La pharmaco-résistance est une complication évolutive fréquente de l'épisode dépressif majeur. La rTMS est une technique de stimulation cérébrale innovante dont l'efficacité antidépressive est maintenant établie.Le premier objectif de notre travail de thèse a été de caractériser les substrats fonctionnels de la dépression pharmaco-résistante à l'aide de la technique TEMP, afin d'identifier des patterns d'anomalies cérébrales qui leur sont propres. Dans un second temps, et sur la base des travaux existant sur les mécanismes d'action de la rTMS, nous avons étudié la valeur prédictive de marqueurs fonctionnels en neuro-imagerie TEMP et par EEG. Enfin, nous avons relié l'effet cérébral de la rTMS révélé par la neuro-imagerie fonctionnelle à son efficacité antidépressive, et de façon plus globale à la qualité de vie, comme recommandé actuellement.Nos résultats montrent l'existence d'un pattern de perfusion cérébrale commun aux patients pharmaco-résistants quel que soit le type de dépression, impliquant les régions fronto-temporales et le cervelet. L'étude TEMP de la perfusion cérébrale et de l'activité cérébrale en l'EEG dans sa bande alpha semble pouvoir prédire de façon satisfaisante, avant traitement, l'amélioration clinique individuelle des patients dépressifs pharmaco-résistants traités par rTMS. L'efficacité antidépressive de la rTMS apparait équivalente quel que soit le côté stimulé, entrainant des modifications de perfusion cérébrale comparables. Enfin, nos résultats ont permis d'identifier des régions cérébrales dysfonctionnelles distinctes et confirment l'interet d'une approche complémentaire de la dépression, par l'évaluation de la qualité de vie. / Treatment-resistance is a common outcome of a major depressive episode. Repetitive transcranial magnetic stimulation has been put forward as a new technique to treat this debilitating illness. The first objective of our thesis was to characterize the functional substrates of treatment-resistant depression (TRD) using SPECT technique, in order to identify specific patterns of brain abnormalities. In a second part, based on existing work on the antidepressant mechanisms of rTMS, we investigated the predictive value of two neurofunctional biomarkers: SPECT and EEG. Finally, we studied brain SPECT perfusion changes underlying therapeutic efficiency and improvement of quality of life, as currently recommended. Our results showed the existence of a common pattern of brain perfusion in treatment-resistant patients involving the fronto-temporal regions and the cerebellum, regardless the type of depression. At baseline, SPECT brain perfusion and alpha EEG band power could predict individual clinical improvement in TRD-patients treated with rTMS. Regardless the stimulated side, the antidepressant efficacy of rTMS consisted in similar changes in cerebral perfusion. Finally, our results have identified distinct dysfunctional brain regions and confirm the interest of a complementary approach to depression, by assessing quality of life.

No description available.

INTRODUÇÃO: A dependência química engloba alterações comportamentais, cognitivas e fisiológicas. A impulsividade está presente em muitos transtornos psiquiátricos. Sobre a impulsividade na dependência química de cocaína, os estudos existentes são relativamente novos. A Estimulação Magnética Transcraniana de repetição (EMTr) é um método capaz de neuromodular o cérebro. Este estudo avaliou os efeitos da EMTr sobre a impulsividade em dependentes de cocaína. MÉTODOS: Em um estudo randomizado, duplamente encoberto, 25 pacientes diagnosticados pelo DSM-IV-TR foram tratados com EMTr de alta frequência ativa (1250 pulsos/dia) ou EMTr placebo. O tratamento consistiu em 1 mês de aplicação de EMTr seguido de 2 meses em acompanhamento ambulatorial semanal em um grupo de prevenção de recaídas. Os pacientes foram avaliados antes do início do tratamento com EMTr (T0) e após o término das aplicações (T1), através dos instrumentos: The Shorter PROMIS Questionnaire, The Schalling Impulsivity Scale e The Leeds Dependence Questionnaire. RESULTADOS: 25 pacientes foram tratados e a análise dos dados demonstraram redução nos índices de impulsividade em ambos os grupos ao longo do tempo, porém, quando comparados entre si, os valores de interação não se mostraram significativos. CONCLUSÃO: Os efeitos da EMTr não diferiram em eficácia terapêutica na redução da impulsividade em dependentes de cocaína, com o efeito ativo correspondendo com o placebo / INTRODUCTION: Chemical addiction involves behavioral, cognitive and physiological alterations. Impulsivity is present in many psychiatric disorders. Studies about impulsivity and cocaine chemical addiction are relatively new. Transcranial Magnetic Stimulation (EMTr) is a method capable of neuromodulation the brain. This study evaluated the effects of EMTr over impulsivity in cocaine addicts. METHODS: This is a randomized doubly covert study with 25 patients diagnosed by the DSM-IV-TR who were treated with active high frequency EMTr (1250 pulses/day) or placebo. Treatment was consisted of one month of application of EMTr followed by 2 months of clinical follow-up in a relapse prevention group. Patients were evaluated before the treatment with EMTr (T0) and after the end of the applications (T1), through the instruments: The Shorter PROMIS Questionnaire, The Schalling Impulsivity Scale and The Leeds Dependence Questionnaire. RESULTS: 25 patients were treated and data analysis showed a reduction in the levels of impulsivity in both groups throughout the time. However, group comparisons did not show statistical differences. CONCLUSION: EMTr\'s effects did not differ in terms of therapeutical efficacy in the reduction of impulsivity in cocaine addicts

Dopamin und Acetylcholin sind wichtige neuromodulatorische Substanzen im menschlichen zentralen Nervensystem mir einem starken Einfluß auf Neuroplastizität. Der spezifische Einfluß dieser Substanzen auf Neuroplastizität wird durch verschiedene Faktoren, unter anderem Dosisabhängigkeit, Hintergrundaktivität neuronaler Netze und Subrezeptorspezifität determiniert. In dieser Dissertation haben wir den dosis- und subrezeptorabhängigen Effekt des cholinergen und dopaminergen Systems auf Neuroplastizität des menschlichen motorischen Kortex untersucht. Transkranielle Gleichstromstimulation (tDCS) und gepaarte assoziative Stimulation (PAS) stellen nicht-invasive Hirnstimulationstechniken dar, die die Erzeugung von Neuroplastizität beim Menschen ermöglichen. Wir haben in unseren Studien tDCS zur Erzeugung nicht-fokaler und PAS zur Erzeugung fokaler synapsenspezifischer Plastizität im motorischen Kortex von gesunden Probanden eingesetzt. In der ersten Studie konnten wir zeigen, daß die Aktivierung nikotinischer Rezeptoren einen fokussierenden Effekt auf fazilitatorische Plastizität hatte, inhibitorische Plastizität aber unabhängig von ihrer Fokalität verhinderte. Somit hat die Aktivierung nikotinerger Rezeptoren ähnliche Effekte wie globale cholinerge Aktivierung auf fazilitatorische, aber differente Effekte auf inhibitorische Plastizität. In der zweiten Studie untersuchten wir die dosisabhängigen Auswirkungen der Dopamin-Vorläufersubstanz l-Dopa auf Neuroplastizität. Bei mittlerer Dosis von l-Dopa war fokale Plastizität unverändert, wohingegen niedrige und hohe Dosen von l-Dopa die Induktion von Plastizität verhinderten. Die Ergebnisse zeigen somit einen klaren nicht-linearen dosisabhängigen Effekt. Aus den Ergebnissen dieser Studien kann geschlossen werden, daß Neuromodulatoren Plastizität im motorischen Kortex des Menschen relevant beeinflussen. Diese Effekte sind Subrezeptor- und Dosis-abhängig.

No description available.

Questions : Cette thèse visait à répondre à deux questions fondamentales : 1) Est-ce que les athlètes qui présentent un historique de commotions cérébrales du sport en conservent des effets délétères à long terme? ; et 2) Est-ce que les effets néfastes des commotions cérébrales récurrentes sur le fonctionnement tant cognitif que moteur sont cumulatifs? Devis expérimental : À l’aide d’un plan d’investigation double-cohorte réalisé avec un groupe d’athlètes évoluant au niveau universitaire et un autre formé d’anciens athlètes universitaires testés plus de trois décennies plus tard, les quatre études qui composent cette thèse ont employé des méthodes raffinées d’investigation des fonctions cognitives et motrices pour en déceler des atteintes persistantes. Méthodologie : Les potentiels évoqués cognitifs ainsi que les tests neuropsychologiques ont permis de sonder le fonctionnement cognitif de ces athlètes alors que la stimulation magnétique transcrânienne, une plateforme de force permettant de mesurer la stabilité posturale ainsi qu’un système d’enregistrement tridimensionnel des mouvements rapides alternatifs ont servi à l’évaluation de l’intégrité du système moteur. Résultats : Cette thèse a permis de déceler des altérations persistentes et cumulatives des fonctions cognitives et motrices. De plus, ces subtiles atteintes observées chez les jeunes athlètes, affectant essentiellement des marqueurs neurophysiologiques sous-cliniques du fonctionnement cognitif et moteur, s’étaient accentuées chez les anciens athlètes universitaires qui montraient un déclin quantifiable tant des fonctions cognitives que motrices. Discussion : Ces résultats suggèrent d’une part que les commotions cérébrales du sport entraînent des altérations cognitives et motrices chroniques qui s’accentuent en fonction du nombre de commotions cérébrales subies. D’autre part, les effets délétères des commotions cérébrales du sport sur le fonctionnement cognitif et moteur combinés à ceux associés au processus de vieillissement entraînent un déclin cognitif et moteur quantifiable en comparaison aux anciens athlètes n’ayant jamais subi de commotions cérébrales. / Question: This thesis aimed to address two fundamental issues: 1) Are there long-lasting effects of sports-related concussion on cognitive and motor functions? and 2) Are the adverse effects of recurrent concussions cumulative? Experimental Design: The cross-sectional thesis design included a group of active university-level athletes as well as a group of former athletes recruited more than three decades after their university years who were tested on neurophysiological measures of both cognitive and motor system functions. Methods: Event-Related potentials and neuropsychological tests were used to assess cognitive functions while transcranial magnetic paradigms were used to assess motor cortex excitability, a force platform was used to assess postural stability and a 3-dimensional recording device was used to track hand position when performing a rapid alternating movement task. Results: This thesis disclosed persistent and cumulative alterations of both cognitive and motor functions after sports concussions. Furthermore, subclinical, neurophysiological alterations found in young concussed athletes were exacerbated in former athletes with concussions who displayed quantifiable cognitive and motor functions decline more than three decades post-concussion. Discussion: These results suggest that sports concussions induce cognitive and motor functions abnormalities that worsen as a function of the number of concussions sustained. Moreover, findings from the present thesis indicate that the deleterious effects of sports concussion on cognitive and motor system functions combined to those associated with the aging process lead to quantifiable decline on both cognition and motor functions.

Spike timing-dependent plasticity (STDP) has been suggested as one of the key mechanism underlying learning and memory. Due to its importance, timing-dependent plasticity studies have been approached in the living human brain by means of non-invasive brain stimulation (NIBS) protocols such as paired associative stimulation (PAS). However, contrary to STDP studies at a cellular level, functional plasticity induction in the human brain implies the interaction among target cortical networks and investigates plasticity mechanisms at a systems level. This thesis comprises of two independent studies that aim at understanding the importance of considering broad cortical networks when predicting the outcome of timing-dependent associative plasticity induction in the human brain. In the first study we developed a new protocol (ipsilateral PAS (ipsiPAS)) that required timing- and regional-specific information transfer across hemispheres for the induction of timing-dependent plasticity within M1 (see chapter 3). In the second study, we tested the influence of individual brain structure, as measured with voxel-based cortical thickness, on a standard PAS protocol (see chapter 4). In summary, we observed that the near-synchronous associativity taking place within M1 is not the only determinant influencing the outcome of PAS protocols. Rather, the online interaction of the cortical networks integrating information during a PAS intervention determines the outcome of the pairing of inputs in M1.

H TMS διακρίνεται έναντι άλλων εργαλείων απεικόνισης λόγω της ικανότητάς της να ενεργοποιεί νευρώνες σε επιλεγμένες φλοιϊκές περιοχές. Η παρούσα μελέτη προσπαθεί να διερευνήσει το νευροφυσιολογικό προφίλ της μυικής προκλητής απάντησης διάμεσου διακρανιακής μαγνητικής διέγερσης (TMS) σε ένα σεβαστό αριθμό ασθενών με σχιζοφρένεια υπό φαρμακευτική αγωγή. Σε 51 ασθενείς υπό φαρμακευτική αγωγή και διάγνωση σχιζοφρένειας και 51 υγιείς μάρτυρες απόλυτα σύμφωνους ως προς το φύλο, το ύψος και την ηλικία με τους ασθενείς που συμμετείχαν καταγράφηκαν κινητικά προκλητά δυναμικά (ΜΕΡ) από τον απαγωγό μυ του αντίχειρα μετά τον ερεθισμό του αντίπλευρου κινητικού φλοιού με ένα κυκλικό πηνίο. Μετρήθηκαν: w RMTh (resting motor threshold): Ο ουδός κινητικής ηρεμίας w SI-max (stimulus intensity for maximum MEP): Η ένταση ερεθίσματος που χρειάζεται για την καταγραφή του μέγιστου κινητικού προκλητού δυναμικού w Post-stimulus silent period: Την ανερέθιστη περίοδο που επάγεται μετά από ένα ερέθισμα που προκαλεί συγκεκριμένη μυική δραστηριότητα w MEP Latency: Λανθάνον χρόνος των κινητικών προκλητών δυναμικών MEP amplitude: Το εύρος των κινητικών προκλητών δυναμικών. Τα βασικά ευρήματα είναι η σαφώς υψηλότερη από τις φυσιολογικές τιμές, τιμή των RMTh και SI-max και τα δύο, ενδείξεις νευρωνικής ευοδωτικής δραστηριότητας στους ασθενείς σε σύγκριση με τους μάρτυρες. Ειδικότερα στην ομάδα των ασθενών που βρίσκονται σε θεραπεία με ζιπρασιδόνη παρουσιάστηκε το υψηλότερο SI-max και στα δύο ημισφαίρια και το υψηλότερο RMTh στο αριστερό ημισφαίριο. Οι ασθενείς στην ομάδα που ελάμβαναν ολανζαπίνη παρουσίασαν το χαμηλότερο RMTh για το αριστερό ημισφαίριο και αυτοί σε θεραπεία με κουατιεπίινη παρουσίασαν τιμές ανάμεσα στις τιμές των δύο προηγούμενων ομάδων. Όταν χρησιμοποιήθηκε ένταση ερεθίσματος (SI) σχετικής τιμής με το RMTh, η ανερέθιστη περίοδος βρέθηκε μεγαλύτερη στους ασθενείς από ότι στους μάρτυρες ενώ δεν παρατηρήθηκε καμία διαφορά ανάμεσα στις δύο μεγάλες ομάδες ασθενών και μαρτύρων όταν χρησιμοποιήθηκε σταθερής έντασης ερέθισμα (SI). Συμπεράναμε, ότι οι αλλαγές στις παραμέτρους που μετρήθηκαν, μπορούν να εξηγηθούν από βασικές μεταβολές της ενδοφλοιϊκής ευοδωτικής κινητικής δραστηριότητας που ακολουθείται από διαφοροποιήσεις της φλοιϊκής αναστολής, οι οποίες μπορούν να αποδοθούν είτε στην σχιζοφρένεια είτε στην φαρμακευτική αγωγή ή στην αλληλεπίδρασή τους. / Trancranial magnetic stimulation (TMS) provides a non-invasive means for exploring physiological alterations of central motor control in a variety of neuropsychiatric diseases. The present study aimed to assess the neurophysiological profile of muscle evoked responses to a standard TMS procedure in a considerable number of medicated patients with schizophrenia. Fifty-one patients with diagnosis of schizophrenia and 51 sex- and age-matched healthy subjects were enrolled in the study. Motor evoked potential (MEP) from abductor pollicis brevis muscle was elicited by stimulation of the contralateral motor cortex with a circular coil. The hot-spot was marked. Were measured: ¨ the resting motor threshold (RMTh), ¨ the stimulus intensity for maximum MEP (SI-max), ¨ the post-stimulus silent period of voluntary muscle activity and ¨ MEP latency and amplitude. The main findings were the significantly higher than normal values for RMTh and SI-max, which are both indices of neuronal excitability. In particular, patients who had ziprasidone in their therapeutic regimen demonstrated the highest SI-max for both hemispheres and highest RMTh for left hemisphere, patients receiving olanzapine demonstrated the lowest RMTh for left hemisphere and those on quetiapine showed intermediate values. Silent period was longer in the patients as opposed to controls when a RMTh-related SI was used and did not differ between the two groups when a fixed SI was used. We concluded that the observed TMS changes could be interpreted by primary alterations of intracortical motor excitability followed by defects of cortical inhibition and should be attributed to schizophrenia, antipsychotic medication or the interaction between both factors.

No description available.

INTRODUÇÃO: A dependência química engloba alterações comportamentais, cognitivas e fisiológicas. A impulsividade está presente em muitos transtornos psiquiátricos. Sobre a impulsividade na dependência química de cocaína, os estudos existentes são relativamente novos. A Estimulação Magnética Transcraniana de repetição (EMTr) é um método capaz de neuromodular o cérebro. Este estudo avaliou os efeitos da EMTr sobre a impulsividade em dependentes de cocaína. MÉTODOS: Em um estudo randomizado, duplamente encoberto, 25 pacientes diagnosticados pelo DSM-IV-TR foram tratados com EMTr de alta frequência ativa (1250 pulsos/dia) ou EMTr placebo. O tratamento consistiu em 1 mês de aplicação de EMTr seguido de 2 meses em acompanhamento ambulatorial semanal em um grupo de prevenção de recaídas. Os pacientes foram avaliados antes do início do tratamento com EMTr (T0) e após o término das aplicações (T1), através dos instrumentos: The Shorter PROMIS Questionnaire, The Schalling Impulsivity Scale e The Leeds Dependence Questionnaire. RESULTADOS: 25 pacientes foram tratados e a análise dos dados demonstraram redução nos índices de impulsividade em ambos os grupos ao longo do tempo, porém, quando comparados entre si, os valores de interação não se mostraram significativos. CONCLUSÃO: Os efeitos da EMTr não diferiram em eficácia terapêutica na redução da impulsividade em dependentes de cocaína, com o efeito ativo correspondendo com o placebo / INTRODUCTION: Chemical addiction involves behavioral, cognitive and physiological alterations. Impulsivity is present in many psychiatric disorders. Studies about impulsivity and cocaine chemical addiction are relatively new. Transcranial Magnetic Stimulation (EMTr) is a method capable of neuromodulation the brain. This study evaluated the effects of EMTr over impulsivity in cocaine addicts. METHODS: This is a randomized doubly covert study with 25 patients diagnosed by the DSM-IV-TR who were treated with active high frequency EMTr (1250 pulses/day) or placebo. Treatment was consisted of one month of application of EMTr followed by 2 months of clinical follow-up in a relapse prevention group. Patients were evaluated before the treatment with EMTr (T0) and after the end of the applications (T1), through the instruments: The Shorter PROMIS Questionnaire, The Schalling Impulsivity Scale and The Leeds Dependence Questionnaire. RESULTS: 25 patients were treated and data analysis showed a reduction in the levels of impulsivity in both groups throughout the time. However, group comparisons did not show statistical differences. CONCLUSION: EMTr\'s effects did not differ in terms of therapeutical efficacy in the reduction of impulsivity in cocaine addicts