<p>Otkrivanje embolusa u cerebralnoj cirkulaciji na egzaktan način moguće je samo upotrebom transkranijalnog doplera. Istraživanje je obuhvatilo 150 ispitanika, obolelih od akutnog ishemijskog cerebrovaskularnog događaja (ishemijskog moždanog udara i tranzitornog ishemijskog ataka) u zoni vaskularizacije a. cerebri medie (ACM), a lečenih na Klinici za neurologiju, Kliničkog centra Vojvodine. Ciljevi istraživanja su obuhvatili određivanje prevalence i frekvence MES kod bolesnika sa akutnim ishemijskim cerebrovaskularnim događajem (TIA, IMU) tokom serijskog monitoringa, utvrđivanje povezanost pojave MES u odnosu na etiologiju ishemijske epizode, procenjivanje efekata terapije (antiagregacione i antikoagulantne) na pojavu MES tokom serijskog monitoringa, i utvrđivanje prediktivnog značaja MES na dalji tok bolesti tj, rani povratni embolizam unutra tri meseca. Utvrdili smo da se mikroembolusi kao markeri aktivne embolizacije mogu registrovati primenom transkranijalnog doplera u akutnoj fazi moždanog udara u određenoj meri. U ispitivanom uzorku metodom transkranijalne detekcije kod 52 (34,7%) bolesnika je registrovana pojava cerebralnih mikroembolusa. Ovi ispitanici su činili MES (+) grupu pacijenata. Kod 98 (65,3%) bolesnika nisu registrovani ES, oni su činili MES (-) grupu pacijenata. Detekcija je vr&scaron;ena u prvih 72h od vremena nastanka IMU ili TIA. Zaključili smo da se serijskim monitoringom registruje smanjenje prevalence i frekvence embolijskih signala. Utvrdili smo da su starija životna dob, hipertenzija i dijabetes statistički značajno povezani sa pojavom mikroembolusnih signala. Najveća zastupljenost mikroembolusa registrovana je u aterotrombotičnom podtipu ishemijskog moždanog udara. Utvrđen je prediktivni značaj aterosklerotske bolesti velikih krvnih sudova na pojavu MES. Registrovana je statistički značajno če&scaron;ća pojava MES kod simptomatske karotidne stenoze, visokog stepena (70-90%), neravne i ulcerisane povr&scaron;ine plaka. Nije utvrđena statistički značajna povezanost pojave MES, kliničkih manifestacija bolesti i neuroradiolo&scaron;kog nalaza. Nije registrovan uticaj antitrombotičke terapije na pojavu mikroembolusnih signala. Zabeležena je veća stopa recidiva IMU i TIA kod bolesnika sa registrovanim cerebralnim mikroembolusima. Utvrđen je prediktivni značaj MES na pojavu recidiva IMU ali ne i prediktivni značaj na pojavu letalnog ishoda.</p> / <p>Detection of emboli in the cerebral circulation to the exact way it is possible only by using transcranial doppler. The study included 150 patients of acute ischemic cerebrovascular events (ischemic stroke and TIA) in a zone of vascularization a. cerebri media (ACM), and treated at the Clinic of Neurology, Clinical Center of Vojvodina Research objectives included the determination of the prevalence and frequency of MES in patients with acute ischemic cerebrovascular accident (TIA, IMU) during serial monitoring, establishing the link between the appearance MES in relation to the etiology of ischemic episodes, assessing the effects of therapy<br />(antiplatelet and anticoagulant) on the occurrence of MES during serial monitoring and determine the predictive value MES in the further course of the disease, ie. return early embolism within three months. We have found that microemboli as markers of active embolization can register by using transcranial Doppler in the acute phase of stroke in certain extent. In the examined sample using transcranial detection with 52 (34.7%) patients the occurrence of cerebral microemboli is registered. These respondents are accounted for MES (+) group of patients. With 98 patients (65.3%) is not registered EC, they account for MES (-) group of patients. Detection was performed during 72 hours from the time of occurrence of ischemic stroke or TIA. We concluded that serial monitoring registers decrease in prevalence and frequency of embolic signals. We found that older age, hypertension, and diabetes are significantly associated with the appearance of microembolic signals. The highest incidence of microemboli was registered in atherothrombotic ischemic stroke subtype. It is determined the predictive significance of atherosclerotic disease of large blood vessels on the occurrence of MES. More common MES is significantly registered with symptomatic carotid stenosis, greater degree (70-90%), uneven surfaces and ulcerated plaque. There was no statistically significant correlation between the occurrence of MES, clinical manifestations and neuroradiological findings. It is not registered impact of antithrombotic therapy on the incidence of microembolic signals. We are noticed thet the higher rate of recurrence of ischemic stroke and TIA patients with cerebral microemboli is registered. The predictive significance of MES in recurrence of ischemic stroke is determined, but not predictive significance of the occurrence of a lethal outcome.</p>

<p>TCD apnea test kao neinvazivna i bezbedna neuroultrasonografska metoda pruža korisne informacije o vazomotornoj reaktivnosti (VMR) u procesu indirektnog sagledavanja funkcionisanja moždane autoregulacije. Vazomotorna reaktivnosti podrazumeva sposobnost dilatacije ili konstrikcije moždanih arteriola nastale kao odgovor na određeni vazoaktivni stimulus, najče&scaron;će ugljen dioksid. Cilj ove doktorske disertacije bio je ispitivanje i analiziranje promene karotidne hemodinamike kod bolesnika sa ishemijskim moždanim udarom (IMU) ili tranzitornim ishemijskim atakom (TIA) i simptomatskom karotidnom stenozom u preoperativnom i tromesečnom postoperativnom periodu, kao i procena revaskularizacionog efekta karotidne endarterektomije (KEA).U istraživanje je uključeno 60 hospitalizovanih bolesnika koji su doživeli prvi IMU i TIA u zoni vaskularizacije arterije cerebri anterior (ACA) i arterije cerebri medije (ACM), svi sa karotidnom stenozom, ACI &ge;70%. Bolesnici su bili hospitalizovani na Klinici za neurologiju, Kliničkog Centra Vojvodine, Klinici za kardiovaskularnu hirurgiju, Instituta za kardiovaskularne bolesti Vojvodine i Klinici za vaskularnu hirurgiju, u Novom Sadu. U odnosu na kliničke manifestacije bolesni i su podeljeni u tri grupe: bolesnici sa TIA i amaurosis fugax, sa parcijalnim infarktom u zoni ACA ili ACM i sa lakunarnim infarktom. Istraživanje je analiziralo uticaj promenljivih i nepromenljivih vaskularnih faktora rizika na pojavu IMU i TIA, ali i na VMR, procenjivanu kroz indeks zadržavanja daha (Breath Holding Index, BHI) ipsilateralno i kontralateralno u odnosu na karotidnu stenozu. Analizirana je povezanost stepena karotidne stenoze sa vrednostima BHI preoperativno, povezanost BHI sa težinom kliničke slike, uticaj kolateralnog krvotoka na VMR, distribucija BHI u pojedinim tipovima IMU i TIA kao i komparacija BHI u pre i u postoperativnom periodu od 30 i 90 dana. Na osnovu sprovedenog istraživanja, do&scaron;lo se do zaključaka da je redukovana VMR preoperativna karakteristika karotidne stenoze ipsilateralno kao i karakteristika različitih tipova IMU i TIA ipsilateralno; postoji negativna korela ija izmeĐu stepena karotidne stenoze i BHI vrednosti. Nije potvrđena hipoteza da veći roj razvijenih kolateralnih puteva uslovljava očuvanu VMR; utvrđena je pozitivna korelacija između BHI vrednosti u preoperativnom i postoperativnom periodu; redukovana VMR ima negativan uticaj na težinu kliničke slike. Prepoznavanje vrednosti TCD apnea testa, koji se može koristiti kao komplementarna metoda drugim vazoaktivnim testovima u praćenju karotidne hemodinamike, od posebne je važnosti neurologu i vaskularnom hirurgu. Time bi se doprinelo daljoj evaluaciji mehanizma nastanka IMU, planiranju terapijskog pristupa i determinisanju prognoze operisanih bolesnika. Činjenica da većina neurolo&scaron;kih odeljenja poseduje TCD aparat, apnea test postaje dostupan svakom neurologu u kliničkom radu, posebno u na&scaron;im uslovima, kada se do drugih drugih, skupljih metoda, te&scaron;ko stiže ili nam ostaju nedostižne.</p> / <p>TCD apnea test, as a noninvasive and safe neuroultrasonographic method, provides useful information about vasomotor reactivity (VMR) in the indirect evaluation of cerebral autoregulation. Vasomotor reactivity is the ability of cerebral arterioles to constrict or to dilate in response to a vasoactive stimulus, mainly carbon dioxide. The aim of this doctoral thesis was to investigate and analyze changes in carotid hemodynamics in patients with ischemic stroke (IS) or transient ischemic attack (TIA) and symptomatic carotid stenosis in the preoperative and three-month postoperative period as well as the assessment of revascularisation effect of carotid endarterectomy (CEA). The study included 60 hospitalized patients who experienced a first ischemic stroke or TIA in the vasularisation area of anterior cerebral artery (ACA) and middle cerebral artery (MCA), all with carotid stenosis &ge;70% ACI. Patients were hospitalized at the Clinic of Neurology, Clinical Center of Vojvodina, Department of Cardiovascular Surgery, Institute of Cardiovascular Diseases and the Department of Vascular Surgery in Novi Sad. Considering clinical manifestations of stroke, the patients were divided into three groups: patients with TIA and amaurosis fugax, with partial infarction in area ACA or ACM and with lacunar infarct. The study analyzed the impact of variabile and unvariable vascular risk factors on the incidence of ischemic stroke and TIA, but also on VMR, evaluated through Breath Holding Index (Breath Holding Index, BHI) on the ipsilateral and contralateral side from carotid stenosis. We analysed the correlation between the degree of carotid stenosis with preoperative values of BHI, BHI correlation to the severity of clinical findings, the impact of collateral circulation to the VMR, distribution of BHI in certain types of ischemic stroke and TIA as well as comparison of BHI in the pre and postoperative period of 30 and 90 days. On the basis of this research came the conclusion that reduced VMR is characteristic of ipsilateral carotid stenosis in preoperative period as well as number of developed collateral characteristics of different types of ipsilateral ischemic stroke and TIA; there is a negative correlation between the degree of carotid stenosis and BHI values. The hypothesis that the greater pathways causes preservation of VMR was not confirmed, while the positive correlation between BHI values in the preoperative and postoperative period was established. Reduced VMR has a negative impact on the degree of clinical picture severity. Recognizing the importance of TCD apnea test method, that can be used as a complementary method to other vasoactive tests in monitoring of carotid hemodynamics, is of special importance to the neurologists and vascular surgeons. This would contribute to the further evaluation of mechanism of ischemic stroke, planning of therapeutic approach and determining the prognosis of treated patients. The fact that most of neurological department has TCD device, apnea test becomes available to every neurologist in clinical work, specially in our conditions, when other methods remain unattainable.</p>

The body of work hereby presented aims at better defining the specific mechanisms underlying cognitive control and flexibility, and to investigate the neural substrates that might support these dynamics. More specifically, the anterior cingulate (ACC), dorsolateral prefrontal (dlPFC) and frontopolar (FPC) cortices have been proposed to play a fundamental role in monitoring and detecting the presence of environmental contingencies that require the recruitment of cognitive control (such as competition between responses in the presence of conflicting information), implementing cognitive control, and supporting higher-order cognitive processing, respectively. This thesis investigates the effects of damage to these regions, and of interference with their activity, on these processes. It also argues for the importance of dissociating possible separate cognitive control components that might differently contribute to behavioural adjustments (such as caution and attention/task-relevant processing), and provides one of the first attempts to quantify them within the parameters of a mathematical model of choice response-time, the Linear Ballistic Accumulator (LBA). The results confirm the crucial role of the dlPFC in modulating behavioural adjustments, as both damage and interference with this region’s activity significantly affect measures of conflict-induced behavioural adaptation. It is hypothesized that dlPFC might drive behavioural adjustments by encoding recent conflict history and/or supporting the automatization of a newly advantageous behavioural strategy during the early stages after a change in conflict levels. When a task does not involve competition between a habit and instructed behaviour, lesions or interference with ACC’s activity do not appear to affect behaviour in a manner that is consistent with the classic conflict-monitoring framework. It is suggested that its role might be better described as a more general monitoring and confirmatory mechanism that evaluates both actual and potential outcomes of an action, in order to proactively guide adjustments away from contextually disadvantageous responses. Finally, lesions to the FPC do not affect abstract-rule integration, but do impair the early stages of acquisition of a new abstract rule, when a previously rewarded rule stops being rewarded, and specifically when acquisition is dependent on self-initiated exploration. This suggests a role for FPC in the evaluation of multiple concurrent options in order to aid the development of new behavioural strategies.

In everyday life we regularly update our expectations about the locations at which sensory events may occur, and about the motor responses that are appropriate in a given situation. The experiments in this thesis investigated the neural correlates of perceptual processes and motor preparation during human decision making, and the regions that causally contribute to decision making in the human brain. In Chapter 3, I used electroencephalography (EEG) to investigate whether alpha-band (~8-14 Hz) oscillations provide a graded index of participants’ preparatory attentional states. Time-frequency analysis revealed that manipulating spatial certainty regarding the location of an upcoming visual target led to parametric changes in the lateralization of preparatory occipito-parietal alpha oscillations, and to parametric modulation of parieto-central beta-band (~15-25 Hz) power typically associated with response preparation. In Chapter 4, I used EEG to investigate whether evolution of lateralization of sensorimotor alpha- and beta-band activity reflected participants’ evolving expectations about an upcoming motor response. Lateralization of activity in both frequency bands varied parametrically with the available evidence, suggesting such lateralized activity correlates with participants’ internal decision variables. Further analysis identified unique contributions to lateralized and non-lateralized oscillatory activity due to the prior evidence, evidence update, and surprise related to the observed information at each stage of the task. In Chapter 5, I extended the paradigm developed in Chapter 4 for use with online repetitive transcranial magnetic stimulation (TMS) and concurrent EEG recording. Delivery of TMS during decision making allowed investigation of the causal role played by a left hemisphere medial intraparietal region that is the putative human homologue of the macaque medial intraparietal cortex (MIP). MIP stimulation disrupted decision-making behaviour by biasing participants’ decisions against contralateral-to-stimulation (i.e., right-handed) responses. Comparison of the magnitude of TMS-induced changes in behaviour and beta-band activity demonstrated that the intraparietal cortex plays a causal role both in decision making and in the appearance of beta-band activity over the motor cortex. In Chapter 6, the broader consequences of the experimental work presented in this thesis are discussed, in addition to promising directions for future research.

La perception de mouvements est associée à une augmentation de l’excitabilité du cortex moteur humain. Ce système appelé « miroir » sous-tendrait notre habileté à comprendre les gestes posés par une tierce personne puisqu’il est impliqué dans la reconnaissance, la compréhension et l’imitation de ces gestes. Dans cette étude, nous examinons de quelle façon ce système miroir s’implique et se latéralise dans la perception du chant et de la parole. Une stimulation magnétique transcrânienne (TMS) à impulsion unique a été appliquée sur la représentation de la bouche du cortex moteur de 11 participants. La réponse motrice engendrée a été mesurée sous la forme de potentiels évoqués moteurs (PÉMs), enregistrés à partir du muscle de la bouche. Ceux-ci ont été comparés lors de la perception de chant et de parole, dans chaque hémisphère cérébral. Afin d’examiner l’activation de ce système moteur dans le temps, les impulsions de la TMS ont été envoyées aléatoirement à l’intérieur de 7 fenêtres temporelles (500-3500 ms). Les stimuli pour la tâche de perception du chant correspondaient à des vidéos de 4 secondes dans lesquelles une chanteuse produisait un intervalle ascendant de deux notes que les participants devaient juger comme correspondant ou non à un intervalle écrit. Pour la tâche de perception de la parole, les participants regardaient des vidéos de 4 secondes montrant une personne expliquant un proverbe et devaient juger si cette explication correspondait bien à un proverbe écrit. Les résultats de cette étude montrent que les amplitudes des PÉMs recueillis dans la tâche de perception de chant étaient plus grandes après stimulation de l’hémisphère droit que de l’hémisphère gauche, surtout lorsque l’impulsion était envoyée entre 1000 et 1500 ms. Aucun effet significatif n’est ressorti de la condition de perception de la parole. Ces résultats suggèrent que le système miroir de l’hémisphère droit s’active davantage après une présentation motrice audio-visuelle, en comparaison de l’hémisphère gauche. / The perception of movements is associated with increased activity in the human motor cortex. This system underlies our ability to understand one’s actions, as it is implicated in the recognition, understanding and imitation of actions. In this study, we investigated the involvement and lateralization of this “mirror neuron” system (MNS) in the perception of singing and speech. Transcranial magnetic stimulation (TMS) was applied over the mouth representation of the motor cortex in 11 participants. The generated motor response was measured in the form of motor evoked potentials (MEPs), recorded from the mouth muscle. The MEPs were compared for the singing and speech conditions in each cerebral hemisphere. Furthermore, to investigate the time course of the MNS activation, TMS pulses were randomly emitted in 7 time windows (ranging from 500 to 3500 milliseconds after stimulus onset). The stimuli for the singing condition consisted in 4-second videos of singers producing a 2-note ascending interval. Participants had to judge whether the sung interval matched a written interval, previously presented on the screen. For the speech condition, 4-second videos of a person explaining a proverb were shown. Participants had to decide whether this explanation matched a written proverb previously displayed on the screen. Results show that the MEP amplitudes were higher after stimulation of the right hemisphere in the singing condition. More specifically, sending TMS pulses between 1000 and 1500 milliseconds over the right hemisphere yielded higher MEPs as compared to the left hemisphere. No effect was found in the speech condition. These results suggest that the right MNS is more activated after an audiovisual motor presentation compared to the left hemisphere.

L’expérience subjective accompagnant un mouvement se construit a posteriori en intégrant différentes sources d’informations qui s’inter-influencent à différents moments tant avant qu’après le mouvement. Cette expérience subjective est interprétée par un modèle d’attribution bayésien afin de créer une expérience d’agentivité et de contrôle sur les mouvements de son propre corps. Afin de déterminer l’apport de l’interaction entre les paramètres considérés par le modèle d’attribution et d’investiguer la présence de disparités inter-individuelles dans la formation de l’expérience subjective du mouvement, une série de 90 pulsations simples de stimulation magnétique transcrânienne (SMT) sur le cortex moteur primaire (M1) suivi de multiples questions sur l’expérience subjective reliée au mouvement provoqué a été effectuée chez 20 participants normaux. Les données objectives du mouvement ont été recueillies par électromyographie (EMG) et capture du mouvement. Un modèle de régression a entre autres été effectué pour chaque participant afin de voir quelle proportion du jugement subjectif pouvait être expliqué par des indices objectifs et cette proportion variait grandement entre les participants. Les résultats de la présente étude indiquent la présence d’une capacité individuelle à se former des jugements subjectifs reflétant adéquatement la réalité comme en témoigne la cohérence entre les différentes mesures d’acuité et plusieurs variables mesurant l’expérience subjective. / Subjective experience is built after the fact by integrating different sources of information that interact with each other at different moments (before, during and after the movement). In order to create subjective experience of agency and control, the characteristics of the movement are interpreted by a Bayesian model. To determine the impact of the interaction between the parameters that enter in that Bayesian attribution model and to investigate possible disparities in the formation of subjective experience of movement between individuals, a series of 90 pulses of single-pulse transcranial magnetic stimulation (TMS) followed by four questions on the subjective experience relative to the movement was conducted on 20 normal subjects. Objective data about the movement was gathered using electromyography (EMG) and motion capture. Individual regression models have been conducted to determine the proportion of the subjective judgements that varied accordingly to the objective parameters of the movement; this proportion varied greatly between participants. The present study proposes that there is an individual capacity to form subjective judgements that adequately represent the reality, as suggested by coherence between different accuracy measures and different variables measuring the subjective experience.

La stimulation magnétique répétitive transcrânienne (rTMS) du cortex moteur à visée antalgique réunit deux conditions extrêmement intéressantes: un accès non invasif à une cible corticale éloquente et, par la modulation de son activité, la possibilité d'influencer le transfert et l'intégration du message nociceptif. L'objectif de cette thèse est d'évaluer comment une approche de recherche clinique permet à la fois de progresser dans la compréhension des mécanismes qui sous-tendent l'effet antalgique de la rTMS et d'optimiser cet effet chez le patient. Une première étude paramétrique, concernant la technique de stimulation, a montré que l'orientation du courant était cruciale pour le développement d'un effet antalgique, l'orientation la plus favorable étant celle activant des interneurones corticaux. Nous n'avons toutefois pas objectivé de modification spécifique d'une composante sensorielle de la douleur en rapport avec cet effet local, ni une influence liée au caractère somatotopique de la stimulation. Ainsi, l'efficacité de la stimulation ne semble pas tributaire de sa localisation en regard de la représentation corticale du territoire douloureux. L'action sur la composante sensorielle de la douleur n'expliquant pas à elle seule l'effet antalgique de la rTMS, nous avons analysé les interactions entre effet antalgique et effet placebo : la rTMS a une efficacité propre, indépendante de l'effet placebo et lorsqu'elle est efficace, elle majore l'effet d'une séance placebo réalisée par la suite, par un phénomène de conditionnement. La rTMS active facilite les mécanismes de contrôle central de la douleur grâce à ses connexions à distance et à son action sur les systèmes endorphiniques, également impliqués dans l'effet antalgique du placebo. A la lumière de ces résultats, nous avons analysé les critères cliniques sur lesquels reposent l'efficacité à long terme des procédures de stimulation épidurale antalgique du cortex moteur et la valeur prédictive de la rTMS: l'efficacité de la rTMS apparaît comme un marqueur utile pour prédire l'efficacité au long cours de la stimulation corticale épidurale, lorsque la douleur est évaluée non seulement dans sa dimension sensorielle pure mais également à travers son retentissement psychologique global. L'ensemble de ces travaux suggère une action multiple de la rTMS s'exerçant probablement dans les 3 sphères (sensori-discriminative, affective et cognitive) qui sous- tendent la perception et le vécu de la douleur chronique / Repetitive transcranial magnetic stimulation (rTMS) of the motor cortex allows a non- invasive access to an eloquent cortical area and, by the modulation of its activity, the possible interference with central integration of pain. ln this thesis we have applied clinical research methods to enhance the understanding of the mechanisms of pain relief by rTMS and to optimize its clinical effect in chronic pain patients. A first parametrical study, concerning technical aspects of the stimulation, showed the crucial role of current orientation to increase the magnitude of analgesic effects, a postero-anterior orientation promoting interneuronal activation being superior to a latero-medial direction. We found neither a selective modification of sensorial component of pain nor a somatotopic effect of the stimulation: indeed, rTMS analgesic efficacy was not dependent upon stimulation being applied to the cortical representation of the painful territory. The impossibility to explain the whole analgesic effect of rTMS by an isolated modulation of sensory components of pain prompted us to study the interactions between real and placebo rTMS analgesic effects. Active rTMS has a specific analgesic effect, and, when efficacious, it was able to enhance the placebo effect of subsequent sham stimulation. The value of rTMS to adequately predict the long-term efficacy of invasive motor cortex epidural stimulation (surgically implanted MCS) was assessed in a further study. The analgesic efficacy of single-point rTMS proved to be useful to predict the long-term outcome of surgically implanted MCS, provided that such outcome assessment was not exclusively founded on pain intensity but also on the psychological consequences of chronic pain. These results suggest that rTMS exerts its analgesic effects at multiple levels, and probably modifies the 3 different spheres (sensori-discriminative, affective and cognitive) at the origin of perception and consequences of chronic pain in daily life

Les mouvements sont le résultat de contractions musculaires dont l’organisation spatio-temporelle est régie par des structures cérébrales et médullaires. Etudier les circuits qui les sous-tendent est une étape indispensable pour renforcer nos connaissances des mécanismes à l’origine de la commande des mouvements volontaires et pour mieux comprendre la pathophysiologie des mouvements anormaux. Les muscles squelettiques sont innervés par les motoneurones alpha de la moelle épinière qui à leur out sont influencés par des neurones des aires corticales motrices. Cette voie descendante constitue la voie corticomotoneuronale (CM) et est responsable de l’exécution des mouvements volontaires. Le cortex moteur primaire est considéré comme une structure clé, au cœur du système, permettant l’intégration complexe de nombreuses influences multi-régions pour conduire aux comportements moteurs adéquats. Les interactions qui existent entre les différents groupes de neurones au sein de M1 influent en dernier lieu sur la sortie motrice. De la balance complexe entre ces influences inhibitrices et excitatrices, locales ou à distance va dépendre l’état d’excitabilité des cellules CM contrôlant les différents muscles. L'objectif de ce travail de thèse était d'étudier comment évoluent certains de ces mécanismes excitateurs ou inhibiteurs du cortex moteur primaire lorsque la commande motrice volontaire d’un muscle de l’index est modifiée. Nous avons étudié le rôle de ces mécanismes dans les changements d’excitabilité de la voie CM qui accompagnent la contraction tonique volontaire du muscle premier interosseus dorsalis (FDI) en comparant une tâche simple mais peu naturelle : l’abduction de l'index, une tâche naturelle plus complexe: la pince pouce-index et la condition de repos musculaire. Nous avons également étudié l’effet de la commande motrice sur l’interaction entre deux de ces mécanismes inhibiteurs l’un à longue latence, la LICI, l’autre à courte latence, la SICI. Enfin nous avons souhaité évaluer le décours temporel de ces mécanismes dans un cadre pathologique tâche-dépendant: la crampe de l’écrivain. Pour cela, nous avons utilisé la technique d’electromyographie de surface pour enregistrer les potentiels moteurs évoqués par la Stimulation Magnétique Transcrânienne. Nous avons mis en évidence une modulation tâche-dépendante de la LICI. Par rapport à la tâche d’abduction simple, la LICI s’estompait plus tôt lors de la tâche de pince pouce-index, traduisant une désinhibition plus précoce lors d’un mouvement plus complexe. Nous avons observé, et ce pour la première fois dans la littérature, une phase de facilitation nette qui suivait cette désinhibition, et qui était absente lorsque le muscle était au repos. Ces résultats sont également visibles dans un muscle voisin du FDI, non engagé dans la tâche; cela suggère que les mécanismes à l’origine de la facilitation sont impliqués dans l’activité volontaire sans spécificité topographique. L’interaction entre la LICI et la SICI n’a pas été modifiée par la tâche effectuée, laissant penser qu’elle n’est pas impliquée dans les changements d’excitabilité tâche-dépendants. Enfin, il apparaît que la désinhibition est retardée chez les sujets dystoniques quand le muscle est engagé dans un mouvement complexe de pince pouce-index mais pas dans une tâche simple d’abduction de l’index en comparaison à des sujets contrôles. Ces résultats illustrent le fait que lors d’un mouvement plus complexe, l’efficacité des circuits inhibiteurs du cortex moteur primaire est modifiée, ce qui permet de réguler l’activité des cellules CM, afin d’adapter la commande motrice au mouvement souhaité. Le fait que cette désinhibition soit retardée dans une tâche complexe (proche de la tâche affectée) mais pas dans une tâche simple chez les patients atteints d’une crampe de l’écrivain suggère que les mécanismes à l’origine de la désinhibition pourraient participer aux troubles moteurs qui caractérisent la maladie. / Movements are evoked by muscles contractions whose spatial organization is mediated by both spinal and cortical components. It is important to investigate the underlying circuitry of movements to extend our knowledge on how voluntary movement are controlled and to better understand the pathophysiology of movements disorders. The spinal alpha motoneurons innervating distal muscles are controlled at least in parts by corticomotoneuronal neurons located in the motor cortical areas. Among them, the primary motor cortex is considered as a key structure, performing a complex integration of multi-regional influences leading to appropriate motor behaviors. Axons from corticomotoneuronal (CM) cells of the primary motor cortex reach the spinal cord via descending motor pathway. CM neurons are influenced by local or distant, inhibitory and excitatory components which determine the balance of excitability. The aim of this thesis was to explore changes of some of the excitatory and inhibitory mechanisms of motor cortex as a function of the task being performed. We assessed the time course of Long-interval Intracortical Inhibition (LICI), Late Cortical Disinhibition (LCD) and Long interval Intracortical Facilitation (LICF), which are mechanisms that potentially act to modulate the output of CM controlling the first dorsal interosseus (FDI) muscle. We compared three conditions : index finger abduction (a simple but not natural task), precision grip between index and thumb ( amore natural and complex task), and rest. We also evaluated the effect of task on interaction between LICI and Short Interval Intracortical Inhibition (SICI). Finally, we assessed the time course of LICI in patients suffering from writer’s cramp. For this purpose, we used surface electromyography to record motor potentials evoked by Transcranial Magnetic Stimulation.We showed a task-dependent change in late inhibitory and disinhibitory components. Compared with abduction task, the LICI induced during precision grip was shorter, suggesting an early disinhibition in more complex task. The disinhibition was followed by a period of facilitation only during the active tasks, i.e. facilitation was not observed when all muscles were at restat rest. However, long interval intracortical facilitation can be observed in a muscle at rest not engaged in an active task if a neighboring muscle is activated. It is therefore likely that mechanisms underlying facilitation are associated with voluntary contraction albeit with lack of topographic specificity. Interaction between LICI and SICI was not modified between tasks, suggesting that it was not involved in task-dependent changes of cortical excitability. Lastly, disinhibition was shown to be delayed in dystonic patients when the FDI was actively engaged in a precision grip but not in index abduction, compared with control subjects. An explanation might be that mechanisms underlying disinhibition are impaired in thumb-index precision grip (a task similar to that inducing unwanted contractions in writer’s cramp). Task-specidic disruption of LICI and late cortical disinhibition may therefore be at least in part responsible for pathophysiology of dystonia. It is likely that during complex task, the efficacy of LICI, and more generally of motor cortex inhibitory mechanisms, is modified to allow adaptation of CM neurons activity to the functional requirements of the motor task being performed.

Introdução: A doença aterosclerótica intracraniana é uma das principais causas de acidente vascular cerebral isquêmico (AVCI) no mundo, porém sua prevalência parece estar subestimada na população brasileira pela carência de estudos na área. O objetivo principal deste estudo foi descrever a frequência e gravidade da estenose intracraniana nos pacientes com AVCI ou ataque isquêmico transitório (AIT), utilizando a ultrassonografia transcraniana colorida (UTC). O objetivo secundário foi correlacionar os achados deste exame com a angiotomografia de crânio (AngioTC). Métodos: estudo observacional e prospectivo, onde foram avaliados pacientes consecutivos com o diagnóstico de AVCI ou AIT admitidos no período de fevereiro de 2014 a dezembro de 2014. A avaliação inicial consistiu na coleta de dados demográficos, epidemiológicos e clínicos e em seguida os pacientes foram submetidos ao exame de UTC através das janelas transtemporais e suboccipital, com o intuito de avaliar a presença de estenose intracraniana. Estenose intracraniana foi graduada em moderada (50- 70%), grave (70-99%) e suboclusão/oclusão (>= 99%). Foram considerados sintomáticos os casos em que houve uma associação entre os novos sinais e sintomas e uma nova área de infarto ao exame de neuroimagem no território da artéria envolvida ou quando o quadro neurológico correspondeu ao território da artéria envolvida. Os pacientes que possuíam UTC e AngioTC em sua avaliação foram comparados de forma cega quanto ao grau de estenose intracraniana seguindo a mesma classificação. Resultados: Foram avaliados 271 pacientes com o diagnóstico de AVCI ou AIT agudos (149 homens, com média de idade de 65,8 ± 12,5), 263 (97%) foram submetidos a exame de circulação intracraniana, sendo a ultrassonografia transcraniana colorida realizada em 168 casos (61,9%). Apenas 25 indivíduos (14,9%) foram excluídos devido a janela transtemporal insuficiente. Dentre os 143 pacientes que puderam ser avaliados adequadamente pela ultrassonografia transcraniana, a prevalência de estenose arterial intracraniana foi de 38,5% (55 casos); sendo sintomática em 25,2% dos casos. A média de idade dos pacientes era de 64 ± 11 anos, 26,9 % eram brancos e 29,4% hipertensos. Os pacientes com estenose intracraniana apresentaram maior pontuação na escala do NIH: 10 (IQ 4 - 19) vs 6 (IQ 3 - 13), maiores níveis de pressão arterial sistólica na admissão: 160 (IQ 145-170) vs 140 (IQ 130 - 155) e menores taxas de HDL: 32 (IQ 27 - 39) vs 36 (IQ 30 - 45). Após análise multivariada, o fator de risco independentemente associado à estenose intracraniana foi a hipertesão arterial sistêmica na admissão (p=0,006). Nos 100 pacientes com ambos os exames, a sensibilidade, especificidade, valor preditivo positivo e valor preditivo negativo da UTC comparada a AngioTC para detecção de estenoses intracranianas moderadas-graves foi de 60%, 73%, 73% e 60%, respectivamente. Conclusões: Encontramos alta frequência de estenose arterial intracraniana entre os pacientes com AVCI agudo e AIT na nossa população, especialmente entre indivíduos portadores de hipertensão arterial sistêmica. A UTC é uma ferramenta não-invasiva que pode ser utilizada para investigação da doença moderada-grave com acurácia moderada quando comparada a AngioTC / Background: Intracranial atherosclerotic disease is a major cause of ischemic stroke in the world, but its prevalence seems to be underestimated in our population by the lack of studies in the area. The aim of this study was to describe the frequency and severity of intracranial stenosis in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA), using the transcranial color-coded sonography (TCCS). The secondary objective was to correlate the TCCS test results with the findings on CT angiography on the same patients. Methods: Prospective observational study that evaluated consecutive patients admitted with a diagnosis of ischemic stroke or TIA during the period February 2014 to December 2014. The initial evaluation consisted of collection of demographic, epidemiological and clinical data and then the patients underwent the examination TCCS through transtemporal and suboccipital windows, in order to assess the presence of intracranial stenosis. Intracranial stenosis was graded moderate (50-70%), severe (70-99%) and subocclusion/occlusion (>= 99%). The cases were considered symptomatic when there was an association between new symptoms and signs and a new infarct area on neuroimaging in the territory of the stenotic artery or when the neurological status corresponded to the territory of that artery. Patients who had TCCS and intracranial angiography in their assessment were blindly compared for the degree of intracranial stenosis following the same classification. Results: We evaluated 271 patients with diagnosis of acute ischemic stroke and TIA (149 men, mean age 65.8 ± 12.5), 263 (97%) underwent examination of intracranial circulation, with the TCCS held in 168 cases (61.9%). Only 25 individuals (14.9%) were excluded due to insufficient transtemporal window. Among the 143 patients who could be evaluated properly by transcranial ultrasound, the prevalence of intracranial arterial stenosis was 38.5% (55 cases); with 25,2% symptomatic cases. The average age of patients was 64 ± 11 years, 26.9% were white and 29.4% hypertensive. Patients with intracranial stenosis had higher scores on the NIHSS: 10 (IR 4-19) vs 6 (IR 3- 13), higher levels of systolic blood pressure at entry: 160 (IR 145-170) vs 140 (IR 130 - 155) and lower HDL rates: 32 (IR 27-39) vs 36 (IR 30-45). After multivariate analysis, the risk factor independently associated with intracranial stenosis was systemic arterial hypertension at admission (p = 0.006). In the 83 patients with both tests, the sensitivity, specificity, positive predictive value and negative predictive value of TCCS compared to CT angiography for detection of intracranial stenosis moderate-severe was 60%, 73%, 73% e 60%, respectively, Conclusions: We found a high frequency of intracranial artery stenosis in patients with acute ischemic stroke and TIA in our population, especially among individuals with hypertension. TCCS is a non-invasive tool that can be used to study moderate-severe disease with moderate accuracy compared to CT angiography

O circuito neuronal relacionado à depressão na doença de Parkinson (DP), assim como os efeitos da terapia antidepressiva nestes pacientes, não é bem estabelecido. Os métodos de neuroimagem podem levar ao melhor conhecimento da patogênese e também dos mecanismos de ação relacionados a um tipo específico de tratamento. Para avaliar as diferenças da atividade neuronal, comparamos 21 pacientes com DP e diagnóstico de depressão e 16 sem depressão através de ressonância magnética funcional (RMf) em uma tarefa cognitiva que inclui percepção emocional e escolha forçada com duas opções. Estes 21 pacientes deprimidos foram aleatorizados em dois grupos de tratamento por 4 semanas: estimulação magnética transcraniana (EMT) ativa sobre o córtex pré-frontal dorsolateral esquerdo ( 5 Hz EMT - 120% do limiar motor) com pílula placebo e EMT placebo com 20 mg diária de fluoxetina. Os pacientes foram submetidos a um experimento de RMf cujo paradigma foi relacionado a eventos apresentação visual de faces de conteúdo emocional. Os pacientes sem depressão realizaram RMf duas vezes (teste reteste) e os deprimidos quatro vezes (duas vezes antes e duas depois do tratamento). As imagens dos pacientes com DP e depressão demonstraram menor atividade no córtex pré-frontal medial quando comparados aos pacientes com DP sem depressão. Ambos os subgrupos de pacientes com DP e depressão apresentaram melhora significativa e similar dos sintomas da depressão. Após o tratamento com EMT ativa observou-se menor atividade do giro fusiforme esquerdo, do cerebelo e do córtex pré-frontal dorsolateral direito e maior atividade do córtex pré-frontal dorsolateral esquerdo e do cíngulo anterior nas imagens de RMf quando comparados àquelas antes do tratamento. Por outro lado a fluoxetina determinou aumento da atividade do córtex pré-motor direito e do córtex pré-frontal medial direito em imagens de RMf realizadas após o tratamento. Observou-se efeito de interação entre os grupos (tempo (pré x pós) versus tipo de tratamento (fluoxetina x EMT)) no córtex préfrontal medial esquerdo sendo maior o aumento no grupo tratado com EMT. Nossos achados mostraram: 1) padrão diferente de atividade cerebral em pacientes com DP com e sem depressão; 2) efeitos antidepressivos da EMT e da fluoxetina foram semelhantes e significativos;e 3) em pacientes com DP e depressão os efeitos da EMT e fluoxetina são associados a diferentes mudanças da atividade cerebral, e em ambos as áreas encontradas são parte da rede neural relacionada à depressão. / The neural circuitry underlying depression in patients with Parkinson\'s disease (PD) is unknown, let alone the treatment effects of antidepressant therapy. Neuroimaging methods can give insights into the pathogenesis of depression and also in the mechanisms of action related to specific treatment choice. In order to evaluate differences between PD patients with and without concomitant depression we studied 21 patients with PD and depression and 16 PD patients without depression using fMRI. All patients were examined using an event-related fMRI paradigm based on visual presentation of faces with emotional content in a two options forced choice task. Furthermore the twenty-one PD depressed patients were randomized in two active treatment groups for 4 weeks: active rTMS over left dorsolateral prefrontal cortex (5 Hz rTMS - 120% motor threshold) with placebo pill and sham rTMS with fluoxetine 20 mg/day. Event-related fMRI with emotional stimuli was performed before and after treatment - in two sessions (test and re-test) at each time point. The same test-retest approach was adopted in the group of non-depressed PD patients. The analysis showed significant differences between depressed and non-depressed PD patients in the medial pre-frontal cortex, with reduced activation as detected by BOLD effect in the later group. The two groups of depressed PD patients showed a had a significant treatment effect, and with similar mood improvement. After rTMS treatment, there were brain activity decreases in left fusiform gyrus, cerebellum and right dorsolateral prefrontal cortex (DLPFC) and brain activity increases in left DLPFC and anterior cingulate gyrus as compared to baseline. In contrast, after fluoxetine treatment, there was brain activity increases in right premotor and right medial prefrontal cortex. There was a significant interaction effect between groups versus time in the left medial prefrontal cortex, suggesting that the activity in this area changed differently in the two treatment groups. Our findings show that medial prefrontal cortex is a critical area in the depression neural circuitry in PD. Antidepressant effects of rTMS and fluoxetine in PD are associated with changes in different areas of the depression-related neural network.