Introdução: Neuromielite óptica (NMO) é uma doença inflamatória desmielinizante do sistema nervoso central associado com auto anticorpo anti-aquaporina 4 (AQP4-Ab) em até 90% dos casos e com anticorpo anti glicoproteína de mielina oligodendrocítica (MOG-IgG) em cerca de 20% dos indivíduos negativos para AQP4-Ab. A apresentação clínica típica do NMO inclui neurite óptica grave (ON), mielite transversa longitudinalmente extensa (MTLE) e lesões do tronco encefálico conhecidas por causar náuseas,vômitos e soluços intratáveis. A dor é um dos sintomas mais frequentes e incapacitantes dessa síndrome. Sabe-se que afeta até 85% dos indivíduos, que é mais intensa e responde menos aos tratamentos usuais quando comparados aos pacientes com esclerose múltipla. O objetivo deste estudo foi caracterizar as síndromes dolorosas em indivíduos na fase crônica livre de recidiva da NMO. A doença também foi considerada um bom modelo para estudar os mecanismos de dor após lesão medular. Métodos: Trata-se de um estudo longitudinal, composto por duas avaliações. A avaliação para entrada no estudo consistiu em um exame neurológico complete padronizado, a fim de determinar as síndromes dolorosas principal e secundária de acordo com seu mecanismo e nível. Os pacientes foram convidados a preencher questionários avaliando a dor (Inventário breve de dor [BPI], Questionário de dor McGill [MPQ], inventário de sintomas de dor neuropática [NPSI]), espasmos tônicos dolorosos, sinal de Lhermitte, incapacidade (EDSS, Barthel ADL), ansiedade e depressão (escala hospitalar de ansiedade e depressão [HADS]), catastrofização (escala de pensamentos catastróficos na dor [PCTS]), disfunção urinária e fecal (questionário de bexiga hiperativa [OABV8], escore de sintomas prostáticos internacionais [IPSS]). Também foram realizados teste quantitativo sensitivo (QST) em área controle (com sensibilidade normal) e área de maior dor e medidas de excitabilidade cortical bilaterais (CE). Imagens prévias de ressonância magnética de encéfalo e medula espinhal foram revistos. Foi realizada uma consulta de acompanhamento entre 6 e 18 meses após a primeira visita, na qual a síndrome dolorosa principal foi reavaliada e os pacientes foram solicitados a preencher questionários (DN-4, BPI, MPQ, BPI, NPSI) sobre a dor. Resultados: Setenta e dois pacientes foram incluídos. Foram identificados 53 (73,6%) indivíduos com dor crônica e 19 (26,3%) sem dor. Quarenta (55,6%) pacientes apresentaram dor neuropática (NP) e 13 (18,1%) dor não neuropática (não-NP). Entre os 53 indivíduos com dor crônica, 38 (71,7%) tinham mais de uma síndrome dolorosa. Dor neuropática no nível sensitivo foi a síndrome dolorosa mais prevalente, sendo observada em 31 doentes (58,5% do total de pacientes com dor). O grupo com dor não-neuropática teve dor lombar como a síndrome mais comum, afetando 8 (61,5%) indivíduos. O grupo com dor neuropática teve um número significativamente maior de dermátomos afetados por alodínea dinâmica (0,8 ± 1,6, comparado a zero dermátomos nos outros 2 grupos, p = 0,004) e estática (0,7 ± 1,3 comparado a 0 no grupo com dor não-neuropática e 0,1 ± 0,5 dermátomos no grupo sem dor). A hiperpatia em nível foi significativamente mais prevalente no grupo com dor neuropática: 39 (97,5%) nesse grupo, contra 10 (76,9%) e 12 (68,4%) nos grupos dor não-neuropática e sem dor (p = 0,013). Os pacientes com dor neuropática apresentaram desempenho significativamente pior quando comparados aos sem dor, no PCS-12 (componente físico do SF-12), (32,5 ± 8 e 43,3 ± 11, respectivamente). O PCS-12 correlacionou-se com a intensidade da dor no BPI nos grupos dor neuropática (r = -0,387, p = 0,014) e não-neuropática (r = -0,734, p = 0,004). Dentro do grupo com dor neuropática, 16 (80%) pacientes relataram prurido na área de dor, enquanto apenas 1 (33,3%) paciente com dor não neuropática relatou o mesmo (p < 0,001). O QST apresentou maiores limiares para a detecção de estímulos quentes dentre aqueles com dor neuropática, quando comparado ao grupo com dor não-neuropática (41,3 ± 5,6 e 36,9 ± 3, respectivamente, p = 0,045). As amplitudes do potencial evocado motor a 120 e 140% foram significativamente menores nos dois grupos com dor quando comparados aos pacientes sem dor. A avaliação de acompanhamento foi realizada em 68 pacientes e 50 (73,5%) relataram dor. A dor neuropática do nível foi novamente a síndrome dolorosa mais prevalente, afetando 29 (58%) indivíduos. Três pacientes inicialmente sem dor relataram na o sintoma na segunda visita. A taxa de incidência de dor foi de 17,7 por 100 pessoas-ano. Onze pacientes que haviam relatado dor na entrada do estudo tinham uma síndrome de dor diferente na segunda avaliação (20,8% da amostra original). O grupo com dor neuropática teve uma diminuição significativa na intensidade do BPI (de 5,6 ± 1,9 para 4,8 ± 2, p = 0,039). O escore total do MPQ diminuiu significativamente em ambos os grupos com dor neuropática (de 9 ± 2,4 para 8 ± 3,1, p = 0,014) e naqueles com dor não-neuropática (9,2 ± 2,5 a 7 ± 4, p = 0,031). Conclusão: A dor é prevalente em pacientes com NMO e a dor neuropática de nível é a síndrome mais comum. A incidência de novas dores e alterações nas síndromes dolorosas não está relacionada à nova atividade inflamatória, mas ao dano estrutural permanente crônico na medula espinhal e tronco cerebral secundário à atividade autoimune prévia. A avaliação das síndromes dolorosas é importante para o tratamento correto desse sintoma e deve ser reavaliada regularmente, mesmo em pacientes sem novas recidivas clínicas / Introduction: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system. It is associated with anti-aquaporin 4 autoantibody (AQP4-Ab) in up to 90% of cases and with anti-myelin oligodendrocyte glycoprotein (MOG-IgG) in around 20% of subjects negative to AQP4-Ab. The typical clinical presentation of NMOSD includes severe optic neuritis (ON), longitudinally extensive transverse myelitis (LETM) and brainstem lesions known to cause intractable nausea, vomiting and hiccups. Pain is one of the most frequent and disabling symptoms in this syndrome. It is known to affect up to 85% of subjects with NMO which is more intense and less responsive to usual treatments when compared to multiple sclerosis patients. The aim of this study was to fully characterise all pain syndromes in individuals in the chronic relapse-free phase of NMO. The disease was also deemed a good model to study pain mechanisms in spinal cord injuries. Methods: This is a longitudinal study, comprised by 2 evaluations. The Baseline study entry visit consisted of a full standardized neurological examination, in order to determine the main and secondary pain syndrome according to its mechanism and level. Patients were requested to fill questionnaires evaluating pain (Douleur Neuropathique-4 [DN-4], brief pain inventory [BPI], Short-form McGill Pain Questionnaire [MPQ], Neuropathic pain symptoms inventory [NPSI]), painful tonic spasms, Lhermitte sign, hiccups, orthostatic intolerance, persistent nausea, pruritus, fatigue (modified fatigue scale), Uhthoff phaenomenon, quality of life (SF-12), disability (EDSS, Barthel ADL), anxiety and depression (Hospital anxiety and depression scale [HADS]), catastrophizing (PCTS), urinary and faecal dysfunction(OABV8,IPSS). Quantitative sensory test (QST) and measures of cortical excitability (CE) were performed. Previous brain and spinal cord MRIs were reviewed. A follow up visit was done between 6 and 18 months after the first visit, in which the main pain syndrome was reassessed and patients again were requested to fil pain questionnaires (DN-4, BPI, MPQ, BPI, NPSI) and report painful tonic spasms and Lhermitte sign. Results: Seventy-two patients were included. We identified 53 (73.6%) patients with chronic pain and 19 (26.3%) without any chronic pain syndrome. Forty (55.6%) patients had neuropathic pain (NP) and 13 (18.1%) had non-neuropathic pain (non-NP). Amongst those 53 subjects with chronic pain, 38 (71.7%) had more than one pain syndrome. NP at the sensory level was the most prevalent pain syndrome, being observed in 31 patients (58.5% of the total pain patients). Amid the non-NP patients, low back pain was the most common pain syndrome, affecting 8 (61.5%) subjects. NP group had a significantly higher number of dermatomes affected by allodynia to brush (0.8 ± 1.6, compared to zero dermatomes in the other 2 groups, p = 0.004) and to pressure (0.7 ± 1.3 compared to no 0 in the non-NP group and 0.1 ± 0.5 dermatomes in the no pain group). At-level hyperpathia affected a significantly proportion of patients with NP: 39 (97.5%) in this group, versus 10 (76.9%) and 12 (68.4%) in the non-NP and no pain groups (p= 0.013). Patients with NP had significantly worse performance when compared to those without pain, in the PCS-12 (physical component of the SF-12), (32.5 ± 8 and 43.3 ± 11, respectively). PCS-12 correlated with BPI intensity pain amid NP (r= -0.387, p= 0.014) and non-NP (r= -0.734, p= 0.004) groups. Within the group with neuropathic pain, 16 (80%) of patients reported itching on the pain area, whereas only 1 (33.3%) patient with non-neuropathic pain reported the same (p < 0.001). QST showed higher thresholds for warm stimuli detection within NP group, when compared to non-NP (41.3 ± 5.6 and 36.9 ± 3, respectively, p= 0.045) group. Motor evoked potential amplitudes at 120 and 140% were significantly lower in both groups with pain when compared to those without pain. The follow up assessment was done in 68 patients and 50 (73.5%) reported pain. At-level NP was the most prevalent syndrome, affecting 29 (58%) subjects. Three patients initially without pain reported it in the follow up visit. Incidence rate of pain was 17.7per 100 persons-year. Eleven patients who had reported pain upon study entry had a different pain syndrome on the second evaluation (20.8% of the original sample). NP group had a significant decrease in BPI intensity (from 5.6± 1.9 to 4.8±2, p= 0.039). MPQ total score significantly decreased in both groups with NP (from 9±2.4 to 8±3.1, p=0.014) and in those with non-NP (9.2±2.5 to 7±4, p=0.031). Conclusion: Pain is prevalent in patients with NMO and at-level NP is the most common syndrome. The incidence of new pain and changes in its syndromes is not related to new inflammatory activity but to the permanent chronic structural damage in the spinal cord and brainstem secondary to previous autoimmune activity. Assessment of pain syndromes is important for its treatment and they should be re-evaluated regularly even in patients without new clinical relapses

En Union Européenne les accidents frontaux font 28% des accidents routiers et sont responsables de 49% de mortalité, les fractures thoraciques étant la cause principale de décès. Les modèles en éléments finis du corps humain sont un outil important pour la simulation de chocs réels et la prédiction des risques d'endommagement. Cette thèse a permis de développer un modèle simple en éléments finis de la cage thoracique suffisamment souple d'utilisation et facilement paramétrable. Ce modèle est validé expérimentalement avant d'être utilisé pour une étude paramétrique. Cette étude a permis de caractériser l'influence de différents paramètres structurels et géométriques sur le comportement de la cage thoracique sous chargement dynamique. Le travail réalisé au cours de cette thèse est divisé en trois parties : Modélisation de la cage thoracique entière avec des éléments finis de type poutre dont les propriétés mécaniques sont déterminées à partir d'essais de flexion trois points sur des segments de côtes et complétées par des éléments de la littérature, Validation du modèle dont les résultats sont suffisamment proches des résultats des essais de chargement dynamique antéro-postérieur menés par Vezin et Berthet [Vez09], Etude paramétrique sur l'influence paramètres, géométrie des sections droites et géométrie globale de la cage thoracique (inclinaison des côtes, forme et taille globale de la cage thoracique). A partir de cette étude nous trouvons que le module d'Young et l'épaisseur du cortical ont une influence identique sur la raideur globale de la cage thoracique ainsi que sur la rotation et la déformation des côtes. Avec l'augmentation de ces deux paramètres la rigidité du thorax augmente et le taux de compression maximal diminue. D'autre part les côtes tournent plus et se déforment moins. La raideur des liaisons costo-verterbales a une influence directe sur la rotation latérale qui diminue avec l'augmentation de cette raideur alors que les déformations augmentent ; tandis que la raideur globale de la cage thoracique est légèrement modifiée. L'inclinaison des côtes est le facteur ayant la plus grande influence sur la déformation des côtes et donc sur le risque d'endommagement : plus les côtes sont proches de la direction de chargement la raideur de la cage thoracique augmente et la déformation des côtes augmente / In the European Union, 28% of road accidents are frontal impacts which provoke 49% of fatalities where the thoracic fractures are the main cause of death. The finite element models of the human body are an important tool for the simulation of real impacts and the prediction of damage. This thesis has led to develop a rib cage simplified finite element model sufficiently flexible and easily customizable. First, this model is experimentally validated and then used in a parametric study. This study allowed us to characterize the influence of different structural and geometric parameters on the behavior of the rib cage under dynamic loading. This work is divided into three parts : Modeling the rib cage using beam elements whose mechanical properties are determined by three-point bending tests on rib segments and supplemented from literature, Validating the model by simulating the anteroposterior dynamic loading tests led by Vezin and Berthet [Vez09], Performing a parametric study on the influence of the mechanical parameters (Young modulus, stiffness of costo-vertebral joints), the geometry of the rib sections and the overall geometry of the rib cage (ribs slope, shape and overall size of the rib cage). This study permitted to find that Young modulus and the thickness of the cortical have the same influence on the overall stiffness of the chest as well as on the rotation and deformation of the ribs. By increasing these parameters, the stiffness of the chest increases and the maximum compression ratio decreases. Besides, we'll find more rotation and less deformation of the ribs. The stiffness of the costoverterbal joints has a direct influence on the lateral rotation : it will decrease by increasing of the stiffness while deformation will increase. However, the overall stiffness of the chest is slightly modified by modifying the costovertebral joint stiffness. The initial inclination of the ribs accordingly to the load direction has the greatest influence on the deformation of the ribs and therefore on the damage risk. When the ribs are closer to the loading direction, the stiffness of the rib cage and the deformation of the ribs increases

Introdução: Ativação exacerbada de processos excitatórios mediados por NMDA e excesso de inibição mediada por GABA são descritos, respectivamente, nas fases agudas e subagudas após o traumatismo cranioencefálico (TCE). No entanto, existem poucos estudos a respeito do funcionamento desses circuitos na fase crônica do TCE. Objetivo: Avaliar a excitabilidade cortical (EC) de pacientes em fase crônica que sofreram TCE, especificamente diagnosticados com lesão axonial difusa (LAD). Métodos: Todos os 31 pacientes adultos foram avaliados após 1 ano, pelo menos, do TCE moderado ou grave. Inicialmente, os pacientes foram submetidos à avaliação de funções executivas - atenção, memória, fluência verbal e velocidade de processamento de informação - por meio de bateria neuropsicológica. Em seguida, a avaliação da EC foi realizada utilizando-se uma bobina circular para aplicar pulsos simples e pareados de estimulação magnética transcraniana na região cortical representativa do abdutor curto do polegar (pollicis brevis) na área M1 de ambos hemisférios. Os parâmetros de EC medidos foram: Limiar Motor de Repouso (LMR), Potenciais Evocados Motores (PEM), Inibição Intracortical de Intervalo Curto (IICIC) e Facilitação Intracortical (FIC). Todos os dados foram comparados aos dados normativos de EC já descritos na literatura e também aos de um grupo controle de pessoas saudáveis. Resultados: Não houve diferença significativa entre os hemisférios direto e esquerdo. Desta forma, os dados foram analisados de forma agrupada (\"pooled data\"). Os valores de LMR e FIC dos pacientes com LAD estavam dentro dos valores de normalidade. No entanto, os valores de PEMs a 120% do LMR, a 140% do LMR e IICIC estavam aumentados (respectivamente p=0,013; p=0,012; p < 0,001): PEM-120% LAD 524,95 [365,42 ; 616,66] versus Controles 303,50 [241,49 ; 399,19]; PEM-140% LAD 1150,00 [960,56 ; 1700,00] vs Controles 670,5 [575,43 ; 1122,78] e IICIC LAD 1,09 [0,82 ; 1,35] vs Controles 0,34 [0,28 ; 0,51]; pp02-Rel LAD 0,85 [0,64 ; 1,36] vs Controles 0,28 [0,20 ; 0,37]; pp04-Rel LAD 1,03 [0,88 ; 1,34] vs Controles 0,38 [0,29 ; 0,62] - sugerindo um possível desarranjo no sistema inibitório (p < 0.001). Os achados neuropsicológicos mostraram alterações na memória, atenção e velocidade de processamento de informação, mas possuíam correlação fraca com os dados de EC. Conclusão: Como os processos inibitórios envolvem circuitos mediados por GABA, além de outros, existe a possível inferência de que a própria fisiopatologia do LAD (rompimento de axônios) possa depletar GABA contribuindo com a desinibição do sistema neural na fase crônica do LAD / Background: Overactivation of NMDA-mediated excitatory processes and excess of GABA-mediated inhibition are described after a brain injury on the acute and subacute phases, respectively. Nevertheless, there are few studies regarding the circuitry on the chronic phase of brain injury. Objective: To evaluate the cortical excitability (CE) on the chronic phase of Traumatic Brain Injury (TBI) victims, specifically diagnosed with Diffuse Axonal Injury (DAI). Method: All 31 adult patients were evaluated after one year, at least, from the moderate and severe TBI. First, all patients underwent a broad neuropsychological assessment to evaluate executive functions - attention, memory, verbal fluency and information processing speed. Then, subsequently, the CE assessment was performed with a circular coil applying single-pulse and paired-pulse transcranial magnetic stimulation over the cortical representation of the abductor pollicis brevis muscle on M1 of both hemispheres. The CE parameters measured were: Resting Motor Threshold (RMT), Motor-Evoked Potentials (MEP), Short Interval Intracortical Inhibition (SIICI), and Intracortical Facilitation (ICF). All data were compared to normative data previously described on literature and to a control group that consisted of healthy subjects. Results: No significant difference between Left and Right hemispheres were found on these DAI patients. Therefore, parameters were analyzed as pooled data. Values of RMT and ICF from DAI patients were found within the normality. However, MEPs and SIICI values were higher on DAI patients (respectively p=0,013; p=0,012; p < 0,001): MEP-120% DAI 524,95 [365,42 ; 616,66] versus Control 303,50 [241,49 ; 399,19]; MEP-140% DAI 1150,00 [960,56 ; 1700,00] vs Control 670,5 [575,43 ; 1122,78] and SIICI DAI 1,09 [0,82 ; 1,35] vs Control 0,34 [0,28 ; 0,51]; pp02-Rel DAI 0,85 [0,64 ; 1,36] vs Control 0,28 [0,20 ; 0,37]; pp04-Rel DAI 1,03 [0,88 ; 1,34] vs Control 0,38 [0,29 ; 0,62] - suggesting a disarranged inhibitory system (p < 0.001). The neuropsychological findings had weak correlation with CE data. Conclusion: As inhibition processes also involve GABA-mediated circuitry, it is likely to infer that DAI pathophysiology itself (disruption of axons) may deplete GABA contributing to a disinhibition of the neural system on the chronic phase of DAI

Il est estimé qu'une fracture se produit toutes les trois secondes autour du monde, accompagné par un risque élevé d'invalidité ou même de mortalité. La connaissance des mécanismes de fractures dans une configuration de chargement représentatif d'une chute semble être d'un intérêt majeur pour le développement de méthodes dédiées à la prédiction du risque de fracture. La ténacité est un paramètre approprié lorsqu'on s'intéresse à ces mécanismes de fracture, elle détermine l'énergie nécessaire pour propager une fissure à travers l'architecture du tissu. L'objectif de cette étude est d'évaluer la ténacité de l'os cortical humain, considérant à la fois des conditions chargement quasi-statique et représentatif d'une chute sur sites anatomiques appariés. L'acquisition d'images en micro-tomographie ainsi qu'une mesure des cross-links ont été réalisées afin d'évaluer leur influence sur les mécanismes fracture du tissu. Les résultats ont montré que dans des conditions quasi-statiques, les différents sites anatomiques présentent des propriétés mécaniques différentes : le radius résiste mieux à une propagation de fissure. Dans des conditions de chute, il n'y a plus de différences entre ces sites, mais la ténacité décroit de façon significative par rapport au chargement standard. L'os cortical résiste mieux à une propagation de fissure dans des conditions quasi-statiques. Les analyses structurales et biochimiques ont montré des différences entre les sites anatomiques qui expliquent les différences mécaniques. Les caractéristiques architecturales du tissu sont déterminantes vis-à-vis des mécanismes de fracture dans des conditions quasi-statiques. Mais leur rôle lors d'une chute est moins évident. Ces résultats impliquent que la microstructure de l'os cortical n'est pas un déterminant majeur vis-à-vis du risque de fracture. De futures études doivent être réalisées afin de déterminer les paramètres décisifs dans des conditions représentatives d'une chute / A fracture is estimated every three seconds in the world, leading to an increased risk of impairment or even mortality. The biomechanical knowledge of bone fracture mechanisms in a fall configuration of loading is of great interests for the development of clinical method for the prediction of the risk of fracture. Toughness seems to be a good candidate to investigate this fracture process as it corresponds to the energy needed to propagate a crack through cortical bone complex microstructure. The aim of this study was thus to evaluate human cortical bone toughness parameter under both quasi-static and fall-like loading conditions paired anatomical locations. Micro-computed tomography images using synchrotron radiation and collagen cross-links maturation measurements were performed to investigate the influence of the tissue architecture on crack propagation. Results found showed that under quasi-static condition, the different anatomical locations present different mechanical behavior. Radius significantly better resist crack propagation than the other studied location. Considering a fall-like loading condition, no more difference is observed between the locations but a significant decreased is measured compare to the first configuration. Human cortical bone has a better capacity to resist crack propagation under a standard quasi-static loading condition. By investigating the tissue morphometric and biochemical parameters, we observed different organization from a location to another that explains the mechanical differences. The architectural features appear to be determinant for crack propagation mechanisms under quasi-static condition, but they play a lesser role under fall-like condition. These results imply that the tissue microstructure is not a determinant when dealing with the prediction of the risk of fracture. Further work has to be done to reach out which parameters are more determinants under a specific fall-like loading condition

Introdução: A osteoartrite de joelhos (KOA) apresenta alta prevalência, principalmente em mulheres. Com o envelhecimento da população esta prevalência irá aumentar. Os tratamentos conservadores apresentam limitada eficácia em expressivo número de pacientes no curso do tratamento . A cirurgia de protetização apresenta altos custos, possibilidade de complicações pós-operatórias graves e ainda que a correção anatômica seja perfeita, em torno de 20% dos pacientes persistem com dor crônica pós-operatória. Portanto, é preciso avançar no conhecimento dos mecanismos fisiopatológicos e estudar novas abordagens terapêuticas para agregar às existentes, visando melhor manejo da dor e para restabelecer a função de maneira mais efetiva. Estas questões motivaram três questões centrais que origiram os três estudos que compõem esta tese. Estudo I: No primeiro estudo avaliamos os mecanismos pelos quais há perpetuação da dor na KOA. Para responder a esta questão buscou respostas aos seguintes objetivos: I) Comparar se a função da via da dor inibitório descendente está associada com o estado de inibição no sistema corticospinal, indexado pelo potencial evocado motor (MEP) e o período de silêncio cortical (CSP) em pacientes com KOA e controles saudáveis. II) Determinar se há correlação entre as medidas de inibição intracortical (CSP, MEP) com alterações na escala de dor numérica (NPS 0-10) na KOA durante a tarefa de modulação condicionada de dor (CPM-task) considerando o efeito da capacidade funcional auto-relatada avaliada pelo Western Ontário and McMaster Universities Index (WOMAC) e uso de analgésicos. Métodos: Estudo transversal, foram incluídas 21 pacientes femininas com KOA e 10 controles saudáveis com idade entre 19 a 75 anos. Os parâmetros de excitabilidade do córtex motor (MEP e CSP) foram avaliados utilizando a estimulação magnética trasncraniana (EMT). Avaliação de dor e a incapacidade pelo WOMAC e a NPS (0-10) durante a CPM-task. Resultados: A média ajustada (DP) do CSP observada em pacientes com OA foi 23,43% menor do que em indivíduos saudáveis [54,54 (16,10) vs. 70,94 (22,87)], respectivamente (P = 0,01). A função do sistema modulador descendente de dor avaliado pela alteração do NPS (0-10) durante o CPM-task foi negativamente correlacionada com o parâmetro de excitabilidade cortical indexado pelo CSP (P = 0,001). O CSP foi negativamente correlacionado com a dor e incapacidade avaliada pelo índice WOMAC. Conclusão: Foi observado um sistema inibitório descendente de dor enfraquecido, corroborando com os achados em outras patologias de dor crônica. Estudo II O segundo estudo buscou determinar se na KOA, uma sessão de IMS (eletroestimulação intramuscular) ativa comparada com sham promove um efeito nos parâmetros de excitabilidade do córtex motor [MEP, inibição intracortical curta - SICI, facilitação intracortical (ICF) e CSP] e nas medidas de dor [limiar de dor a pressão (PPT); escala visual analógica de dor (VAS) e mudança na escala de dor numérica (NPS0-10) durante a CPM-task]. Esse estudo também se propôs a determinar se o fator neurotrófico derivado do cérebro (BDNF) sérico medeia o efeito desta estimulação no sistema cortico-espinhal, tal como avaliado pelo MEP e pelo PPT. Métodos: Foram incluídas 26 mulheres com KOA, com idade entre 50 a 75 anos. Elas foram divididas randomicamente para receber uma sessão de 30 minutos de IMS ativa (n = 13) ou IMS sham (n = 13) por meio de eletroestimulação com frequência de 2 Hz. As agulhas foram inseridas paravertebrais em nível da saída das raízes lombares de L1 a S2 e nos músculos cuja inervação corresponde a essas raízes e que sustentam a articulação do joelho (vasto medial, reto anterior, vasto lateral, tibial anterior e inserção da pata anserina). Os desfechos foram as medidas de dor (VAS, PPT, NPS durante CPM-task) e parâmetros de excitabilidade (MEP, CSP, SICI, ICF) realizados antes e imediatamente após a intervenção. Resultados: a IMS ativa comparado com sham diminuiu o MEP em 31,61% [intervalo de confiança (IC) 95%, 2,34-60,98]. Para os resultados secundários, IMS reduziu o ICF e aumentou o CSP. A IMS melhorou a dor relatada no VAS, o PPT e a pontuação do NPS (0-10) durante a CPM-task. O BDNF foi negativamente correlacionado com o PPT (r = 20,56). Conclusão: Obtivemos resultados demonstrando melhora da dor e reforço do sistema cortico-espinhal inibitório comparado ao tratamento sham com IMS. Estudo III O terceiro estudo buscou: 1) Avaliar se a utilização da ETCC (estimulação transcraniana de corrente contínua) combinada a IMS pode promover um resultado melhor de modulação da via cortico-espinhal de dor através da potenciação dos efeitos dos dois tratamentos; comparado a cada um deles isoladamente e ao tratamento sham. 2) Avaliar a capacidade da ETCC em reforçar o sistema inibitório descendente de dor e modular a excitabilidade neuronal através da VAS, PPT e NPS durante CPM-task. Além disso, avaliamos se o BDNF sérico poderia prever o efeito da terapia no final do tratamento. Métodos: 60 mulheres de 50 a 75 anos. Randomizadas em um de quatro grupos: ETCC+IMS, ETCC+IMS sham, ETCC sham+IMS, ETCC sham+IMS sham. Receberam 5 sessões de tratamento: ETCC anodal, lado contrário ao joelho acometido, 2mA, 30 min. IMS: estimulação com freqüência de 2Hz, 30 min; agulhas colocadas a 2cm de L1 á S2, nos músculos vasto medial, vasto lateral, reto anterior, tibial anterior e na inserção da pata anserina. Resultados: O a-tDCS + a-IMS mostrou os melhores resultados com diferença significativa na dor (VAS) [média (DP) relacionadas ao tratamento (pós e pré): 0.46 (0.04) vs. 6.32 (1.97); 95%CI -5.42 (-8.24 to -4.36), p=.003] e funcionalidade. Esse resultado iniciou na primeira sessão e manteve-se ao longo do estudo. A-tDCS+a-IMS foi o único capaz de modificar o sistema inibitório descendente de dor. Conclusão: Obtivemos melhora da dor e capacidade funcional com IMS, ETCC e ETCC+IMS. Mas somente o grupo de tratamento ETCC+IMS demonstrou capacidade de modificação do sistema inibitório descendente de dor. / Background: Knee osteoarthritis (KOA) has a high prevalence, especially in women. With the aging of the population this prevalence will increase. Conservative treatments have limited efficacy in expressive number of patients in the course of the treatment. The total knee replacement surgery presents high costs, possibility of serious postoperative complications and although the anatomical correction is perfect, around 20% persist with chronic postoperative pain. Therefore, it’s necessary to advance in the knowledge of pathophysiological mechanisms and to study new therapeutic approaches to add to the existing ones, aiming to better manage pain and to restore function more effectively. These questions motivated three central questions that originated the three studies that compose this thesis. Study I In the first study we evaluated the mechanisms by which there is perpetuation of pain in knee osteoarthritis and to answer this question sought to answer the following objectives: I) To compare if the function of the descending inhibitory pain pathway is associated with the state of inhibition in the corticospinal system, indexed by the motor evoked potential (MEP) and the cortical silent period (CSP) in patients with KOA and healthy controls. II) To determine if there is a correlation between the intracortical inhibition measures (CSP, MEP) with changes in the numerical pain scale (NPS 0-10) in the KOA during the task of conditioned pain modulation (CPM-task) considering the effect of the self-reported function evaluated by the Western Ontario and McMaster Universities Index (WOMAC) and the use of analgesics. Methods: A cross-sectional study included 21 female patients with KOA and 10 healthy controls aged 19-75 years old. Motor cortex excitability parameters (MEP and CSP) were assessed using transcranial magnetic stimulation (TMS). Pain assessment and disability by WOMAC and NPS (0-10) during the CPM-task. Results: The adjusted mean (SD) of CSP observed in patients with OA was 23.43% lower than in healthy subjects [54,54 (16,10) vs 70.94 (22.87)], respectively (P = 0.01). The function of the descending pain modulatory system evaluated by the NPS (0-10) change during the CPM-task was negatively correlated with the cortical excitability parameter indexed by CSP (P = 0.001). CSP was negatively correlated with pain and disability assessed by the WOMAC index. Conclusion: It was observed a descending pain inhibitory system weakened, corroborating the findings of other chronic pain conditions. Study II The second study sought to determine if one active IMS session compared to sham promoted an effect on motor cortex excitability (MEP, short intracortical inhibition - SICI, intracortical facilitation (ICF) and CSP and in the pain measures [pressure pain threshold (PPT); Visual analogue pain scale (VAS) and numerical pain scale change (NPS0-10) during the CPM-task]. This study also aimed to determine whether serum brain-derived neurotrophic factor (BDNF) mediates the effect of this stimulation on the cortico-spinal system, as assessed by MEP and PPT. Methods: Twenty-six women with KOA, aged 50-75 years old, were included. They were randomly divided to receive a 30-minute session of active IMS (n = 13) or IMS sham (n = 13) by electrostimulation with a frequency of 2 Hz. The needles were inserted paravertebral at the level of the lumbar roots exit from L1 to S2 and in the muscles whose innervation corresponds to these roots and which support the knee joint (vastus medialis, rectus anterior, vastus lateral, tibialis anterior and insertion of the anserine paw). The outcomes were pain measures (VAS, PPT, NPS during CPM-task) and excitability parameters (MEP, CSP, SICI, ICF) performed before and immediately after the intervention. Results: the active IMS compared with sham decreased the MEP by 31.61% [confidence interval (CI) 95%, 2.34-60.98]. For the secondary outcomes, IMS reduced ICF and increased CSP. IMS improved pain reported in VAS, PPT, and NPS score (0-10) during the CPM-task. BDNF was negatively correlated with PPT (r = 20.56). Conclusion: We obtained results demonstrating improvement of pain and enhancement of the inhibitory corticospinal system compared to sham treatment with IMS. Study III The third study aimed to: 1) Evaluate if the use of the combined tDCS (transcranial direct current stimulation) to IMS can promote a better result of modulation of the corticospinal pain pathway through the potentiation of the effects of the two treatments; compared to each of them alone, and with the sham treatment. 2) To evaluate the ability of the tDCS to strengthen the descending inhibitory pain system and to modulate neuronal excitability through VAS, PPT and NPS during CPM-task. In addition, we evaluated whether serum BDNF could predict the effect of therapy at the end of treatment. Methods: 60 women aged 50 to 75 years old. Randomized in one of four groups: tDCS + IMS, tDCS + IMS sham, tDCS sham + IMS, tDCS sham + IMS sham. They received 5 sessions of treatment: anodal tDCS, opposite side to affected knee, 2mA, 30 min. IMS: stimulation with frequency of 2Hz, 30 min; needles placed at 2 cm from L1 to S2, in the vastus medialis, vastus lateralis, rectus anterior, tibialis anterior and insertion of the anserine paw. Results: a-tDCS + a-IMS showed the best results with significant difference in pain (VAS) [mean (SD) related to treatment (post and pre): 0.46 (0.04) vs. 6.32 (1.97); 95% CI -5.42 (-8.24 to -4.36), p = .003] and functionality. This result started in the first session and was maintained throughout the study. A-tDCS + a-IMS was the only one able to modify the descending inhibitory pain system. Conclusion: We achieved improved pain and functional capacity with IMS, tDCS and tDCS + IMS. But only the tDCS + IMS treatment group demonstrated ability to modify the descending inhibitory pain system.

A atrite reumatóide é uma doença inflamatória crônica, sem cura, que afeta cerca de 1% da população mundial entre 35 e 65 anos, cujos sinais e sintomas incluem dor, edema, rigidez, degeneração e deformidades articulares. O atual tratamento da artrite reumatóide consiste no uso de drogas anti-reumáticas modificadores de doença (DMARDs), porém são compostos caros e imunossupressivos que podem elevar o risco de infecções graves e malignidades. No presente estudo, analisamos o nervo vago como potencial imunomodulador da inflamação que ocorre na artrite reumatóide experimental. Nossos resultados indicam que a estimulação vagal aferente controla a inflamação articular por meio da ativação de áreas encefálicas simpatoexcitatórias, tais como o núcleo paraventricular do hipotálamo (PVN) e o locus coeruleus (LC). A estimulação do PVN ou do LC diminui a inflamação na articulação, mas somente a integridade do LC foi obrigatória para o controle vagal da inflamação na artrite. A estimulação elétrica cortical direcionada para o córtex parietal ativou o LC e o PVN, mimetizando a ativação vagal, porém induziu um melhor controle da inflamação. Esses resultados sugerem a existência de um mapa encefálico neuroimune capaz de controlar a artrite sem causar efeitos colaterais observáveis. / There is no cure for rheumatoid arthritis affecting over 1% of the world population between 35 e 65 years old suffering chronic inflammation causing pain, swelling, stiffness, degeneration e joint deformities. Disease-modifying anti-rheumatic drugs (DMARDs) are expensive e immunosuppressive, increasing the risk of severe infections e malignancies. Here, we analyzed the potential of the vagus nerve to control experimental arthritic inflammation. Our results indicate that the afferent vagus nerve controls arthritic joint inflammation by activating specific sympatho-excitatory brain areas, such as the paraventricular hypothalamic nucleus (PVN) e the locus coeruleus (LC). PVN or LC stimulation decreased articular inflammation, but only LC integrity was necessary for vagal control of arthritic inflammation. Cortical electrical stimulation above the parietal cortex activated LC e PVN, mimicked vagal activation but induced a better control of arthritic joint inflammation. These results suggest a neuroimmune brain map to control side-specific lateral arthritic joint inflammation without noticeable side effects.

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No. of bitstreams: 1 fernandes_ra_me_araca_int.pdf: 2718642 bytes, checksum: 4dea3e0dc607519bbdbdb41a172e9277 (MD5) Previous issue date: 2019-01-18 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo desse estudo foi inferir a Densidade Mineral óssea (DMO) a partir da imagem radiográfica (Raios-X) usando como referência a DMO de uma escada de alumínio mensurada por Absorciometria por de Duas-Energias (DXA). Para isso foram utilizadas 30 amostras de tecido ósseo cortical e 30 amostras de tecido ósseo trabecular de osso bovino “in vitro”. Foram mensurados neste estudo a Densidade Mineral Óssea (DMO), o Conteúdo Mineral Ósseo (CMO) ambos obtidos pelo densitômetro LUNAR®–DPX ALPHA; a Quantidade Mineral Óssea (QMO) massa das cinzas após a calcinação das amostras; a densidade real das amostras (dReal=massa/volume). Foram feitas 10 tomadas de RX com as 60 amostras, entremeadas pela escada de alumínio (referencial densitométrico). A correlação entre as técnicas (DR-tons de cinza e DXA g/cm2) gerou equações de regressão para cada uma das dez radiografias e permitiu inferir a densidade mineral óssea (DMODR), obtida através da conversão dos tons de cinza em densidade radiográfica pelo software ImageJ® para cada uma das 10 tomadas radiográficas; calculou-se então a média da densidade mineral óssea calculada pela densitometria radiográfica (XDMODR) de todas as dez radiografias. Foi observado que a média da densidade real das amostras foi de 2,2±0,23g/cm2 e 1,05±0,09g/cm2 enquanto que a média da densidade mensurada pelo DXA foi de 0,73±0,11g/cm2 e 0,22±0,11g/cm2, observou que a media da DMODR ficou em 0,93±0,11g/cm2 e 0,34±0,14 g/cm2 para o osso cortical e trabecular respectivamente. A média da CMO foi de 0,19±0,9g e 0,08±0,02g e a media da QMO 0,14±0,04g e 0,05±0,03g para o osso cortical e trabecular respectivamente. Foi possível obter bons coeficientes de determinação entre todas as variáveis estudadas: CMO e QMO, R2 =0,747; DMO e dReal com R2 = 0,765; dReal e DMODR; DMO e XDMODR, respectivamente 0,764 e 0,856. Para as correlações foram usadas amostras de dois tecidos ósseos cortical e trabecular, o que sugere distinção entre as amostras com as metodologias utilizadas / The aim of this study was to infer the bone mineral density (BMD) from the radiographic image (X-X) with reference to the BMD of an aluminum step wedge measured by absorptiometry Dual-energy (DXA). For this we used 30 samples of cortical bone 30 and cancellous bone tissue samples of bovine bone "in vitro". Were measured in this study Bone Mineral Density (BMD), bone mineral content (BMC) both obtained by densitometer LUNAR® DPX-ALPHA; Volume Bone Mineral (QMO) mass of ash after calcination of the samples; the real density of the samples (dReal = mass / volume). 10 taken RX were made with the samples 60, interspersed by aluminum step wedge (densitometric reference). The correlation between the techniques (gray DR-tones and DXA g / cm 2) generated regression equations for each of the ten X-rays and allowed to infer bone mineral density (DMODR) obtained by converting grayscale radiographic density by ImageJ® for each of the 10 radiographic taken. It was then calculated average bone mineral density calculated by X-ray densitometry (XDMODR) radiographs of all ten. Was observed that the average true density of the samples was 2.2±0.23g/cm2 and 1.05±0.09g/cm2 while the average density measured by DXA was 0.73±0.11g/cm2 and 0.22±0.11g/cm2 interesting that the average DMODR was 0.93±0.11g/cm2 and 0.34±0.14g/cm2 for cortical and cancellous bone respectively. The average of the BMC was 0.19±0.08g and 0.9±0.02g, and the average QMO 0.14±0.04g and 0.05±0 03g for cortical and cancellous bone respectively. It was possible to obtain good determination coefficients between all variables: BMC and QMO, R2 = 0.747; BMD and dReal with R2 = 0.765; dReal and DMODR; BMD and XDMODR respectively 0.764 and 0.856. For correlations were used two samples of cortical and cancellous bone tissues, suggesting a difference between the samples with the methodologies used.

Le cortex cérébral primate a subi des modifications majeures pendant l'évolution qui ont permis le développement de fonctions cognitives supérieures. Un accroissement massif a eu lieu avec l'extension spécifique des couches supragranulaires et une forte expansion tangentielle. Le cortex primate ne possède pas uniquement davantage de neurones, comparé au rongeur, mais aussi des différences qualitatives. Ceci suggère des différences qualitatives pendant le développement du cortex.Une zone proliférative corticale supplémentaire a été identifiée chez le singe macaque: la zone subventriculaire externe (OSVZ) supposée être impliquée dans l'expansion du cortex primate. Mais les propriétés des précurseurs de l'OSVZ restent mal connues. Des techniques de microscopie en temps réel et d'immunofluorescence ont permis de réaliser une description exhaustive des précurseurs de l'OSVZ et de leurs propriétés chez le singe macaque.Nos résultats mettent en évidence des différences primates/rongeurs majeures. Les observations en temps réel révèlent des capacités prolifératives bien plus importantes des précurseurs. Les précurseurs primates de l'OSVZ présentent des taux de prolifération variables pendant la corticogenèse liés à la cinétique du cycle cellulaire. Nos enregistrements ont permis la génération d'une grande base de données de propriétés et lignages de précurseurs et la mise en évidence d’une diversité morphologique inattendue. 5 types ont été identifiés. Impliqués dans des lignages complexes, chaque type a la capacité de s'auto-renouveler et de générer directement des neurones. Parallèlement, nous avons développé une méthode de classification non supervisée des précurseurs corticaux. Cette technique a identifié les mêmes 5 types de précurseurs.Les résultats de cette thèse apportent de nouveaux éléments dans la compréhension des spécificités de la corticogenèse primate qui contribuent à l'expansion corticale et au développement de capacités cognitives supérieures. / The primate cerebral cortex underwent major modifications during evolution that enabled the development of high cognitive functions. A massive enlargement occurred with the specific expansion of the supra granular layers and the apparition of new frontal areas. Not only quantitative differences are found compared to the rodent but also qualitative differences. This points to potential qualitative differences in primate cortical development. An extra proliferating zone had already been identified during macaque corticogenesis: the outer subventricular zone (OSVZ). This zone is assumed to play a key role in the expansion of the primate cortex but the cellular and functional properties of OSVZ precursors remain elusive. We used quantitative long-term time-lapse video-microscopy (TLV) and immunofluorescence in and ex vivo to perform a detailed and exhaustive description of OSVZ precursor types and proliferative abilities at different stages of macaque cortical development. Our results highlight major rodent/primate differences. TLV observations revealed a much higher proliferative potential of OSVZ compared to the rodent SVZ. We report variable rates of proliferation linked to cell-cycle duration in a stage-specific manner. TLV recordings allowed the formation of a large database of primate precursor properties and lineages. This dataset unravelled an unexpectedly high diversity of OSVZ precursor morphologies. Five precursor types were identified. Involved in complex lineages, each precursor type can self-renew and directly generate neurons. In a parallel approach, we developed an unbiased clustering tool to automatically classify cortical precursors. This technique returned the same five precursor types as the morphological categorization. The results of this PhD thesis provide new insights into primate specificities during corticogenesis that contribute to cortical expansion and to the development of higher cognitive abilities.

L’excès de synchronisation dans le réseau cortico-sous-cortical est une caractéristique majeure de la maladie de Parkinson. La stimulation cérébrale profonde (DBS) à haute fréquence (HF) des ganglions de la base modifie ces synchronies et améliore significativement les troubles moteurs. Il n’était pas encore connu si l’excès de synchronisation dans le cortex moteur primaire (M1) est présent avant les signes moteurs et si la modulation antidromique des réseaux corticaux via la stimulation HF de la voie hyperdirecte cortico-subthalamique suffit à le désynchroniser. Nous avons étudié la synchronisation des activités spontanées dans M1 de souris juvéniles PINK1 -/-, modèle génétique de Parkinson (PARK6) par imagerie calcique bi-photonique in vitro et l’avons comparée à celle de souris contrôle (P14-P16). Nous avons testé l’impact de la stimulation HF des fibres cortico-subthalamiques (région subthalamique) sur ces synchronies corticales. A un stade précoce, les réseaux M1 présentent un excès de synchronisation et, dans notre modèle de tranche, la DBS HF normalise le patron de synchronisation, plaidant pour un rôle primordial de la modulation antidromique de l’activité corticale via la voie hyperdirecte. En conclusion, nous proposons, grâce à ce modèle génétique progressif, que (1) des activités de réseau pathologiques sont présentes dans M1 bien avant les premiers signes moteurs et (2) que la modulation par voie antidromique de ces réseaux corticaux est un mécanisme essentiel d’action de la DBS HF. Ces résultats montrent qu’une pathologie dégénérative est détectable très tôt dans le développement (neuroarchéologie) mais ne s’exprimer somatiquement que tardivement. / The excess of synchronization of neuronal activities within the cortico-basal ganglia network is a hallmark of the pathophysiology of Parkinson’s disease. High frequency deep brain stimulation (DBS) applied to various basal ganglia nuclei dampens the synchronized activity in the whole network, and brings about a significant motor improvement. However it is not to date established whether an early presymptomatic abnormal pattern of synchronization is present in the primary motor cortex long before motor signs, nor whether its antidromic modulation via the hyperdirect cortico-subthalamic pathway is sufficient to remove its excess of synchronization. To answer these questions we studied the synchronization of spontaneous activities in the primary motor cortex of PINK-/- mice (genetic rodent model of Parkinson’s (PARK6), a progressive model) and compared it with age-matched control mice (P14-16 (wild-type)) by means of two-photon calcium imaging. Secondly, we analyzed in vitro the impact of the high frequency stimulation of cortico-subthalamic fibers on the pattern of synchronization of cortical networks. We show that, (1) at an early stage of development, there is an excess of synchronized activity in primary motor cortical networks and that, (2) antidromic modulation of cortical activity is a key mechanism to account for the normalization of hyper synchronized activity. These results show that a neurodegenerative adult pathology may begin early during development (neuroarcheology) though clinical signs appear late in adulthood. Moreover, antidromic invasion of a network seems to be a key mechanism of deep brain stimulation.

Des mutations hétérozygotes faux-sens dans le gène de la tubuline gamma TUBG1, ont été identifiées dans le contexte des malformations du développement cortical, associées à une déficience intellectuelle et à l'épilepsie. Ici, nous avons étudié par la technique d’électroporation in-utero et par des études in vivo, l’effet de quatre de ces variantes sur le développement cortical. Nous montrons que les mutations dans TUBG1 affectent le positionnement neuronal dans la plaque corticale, en perturbant la locomotion des neurones nouvellement nés, mais sans affecter la neurogenèse. Nous proposons que la γ-tubuline mutante affecte le fonctionnement global de ses complexes, et en particulier leur rôle dans la régulation de la dynamique des microtubules. De plus, nous avons développé un modèle de souris knock-in Tubg1Y92C/+ et évalué les conséquences de la mutation sur le développement cortical, les caractéristiques neuroanatomiques et le comportement. Les souris mutantes présentent une microcéphalie globale, des anomalies du néocortex et de l'hippocampe, des altérations du comportement et une susceptibilité épileptique. Ainsi, nous montrons que les souris Tubg1Y92C/+ miment au moins partiellement le phénotype humain et représentent donc un modèle pertinent pour d'autres investigations de la physiopathologie des malformations du développement cortical. / Missense heterozygous variants in the gamma tubulin gene TUBG1 have been linked to malformations of cortical development, associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning within the cortical wall, by a disrupting the locomotion of newly born neurons but without affecting neurogenesis. We propose that mutant γ-tubulin affects overall functioning of γ-tubulin complexes, and in particular their role in the regulation of microtubule dynamics. Additionally, we developed a knock-in Tubg1Y92C/+ model and assessed consequences of the mutation on cortical development, neuroanatomical features and behaviour. Mutant mice present with global microcephaly, neocortical and hippocampal abnormalities, behavioural alterations and epileptic susceptibility. Thus, we show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of malformations of cortical development.