Šio darbo metu tirta skirtingų rTMS parametrų įtaka galvos smegenų bioelektriniam aktyvumui. Atlikus EEG duomenų spektrinę analizę, pademonstruota, jog aukšto dažnio rTMS virš KPFDLŽ, skirtingai nuo žemo dažnio rTMS virš DPFDLŽ, stimuliuojant aštuoniukės formos rite, statistiškai patikimai padidina alfa bangų dažnių diapazono absoliučią galią dešiniajame pusrutulyje. Paminėtina ir tai, kad po gydymo kurso rTMS aštuoniukės formos rite Kleino protokolu, skirtingai nei klasikiniu protokolu, frontalinėje srityje alfa bangų dažnio diapazone statistiškai reikšmingai sumažėja (F7-F8)/(F7+F8) asimetrijos koeficientas. Svarbu pažymėti, jog po rTMS stimuliacijos apvalia rite, palyginus su stimuliacija aštuoniukės formos rite, registruojami labiau išplitę, sudėtingesni smegenų bioelektrinio aktyvumo pokyčiai. / Recently rTMS emerged as a new clinical tool for the treatment of major depressive disorder. rTMS is noninvasive and easily tolerated method that is able to alter bioelectrical brain activity. This phenomenon is achieved by using alternating magnetic fields to induce electric currents in cortical tissue. Nowadays it is widelly accepted that lateralized alterations in brain activity might play a role in depressive symptoms. It has been found that major depressive disorder patients exhibit greater right frontal activity in contrast to left frontal hypoactivation (it should be noted, that cortical activity is inversely related with alpha power). Therefore rTMS is a potential method that can help to re-eastablish normal brain activity. In this study we examined effects of different rTMS parameters (protocols and stimulation coils) on bioelectrical brain activity modulation in patients with the treatment resistant major depressive disorder. It was shown that 10 Hz stimulation with the figure-eight coil over the left prefrontal area increases alpha power in the right hemisphere. In addition, it was demonstrated that 1 Hz stimulation over the left prefrontal cortex changes frontal alpha asymmetry. It should be underlined, that there appears to be no significant difference in clinical efficacy between the two protocols. It was also demonstrated that changes in frontal alpha asymmetry tend to correlate with the outcome of the treatment. Furthermore, it was shown that stimulation with... [to full text]

La commande de la ventilation chez l'humain est capable d'adaptation persistante qui repose sur des mécanismes de type LTP. Différentes techniques permettant l'induction de plasticité sont couramment utilisées mais leur application au contrôle ventilatoire n'a fait l'objet que de très peu de travaux.L'objectif de cette thèse est (1) examiner la possibilité d'induire des mécanismes de type LTP par la rTMS et la tsDCS en deux sites de la commande ventilatoire destinée au diaphragme, l'AMS et les métamères C3-C5 ; (2) évaluer les conséquences sur le profil ventilatoire en ventilation de repos et lorsque la ventilation est artificiellement contrainte. Nous avons examiné les effets d'un conditionnement inhibiteur appliqué par rTMS en regard de l'AMS sur l'excitabilité corticophrénique. Nous avons observé la présence d'une diminution persistante de cette excitabilité et en avons tiré la proposition qu'en ventilation de repos l'AMS augmente l'excitabilité de la commande ventilatoire à l'éveil. Nous avons alors considéré les conséquences de la rTMS sur la ventilation expérimentalement contrainte. Les modifications du profil ventilatoire induites par la rTMS sont en faveur d'une participation de l'AMS à la production ou au traitement de la copie d'efférence. Dans une 3ème étude, nous avons examiné les effets de la tsDCS au niveau C3-C5 sur l'excitabilité corticophrénique et sur le profil ventilatoire. L'augmentation de cette excitabilité et du volume courant nous a conduit à suggérer la possibilité d'induire une plasticité respiratoire au niveau spinal.L'ensemble de ces résultats nous permet d'envisager des perspectives thérapeutiques à l'utilisation de la rTMS et de la tsDCS. / A salient feature of the ventilatory control system is its ability to persistently adapt its behaviour. This stems from long-term plasticity mechanisms similar to those described for the neural control in general. Plasticity can be induced by various non-invasive stimulation techniques(e.g. rTMS, TDCS, tsDCS) that are commonly used but have not be systematically applied to ventilatory plasticity. The aim of this thesis is twofold: (1) to examine the possibility of inducing LTP by rTMS and tsDCS at two sites of the ventilatory control system, namely the SMA and the phrenic motoneurons: (2) to evaluate the impact of such plasticity on breathing pattern during spontaneous ventilation and inspiratory threshold loading. We examined the effects of an inhibitory rTMS paradigm applied to the SMA on corticophrenic excitability. We observed a persistent decrease in corticophrenic excitability and therefore proposed that the SMA participates in the increased resting state of the ventilatory motor system during wake. Then we considered the consequences of rTMS on breathing pattern during ITL. The corresponding modifications support a contribution of the SMA to the production or processing of an ventilatory efference copy. In a third study, we examined the effects of a tsDCS delivered to C3-C5 on the corticophrenic excitability and on the respiratory pattern. Increased corticophrenic excitability and tidal volume were observed. This suggests that respiratory plasticity takes place at the spinal level. Taken together, these results open the perspective of harnessing respiratory plasticity as a therapeutic tool in disorders altering the ventilatory command.

Four experiments, using both humans and monkeys as participants, were conducted to investigate the similarities and differences in human and nonhuman primate numerical cognition. In Experiment 1 it was determined that both humans and monkeys display a SNARC effect, with similar symbolic distance effects for both species. In addition, both species were found to respond faster to congruent stimulus pairs. In Experiment 2 both species were found accurately to recognize quantitative stimuli when presented for durations of 150 msec in a divided visual field paradigm. Performance for humans and monkeys for numerals and dot-patterns was almost identical in terms of accuracy and response times. In Experiment 3 participants were required to make relative numerousness judgments in a divided visual field paradigm. Both species responded faster and more accurately to stimuli presented to the right visual field. Species differences appeared, with monkeys performing equally well on both trial types whereas the humans performed better on numeral trials than on dot trials. In Experiment 4 repetitive transcranial magnetic stimulation (rTMS) was combined with the divided visual field paradigm. Accuracy was significantly disrupted for both species when compared to a no stimulation condition. A facilitation effect was also evident with both species exhibiting significant decreases in response time for all trials. Right-handed participants took longer to respond to stimuli presented to the left visual field. These findings add to the body of knowledge regarding both the similarities and differences of how quantitative stimuli are processed by humans and monkeys.

Ce travail de thèse a pour principal objectif d'évaluer, au moyen de l'électro-encéphalographie de haute densité (EEG-HD), la plasticité de la représentation somato-sensorielle de la main chez l'Homme induite par neurostimulation non-invasise. Cette étude a pris sa source dans le constat que la stimulation cérébrale du cortex moteur représente une alternative thérapeutique efficace pour les patients qui souffrent de douleurs neuropathiques pharmaco-résistantes. Les mécanismes responsables de l'analgésie induite par la stimulation magnétique trans-crânienne répétitive (rTMS) sont encore mal connus, mais la séduisante hypothèse selon laquelle la stimulation du cortex moteur pouvait induire une plasticité dans le cortex somatosensoriel a été évoquée. Nos travaux de thèse s'attachent à déterminer, chez le sujet sain, les effets de la rTMS réalisée en regard de l'aire motrice de la main sur sa représentation somatotopique dans le cortex somatosensoriel. Dans le premier chapitre de ce document nous décrivons les réseaux anatomiques de transmission et perception somesthésique, avant de revoir dans le Chapitre 2 la littérature pertinente sur la représentation somatotopique du cortex sensoriel primaire (S1). De nombreuses études démontrent que cette représentation n'est nullement figée, mais peut au contraire évoluer suite à des lésions somatosensorielles sous-corticales ou corticales ; la littérature spécifique à ce phénomène de plasticité post-lésionnelle est revue dans le Chapitre 3, ainsi que les données suggérant le rôle de cette plasticité dans le développement de douleurs neuropathiques. Les patients souffrant de ce type de douleurs peuvent avoir recours à la stimulation du cortex moteur, notamment au moyen de techniques non invasives comme la rTMS. Les particularités techniques et les effets physiologiques de cette méthode sont tout d'abord présentés dans le Chapitre 4, avant d'exposer les effets analgésiques de la rTMS. Les travaux réalisés au cours de cette thèse sont exposés sous forme d'articles (Chapitres 5 & 6). Nous avons dans un premier temps cherché à déterminer une méthodologie robuste qui permet d'évaluer la représentation somatotopique de la main à l'aide des Potentiels Evoqués Somesthésiques (PES) obtenus par la stimulation de quatre sites distincts de la main (Auriculaire-Pouce-Nerf Cubital-Nerf Radial). La détermination de la représentation corticale de la main dans S1 était plus reproductible et robuste sur les réponses précoces de l'aire 3b (N20/P20) que sur celle des aires 1-2 (P45). Une estimation adéquate de l'étendue de la main basée sur le couple " pouce - nerf cubital " était possible avec 64 et 128 électrodes. Lorsque l'étendue de la main était considérée avec le couple de stimulation standard " auriculaire - pouce ", le plus haut niveau d'échantillonnage spatial était nécessaire. C'est pourquoi nous avons choisi le premier couple pour l'étude des possibles changements de la représentation corticale de la main suite à l'application de la rTMS, sous deux modalités distinctes (20 Hz et mode theta-burst intermittent -iTBS). Les deux modes de rTMS entraînent une certaine plasticité de la représentation somatotopique de la main dans S1, avec toutefois quelques nuances : les changements liés au mode " theta burst " étaient variables d'un sujet à l'autre et non significatifs sur la mesure d'étendue de la main. La rTMS à 20 Hz quant à elle, induisait des modifications très significatives et bien reproductibles. De plus, ce mode de stimulation était le seul à induire une augmentation du seuil nociceptif. Ces différences peuvent s'expliquer par des mécanismes d'action différents ou par des différences dans le nombre total de stimuli corticaux administrés. Bien que nos résultats suggèrent que la rTMS à haute fréquence est capable d'induire des modifications plastiques significatives et d'augmenter la représentation corticale de la région stimulée, il reste à déterminer si cette plasticité est à même d'être modifié par la rTMS à 20 Hz chez des patients souffrant de douleurs neuropathiques, et dans ce cas si elle est ou non associée aux effets analgésiques induits par ce type de technique non invasive.

La douleur neuropathique centrale est une affection fréquente dont le traitement est complexe. En raison d’un important taux de résistance aux traitements pharmacologiques, des techniques de neuromodulation ont été développées. Parmi elles, on retrouve les stimulations du cortex moteur primaire (ou gyrus précentral), invasive (i.e. stimulation électrique épidurale, eMCS) et non-invasive (i.e. stimulation magnétique transcrânienne répétitive, rTMS). Ces techniques restent limitées par différents paramètres. La rTMS a principalement été étudiée à travers des séances uniques, et son efficacité comme moyen thérapeutique au long cours reste mal connue. La eMCS souffre d’un manque de prédicteurs individuels d’efficacité suffisamment robustes pour sélectionner à bon escient les candidats à la chirurgie. Enfin, le cortex moteur primaire est une cible de découverte empirique, et d’autres cibles sont à envisager pour améliorer les résultats de ces neuromodulations corticales. Notre travail avait pour objectif l’amélioration des connaissances vis à vis de ces différentes limites. Il s’est articulé autour de 3 axes principaux :- L’étude de la rTMS en séances répétées, au long cours, comme moyen thérapeutique à part entière. - L’étude de la rTMS en séances répétées comme moyen de prédiction de la réponse antalgique à la eMCS.- Le développement de méthodes permettant la localisation fiable et reproductible du cortex pré-frontal dorsolatéral comme cible alternative de stimulation. / Central neuropathic pain is a frequent and hard to treat condition. Because of a large amount of drug-refractoriness, neuromodulation techniques have been developed. Among them, the mostly used is motor cortex stimulation, which can be both invasive (epidural motor cortex stimulation (eMCS)) and non-invasive (repetitive magnetic transcranial stimulation (rTMS)). These techniques remain limited by different problems: On one side, rTMS has been mainly studied through unique session practice and its use for pain therapy in a long-term scale remains not well understood. On the other side, eMCS suffers from a lack of predictability: A great proportion of patients present an insufficient relief, making eMCS less and less used. Finally, the motor cortex target is a chance discovery, and some other targets could be intended to improve the results. This work had the increase of knowledge about cortical stimulations as a main goal, especially about their different limitations. This work concentrated on 3 aims: - The study of chronic, repeated sessions of rTMS, used as a long-term tool for pain therapy. - The study of repeated rTMS sessions to predict eMCS.- The development of reliable tool to help to localize others cortical targets.

La douleur neuropathique centrale est une séquelle fréquente après une atteinte du système nerveux centrale. L’impact négatif de ces douleurs sur la qualité de vie des patients ainsi que l’efficacité modérée (40% de répondeurs) des traitements de 1ère intention font de la recherche de thérapies alternatives un enjeu clinique majeur. Depuis plusieurs années, la technique de stimulation magnétique transcrânienne répétée (rTMS) est présentée comme un outil intéressant pour soulager ce type de douleur sans pour autant que son efficacité clinique n’ait été clairement démontrée. Ce travail de thèse s’attache donc à investiguer l’efficacité de la rTMS pour traiter les douleurs neuropathiques centrales. Nous avons dans un premier temps mis en évidence, dans une étude observationnelle, qu’un minimum de 4-5 séances sur deux mois de rTMS à 20HZ sur le cortex moteur primaire (M1) produit un soulagement de la douleur pouvant se maintenir même après une année de stimulation. Afin d’écarter un possible effet placebo, nous avons objectivé l’efficacité antalgique en répliquant ce protocole dans une étude clinique randomisée, contrôlée, en groupes croisés. Les résultats obtenus confirment ceux de l’étude observationnelle puisque que l’effet antalgique de la rTMS active était significativement supérieure à la stimulation placebo pour le critère principal (% de soulagement, +33%) ou l’intensité douloureuse (EVA, -19%), avec 47% de répondeurs. Pour les patients non-répondeurs à la stimulation de M1, nous avons également testé contre placebo, dans une étude randomisée, l’efficacité d’une cible alternative : le cortex somesthésique secondaire (S2). Aucun des patients n’a été soulagé par cette stimulation mais le faible effectif de cette étude ne nous permet pas de conclure définitivement à l’absence d’effet antalgique. Enfin, compte tenu de l’utilisation croissante de nouvelles cibles corticales plus profondes, nous avons à partir de l’enregistrement du champ-magnétique produit par la rTMS dans différents milieux (l’air et modèle ex-vivo), proposé un modèle de distribution de ce champ selon la profondeur de la cible et le type de sonde de stimulation utilisé. Pour conclure, ces travaux objectivent l’effet antalgique de 4 séances de rTMS à 20Hz de M1 sur les douleurs neuropathiques centrales, validant ainsi son utilisation lorsque les traitements de 1ère intention ont échoué. Les résultats obtenus par la stimulation de S2 ainsi que par la modélisation du champ magnétique doivent permettre à de futures études d’explorer de nouvelles cibles corticales pour les patients qui restent encore en échec de traitement. / Central neuropathic pain is a common sequelae after central nervous system injury. Its negative consequences on the quality of life and the moderate efficacy (40% of responders) of first-line treatments make the search for alternative therapies a major clinical challenge. For several years, the technique of repeated transcranial magnetic stimulation (rTMS) is presented as an interesting tool to relieve this sort of pain even though its clinical efficacy has not been clearly demonstrated. The aim of this thesis was to investigate the effectiveness of rTMS to relieve central neuropathic pain.We first demonstrated, in an observational study, that a minimum of 4-5 sessions over two months of rTMS at 20HZ on the primary motor cortex (M1) produces pain relief that can be maintained even after a year of stimulation. In order to rule out a possible placebo effect, we objectified the analgesic efficacy by replicating this protocol in a randomized, controlled, cross-over clinical study. The results obtained confirm those of the observational study since the analgesic effect of the active rTMS was significantly greater than the placebo stimulation for the main criterion (% of pain relief, +33%) or pain intensity (VAS, -19%), with 47% of responders. For patients who did not respond to M1 stimulation, we also tested the efficacy of an alternative target in a randomized study: the secondary somatosensory cortex (S2). None of the patients were relieved by this stimulation, but the small size of this study does not allow us to definitively conclude that there is no analgesic effect. Finally, given the increasing use of new deeper cortical targets in rTMS for pain treatment, we have from the recording of the magnetic field produced by the rTMS in different media (air and ex-vivo model), proposed a magnetic-field distribution model according to the depth of the target and the type of stimulation coils used.To conclude, this work objectify the analgesic effect of 4 rTMS sessions at 20 Hz of M1 to relieve central neuropathic pain, validating its use when first-line treatments have failed. The results obtained by S2 stimulation as well as magnetic field modeling should allow future studies to explore new cortical targets for patients who are still failing treatment

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A depressão pós-parto (DPP), tal como o episódio depressivo maior, é uma manifestação psiquiátrica comum, caracterizada pela presença de alterações de humor, cognitivas, comportamentais, psicomotoras e vegetativas. Afeta a qualidade da interação mãe-bebê prejudicando a responsividade materna o que pode repercurtir negativamente na manutenção salutar do desenvolvimento da criança. Esta manifestação apresenta prevalência estimada entre 10 e 20%, considerando as mulheres que desenvolvem sintomas nas primeiras semanas depois do parto. As opções de tratamento incluem drogas antidepressivas e eletroconvulsoterapia (com anestesia). Porém, como ambas terapêuticas envolvem abordagens farmacológicas, há contra-indicação devido à toxidade que impediria a amamentação. Entretanto, existe uma preocupação sobre como garantir a eficácia do tratamento sem prejudicar o bebê. A Estimulação Magnética Transcraniana Repetitiva (EMTr), por ser uma técnica já consagrada quanto a eficácia antidepressiva, não toxicológica, indolor, não invasiva e bem tolerada para estimular o cérebro, parece ser uma boa alternativa de tratamento. Nos quadros depressivos em geral, são observados prejuízos substanciais a várias funções cognitivas cujas alterações cognitivas apresentadas são, em grande parte, semelhantes àquelas relacionadas a alterações do funcionamento do córtex pré-frontal. A função executiva é um dos principais domínios cognitivos afetados nos transtornos depressivos, geralmente avaliada por testes como Trail Making e o teste de Stroop. A presença de depressão em pacientes puerperais parece intensificar as alterações cognitivas, especialmente as funções associadas ao lobo frontal, além do que, também prejudicam o comportamento causando danos no funcionamento social global. No presente estudo, randomizado, controlado e duplo-cego, investigaram-se os possíveis efeitos da EMTr no funcionamento cognitivo e sua repercussão comportamental: Estimulação Magnética Transcraniana de repetição (EMTr) aplicada ao córtex prefrontal dorsolateral esquerdo (CPFDLE). Uma amostra inicial de dez pacientes com DPP foram distribuídos em dois grupos. Sete participantes de um dos grupos receberam EMTr ativa e três, do grupo controle, EMTr placebo. Os parâmetros utilizados na EMTr foram: freqüência de 5 Hz, intensidade de 120% do limiar motor, em intervalos de 10 segundos ligado e 20 segundos desligado, com 25 séries por dia (2500 pulsos), durante 20 dias (quatro semanas) com dois dias de pausa semanal. Os pacientes e os avaliadores eram cegos ao tipo de tratamento de cada grupo. A avaliação neuropsicológica se deu através de testes cognitivos relacionados às funções prejudicadas em quadros depressivos e com a área estimulada (CPFDLE). Foram também aplicadas as escalas de Adequação Social (EAS) de Weissmann e Bothwell para avaliar o comportamento funcional social global, de depressão de Hamilton, 17 itens, e de depressão pós-parto de Edinburgh. As avaliações foram realizadas em três momentos: antes do início do tratamento (T0), após 4 semanas (T2) e após 6 semanas (T3). Como principais resultados foram observadas: melhora significativa no quadro depressivo ao longo do tratamento e um melhor ajustamento comportamental no funcionamento social global geral, especialmente no contexto das relações familiares; ausência de efeitos negativos em todos os testes cognitivos após o tratamento com EMTr; desempenho superior do grupo EMTr ativa em comparação com o grupo EMTr placebo, principalmente no teste de Rey auditory Verbal Learning (RAVLT) evocação pós-interferência e tardia pós-trinta minutos, no teste Trail Making Parte A e no teste de Stroop Cores. Além disso, o melhor desempenho cognitivo observado no grupo EMTr ativa viii comparado ao grupo EMTr placebo, entre T0 e T4, foi mantido na semana 6 (T6) e por vezes até melhorou sutilmente, indicando que o efeito da estimulação mantém-se estável por, pelo menos 2 semanas após o término do tratamento. Discutem-se como possíveis fatores para esses resultados: ação local da EMTr, alteração dos níveis de alguns neurotransmissores como dopamina e serotonina, relação com a melhoria do quadro depressivo e possível efeito de aprendizado pela repetição em curto período de tempo entre as testagens. Concluí-se que, baseados em uma amostra de apenas 10 pacientes, a EMTr, no que diz respeito aos efeitos antidepressivos, no comportamento frente ao funcionamento social global e às funções cognitivas, não produziu efeitos negativos e sim, produziu alguns efeitos positivos. Esta melhora é de fundamental importância, para o bem estar da mãe e conseqüentemente para o desenvolvimento neuropsicomotor, afetivo e comportamental do bebê. Isto trará desdobramentos que poderão perdurar por toda uma vida para esta criança. Além disto, a segurança da EMT, já amplamente comprovada em outros estudos, poderá, em um futuro próximo, torná-la terapêutica de primeira escolha para este grupo de pacientes. / The postpartum depression (PPD) as the major depressive episode is a common psychiatric manifestation, characterized by the presence of mood, cognitive, behavioral, psychomotor and vegetative changes. It affects the quality of mother-infant interaction jeopardizing the maternal responsiveness, which may adversely affect the maintenance of a healthy development of children. This event presents the estimated dominance between 10 and 20%, taking into account women who develop symptoms in the first weeks after delivery. Treatment options include antidepressant drugs and electroconvulsive therapy (with anesthetic). However, as both treatments involve pharmacological approaches, there is counter-indication because of toxicity that would preclude breastfeeding. Nevertheless, there is concern about the efficiency of the treatment without causing any harm to the baby. The repetitive Transcranial Magnetic Stimulation (rTMS), as it is a technique already established for antidepressant efficacy, non-toxic, painless, non-invasive and well-tolerated to stimulate the brain, it seems to be a good alternative for treatment. For general depressive conditions, substantial damages have been noticed to several cognitive functions, in which the presented cognitive changes are, in large part, similar to those related to changes in the functioning of the pre-frontal cortex (PFC). The executive function is one of the major cognitive domains affected in depressive disorders, usually assessed by tests such as Trail Making and Stroop test. The presence of depression in puerperal patients seems to strengthen cognitive changes; especially those associated to frontal lobe functions, in addition to that, it also affects the behavior causing harm to the overall social functioning. In this study, randomized, controlled and double-blind, possible effects of rTMS in the cognitive functioning and its behavioral effect were assessed: Repetitive Transcranial Magnetic Stimulation (rTMS) applied to left-dorsum-lateral-prefrontal-cortex (LDLPC). An initial sample of ten patients with PPD was divided into two groups. Firstly, seven participants in one of the groups received active rTMS and, three, of the control group, placebo rTMS. The parameters used in rTMS were: frequency of 5 Hz, intensity of 120% of the motor threshold, at intervals of 10 seconds on and 20 seconds off, with 25 sets per day (2500 pulses), during 20 days (four weeks) with two days of rest per week. Patients and evaluators were blinded to the type of treatment for each group. The neuropsychological assessment was carried out by means of cognitive tests related to impaired functions in depressive conditions and with the stimulated area (LDLPC). Social Adjustment Scal (SAS-SR) of Weissmann & Bothwell was also applied to assess the overall social functional behavior, of Hamilton depression, 17 items, and Edinburg postpartum depression. Evaluations were performed on three occasions: before starting the treatment (T0), after 4 weeks (T2) and after 6 weeks (T3). The main results were: significant improvement regarding the depression condition throughout the treatment and a better behavioral adjustment in the general overall social functioning, especially in the context of family relationships, lack of negative effects on all cognitive tests after treatment with rTMS; superior performance of the active rTMS group compared to the placebo rTMS group, especially in the Rey Auditory Verbal Learning Test (RAVLT) post-interference and late evocation after thirty minutes in the Trail Making Test - Part A and the Colors - Stroop Test. Further, the best cognitive performance was observed in the active rTMS group compared to placebo rTMS group, between T0 and T4, was maintained at week 6 (T6) and sometimes even improved slightly, indicating that the effect of the stimulation remains stable by at least 2 x weeks after the end of the treatment. It has been discussed as possible factors for these results: local rTMS action, change in the levels of some neurotransmitters such as dopamine and serotonin, relationship with the improvement of the depressive condition and possible learning effect by repetition within a short period of time between tests. Ergo, based on a sample of only 10 patients, the rTMS, regarding antidepressant effects, the behavior compared to the overall social functioning and cognitive functions, it did not yield negative effects, however it rendered some positive effects. This improvement is of primary importance for the welfare of the mother hence to the babys neuro-psychomotor, emotional and behavioral development. This will bring further outcomes that may last for the whole life for this child. In addition, the safety of TMS, which has been already proven in other researches, may, in the near future, make it a first-choice therapy for this group of patients

La stimulation magnétique transcranienne (SMT) est une technique non invasive qui permet de stimuler le cerveau. Les SMT répétitives (SMTr), c'est-à-dire l'application de nombreuses impulsions magnétiques, sont capable d'induire des modifications de longue durée de l'excitabilité neuronale. La SMT s'est développée dans un but thérapeutique et scientifique. Les effets après la SMTr sur le cortex moteur sont bien documentés chez les individus sains, mais on en sait moins sur la stimulation du cortex préfrontal dorso-latéral (DLPFC).L'objectif de cette thèse était de comparer différents protocoles SMTr sur des sujets sains et de trouver des marqueurs électroencéphalograpiques (EEG) de la réponse ou pas à la thérapie SMTr dans la dépression majeure et bipolaire. La principale originalité de la méthode présentée est la comparaison intra-sujet d'effets entre-protocoles et le développement de techniques de localisation de sources.Nous avons étudié chez 20 sujets sains comment les oscillations corticales sont modulées suite à quatre protocoles SMTr actifs différents, et à un protocole sham utilisé comme contrôle, du DLPFC gauche et en comparant la puissance spectrale d'EEG avant et après SMTr de durée de 15 minutes. Le spectre EEG a été estimé grâce à la transformée de Fourier rapide (FFT) et partitionné en bandes de fréquence selon la classification commune.Nous avons trouvé pour chaque protocole actif une diminution significative de puissance delta et theta sur les électrodes préfrontales gauches, principalement localisées dans le DLPFC gauche. Dans des bandes de fréquences plus hautes, la diminution de puissance dans le DLPFC a été de plus observée dans le DLFPC controlatéral et dépend du protocole de stimulation. Parce que les activités delta et theta sont généralement associées à l'inhibition corticale, ces résultats suggérent que la SMTr du DLPFC diminue transitoirement l'inhibition corticale locale. Aussi, les oscillations d'EEG rapides sont associées à l'excitabilité corticale et on peut conclure que des diminutions observées non spécifiques dans l'activité rapide localisée dans le DLPFC suggérent également une réduction de l'excitabilité corticale.Dans la deuxième expérience, nous avons travaillé sur groupe de patients, souffrant de trouble dépressif majeur (MDD) et de trouble bipolaire (BP). Dans cette étude ouverte, nous avons cherché à déterminer s'il existe des différences d'EEG de repos dans l'activité cérébrale entre patients BP et MDD, et entre les répondeurs et non-répondeurs à la SMTr à 10 Hz en étudiant des biomarqueurs d'EEG. Le protocole SMTr à 10 Hz étaient le même entre patients MDD et BP. Les propriétés EEG dans les deux troubles dépressifs ont été étudiées, en comparant la puissance spectrale des enregistrements pré- et post-SMTr EEG au cours des sessions thérapeutiques chez les patients répondeurs et non-répondeurs.La conclusion est qu'il est possible de distinguer les répondeurs des non-répondeurs au traitement SMTr. Les répondeurs avaient une puissance en basse fréquence plus importante. Une augmentation de puissance alpha a aussi été observée au niveau du cortex cingulaire ventral dans les deux groupes. La comparaison des MDD et BP a révélé une activité significativement plus élevée dans la puissance des bandes thêta et bêta chez les patients BP, principalement localisée dans le cortex préfrontal.

A depressão pós-parto (DPP), tal como o episódio depressivo maior, é uma manifestação psiquiátrica comum, caracterizada pela presença de alterações de humor, cognitivas, comportamentais, psicomotoras e vegetativas. Afeta a qualidade da interação mãe-bebê prejudicando a responsividade materna o que pode repercurtir negativamente na manutenção salutar do desenvolvimento da criança. Esta manifestação apresenta prevalência estimada entre 10 e 20%, considerando as mulheres que desenvolvem sintomas nas primeiras semanas depois do parto. As opções de tratamento incluem drogas antidepressivas e eletroconvulsoterapia (com anestesia). Porém, como ambas terapêuticas envolvem abordagens farmacológicas, há contra-indicação devido à toxidade que impediria a amamentação. Entretanto, existe uma preocupação sobre como garantir a eficácia do tratamento sem prejudicar o bebê. A Estimulação Magnética Transcraniana Repetitiva (EMTr), por ser uma técnica já consagrada quanto a eficácia antidepressiva, não toxicológica, indolor, não invasiva e bem tolerada para estimular o cérebro, parece ser uma boa alternativa de tratamento. Nos quadros depressivos em geral, são observados prejuízos substanciais a várias funções cognitivas cujas alterações cognitivas apresentadas são, em grande parte, semelhantes àquelas relacionadas a alterações do funcionamento do córtex pré-frontal. A função executiva é um dos principais domínios cognitivos afetados nos transtornos depressivos, geralmente avaliada por testes como Trail Making e o teste de Stroop. A presença de depressão em pacientes puerperais parece intensificar as alterações cognitivas, especialmente as funções associadas ao lobo frontal, além do que, também prejudicam o comportamento causando danos no funcionamento social global. No presente estudo, randomizado, controlado e duplo-cego, investigaram-se os possíveis efeitos da EMTr no funcionamento cognitivo e sua repercussão comportamental: Estimulação Magnética Transcraniana de repetição (EMTr) aplicada ao córtex prefrontal dorsolateral esquerdo (CPFDLE). Uma amostra inicial de dez pacientes com DPP foram distribuídos em dois grupos. Sete participantes de um dos grupos receberam EMTr ativa e três, do grupo controle, EMTr placebo. Os parâmetros utilizados na EMTr foram: freqüência de 5 Hz, intensidade de 120% do limiar motor, em intervalos de 10 segundos ligado e 20 segundos desligado, com 25 séries por dia (2500 pulsos), durante 20 dias (quatro semanas) com dois dias de pausa semanal. Os pacientes e os avaliadores eram cegos ao tipo de tratamento de cada grupo. A avaliação neuropsicológica se deu através de testes cognitivos relacionados às funções prejudicadas em quadros depressivos e com a área estimulada (CPFDLE). Foram também aplicadas as escalas de Adequação Social (EAS) de Weissmann e Bothwell para avaliar o comportamento funcional social global, de depressão de Hamilton, 17 itens, e de depressão pós-parto de Edinburgh. As avaliações foram realizadas em três momentos: antes do início do tratamento (T0), após 4 semanas (T2) e após 6 semanas (T3). Como principais resultados foram observadas: melhora significativa no quadro depressivo ao longo do tratamento e um melhor ajustamento comportamental no funcionamento social global geral, especialmente no contexto das relações familiares; ausência de efeitos negativos em todos os testes cognitivos após o tratamento com EMTr; desempenho superior do grupo EMTr ativa em comparação com o grupo EMTr placebo, principalmente no teste de Rey auditory Verbal Learning (RAVLT) evocação pós-interferência e tardia pós-trinta minutos, no teste Trail Making Parte A e no teste de Stroop Cores. Além disso, o melhor desempenho cognitivo observado no grupo EMTr ativa viii comparado ao grupo EMTr placebo, entre T0 e T4, foi mantido na semana 6 (T6) e por vezes até melhorou sutilmente, indicando que o efeito da estimulação mantém-se estável por, pelo menos 2 semanas após o término do tratamento. Discutem-se como possíveis fatores para esses resultados: ação local da EMTr, alteração dos níveis de alguns neurotransmissores como dopamina e serotonina, relação com a melhoria do quadro depressivo e possível efeito de aprendizado pela repetição em curto período de tempo entre as testagens. Concluí-se que, baseados em uma amostra de apenas 10 pacientes, a EMTr, no que diz respeito aos efeitos antidepressivos, no comportamento frente ao funcionamento social global e às funções cognitivas, não produziu efeitos negativos e sim, produziu alguns efeitos positivos. Esta melhora é de fundamental importância, para o bem estar da mãe e conseqüentemente para o desenvolvimento neuropsicomotor, afetivo e comportamental do bebê. Isto trará desdobramentos que poderão perdurar por toda uma vida para esta criança. Além disto, a segurança da EMT, já amplamente comprovada em outros estudos, poderá, em um futuro próximo, torná-la terapêutica de primeira escolha para este grupo de pacientes. / The postpartum depression (PPD) as the major depressive episode is a common psychiatric manifestation, characterized by the presence of mood, cognitive, behavioral, psychomotor and vegetative changes. It affects the quality of mother-infant interaction jeopardizing the maternal responsiveness, which may adversely affect the maintenance of a healthy development of children. This event presents the estimated dominance between 10 and 20%, taking into account women who develop symptoms in the first weeks after delivery. Treatment options include antidepressant drugs and electroconvulsive therapy (with anesthetic). However, as both treatments involve pharmacological approaches, there is counter-indication because of toxicity that would preclude breastfeeding. Nevertheless, there is concern about the efficiency of the treatment without causing any harm to the baby. The repetitive Transcranial Magnetic Stimulation (rTMS), as it is a technique already established for antidepressant efficacy, non-toxic, painless, non-invasive and well-tolerated to stimulate the brain, it seems to be a good alternative for treatment. For general depressive conditions, substantial damages have been noticed to several cognitive functions, in which the presented cognitive changes are, in large part, similar to those related to changes in the functioning of the pre-frontal cortex (PFC). The executive function is one of the major cognitive domains affected in depressive disorders, usually assessed by tests such as Trail Making and Stroop test. The presence of depression in puerperal patients seems to strengthen cognitive changes; especially those associated to frontal lobe functions, in addition to that, it also affects the behavior causing harm to the overall social functioning. In this study, randomized, controlled and double-blind, possible effects of rTMS in the cognitive functioning and its behavioral effect were assessed: Repetitive Transcranial Magnetic Stimulation (rTMS) applied to left-dorsum-lateral-prefrontal-cortex (LDLPC). An initial sample of ten patients with PPD was divided into two groups. Firstly, seven participants in one of the groups received active rTMS and, three, of the control group, placebo rTMS. The parameters used in rTMS were: frequency of 5 Hz, intensity of 120% of the motor threshold, at intervals of 10 seconds on and 20 seconds off, with 25 sets per day (2500 pulses), during 20 days (four weeks) with two days of rest per week. Patients and evaluators were blinded to the type of treatment for each group. The neuropsychological assessment was carried out by means of cognitive tests related to impaired functions in depressive conditions and with the stimulated area (LDLPC). Social Adjustment Scal (SAS-SR) of Weissmann & Bothwell was also applied to assess the overall social functional behavior, of Hamilton depression, 17 items, and Edinburg postpartum depression. Evaluations were performed on three occasions: before starting the treatment (T0), after 4 weeks (T2) and after 6 weeks (T3). The main results were: significant improvement regarding the depression condition throughout the treatment and a better behavioral adjustment in the general overall social functioning, especially in the context of family relationships, lack of negative effects on all cognitive tests after treatment with rTMS; superior performance of the active rTMS group compared to the placebo rTMS group, especially in the Rey Auditory Verbal Learning Test (RAVLT) post-interference and late evocation after thirty minutes in the Trail Making Test - Part A and the Colors - Stroop Test. Further, the best cognitive performance was observed in the active rTMS group compared to placebo rTMS group, between T0 and T4, was maintained at week 6 (T6) and sometimes even improved slightly, indicating that the effect of the stimulation remains stable by at least 2 x weeks after the end of the treatment. It has been discussed as possible factors for these results: local rTMS action, change in the levels of some neurotransmitters such as dopamine and serotonin, relationship with the improvement of the depressive condition and possible learning effect by repetition within a short period of time between tests. Ergo, based on a sample of only 10 patients, the rTMS, regarding antidepressant effects, the behavior compared to the overall social functioning and cognitive functions, it did not yield negative effects, however it rendered some positive effects. This improvement is of primary importance for the welfare of the mother hence to the babys neuro-psychomotor, emotional and behavioral development. This will bring further outcomes that may last for the whole life for this child. In addition, the safety of TMS, which has been already proven in other researches, may, in the near future, make it a first-choice therapy for this group of patients