La "chirurgie éveillée du cerveau" consiste à retirer des tumeurs cérébrales infiltrantes (gliomes de bas grade, GIBG) à progression lente chez un patient éveillé. Une cartographie anatomo-fonctionnelle du cerveau est réalisée par stimulation électrique directe (SED) des zones proches de la tumeur afin de discriminer les aires cérébrales fonctionnelles de celles qui ne le sont plus. Les effets inhibiteurs de la stimulation sont mis en évidence par les tests neuropsychologiques réalisés par le patient lors de la chirurgie. Cependant, la SED est paramétrée de manière totalement empirique bien qu’utilisée de façon standardisée. De plus, si ses effets comportementaux sont mis en avant, ses effets électrophysiologiques restent plus méconnus. La conservation de la relation entre électrophysiologie (potentiel évoqué, PE) et comportement (fonction) est cruciale lors de chirurgies des GIBG : l’analyse des PE en temps réel permettrait une identification de ces relations au cours même de la chirurgie.Pour cela, nous avons réalisé des enregistrements peropératoires de l’activité électro-corticographique (ECoG) du cortex (CPP, n° ID-RCB : 2015-A00056-43). L’étude de ces enregistrements a permis de mesurer les effets electrophysiologiques de la SED corticale et sous-corticale, en évaluant la réponse du cerveau à la stimulation au travers des PE. Une chaine d'acquisition spécifique à la mesure de l'ECoG a été développée afin de pouvoir à terme mesurer et visualiser les PE en temps réel. De plus, un algorithme de post-traitement a été implémenté afin de réduire la contamination du signal par l’artefact de stimulation.Mieux comprendre les mécanismes sous-jacents à la SED, notamment au travers de la mesure des réponses électrophysiologiques, doit permettre de proposer des protocoles peropératoires plus objectifs afin d'améliorer la planification chirurgicale et la qualité de vie des patients. / The ‘Awake brain surgery’ consists in removing some slow-growing infiltrative brain tumor (low grade glioma, LGG) in a patient, to delay its development while preserving the functions. An anatomo-functional mapping of the brain is performed by electrically stimulating brain areas near the tumor to discriminate functional versus nonfunctional areas. The inhibitory effects of this direct electrical stimulation (DES) are evidenced by the neuropsychological tests undergone by the patient during the tumor resection. However, the DES parameters are empirically set even though its use is standardised. Moreover, even if its behavioural effects are well known, its electrophysiological effects have been partially depicted.Preserving the relationship between electrophysiology (evoked potential, EP) and behaviour (function) is crucial in LGG surgery.Intra-operative electrocorticographic recordings (ECoG) of the brain activity were thus performed (CPP, n° ID-RCB : 2015-A00056-43). The electrophysiological effects of cortical and subcortical DES on brain activity have been highlighted, by assessing the response of the brain to the stimulation through EP recordings analysis. A new acquisition set-up has also been specifically developed for ECoG recordings in order to measure and eventually visualise the EP in real-time. Furthermore, a post-processing algorithm has been implemented to reduce the signal disturbances induced by the stimulation artefact.A better understanding of the underlying DES mechanisms, in particular through the measurement of electrophysiological responses, should enable designing more perfected protocols in order to improve the surgical planning, and quality of life of the patients.

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.

L’objectif général de ce travail doctoral était de comparer les effets de la fatigue musculaire des quadriceps femoris après un exercice musculaire volontaire (VOL) et un exercice musculaire électroinduit (ES) sur le contrôle postural bipodal, ainsi que sur la fatigue centrale. Les résultats montrent qu’à l’issue d’une tâche fatigante unilatérale ou bilatérale, l’exercice ES dégrade davantage la force usculaire que l’exercice VOL. Cependant, le contrôle postural bipodal est indifféremment perturbépar les deux exercices. En outre, les vitesses de récupération des capacités posturales et de force musculaire ne diffèrent pas à l’issue des exercices. Par ailleurs, l'exercice VOL altère davantage la commande centrale que l'exercice ES (immédiatement à l’issue de l’effort), tandis que celui-ci retarde l’apparition de la fatigue centrale et la maintient plus longuement. Etant donné que l'exercice VOL estinduit par la commande centrale et que l'exercice ES est généré par une stimulation artificielle externe, on peut émettre l’hypothèse que l'exercice VOL produit essentiellement une fatigue supraspinale, tandis que l'exercice ES engendre surtout une fatigue spinale. / The overall objective of this thesis was to compare the effect of fatigue of the quadriceps femoris after fatiguing voluntary contractions (VOL) and fatiguing neuromuscular electrical stimulation (ES) on bipedal postural control, and central fatigue. The results show that after unilateral or bilateral muscle fatigue, the ES exercise affected the muscle strength more than the VOL exercise. However, bipedal postural control was similarly deteriorated for both exercises. Moreover, the recovery speeds of postural control and muscle strength abilities did not differ for the both exercises. In addition, the VOL exercise alters central drive quicker than the ES exercise immediately after their completion while the ES exercise delays and prolongs the central fatigue. As the VOL exercise is induced by central command and the ES exercise is generated by artificial external stimulation, one can hypothesize that the VOL exercise especially produces supraspinal fatigue, while the ES exercise especially engenders spinal fatigue.

La schizophrénie (SZ) est une pathologie psychiatrique chronique et invalidante dont les conséquences fonctionnelles sont principalement liées à des déficits cognitifs. Ceux-ci sont étroitement associés à des déficits de perception auditive précoce d’informations de bas niveaux telle que la hauteur sonore. La perception auditive précoce peut s’évaluer avec un paradigme comportemental simple appelé « tone-matching » (appariement tonal AT), dans le lequel les sujets doivent discriminer activement entre deux sons courts (300-ms) d’une même paire séparés par un intervalle bref (500-ms). Les performances d’AT reflètent un processus cognitif de comparaison préattentionnelle se déroulant au sein du système auditif central (SAC). Le SAC est constitué du noyau géniculé médian du thalamus (MGN), de l’aire corticale auditive précoce (EA) et de l’aire corticale auditive associative (AA). Cependant, les dysfonctionnements du SAC sous-tendant les déficits d’AT dans la SZ restent mal connus. De plus, ces déficits sont élevés mais hétérogènes selon les cohortes. Ce travail de thèse propose de caractériser le fonctionnement du SAC associé aux performances d’AT chez les sujets SZ afin de mieux comprendre la physiopathologie du trouble et de développer des traitements ciblés. L’hypothèse guidant les 4 études expérimentales de ce travail est que des altérations psychophysiques et neurophysiologiques spécifiques du SAC sont impliquées dans les déficits d’AT dans la SZ. Nos études psychophysiques utilisant différents paradigmes de « tone-matching » ont montré 1) un déficit d’AT de magnitude croissante pour l’intensité, la hauteur et la longueur des stimuli auditifs chez les sujets SZ (n=29), 2) un déficit d’appariement de trios de sons médiant une corrélation entre les déficits d’appariement de paires de sons (AT proprement dit) et l’identification de phrases émotionnelles (n=27). Ces résultats démontrent que les sujets SZ présentent différents niveaux de déficits d’AT selon le type de caractéristique acoustique, ainsi que des niveaux de déficits hiérarchiquement organisés entre les types de complexité des stimuli auditifs perçus. 3) Nos approches neurophysiologiques ont montré une distribution bimodale des performances d’AT chez les sujets atteints de SZ (n=310) avec un 1er groupe présentant une réduction significative de ces performances associée à une réduction de la connectivité fonctionnelle de repos à l’IRM entre les différentes régions du SAC (MGN-EA, MGN-AA et EA-AA impliquant particulièrement des sous-régions AA adjacentes à l’EA) et un 2nd ne présentant pas de déficits d’AT mais une réduction plus modérée de la connectivité uniquement entre EA-AA. Ces résultats démontrent que les performances d’AT permettent de séparer deux sous-types de SZ présentant des patterns topographiques spécifiques de dysconnectivité fonctionnelle de repos au sein du SAC. 4) Les résultats préliminaires de l’étude de l’effet d’une procédure de stimulation électrique transcrânienne non invasive (tES) ciblant le SAC gauche (2mA, 10x20min) montrent une modulation significative des performances d’AT après la procédure de stimulation chez les sujets SZ (n=2). Cela suggère que les déficits d’AT pourraient être dépendants de mécanismes d’excitabilité et de plasticité des neurones du SAC modulables par tES. Pris ensembles, ces résultats confirment l’influence d’altérations mécanistiques du SAC sur les déficits d’AT dans la SZ, dont les spécificités anatomo-fonctionnelles seront à confirmer par des études de validation et des explorations neurophysiologiques « temps réel » du SAC en situation d’AT. En perspective, comme les paradigmes de « tone-matching » peuvent être implémentés facilement en pratique clinique, ces nouvelles donnés pourront permettre de différencier facilement des sous-types physiopathologiques de patients, et de développer des approches thérapeutiques ciblées sur le SAC à la fois en tES et en entraînement cognitif sensoriel / Schizophrenia (SZ) is a chronic brain disorder with outcome primarily driven by deficits in cognition. These have been related to impaired discrimination of basic auditory information such as pitch, as assessed in tone-matching behavioral paradigms in which subjects are asked to actively discriminate between two short pure tones (300-ms) following a brief delay (500-ms). More specifically, tone-matching indexes early, pre-attentive comparison mechanisms occurring in the central auditory system (CAS, divided into thalamic medial geniculate nucleus (MGN), early auditory (EA) and association auditory (AA) cortical areas). Therefore, characterisations of the CAS functioning associated with tone-matching abilities in SZ individuals may be useful drivers for pathophysiology understanding and therapeutic development. First, we aimed at exploring tone-matching abilities in SZ across major acoustic features (length, pitch, intensity) and different levels of complexity (2-tones, 3-tones, emotional sentences) using psychophysical testing. We predicted that patients would display differential deficits across acoustic features, and present a mediated relationship between tone-matching levels of complexity. Second, we investigated the CAS functioning associated with tone-matching at a neurophysiological level, using resting-state functional connectivity MRI (rsFC-MRI) and CAS-targeted transcranial electrical stimulation (left fronto-temporal tES, 2mA, random noise current, ten 20-min twice-daily sessions). We predicted that functional dysconnectivity within the CAS would be associated with tone-matching impairments, and that tES would significantly modulate these impairments in patients. As complementary, we reviewed historical aspects of basic auditory explorations in SZ and studies investigating basic auditory-training approaches as a potential remediative treatment. Psychophysical studies demonstrated more prominent deficits for length than pitch and, in turn, than intensity (n=29), and showed that 3-tones discrimination mediates the correlation between 2-tones and auditory emotion recognition deficits (n=27). Neurophysiological approaches showed that tone-matching performances are bimodally distributed across SZ subjects (n=310), with one group (SZ-) showing significant reductions in both tone-matching and rsFC-MRI in regions of the bilateral CAS (i.e., between MGN and both EA and AA, as well as reductions between EA and AA, particularly involving parcels which are immediately adjacent to EA), and one group (SZ+) showing intact tone-matching and significant reductions only in EA-AA connectivity. The investigation of CAS-targeted tES impact on tone-matching abilities in patients is still ongoing, but preliminary results demonstrated significant modulations of tone-matching scores after the tES procedure (n=2). Our results demonstrate that SZ individuals present with different patterns of tone-matching deficits across acoustic features, but similar yet hierarchical levels of impairments for processing of simple vs. more complex auditory stimuli. Nevertheless, both feature- and complexity- dependant tone-matching deficits might be associated with different types of anatomo-functional underpinnings in the CAS. In addition, we showed that tone-matching measure segregates between discrete SZ subgroups presenting distinct topographic patterns of functional dysconnectivity in the CAS. Finally, tone-matching deficits might be related to neuronal excitability and plasticity mechanisms in the SAC that are modulated by tES. As tone-matching paradigms can be readily implemented within routine clinical settings, these experimental results may be useful to permit differentiation of discrete subtypes of SZ and to develop both non-invasive brain stimulation and remediative approaches

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La douleur est une expérience subjective multidimensionnelle accompagnée de réponses physiologiques. Ces dernières sont régulées par des processus cérébraux qui jouent un rôle important dans la modulation spinale et cérébrale de la douleur. Cependant, les mécanismes de cette régulation sont encore mal définis et il est essentiel de bien les comprendre pour mieux traiter la douleur. Les quatre études de cette thèse avaient donc comme objectif de préciser les mécanismes endogènes de modulation de la douleur par la contreirritation (inhibition de la douleur par une autre douleur) et d’investiguer la dysfonction de ces mécanismes chez des femmes souffrant du syndrome de l’intestin irritable (Sii). Dans un premier temps, un modèle expérimental a été développé pour mesurer l’activité cérébrale en imagerie par résonance magnétique fonctionnelle concurremment à l’enregistrement du réflexe nociceptif de flexion (RIII : index de nociception spinale) et des réponses de conductance électrodermale (SCR : index d’activation sympathique) évoqués par des stimulations électriques douloureuses. La première étude indique que les différences individuelles d’activité cérébrale évoquée par les stimulations électriques dans les cortex orbitofrontal (OFC) et cingulaire sont associées aux différences individuelles de sensibilité à la douleur, de réactivité motrice (RIII) et de réactivité autonomique (SCR) chez des sujets sains. La deuxième étude montre que l’analgésie par contreirritation produite chez des sujets sains est accompagnée de l’inhibition de l’amygdale par OFC et d’une modulation du réflexe RIII par la substance grise périaqueducale (PAG) et le cortex somesthésique primaire (SI). Dans les troisième et quatrième études, il est montré que la contreirritation ne produit pas d’inhibition significative de la douleur et du réflexe RIII chez les patientes Sii en comparaison aux contrôles. De plus, les résultats indiquent que la sévérité des symptômes psychologiques est associée au déficit de modulation de la douleur et à une hypersensibilité diffuse chez les patientes Sii. Dans l’ensemble, cette thèse précise le rôle de certaines structures cérébrales dans les multiples composantes de la douleur et dans l’analgésie par contreirritation et montre que les patientes Sii présentent une dysfonction des mécanismes spinaux et cérébraux impliqués dans la perception et la modulation de la douleur. / Pain is a subjective experience comprising multiple dimensions and is accompanied by physiological responses. These responses are regulated by neural processes that play a crucial role in cerebral and spinal modulation of pain. However, the mechanisms of this regulation are still not clear and a better understanding of these processes is essential in order to treat pain effectively. The four studies of this thesis were intended to define the central mechanisms of endogenous pain modulation by counterirritation (application of two competing noxious stimuli) and to investigate the dysfunction of these mechanisms in female patients with irritable bowel syndrome (IBS). First, an experimental model was developed in which functional magnetic resonance imaging was used to measure brain activity concurrently to the recording of the nociceptive flexion reflex (RIII: an index of spinal nociceptive processes) and skin conductance responses (SCR: an index of sympathetic activation). The first study indicates that individual differences in shock-evoked brain activity in the orbitofrontal (OFC) and cingulate cortices are associated with individual differences in pain sensitivity, motor reactivity (RIII), and autonomic reactivity (SCR) in healthy volunteers. In the second study, it is shown that counterirritation analgesia produced in healthy volunteers is accompanied by the inhibition of the amygdala by the OFC, and the inhibition of the RIII reflex by the periacqueductal gray matter (PAG) and the primary somatosensory cortex (SI). In the third and fourth studies, pain and RIII reflex were not significantly modulated by counterirritation in patients with IBS in comparison to healthy controls. Furthermore, the severity of psychological symptoms was associated with pain modulation deficits and diffuse hypersensitivity in IBS patients. Together, the results of these studies clarify the functions of pain-related activity in specific brain structures and the mechanisms underlying counterirritation analgesia. Moreover, it is concluded that patients with IBS show a dysfunction of cerebral and spinal processes involved in both the perception and modulation of pain.

La stimulation éléctrique fonctionnelle (SEF) peut améliorer de manière significative la mobilité des blessés médullaires ainsi que la stabilité et la prévention des effets secondaires. Dans le domaine de la SEF pour les membres inférieurs, le couple articulaire doit être fournie de façon appropriée pour effectuer le mouvement prévu afin de maintenir l'équilibre postural. Toutefois, les changements d'état du muscle telle que la fatigue musculaire est une cause majeure qui dégrade ses performances. En outre, la plupart des patients, dont la blessure médulaire est complète, n'ont pas le retour sensorielle qui permet de détecter la fatigue. De plus, et les capteurs de couples in-vivo ne sont pas disponibles à l'heure actuelle. Les systèmes conventionnels de commande SEF sont soit en boucle ouverte ou en boucle fermée mais cependant pas assez robustes aux changements d'état du muscle. L'objectif de cette thèse est le développement de la prédiction du couple articulaire et de la commande en boucle fermée afin d'améliorer les performances de la commande SEF en termes de précision, de robustesse et de sécurité pour les patients. Afin de prédire le couple articliare induit de la SEF, l'électromyographie (EMG) induit est utilisée pour corréler l'activité musculaire éléctrique et mécanique. Bien que la fatigue musculaire représente une variation dans le temps, une dépendance aux sujets et aux protocoles, la méthode proposée d'identification adaptative, basée sur le filtre de Kalman, est capable de prédire le couple articlaire variant dans le temps de manière systématique. La robustesse de la prédiction du couple articulaire a été evaluée lors d'une tâche de suivi de la fatigue en expérimentation chez des sujets blessés médullaires. Les résultats montrent une bonne performance de suivi des variations d'état des muscles en présence de fatigue et face à d'autres perturbations. Basée sur les performances de precision de la méthode prédictive proposée, une nouvelle stratégie de commande utilisant le retour EMG, "EMG-Feedback Predictive Control (EFPC)", est proposée afin de contrôler de manière adaptative les séquences de stimulation en compensant la variation dans le temps de l'état du muscle. De plus, cette stratégie de commande permet explicitement d'éviter d'appliquer une stimulation excessive aux patients, et de générer les séquences de stimulation appropriées pour obtenir la trajectoire désirée des couples articulaires.

Healthy bone is bombarded with many different mechanical strain derived signals during normal daily activities. One of these signals is present as a direct connective tissue strain on the cells. However, there is also the presence of an electrically charged streaming potential during this straining. The electrical potential is created from the movement of charged fluid through the small bone porosities. To date, little focus has been applied to elucidating the possible synergistic effects of these two stimulants. The aim of this project was to evaluate the effects of mechanical strain and indirect electrical stimulation upon the development of bone forming osteoblast cells and any possible synergistic effects of the two stimulants. This aim was achieved by using a novel device, designed and developed with the capability of creating a cell substrate surface strain along with an exogenous electrical stimulant individually or at the same time. Proliferation and differentiation were determined as a measure of cellular development. The indirect electrical stimulation was achieved through the use of a pulsed electromagnetic field (PEMF) while the mechanical strain was produced from dynamic stretching of a deformable cell substrate. Strain and strain rate were modelled from recent studies proposing that relatively high frequency, low strain osteogenic mechanical stimulants are more indicative of what healthy bone would be experiencing during normal activities. The PEMF signal mimicked a clinically available bone growth stimulator signal. Results showed a PEMF stimulus on monolayers of SaOS-2 and MG-63 osteoblast-like cells leads to a depression in proliferation. A concomitant increase in alkaline phosphatase production was also observed for the SaOS-2 cultures, but not for the MG-63 cell line. It was hypothesised that this was due to the MG-63's lack of phenotypic maturity compared to the SaOS-2 cells. Mechanical strain of the cell substrate alone, at a relatively high frequency (5Hz) but small strain, did not significantly effect either cell proliferation or differentiation for the MG-63 cells. However, when the electrical and mechanical stimulants were combined a significant increase in cellular differentiation occurred with MG-63 cultures, revealing a possible synergistic effect of these two stimulants on the development of bone cells.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Este estudo teve como objetivo verificar, através de uma revisão sistemática de ensaios clínicos aleatorizados, os benefícios da estimulação elétrica funcional endovaginal ou dos tratamentos conservadores às pacientes com incontinência urinária de esforço, e demonstrar qual modalidade de tratamento conservador apresenta melhores resultados na terapêutica dessas mulheres: a estimulação elétrica funcional endovaginal, em comparação com os cones vaginais ou a realização de exercícios perineais. Para tanto, foram realizadas buscas nas principais bases de dados científicos, por estudos que atendessem a pergunta da pesquisa, tipo de intervenção e tipo de participantes selecionados. Destes, foram selecionados 7 estudos que foram submetidos à análise dos revisores, que avaliaram os seguintes desfechos: episódios de perda urinária, quantificação das perdas urinárias através do pad-test, força da musculatura perineal, qualidade de vida, volume residual, capacidade cistométrica máxima, melhora dos sintomas, satisfação e cura. Todas as terapias pesquisadas apresentaram melhora dos sintomas da incontinência urinária de esforço; no entanto, segundo os desfechos avaliados, apresentaram diferença no resultado comparativo. Quanto às perdas urinárias, ao pad-test e à força da musculatura perineal, a realização dos exercícios pélvicos obteve os melhores resultados. Já a terapia por estimulação elétrica endovaginal e a terapia com os cones apresentaram resultados semelhantes, não sendo encontrada diferença significativa em nenhum dos desfechos analisados. De acordo com os achados obtidos nesta revisão sistemática, entendemos que o tratamento pela estimulação elétrica traz benefícios às pacientes com incontinência urinária de esforço. Os exercícios pélvicos demonstraram ser a terapia que reduz mais significativamente os sintomas ocasionados por esta condição / This study aimed to verify, through a systematic review of randomized clinical trials, if the endovaginal functional electrical stimulation provides or not benefits to patients with stress urinary incontinence, and show what kind of conservative treatment produces better results in the treatment of these women: endovaginal functional electrical stimulation, vaginal cones or perineal exercises. To do so, we searched in major scientific databases for studies that met the research question, type of intervention and type of selected participants. Of these, seven studies were selected and analyzed by the reviewers who assessed the following outcomes: frequency of urinary leakage, quantification of urinary leakage through the pad-test, perineal muscle strength, quality of life, residual volume, maximum cystometric capacity, improvement, satisfaction and healing. All therapies surveyed showed improvement of symptoms of stress urinary incontinence; however, according to the outcome parameters, they showed differences in the comparative result. As for urinary leakage, the pad-test and strength of the perineal muscles, the pelvic exercises achieved the best results. The electrical stimulation therapy and transvaginal cone therapy showed similar results, no significant difference was found in any of the outcomes. According to the findings of this systematic review, we believe that treatment by electrical stimulation is beneficial to patients with stress urinary incontinence. The pelvic exercises have proven to be the therapy that more significantly reduces the symptoms caused by this 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.