui a permis un enrichissement considérable des profils protéiques observés en spectrométrie de masse. La reproductibilité et la possibilité d'automatiser intégralement la préparation des échantillons font de notre approche une solution adaptée à la recherche de marqueurs moléculaires diagnostiques de la MP dans le LCR. Nous avons aussi démontré l'intérêt de notre approche pour l'analyse protéomique du plasma et du globule rouge. Enfin, nous avons évalué la possibilité d'utiliser ces NPs in vivo, pour une capture des protéines directement dans la circulation sanguine. / Proteomics analysis of pathological brain tissue in Parkinson's disease (PD) is of great importance to understand the molecular aetiology of degeneration and to develop curative treatments. To date, published studies have been restricted to the analysis of human post-mortem tissue samples, frequently derived from advanced disease stage and potentially altered by several factors. In this project we took advantage of the temporary access to PD patient's brain during electrode implantation to obtain in vivo molecular information from cerebral tissue at earlier stage of the disease. We further developed a dedicated tool to improve our tissue harvesting approach, and validated its efficiency and non-lesion effects in vivo in monkeys. This work opens the way to the proteomic analysis of fresh human brain samples to elucidate molecular causes of degeneration in PD. However such tissue investigation approach remains invasive and cannot be used in routine clinical screening for PD diagnosis. Proteomics analysis of cerebrospinal fluid (CSF) constitutes a promising alternative to identify neuropathological diagnosis markers. For this purpose, we developed a nanoparticle-assisted strategy enabling the enrichment of CSF proteins detection by mass spectrometry. Reproducibility and high throughput potentiality of our approach demonstrate its compatibility with clinical proteomics for PD diagnosis biomarker research in CSF. We also demonstrated the interest of this NP strategy for plasma and red blood cells proteome analysis. Finally, we evaluated the ability to use these NPs for in vivo protein harvesting in blood.