Dissertations / Theses on the topic 'Transcranial magnetic stimulation'

La tesi descrive la stimolazione magnetica transcranica, un metodo di indagine non invasivo. Nel primo capitolo ci si è soffermati sull’ anatomia e funzionalità del sistema nervoso sia centrale che periferico e sulle caratteristiche principali delle cellule neuronali. Nel secondo capitolo vengono descritte inizialmente le basi fisico-tecnologiche della strumentazione stessa, dando particolare attenzione ai circuiti che costituiscono gli stimolatori magnetici ed alle tipologie di bobine più utilizzate. Successivamente si sono definiti i principali protocolli di stimolazione evidenziandone le caratteristiche principali come, ampiezza, durata e frequenza dell’impulso. Nel terzo capitolo vengono descritti i possibili impieghi della stimolazione in ambito sperimentale e terapeutico. Nel quarto ed ultimo capitolo si evidenziano i limiti, della strumentazione e dell’analisi che la stessa permette, andando a definire i parametri di sicurezza, i possibili effetti indesiderati, il costo dell’apparecchiatura e l’uso combinato con altre tecniche specifiche

The Transcranial Magnetic Stimulation (TMS) is a non-invasive technique to stimulate the brain, with main applications in depression treatment and pre-operative planning (via functional motor mapping and speech mapping). On average, a TMS treatment session lasts for 30 minutes and coil handling/positioning might become a strenuous task for the operator. A robotic arm could be used to replace the human operator during the coil positioning tasks allowing the doctor to focus on the data analysis phase. In this thesis, a navigated TMS Robotic Assistant is designed, implemented and integrated with a commercial TMS system to automate the TMS sessions. Two different navigation approaches are investigated: i) with fixed head position, ii) with head movement compensation. To assess the performances of the implemented Robotic Assistant, several experimental sessions are carried out; the results satisfy the expectations, with an accuracy error of 3.5 mm for stimulation targets, which decreases below 2 mm with repeated stimulus. Most of the functional requirements are fulfilled, however further investigations are needed to improve the proposed methods and implement new functionalities to obtain an enhanced version of nTMS Robotic Assistant.

PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO<br>CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO<br>Um estudo do atual estado da confiabilidade metrológica da Estimulação Magnética Transcraniana (TMS) é apresentado. A questão da segurança é abordada em três aspectos principais: A segurança e desempenho dos equipamentos de TMS; a segurança em relação aos limites de exposição para operadores do equipamento e pacientes; e a segurança do protocolo terapêutico e dos parâmetros de tratamento. Propostas para um protocolo de relatório harmonizado e a base de uma possível futura norma técnica para equipamentos de TMS também são apresentadas. Os resultados de simulações e medições da densidade de fluxo magnético emitido por equipamentos de TMS de duas marcas são relatados, com os cálculos correspondentes das distâncias seguras em relação a exposição de operadores do equipamento, usando os métodos promulgados pelas diretrizes da Comissão Internacional de Proteção Contra a Radiação Não Ionizante (ICRNIP). Estas distâncias são então comparadas com estimativas prévias encontradas na literatura. O desenvolvimento das rotinas de simulação e do sistema de medição é descrito, incluindo possíveis futuras aplicações em outros estudos e aspectos metrológicos de incerteza de medição.<br>A study of the current status of the metrological reliability of Transcranial Magnetic Stimulation (TMS) is presented. The matter of safety is approached in three major aspects: The safety and performance of the TMS devices; the safety regarding exposure limits for patients, staff and the general public; and the safety of the therapeutic protocol and of the treatment parameters. Proposals for a harmonized reporting framework and the basis for a possible future TMS safety and performance technical standard are also presented. The results of simulations and measurements of the magnetic flux densities emitted by two brands of TMS devices are reported, with the corresponding calculations for the safe distances regarding staff exposure, using the methods promulgated by the guidelines of the International Commission on Non Ionizing Radiation Protection (ICNIRP). These distances are compared to the previous estimates found in literature. The development of both the simulation routines and the measurement system are described, including possible future applications in other studies and metrological aspects of measurement uncertainty.

This thesis explores the effects of transcranial magnetic stimulation (TMS) on conscious perception and visual processing. Chapter 1 addresses issues of experimental design. Two broad classes of TMS intervention were used and are reported in separate chapters. Chapter 2 involves repetitive ‘off-line’ TMS combined with neuroimaging techniques. Chapter 3 employs ‘on-line’ TMS applied with temporal specificity to track the passage of information through early visual cortex. Chapter 4 is a general discussion primarily concerned with the issues encountered experiments oriented towards consciousness.

The use of robots to assist neurologists in Transcranial Magnetic Stimulation (TMS) has the potential to improve the long term outcome of brain stimulation. Although extensive research has been carried out on TMS robotic system, no single study exists which adequately take into account the control of interaction of contact force between the robot and subject’s head. Thus, the introduction of force feedback control is considered as a desirable feature, and is particularly important when using an autonomous robot manipulator. In this study, a force-controlled TMS robotic system has been developed, which consists of a 6 degree of freedom (DOF) articulated robot arm, a force/torque sensor system to measure contact force and real-time PC based control system. A variant of the external force control scheme was successfully implemented to carry out the simultaneous force and position control in real-time. A number of engineering challenges are addressed to develop a viable system for TMS application; simultaneous real-time force and position tracking on subject’s head, unknown/varies environment stiffness and motion compensation to counter the force-controlled instability problems, and safe automated robotic system. Simulation of a single axis force-controlled robotic system has been carried out, which includes a task of maintaining contact on simulated subject’s head. The results provide a good agreement with parallel experimental tests, which leads to further improvement to the robot force control. An Adaptive Neuro-Fuzzy Force Controller has been developed to provide stable and robust force control on unknown environment stiffness and motion. The potential of the proposed method has been further illustrated and verified through a comprehensive series of experiments. This work also lays important foundations for long term related research, particularly in the development of real-time medical robotic system and new techniques of force control mainly for human-robot interaction. KEY WORDS: Transcranial Magnetic Stimulation, Robotic System, Real-time System, External Force Control Scheme, Adaptive Neuro-Fuzzy Force Controller

Transcranial Magnetic Stimulation (TMS) is an excellent and non-invasive technique for studying the human brain. Accurate placement of the magnetic coil is required by this technique in order to induce a specific cortical activity. Currently, the coil is manually held in most of stimulation procedures, which does not achieve the precise clinical evaluation of the procedure. This thesis proposes a robotic TMS system to resolve these problems as a robot has excellent locating and holding capabilities. The proposed system can track in real-time the subject’s head position and simultaneously maintain a constant contact force between the coil and the subject’s head so that it does not need to be restrained and thus ensure the accuracy of the stimulation result. Requirements for the robotic TMS system are proposed initially base on analysis of a serial of TMS experiments on real subjects. Both hardware and software design are addressed according to these requirements in this thesis. An optical tracking system is used in the system for guiding and tracking the motion of the robot and inadvertent small movements of the subject’s head. Two methods of coordinate system registration are developed base on DH and Tsai-lenz’s method, and it is found that DH method has an improved accuracy (RMS error is 0.55mm). In addition, the contact force is controlled using a Force/Torque sensor; and a combined position and force tracking controller is applied in the system. This combined controller incorporates the position tracking and conventional gain scheduling force control algorithms to monitor both position and force in real-time. These algorithms are verified through a series of experiments. And it is found that the maximum position and force error are 3mm and 5N respectively when the subject moves at a speed of 20mm/s. Although the performance still needs to be improved to achieve a better system, the robotic system has shown the significant advantage compared with the manual TMS system. Keywords—Transcranial Magnetic Stimulation, Robot arm, Medical system, Calibration, Tracking

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006.<br>Includes bibliographical references (p. 281-301).<br>This thesis will explore the use of Transcranial Magnetic Stimulation (TMS) and Transcranial DC Stimulation (tDCS) as modalities for neuropathology treatment by means of both experimental and modeling paradigms. The first and primary modality that will be analyzed is Transcranial Magnetic Stimulation (TMS). TMS is a technique that uses the principle of electromagnetic induction to focus induced currents in the brain and modulate cortical function. These currents can be of sufficient magnitude to depolarize neurons, and when these currents are applied repetitively (repetitive Transcranial Magnetic Stimulation (rTMS)) they can modulate cortical excitability, decreasing or increasing it, depending on the parameters of stimulation. This thesis will explore important facets of the electromagnetic field distributions and fundamental electromagnetic interactions to lay the foundation for future development of a more complete neural model and improved stimulation techniques. First, TMS will be analyzed as a technique used in normal healthy subjects. Finite element modeling (FEM) studies will be explored for realistic healthy human head models with a particular focus placed on the TMS induced cortical currents and their dependency on coil position, normal tissue anatomy, and the electromagnetic tissue properties.<br>(cont.) This component of the thesis will also include experimental work focused on exploring the in-vivo tissue conductivity and permittivity values used in TMS studies and their impact on stimulation (including a detailed literature review). The next component of the thesis will explore the use of TMS in subjects suffering from various pathologies. The first pathological condition that will be analyzed is cortical stroke. FEM studies will be evaluated and compared to the healthy head models to assess how the cortical modifications brought on at an infarction site can alter the TMS induced current densities. We will also include a laboratory study that assesses the efficacy of TMS in stroke treatment, where repetitive TMS (rTMS) was applied to the unaffected hemisphere to decrease inter-hemispheric inhibition of the lesioned hemisphere and improve motor function in stroke patients. Next, the use of TMS in conditions of brain atrophy will be assessed through modeling analyses. This component will also include an evaluation of the clinical work in the field and ways in which the current density alterations caused by the atrophy have led to clinical misconceptions. Transcranial DC Stimulation (tDCS) will be the second modality analyzed through modeling and experimental work.<br>(cont.) In tDCS, the cerebral cortex is stimulated through a weak dc current in a non-invasive and painless manner and can modulate cortical excitability like TMS. We will define finite element head models of tDCS for both normal and pathologic cases and evaluate the use of tDCS in the clinic in a stroke treatment experiment (analogous to the one completed with TMS). Finally, we will assess and compare these forms of brain stimulation to other forms of neurological treatment and conclude with proposed future improvements to the field of non-invasive brain stimulation.<br>by Tim Wagner.<br>Ph.D.

Human motor system plasticity can be quantified using single pulse transcranial magnetic stimulation (TMS) to measure corticospinal excitability. TMS can be used to produce excitability maps and to examine the stimulus-response (SR) relationship. The overall aims of this thesis are (1) to demonstrate that TMS mapping and SR curves can be acquired much faster than has been traditionally possible and (2) that these techniques can be used to study internally externally driven plasticity. By modifying the TMS delivery, it is demonstrated that both the TMS map and the SR curve can be reliably produced in approximately two minutes. These techniques were then used to examine internally driven plasticity via mirror training and visuomotor tracking learning and externally driven plasticity via transcranial alternating current stimulation. Changes in corticospinal excitability were found to be variable both for internally as externally driven plasticity. Nonetheless, these studies highlight that it is possible to rapidly assess changes in corticospinal excitability.

This thesis explored a number of methodological issues present in motor cognition research using transcranial magnetic stimulation (TMS). The facilitatory effect of the corticospinal pathway during observation of simple hand actions was also investigated. TMS was applied to the motor cortex during action observation and the resulting MEP peak-to-peak amplitudes were analysed. A series of four studies were conducted to test whether a motor facilitation effect specific to the muscles involved in the observed actions were obtained, while simultaneously investigating five prominent methodological concerns in TMS research. In Study 1 the issue of choosing the optimal control condition was investigated. The MEP facilitation obtained during action observation (ball pinch) was compared to two commonly used control conditions (fixation cross and static image). Consistent with published literature, the action condition resulted in larger MEP amplitudes than the controls. There was no statistical difference in MEP amplitude between the two resting conditions. It was argued, however, that the static image allows for more accurate comparison with the action condition by providing meaningful visual cues without the associated action. In Study 2, the effect of short-term physical execution on the relationship between observed actions and neural activity was explored. The motor facilitation effect was present during action observation. This was not enhanced following execution of the observed action which is in contrast with the literature that shows the observation-execution matching system tuned to familiarity with an action. In TMS studies, different stimulation timings are included in order to reduce anticipatory effects of the TMS pulse. While the different timings are usually analysed together, in Studies 1 and 2, the two stimulation timings were analysed separately. As a consequence, a motor facilitation effect was only evident for the earlier stimulation timing of 6250ms in Study 1. When participants executed the action prior to observing it in Study 2, there was no effect of stimulation timing, leading to speculation that the prior execution may have had some effect on the attentional demands during the subsequent observation. Studies 3 and 4 explored two general methods concerns regarding the motor hotspot and stimulation intensity. In Study 3, the muscle- vi specificity notion was explored via observation of index finger and little finger movements versus observation of a static hand, with the corresponding muscles tested at their individual hotspots. This was a novel approach as one hotspot is typically used for all muscles under investigation. The choice of motor hotspot, however, did not significantly affect the muscle-specific findings, providing further support for the muscle-specific motor facilitation findings reported in the literature. Finally, Study 4 investigated the concept of stimulation intensity. TMS action observation studies differ in the stimulation intensities used, typically ranging from 110% to 130% of resting motor threshold. Since the motor response obtained through TMS may be affected depending on the stimulation intensity used, two stimulation intensities were employed (high vs. low) during observation of finger movements. A motor facilitation effect was reported in the low intensity stimulation, which was expected given that near threshold intensities are more representative of the ongoing level of cortical excitability. No motor facilitation effect was shown in the high intensity stimulation, possibly due to the nature of high stimulation intensities on the corticospinal pathway, or simply because the low intensity stimulations were always delivered before the high intensity stimulations. In light of the stimulation timing findings of Study 1, this may have resulted in participants getting distracted or fatigued, focussing their attention elsewhere (and therefore lowering MEP amplitudes) during the latter high stimulations. From the results presented in these studies, it is clear that there is a muscle specific motor facilitation during action observation and its characteristics are influenced by many procedural, technical and cognitive and attentional factors. This thesis provides a much needed critical analysis into the methods and methodologies commonly adopted in this area of research. It is essential to continue to explore the methods employed in TMS motor cognition studies, making them accepted universally and scientifically rigorous.

Neuronavigation and transcranial magnetic stimulation (TMS) are valuable tools in clinical and research environment. Neuronavigation provides visual guidance of a given instrument during procedures of neurological interventions, relative to anatomic images. In turn, TMS allows the non-invasive study of cortical brain function and to treat several neurological disorders. Despite the well-accepted importance of both techniques, high-cost of neuronavigation systems and limited spatial accuracy of TMS in targeting brain structures, limit their applications. Therefore, the aim of this thesis was to i) develop an open-source, free neuronavigation software, ii) study a possible combination of neuronavigation and 3D printing for surgical planning, and iii) construct a multi-channel TMS coil with electronic control of electric field (E-field) orientation. In the first part, we developed and characterized a neuronavigation software compatible with multiple spatial tracking devices, the InVesalius Navigator. The created co-registration algorithm enabled tracking position and orientation of instruments with an intuitive graphical interface. Measured accuracy was similar to that of commercial systems. In the second part, we created 3D printed models from patients with neurological disorders and assessed the errors of localizing anatomical landmarks during neuronavigation. Localization errors were below 3 mm, considered acceptable for clinical applications. Finally, in the last part, we combined a set of two thin, overlapping coils to allow electronic control of the E-field orientation and investigated how the motor evoked responses depend on the stimulus orientation. The developed coil enabled the stimulation of the motor cortex with high angular resolution. Motor responses showed the highest amplitude and lowest latency with E-field approximately perpendicular to the central sulcus. In summary, this thesis provides new methods to improve spatial accuracy of techniques to brain interventions.<br>A neuronavegação e a estimulação magnética transcraniana (EMT ou TMS, do termo em inglês transcranial magnetic stimulation) têm sido apresentadas como ferramentas valiosas em aplicações clínicas e de pesquisa. A neuronavegação possibilita a localização de instrumentos em relação a imagens anatômicas durante procedimentos de intervenção neurológica. Por sua vez, a EMT permite o estudo não invasivo da função cerebral e o tratamento de doenças neurológicas. Apesar da importância de ambas as técnicas, o alto custo dos sistemas de neuronavegação e a reduzida precisão espacial da EMT em ativar estruturas cerebrais limitam suas aplicações. Sendo assim, o objetivo desta tese foi: i) desenvolver um software de neuronavegação gratuito e de código aberto, ii) estudar a combinação entre neuronavegação e impressão 3D para planejamento cirúrgico, e iii) construir uma bobina de EMT multicanal com controle eletrônico da orientação do campo elétrico (CE). Na primeira parte, desenvolvemos e caracterizamos um software de neuronavegação compatível com vários rastreadores espaciais, o InVesalius Navigator. O algoritmo criado possibilitou o rastreamento de instrumentos por uma interface gráfica intuitiva. A precisão medida foi semelhante à de sistemas comerciais. Na segunda parte, imprimimos modelos 3D de pacientes com patologias neurológicas e avaliamos os erros de localização de marcos anatômicos durante a neuronavegação. Os erros de localização foram inferiores a 3 mm, considerados aceitáveis para aplicações clínicas. Por fim, na última parte, combinamos duas bobinas sobrepostas para controlar eletronicamente a orientação do CE, e investigamos como as respostas motoras evocadas dependem da orientação da corrente. A bobina desenvolvida possibilitou estimular o córtex motor com alta resolução angular. As respostas motoras apresentaram maior amplitude e menor latência para orientação do CE aproximadamente perpendicular ao sulco central. Em suma, esta tese fornece novos métodos para melhorar a precisão espacial de técnicas de intervenção com o cérebro.

Transcranial magnetic stimulation (TMS) is a modern non invasive method of drug resistant psychiatric disorder treatment. TMS physiology research is hindered by variable, often controversial results. In most studies main attention is being focused on immediate effects after single TMS procedure rather than the influence of a complete therapy course. It is considered that variability of results in TMS practice is caused by different stimulation parameters and imprecision of stimulated area placement in the brain. Although TMS therapy is often viewed as a milder alternative to electroconvulsive therapy (ECT), comparative physiological studies of these two methods are very rare. The aim of this study was to evaluate the effect of rTMS therapy course on bioelectrical brain activity and compare it to an ECT effect. Research included the effect of high and low frequency (10 Hz and 1 Hz) TMS on EEG band power spectrum and auditory evoked potential P300, using both standard and neuronavigated target positioning. TMS evoked EEG changes were also compared to the changes of ECT. Change dynamics after several months of TMS therapy were also measured. Results showed that after TMS therapy the most notable change in the brain occurs in the form of delta power increase. When using standard positioning 10 Hz TMS evokes more diverse and intense EEG band power spectrum changes than the 1 Hz TMS. Application of neuronavigation system decreases theta and alpha band power changes in 10 Hz TMS... [to full text]<br>Transkranijinė magnetinė stimuliacija (TMS) – tai modernus neinvazinis vaistams rezistentiškų psichiatrinių sutrikimų gydymo būdas. Fiziologiniai TMS tyrimai pasižymi įvairiais, dažnai prieštaringais rezultatais, daugeliu atvejų didžiausias dėmesys skiriamas betarpiškiems poveikiams po vienos TMS procedūros, bet ne po pilno terapinio kurso. Manoma, kad rezultatų įvairovę TMS praktikoje įtakoja skirtingi stimuliacijos parametrai ir netikslumai parenkant stimuliuojamą zoną smegenyse. Nors TMS terapija dažnai traktuojama kaip švelnesnė alternatyva elektros impulsų terapijai (EIT), palyginamųjų fiziologinių šių metodikų tyrimų labai trūksta. Darbo tikslas buvo įvertinti TMS terapijos kurso poveikį bioelektriniam galvos smegenų aktyvumui ir palyginti jį su EIT terapijos poveikiu. Buvo tirta aukšto ir žemo dažnių (10 Hz ir 1 Hz) TMS terapijos įtaka EEG dažnių galios spektrui bei sukeltiniam klausos potencialui P300, naudojant standartinį ir neuronavigacinį taikinio pozicionavimą. TMS sukelti EEG pokyčiai palyginti su EIT terapijos sukeltais EEG pokyčiais, išmatuota TMS terapijos sąlygotų pokyčių dinamika kelių mėnesių bėgyje. Rezultatai parodė, kad TMS terapijos pasekoje smegenyse ryškiausiai padidėja delta dažnio galia. Naudojant standartinį pozicionavimą 10 Hz TMS sukėlė įvairesnius ir intensyvesnius EEG galios spektro pokyčius nei 1 Hz TMS. Pritaikius neuronavigacinę sistemą 10 Hz TMS atveju sumažėjo teta ir alfa dažnių galios pokyčiai. Praėjus keliems mėnesiams nuo TMS... [toliau žr. visą tekstą]

An important aspect of cognitive neuroscience is to localise specific brain regions involved in cognitive tasks, and to determine the mediating brain processes. There are several investigative approaches towards this, but amongst them, only transcranial magnetic stimulation (TMS) is able to interfere with the brain in such a way as to show the critical involvement of a brain region in a particular behaviour. TMS can be applied in normal subjects during the performance of a cognitive task and the resulting disruption of activity in the targeted brain region leads to an alteration in, or suspension of, behaviour consequent upon that brain activity. More recently, another brain stimulation technique has emerged that may also be able to contribute to the investigation of human cognition. Transcranial direct current stimulation (tDCS) applies a weak direct current to a targeted brain region, modulating cortical excitability and thereby altering the behavioural output. tDCS may be able to provide information that complements TMS and other investigative techniques by modulating behaviour in a way that depends on the role the brain region is carrying out in the task. This thesis describes a series of experiments in which TMS and tDCS were applied to two well-studied cognitive behaviours, working memory (WM) and mental rotation (MR). WM is the temporary retention of information that can be manipulated in order to guide behaviour. The most popular psychological model of WM proposes a multi-modal central executive (CE) that acts upon information stored in dedicated buffers (Baddeley, 1986). The dorsolateral prefrontal cortex (DLPFC) is a strong candidate as a key CE node (D'Esposito & Postle, 2000; Petrides, 2000b; Smith & Jonides, 1997; Stuss & Knight, 2002). MR is a visuo-cognitive process by which an image can be mentally modified into an orientation other than the one in which it is displayed (Corballis & McLaren, 1984). The area centred around the intraparietal sulcus is a brain key region for MR (Alivisatos & Petrides, 1996; Harris et al., 2000; Jordan et al., 2001). The work presented in this thesis examines the roles of the DLPFC and posterior parietal cortex (PPC) in WM and MR, respectively, and also highlights some of the methodological issues that are necessary to consider in order to produce reliable virtual lesions. The studies were carried out in young healthy volunteers, and were approved by the institutional ethics committee. In one study, repetitive TMS (rTMS) was shown to disrupt the manipulation of verbal information held in WM when administered over the right DLPFC, a result which supports a process-based segregation of the human prefrontal cortex for WM. Low- and high-frequency rTMS did not disrupt performance on another popular test of executive processing, n-back, a result which suggests that specific stimulation and task conditions must be met in order to produce virtual lesions, but also questions the critical importance of recruitment of the DLPFC for a running span task. rTMS applied to the right PPC replicated results from a previous TMS investigation, supporting the critical role this region in the rotation of images (Harris & Miniussi, 2003). When the left PPC was stimulated, impairment was produced only for the rotation of inverted stimuli. A role for the left PPC in the rotation of objects-as-a-whole is proposed based on these findings. The use of tDCS in the investigation of WM and MR is amongst the first to be described. Stimulation of the left DLPFC led to decreased performance accuracy on a verbal WM task in a polarity-specific manner. The pattern of results produced supports the role of the DLPFC as a node of a CE. tDCS over the left DLPFC did not modulate n-back task performance, a result which supports the TMS results that the involvement of the left DLPFC is not critical to the successful performance of the n-back task, although methodological issues remain of concern in relation to this conclusion. MR was not affected by tDCS applied to the right PPC and this result is most likely a direct demonstration of the importance of electrode montage. In conclusion, these studies show that rTMS and tDCS can be usefully applied to create virtual cortical lesions or modulate cortical excitability during the performance of cognitive tasks in humans, and can play an important role in investigating cognitive neuropsychological models. More widespread use of these techniques to complement lesion studies and functional neuroimaging is recommended.

Repetitive transcranial magnetic stimulation (rTMS) at certain frequencies increases thresholds for motor evoked potentials and phosphenes following stimulation of motor or visual cortex. Consequently rTMS is often assumed to introduce a "virtual lesion" in stimulated brain regions, with correspondingly diminished behavioral performance. Here we investigated the effects of rTMS to visual cortex on subjects' ability to perform visual psychophysical tasks. Contrary to expectations of a visual deficit, we find that rTMS often improves the discrimination of visual features. For coarse orientation tasks, discrimination of a static stimulus improved consistently following theta-burst stimulation of the occipital lobe. Using a reaction-time task, we found that these improvements occurred throughout the visual field and lasted beyond one hour post-rTMS. Low-frequency (1 Hz) stimulation yielded similar improvements. Finally, we observed improved depth discrimination following high-frequency rTMS to V3A, and these effects were highly task-specific, yielding improved discrimination of disparity but not orientation. Overall our results suggest that rTMS generally improves or has no effect on visual acuity, with the nature of the effect depending on the type of stimulation and the task. We interpret our results in the context of an ideal-observer model of visual perception.<br>La stimulation magnétique transcrânienne répétitive (rTMS) à certains seuils fréquences augmente pour potentiels évoqués moteurs et phosphènes suite d'une stimulation du moteur ou du cortex visuel. Par conséquent rTMS suppose souvent de mettre en place une lésion «virtuel» des régions cérébrales sollicitées, avec des performances comportementales réduit d'autant. Ici, nous avons étudié les effets de la rTMS au cortex visuel sur l'aptitude des sujets d'effectuer des tâches visuelles psychophysiques. Contrairement aux attentes d'un déficit visuel, nous constatons que rTMS améliore souvent la discrimination des caractéristiques visuelles. Pour les tâches d'orientation grossière, de la discrimination d'un stimulus statique améliorée à la suite constamment theta-burst stimulation du lobe occipital. L'utilisation d'un temps de réaction tâche, nous avons constaté que ces améliorations se sont produites tout au long du champ visuel et a duré plus d'un heure après l'rTMS. Basse fréquence (1 Hz) stimulation permis des améliorations similaires. Enfin, nous avons observé une meilleure discrimination en profondeur suivant à haute fréquence rTMS à V3A, et ces effets ont été très tâches spécifiques, ce qui donne de faciliter la distinction de disparité, mais pas l'orientation. L'ensemble, nos résultats suggèrent que rTMS améliore de manière générale ou n'a pas d'effet sur l'acuité visuelle, avec la nature de l'effet en fonction du type de stimulation et de la tâche. Nous interprétons nos résultats dans le contexte d'un modèle idéal-observateur de la perception visuelle.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that is able to modulate cortical activity beyond the stimulation period. The residual aftereffects are akin to the plasticity mechanism of the brain and suggest the potential use of rTMS for therapy. In parallel, there is evidence that altered oscillatory brain rhythms and network dynamics may lead to symptoms of neuropsychiatric disorders. However, the rTMS interference upon cortical and network oscillatory activity remains relatively unknown. Despite this uncertainty, rTMS continues to be used to alleviate symptoms of neuropsychiatric disorders. By combining rTMS and electroencephalography (EEG), the thesis explored the local and network cortical plasticity in healthy humans through the characteristics of oscillatory brain rhythms. We investigated cortical and network oscillatory activity following simple rTMS protocols and continuous theta burst stimulation (cTBS) to the primary motor cortex. The measurements of rTMS-induced aftereffects were quantified by the direct electrophysiology index of EEG and the indirect behavioural measures of motor evoked potentials (MEPs). The results of the experiments showed that rTMS was able to transiently modulate cortical brain rhythms, especially low frequency theta oscillations. The significance of this finding is the possible involvement of independent cortical theta generators besides mu and beta generators over the motor network with different reactivity to rTMS protocols. However, long-term potentiation/depression (LTP-/LTD)-like mechanisms may not be the only mechanisms that drive the rTMS aftereffects as shown by the dissociation between EEG and MEPs cortical output. Here, we explore alternative explanations that drive the EEG oscillatory modulations post rTMS. The significant of this work is the ability of rTMS to transiently modify the internal state of the brain by altering brain oscillations particularly low-frequency brain rhythms. This finding offers exciting possibilities for future clinical trials to explore the use of non-invasive brain stimulation to reverse abnormal synchronisation in neuropsychiatric disorders.

Despite its widespread use, a striking lack of knowledge exists regarding the mechanism of action of transcranial magnetic stimulation (TMS). This thesis describes the physiological characterisation of repetitive TMS (rTMS) to the motor system by means of functional magnetic resonance imaging (fMRI). A detailed analysis of imaging artefacts arising from the simultaneous application of TMS-fMRI was conducted and subsequently, strategies were presented for unperturbed TMS-fMRI. Physiological responses during subthreshold high-frequency rTMS of the primary sensorimotor cortex (Ml/Sl) were visualised within distinct cortical motor regions, comprising PMd, SMA, and contralateral Ml/Sl, while no significant responses were evidenced in the area of stimulation. Repetitive TMS during or before motor behaviour illustrated the context- dependence of rTMS-induced activity changes. The first demonstration of TMS-fMRI at 3 Tesla provided evidence that subthreshold rTMS can activate distinct networks including subcortical motor regions. The subthreshold nature of rTMS was confirmed by simultaneous electromyographic recordings from the target muscle. Stimulation of the dorsal premotor cortex provided evidence that rTMS- evoked local activity changes depend on the input function. The capability of TMS to target distinct networks in the human brain was confirmed. TMS targets a set of cortical and subcortical structures. Local responses may not invariably be elicited, indicating that low levels of synaptic activity, as occurring at low-intensity stimulation, do not necessarily evoke corresponding changes in cortical haemodynamics. It is concluded that combined TMS-fMRI offers a means to assess the mechanism of action of TMS at high spatial and temporal resolution.

The goal of this thesis was to examine the subcortical storage and triggering hypothesis proposed by Valls-Solé et al. (1999) and Carlsen et al. (2004b). This hypothesis suggests movements that can be prepared in advance of an imperative stimulus are stored and triggered from subcortical areas without cortical involvement by a startling acoustic stimulus (SAS). The rapid release of prepared movements by a SAS has been termed the StartReact effect, and premotor reaction times (PMTs) <70 ms are often observed. We used transcranial magnetic stimulation (TMS) to probe cortical involvement in the StartReact effect. In Experiment 1 we examined whether a TMS-induced cortical silent period could delay the release of movement by a SAS. Thirteen participants performed 20° wrist extension movements as fast as possible in response to either a control tone (82.3 dB) or a SAS (123.2 dB). During selected control and startle trials, suprathreshold TMS was delivered to the contralateral primary motor cortex (M1) 50 or 70 ms prior to mean PMT. Startle PMTs were faster than control PMTs, while TMS significantly delayed movement onset in control and startle trials compared to No TMS or Sham TMS conditions. Additionally, TMS facilitated the size of the first agonist burst (AG1) in both control and startle trials. Experiment 1 provided evidence for the involvement of M1 in the StartReact effect, however, it was possible that suprathreshold TMS disrupted subcortical startle reflex pathways. Experiment 2 utilized subthreshold TMS to M1, which has been shown to reduce ongoing EMG activity during a voluntary contraction by activating inhibitory cortical interneurons and not descending motor pathways (Davey, et al., 1994). TMS was delivered to the contralateral M1 during AG1 activity in random control and startle trials. Despite all seven participants displaying TMS-induced suppression in isometric wrist extension, EMG suppression was observed in only one participant in control and startle trials. Data are discussed with respect to a recent model of preparation and initiation proposed by Carlsen et al. (in press).

The present work introduces a synthesis of neocerebellar state estimation and feedforward control with multi-level language processing. The approach combines insights from clinical, imaging, and modelling work on the cerebellum with psycholinguistic and historical linguistic research. It finally provides the first experimental attempts towards the empirical validation of this synthesis, employing transcranial magnetic stimulation. A neuroanatomical locus traditionally seen as limited to lower sensorimotor functions, the cerebellum has, over the last decades, emerged as a widely accepted foundation of feedforward control and state estimation. Its cytoarchitectural homogeneity and diverse connectivity with virtually all parts of the central nervous system strongly support the idea of a uniform, domain-general cerebellar computation. Its reciprocal connectivity with language-related cortical areas suggests that this uniform cerebellar computation is also applied in language processing. Insight into the latter, however, remains an elusive desideratum; instead, research on cerebellar language functions is predominantly involved in the frontal cortical-like deficits (e.g. aphasias) seldom induced by cerebellar impairment. At the same time, reflections on cerebellar computations in language processing remain at most speculative, given the lack of discourse between cerebellar neuroscientists and psycholinguists. On the other hand, the fortunate contingency of the recent accommodation of these computations in psycholinguistic models provides the foundations for satisfying the desideratum above. The thesis thus formulates a neurolinguistic model whereby multi-level, predictive, associative linguistic operations are acquired and performed in neocerebello-cortical circuits, and are adaptively combined with cortico-cortical categorical processes. A broad range of psycholinguistic phenomena, involving, among others, "pragmatic normalization", "verbal/semantic illusions", associative priming, and phoneme restoration, are discussed in the light of recent findings on neocerebellar cognitive functions, and provide a rich research agenda for the experimental validation of the proposal. The hypothesis is then taken further, examining grammaticalization changes in the light of neocerebellar linguistic contributions. Despite a) the broad acceptance of routinization and automatization processes as the domain-general core of grammaticalization, b) the growing psycholinguistic research on routinized processing, and c) the evidence on neural circuits involved in automatization processes (crucially involving the cerebellum), interdisciplinary discourse remains strikingly poor. Based on the above, a synthesis is developed, whereby grammaticalization changes are introduced in routinized dialogical interaction as the result of maximized involvement of associative neocerebello-cortical processes. The thesis then turns to the first steps taken towards the verification of the hypothesis at hand. In view of the large methodological limitations of clinical research on cerebellar cognitive functions, the transcranial magnetic stimulation apparatus is employed instead, producing the very first linguistic experiments involving cerebellar stimulation. Despite the considerable technical difficulties met, neocerebellar loci are shown to be selectively involved in formal- and semantic-associative computations, with far-reaching consequences for neurolinguistic models of sentence processing. In particular, stimulation of the neocerebellar vermis is found to selectively enhance formal-associative priming in native speakers of English, and to disrupt, rather selectively, semantic-categorical priming in native speakers of Modern Greek, as well as to disrupt the practice-induced facilitation in processing repeatedly associated letter strings. Finally, stimulation of the right neocerebellar Crus I is found to enhance, quite selectively, semantic-associative priming in native speakers of English, while stimulation of the right neocerebellar vermis is shown to disrupt semantic priming altogether. The results are finally discussed in the light of a future research agenda overcoming the technical limitations met here.

This thesis describes a study of 70 patients with epilepsy and a normal control group. Subjects were studied with Transcranial Magnetic Brain Stimulation using a variety of parameters including measurement of motor evoked potentials, active and resting motor threshold, paired pulse inhibition and facilitation and cortical silent period. Data from normal subjects, 40 patients with temporal lobe epilepsy (TLE) and 17 patients with neocortical epilepsy was collected. The following data were acquired from some or all of each group: resting motor threshold (RMT), active motor threshold (AMT), cortical silent period (CSP), and conditioning-test stimulation data from which were derived measures of intracortical inhibition (SICI) and facilitation (SICF). Data were also obtained regarding drug treatment and seizure timing. Groups of subjects were compared. TLE patients were studied serially to examine the effects of seizures on TMS parameters. The main findings were that the groups differed regarding RMT and AMT, probably reflecting drug treatment; the patients groups differed in SICF; serial studies of the TLE patients showed changes in SICI and SICF which preceded seizures. RMT and AMT were elevated following seizures. Comparing the TLE and neocortical patient groups, there was higher SICF in the mTLE group. The difference between the patient groups demonstrates that epilepsies arising from distinct areas of the brain effect cortical excitability measured from the motor cortex in different ways. Repetitive TMS (rTMS) was undertaken in 11 subjects with refractory localisation related epilepsy. No effect of rTMS on the number of EEG spikes was seen as a result of a single session of rTMS, suggesting a variety of possibilities; rTMS may have no beneficial effect on focal seizures; the stimulus parameters may have been unsuitable; the chosen outcome measure – number of spikes – may be too inherently variable to show an effect after a relatively brief period of rTMS.

Millions of people suffer from tinnitus, a disorder for which there is currently no effective treatment or cure. My dissertation work provides insight into the neural correlates of this pervasive hearing disorder and examines how a newly emerging therapy, transcranial magnetic stimulation (TMS), affects the central auditory system in the generation of the tinnitus percept. This work has a multifold focus of: i) developing and modeling the function of a miniature magnetic coil that can be used for TMS in rodents, ii) establishing a reliable mouse model of tinnitus that can be used for assessing TMS treatment-induced changes, iii) measuring the behavioral alterations and neural changes induced by TMS throughout the auditory system in mice with tinnitus, and iv) to assay underling molecular changes in the auditory cortex (AC) related to TMS and tinnitus. Chapter 1 gives an overview of the current research on tinnitus and TMS. Chapter 2 establishes a reliable neural and behavioral assay of verifying tinnitus in a mouse model and provides further evidence that the underlying hyperactivity associated with tinnitus is initiated in the brainstem following reduced afferent input. The remainder of the dissertation examines the modulation of tinnitus in the auditory central nervous system using a miniature TMS coil. Chapter 3 of the dissertation details the creation and evaluation of a rodent-sized TMS coil, which could increase the overall effectiveness and applicability for human treatment. TMS is currently an FDA approved treatment of depression and has been shown to decrease tinnitus perception in human clinical trials, albeit with variable results. There have been few published studies of tinnitus modulation by TMS using animal models and therefore little is known about the molecular and neural bases of this potential tinnitus treatment. TMS is thought to be therapeutic because the magnetic flux generated from the electromagnetic coil induces an electric field in the brain, altering ion flow and subsequently neural function, as the excitation and inhibition of cortical networks become synchronized to the magnetic pulse. Chapter 4 demonstrates that TMS with our custom-designed miniature rodent coil can successfully reduce behavioral evidence of tinnitus in a mouse model, mainly through activating inhibitory networks in the AC. It also shows that presynaptic activity is altered in the upper layers of the AC responsible for intralaminar processing and sound perception. Finally, chapter 5 describes an in-depth proteomic analysis of over 3000 proteins from the AC, which shows that TMS and noise-induced tinnitus alter the expression of several key proteins and pathways that play a critical role in cortical excitatory and inhibitory activation. The results of this work are also important because they are the first animal model to demonstrate neural changes during TMS-treated tinnitus, creating a paradigm that can be used for optimizing parameters to improve clinical outcomes in human trials.

2007/2008<br>The neurophysiology of the monkey and human brain shows that transformation of visuomotor coordinates is related to the activation of a distributed and complex population of parietal, premotor and motor neurons. We can think about these circuits like different cortical areas activated in different times during reaching and grasping planning and execution, with different relations and communications among them. In this theoretic field, my PhD project was aimed at investigating the organization of planning and execution of visually guided reaching movements in the human brain, by means of Transcranial Magnetic Stimulation (TMS) in healthy subjects. I obtained a temporal and spatial map of both hemispheres, in order to refine available information about this complex system. In the contra-lateral hemisphere, an acceleration of reaction time was found when delivering TMS, on superior occipital lobe, at 50% of medium reaction time, without preferences for reaching direction in the peripersonal space. With the same time of stimulation, an acceleration of reaction times was also evident when stimulating the region of the parieto-occipital sulcus, but only for straight-forward reaching. Finally, in posterior superior parietal lobule slower reaction times were evident when TMS was delivered at 75% of the medium reaction time, but only for straight-forward reaching. Another facilitation of reaction time was evident in one of the five points stimulated in left parietal cortex, when TMS was delivered at 75% of medium reaction time, with no peripersonal space preferences. In dorsal premotor cortex another facilitation in reaction time was found, when TMS was delivered at 75% of medium reaction time, again with no peripersonal space preferences. Finally, I investigated the right hemisphere in cortical points homologue to those of the left hemisphere. Results indicated that only the region of the dorsal parieto-occipital sulcus is bilaterally involved. In fact, slower reaction times were evident when TMS was delivered at 75% of the medium reaction time. This indicates temporal differences in activation between left and right parieto-occipital sulcus. In all the effective points, the execution of control experiments showed that findings were specifically related to the planning of reaching movements, excluding the possibility of attentional, motor or perceptual effects, and that they were not due to diffusion of current to primary motor cortex. When delivering TMS during execution of reaching movements, effects were evident only when pulses were applied at 50% of medium movement time. In particular, a delay in movement time was evident in the parietal and premotor regions. Also in this case, control experiments excluded that effects were due to current diffusion to primary motor cortex and assured the specificity of the effect for visually-guided reaching. Present findings suggest that planning of reaching with right hand in healthy subjects starts early in left superior occipital cortex and in parieto-occipital region. Successively, a parallel and diffuse pattern of activation is evident. This pattern involves a specific point of superior parietal lobule in a ventral and rostral left parietal position, and a more anterior point of the premotor dorsal cortex, where a parallelism in activation could be speculated. Moreover, an interference in late motor planning in right and ipsilateral parieto-occipital cortex was evoked, that could be in strict functional and temporal relation with the homologue result obtained in left parieto-occipital region. Consequently, it could be suggested that even if planning of reaching movements relies principally on contra-lateral hemisphere, a bilateral involvement might also occur at least in parieto-occipital cortex. On the other hand, cortical structures in contra-lateral hemisphere seem to be involved in the control of on-line reaching movements only when the hand is approaching the target. In the present study, effects were reported only for parietal and premotor cortices. This suggests that the affected areas might be more involved in the control of on-line movements, confirming the pivotal role of the parietal cortex in managing visuomotor information. In conclusion, this research project contributes to the understanding of the cortical dynamics involved in the planning and control of reaching movements. Specifically, new insights are provided about the temporal involvement of the different cortical regions being part of the process.<br>Il raggiungimento e la prensione di un oggetto sotto la guida visiva sono movimenti che i soggetti sani riescono a realizzare molto semplicemente. La neurofisiologia del sistema nervoso centrale ha dimostrato che le trasformazioni visuo-motorie, necessarie per l’implementazione di questi movimenti, si basano sull’attivazione di una distribuita e complessa popolazione di neuroni parietali, motori e promotori della corteccia cerebrale. Possiamo immaginare tali circuiti come differenti regioni corticali che si attivano durante diverse finestre temporali, con diversi gradi di relazione ed elementi di comunicazione tra loro. Per capire meglio l’esatto ruolo giocato dalle diverse regioni parietali e frontali durante la pianificazione e l’esecuzione dei movimenti di raggiungimento e di prensione, sono stati eseguiti esperimenti su un totale di 269 volontari sani e consenzienti (età 19-56 anni, età media e deviazione standard 26.1 ± 6.4 anni), cui veniva applicata una Stimolazione Magnetica Transcranica (TMS) durante l’esecuzione di un compito visuo-motorio. I soggetti venivano fatti sedere comodamente, chiedendo loro di iniziare il compito con gli occhi chiusi e con la mano destra mantenuta in posizione di riposo sopra un sensore ottico (che permetteva di misurare il tempo di reazione), posizionato centralmente rispetto al loro corpo. Un segnale acustico indicava ai soggetti di aprire gli occhi e di raggiungere il più velocemente e accuratamente possibile un oggetto posizionato sul tavolo a 35 cm di distanza di fronte a loro, oppure spostato di 40° a destra o a sinistra. Ai soggetti veniva richiesto di mantenere sempre lo sguardo in posizione centrale per tutta la durata dell’esperimento. L’oggetto era collegato ad un sensore tattile, utile per registrare i tempi di movimento (cioè il tempo che intercorreva dal momento in cui la mano lasciava il sensore ottico fino al raggiungimento dell’oggetto). La TMS è stata somministrata al 25%, al 50%, al 75% e al 90% del tempo di reazione medio o al 25% e al 50% del tempo di movimento medio di ogni soggetto. Sono stati stimolati 33 punti corticali, comprendendo entrambi gli emisferi. In ogni esperimento, per ognuno dei punti corticali investigati, sono state raccolte 42 prove (21 con TMS e 21 senza), ugualmente distribuite nello spazio peripersonale. In linea generale, in ogni esperimento, cinque punti corticali sono stati stimolati nella corteccia parieto-occipitale dorsale, cinque nella corteccia parietale superiore e cinque nella corteccia premotoria dorsale, in entrambi gli emisferi. I risultati ottenuti dimostrano l’esistenza di un circuito ben definito nell’emisfero sinistro, che parte dalla corteccia occipitale per arrivare fino alla corteccia premotoria, dove è stato possibile interagire tramite somministrazione di TMS, ottenendo soprattutto un accorciamento dei tempi di reazione. Infatti, un’accelerazione dei tempi di reazione è stata individuata somministrando la TMS al 50% di essi nel lobo occipitale superiore, senza però individuare preferenze di direzione nello spazio peripersonale. Successivamente, nello stesso momento di stimolazione, è stato possibile individuare un’accelerazione dei tempi di reazione anche nel solco parieto-occipitale, ma solo quando il soggetto realizzava un movimento di raggiungimento verso il centro. Anche nella corteccia parietale superiore è stato possibile osservare un effetto facilitatorio nei tempi di reazione. In questo caso però, la TMS è stata somministrata al 75% del tempo di reazione medio: l’effetto si manifestava senza preferenze direzionali nello spazio peripersonale. Infine, nella corteccia premotoria dorsale è stato possibile individuare un ultimo effetto di facilitazione sui tempi di reazione, ancora una volta quando la TMS veniva somministrata al 75% del tempo di reazione medio, e senza preferenze direzionali nello spazio peripersonale. Tempi di reazione rallentati sono stati evocati solamente nella parte posteriore del lobulo parietale superiore, quando la TMS veniva somministrata al 75% del tempo di reazione medio dei soggetti, solamente nei movimenti di raggiungimento diretti verso il centro. Per quanto riguarda l’emisfero destro, quando la TMS è stata somministrata nei punti corticali omologhi a quello di sinistra, sono stati individuati solamente tempi di reazione più lenti dopo stimolazione parieto-occipitale al 75% del tempo di reazione medio, senza preferenze spaziali peripersonali. Quando la TMS è stata somministrata durante l’ esecuzione del movimento, quattro punti sono stati stimolati nella corteccia parieto-occipitale dorsale, cinque nella corteccia parietale e cinque nella corteccia dorsale premotoria, solamente nell’emisfero di sinistra. I risultati indicano che la TMS è stata efficace esclusivamente quando è stata applicata al 50% del tempo di movimento medio. In particolare, un ritardo nei tempi di movimento è stato individuato in un punto della corteccia parietale superiore e in un punto della corteccia premotoria dorsale. In entrambi i casi, non è stato possibile evidenziare alcuna preferenza nello spazio peripersonale. I risultati raccolti confermano che la pianificazione dei movimenti di raggiungimento eseguiti con la mano destra inizia precocemente nella corteccia occipitale superiore di sinistra e nella regione parieto-occipitale dello stesso lato, proseguendo poi fino a raggiungere la corteccia premotoria dorsale. Questo indica la presenza di un circuito specifico posizionato dorsalmente, con una tempistica di attivazione che fluisce in direzione postero-anteriore. E’ stato evidenziato anche come l’emisfero ipsilaterale partecipi a tale processo, dato che è stata verificata la possibilità di interferire con la pianificazione dei movimenti di raggiungimento nella corteccia parieto-occipitale ipsilaterale. Inoltre, considerando l’effetto facilitatorio della TMS quando veniva applicata nell’emisfero sinistro al 50% del tempo di reazione medio, e quello inibitorio al 75% dello stesso quando veniva applicata all’emisfero destro, può essere ipotizzata l’esistenza di una chiara differenza di attivazione temporale tra corteccia parieto-occipitale di destra e di sinistra. Infatti, anche se la pianificazione dei movimenti di raggiungimento si basa principalmente sulla corteccia controlaterale, abbiamo dimostrato l’esistenza di un’attivazione bilaterale, almeno nella corteccia parieto-occipitale. Il coinvolgimento delle strutture corticali nel controllo on-line dei movimenti di raggiungimento è stato dimostrato essere più efficace quando la mano sta per raggiungere il suo obiettivo. In questo studio, gli effetti della TMS sono stati evidenziati nella corteccia parietale anteriore e nella corteccia premotoria, e non in regioni parieto-occipitali. Ciò suggerisce che le aree coinvolte potrebbero partecipare al controllo on-line del movimento di raggiungimento in misura maggiore rispetto a regioni corticali posteriori, confermando il loro ruolo centrale nella gestione delle informazioni visuo-motorie. La novità dello studio consiste nella realizzazione di una mappatura completa del circuito di integrazione di coordinate visuo-motorie deputato alla pianificazione e all’esecuzione dei movimenti di raggiungimento, grazie all’applicazione della TMS e la conseguente possibilità di interagire con tale sistema. Nello specifico, vengono proposte delle nuove evidenze a proposito del coinvolgimento temporale delle differenti regioni corticali che fanno parte del processo.<br>XXI Ciclo<br>1980

The classical mirror neuron theory of action understanding asserts that when we observe an action, the representations that are engaged for performing it, are automatically activated. In order to do gain information about the role of the simulation in action understanding a state dependent TMS experiment has been carried out. The fundamental idea is to adapt a neural population in the motor system and then testing the effects of this adaptation when participants categorize visually presented actions. The second aim of the present work is to find a paradigm, or a particular cognitive set, that does not allow the simulation process to take place when the participants are observing actions. This step will be important in testing whether the simulation process is necessary in order to understand a visually presented action.

The classical mirror neuron theory of action understanding asserts that when we observe an action, the representations that are engaged for performing it, are automatically activated. In order to do gain information about the role of the simulation in action understanding a state dependent TMS experiment has been carried out. The fundamental idea is to adapt a neural population in the motor system and then testing the effects of this adaptation when participants categorize visually presented actions. The second aim of the present work is to find a paradigm, or a particular cognitive set, that does not allow the simulation process to take place when the participants are observing actions. This step will be important in testing whether the simulation process is necessary in order to understand a visually presented action.

Transcranial magnetic stimulation (TMS) is a non-invasive technique used to reversibly modulate the activity of cortical neurons using time-varying magnetic fields. Recently TMS has been used to demonstrate the functional necessity of human cortical areas to visual tasks. For example, it has been shown that delivering TMS over human visual area V5/MT selectively disrupts global motion perception. The temporal resolution of TMS is considered to be one of its main advantages as each pulse has a duration of less than 1 ms. Despite this impressive temporal resolution, however, the critical period(s) during which TMS of area V5/MT disrupts performance on motion-based tasks is still far from clear. To resolve this issue, the influence of TMS on direction discrimination was measured for translational global motion stimuli and components of optic flow (rotational and radial global motion). The results of these experiments provide evidence that there are two critical periods during which delivery of TMS over V5/MT disrupts performance on global motion tasks: an early temporal window centred at 64 ms prior to and a late temporal window centred at 146 ms post global motion onset. Importantly, the early period cannot be explained by a TMS-induced muscular artefact. The onset of the late temporal window was contrast-dependent, consistent with longer neural activation latencies associated with lower contrasts. The theoretical relevance of the two epochs is discussed in relation to feedforward and feedback pathways known to exist in the human visual system, and the first quantitative model of the effects of TMS on global motion processing is presented. A second issue is that the precise mechanism behind TMS disruption of visual perception is largely unknown. For example, one view is that the “virtual lesion” paradigm reduces the effective signal strength, which can be likened to a reduction in perceived target visibility. Alternatively, other evidence suggests that TMS induces neural noise, thereby reducing the signal-to-noise ratio, which results in an overall increase in threshold. TMS was delivered over the primary visual cortex (area V1) to determine whether its influence on orientation discrimination could be characterised as a reduction in the visual signal strength, or an increase in TMS-induced noise. It was found that TMS produced a uniform reduction in perceived stimulus visibility for all observers. In addition, an overall increase in threshold (JND) was also observed for some observers, but this effect disappeared when TMS intensity was reduced. Importantly, susceptibility to TMS, defined as an overall increase in JND, was not dependent on observers’ phosphene thresholds. It is concluded that single-pulse TMS can both reduce signal strength (perceived visibility) and induce task-specific noise, but these effects are separable, dependent on TMS intensity and individual susceptibility.

The flexibility, adaptability, and learning ability of the brain involves synaptic plasticity, where synapses between neurons strengthen or weaken. Synaptic plasticity is multiscale in space and time, involving many mechanisms and molecular pathways. In addition, the plasticity of neural systems may change due to developmental or homeostatic effects, known as metaplasticity. Most experiments on plasticity involve in vitro or invasive experiments on animals, where neurons are artificially stimulated by external electrodes. In reality, each neuron strongly interacts with thousands of other neurons, giving macroscopic, system-level plasticity. Therefore, the results of traditional experiments may or may not resemble in vivo plasticity in the human brain. Transcranial magnetic stimulation (TMS) is a recent noninvasive human brain stimulation technique with scientific and potentially therapeutic benefits. By stimulating the brain with magnetic pulses, it induces macroscopic eddy currents to induce system-level plasticity. However, despite the wealth of TMS experimental results, there exists no good quantitative theory that can explain these phenomena. This thesis incorporates existing knowledge in microscopic plasticity into a neural field theory to formulate a system-level plasticity theory, and reproduces existing TMS experimental results and signatures, including repetitive TMS (rTMS) frequency dependence and system level spike-timing dependent plasticity (STDP) as seen in paired associative stimulation (PAS), as well as strongly nonlinear phenomena including continuous and intermittent theta-burst stimulation (cTBS and iTBS, respectively), dosage dependence reversal in TBS induced plasticity, and inter-subject differencess in TBS response. This contributes to the theoretical understanding of TMS, and enables predictions and recommendations for further experiments and TMS protocol optimizations. The reproduction of experimental results also serves as verification of both the neural field theory, and the microscopic plasticity theories. The following chapters are closely based on papers that are either published or submitted. Each chapter is therefore a self contained unit, with some overlap in introductory material and description of methods. Chapter 1 presents an overview of the relevant background material: first, we present an overview of plasticity from the anatomical scale, to the neural scale, to the synaptic scale. Second, we focus on a brief review of synaptic plasticity and associated theoretical models. Lastly, we introduce TMS and related experimental results. Chapter 2 explores the neural field theory of a popular STDP plasticity rule. The frequency dependence, dynamics, and stability of the theory in Fourier space is explore. Synaptic dynamics is reduced into four classes, where three exhibit instability, and the remaining class requires unphysiological parameters. Chapter 3 incorporates calcium dependent plasticity in neural field theory, with applications to TMS. Calcium dependent plasticity (CaDP), which is a physiologically based plasticity theory, is explored in the system level, to predict repetitive TMS frequency dependence as well as the experimental result of paired associative stimulation (PAS). Together with previous pharmacological evidence, this theory presents a strong candidate for the mechanism behind TMS. This plasticity rule is stable, where spike rate adaptation is also predicted. Chapter 4 introduces metaplasticity into the neural field theory of CaDP of the previous chapter, to predict the nonlinearities found in existing TMS experiments. Guided by experimental results, metaplasticity is formulated so that plasticity signals trigger metaplasticity to modulate further plasticity signals, and is followed by a signal transduction delayed plasticity expression. This formulation is analogous to BCM metaplasticity, with calcium concentration being the measure of averaged activity. Simulations indicate that this model gives homeostatic effects, and oscillation around homeostatic stability under stimulation accounts for the nonlinear experimental results. Thereby, recommendations for future experiments with testable predictions and rTMS optimization are made. Finally, Chapter 5 summarizes the results of this thesis and their implications and suggests avenues for future studies.

This thesis explored three main areas of acute itch: firstly, how to reliably measure it; secondly, whether it is of a multi-dimensional nature, and lastly, which brain regions are crucial in the process. Chapter 2 reports an experiment that directly compared the re-test reliability of three commonly used measurement scales (pVAS, tVAS and gLMS). The general Labelled Magnitude Scale (gLMS) generated the least variance in itch intensity ratings between testing sessions and was therefore taken as the most reliable and administered for the following experiments. Chapter 3 and 4 explored the dimensionality of histamine and cowhage induced itch. The aims of these chapters were, (1) to explore any changes in the time-course and peak of itch intensity/unpleasantness, induced by varying stimuli doses, (2) to examine any dissociation between itch intensity and unpleasantness, which would indicate that they are dissociable dimensions. The results demonstrated that there was a significant linear trend for both intensity and unpleasantness, however there was no significant difference between the dimensions. Based on these results, it was decided that only the intensity should be measured in the following transcranial magnetic stimulation (TMS) experiment, as the unpleasantness dimension did not appear to add any additional information. Chapter 5 describes a TMS study, investigating which brain areas have a necessary function in the process of histamine and cowhage induced itch. The aim was to explore any differences in the perceived itch intensity, after brain stimulation to the somatosensory cortices (S1 and S2) and the inferor frontal gyrus (IFG), in comparison to the control area (superior parietal lobe; SPL). The results demonstrated that only TMS to S1 significantly reduced the itch intensity when administered via the histamine prick test. There was also a significant reduction of the wheal induced in the S1 and IFG condition. There was however, no significant reduction of the flare for any condition. There was also no significant difference in itch intensity or skin response, for any of the brain regions stimulated when cowhage was administered. In summary, the results indicate that S1 has a crucial role in the processing of itch intensity, and that the histamine prick test and TMS are ideal for exploring this. More investigation is necessary however, to explore the role of S2 and the IFG in itch perception.

This thesis describes a series of studies, involving healthy subjects and a carefully selected stroke patient, in which the techniques of Transcranial Magnetic Stimulation (TMS) and Signal Detection Theory (SDT) were combined to explore processing in the posterior parietal cortex (PPC) and the phenomenon of unilateral spatial neglect: 1) A new SDT-based TMS 'hunting' technique was developed and then employed successfully over the right PPC. This revealed a cortical node which could be modulated with 'online' 10Hz-TMS to exert control over subjects' visuospatial perception. 2) By targeting this 'hotspot' and an equivalent area in the left PPC with disruptive 'cTBS' (continuous 'Theta Burst' simulation), neglect-like effects in the healthy brain could be induced and alleviated. These effects were quantified using a newly developed, fully balanced, bihemifield detection paradigm 3) By using TMS to map visuospatial function over healthy right PPC, the 'hotspot' could be enlarged after exposure to excitatory, intermittent TBS (iTBS). 4) cTBS was applied to the left PPC of a patient with a right sided stroke and visuospatial neglect. In doing this, neglect and its alleviation were described for the first time in fully balanced SDT terms. 5) The cerebellum was targeted in healthy subjects with 1Hz inhibitory TMS which induced a shift in their subjective midline for 'imaginary' but not 'real' space, as measured with number or physical line bisection respectively. These TBS studies lend support to Kinsbourne's hemispheric rivalry hypothesis and suggest that the extent of 'spatially eloquent' cortex in the right PPC can be increased. Both strategies could be useful in larger therapeutic studies of patients suffering from USN after right sided brain injury. The final study opens up an additional therapeutic target for patients with imaginal neglect and, for the first time, implicates the cerebellum in number line bisection.

The coordination of movement, from the process of deciding how to move to the accurate execution of that movement, is what allows for successful interaction with the environment. The study of the motor cortex provides insight into what constitutes normal and abnormal patterns of movement. Research using a non-invasive brain stimulation technique called transcranial magnetic stimulation (TMS) has suggested that intracortical facilitation, that is facilitatory neural activity in the primary motor cortex, plays an important role in motor control. One form of facilitation known as short-interval intracortical facilitation (SICF), can be measured using a paired-pulse protocol of TMS. However, the reliability of this protocol has yet to be established. The current study aimed to investigate the test-retest reliability of paired-pulse TMS to measure SICF in healthy younger adults (N = 16). In addition, the current study explored the relationship between SICF and manual dexterity as measured by the Purdue pegboard test. Results indicated excellent test-retest reliability of SICF magnitude. Finally, SICF magnitude was found to be positively associated with right-hand performance in the Purdue pegboard test. Taken together, the findings of the current study suggest that SICF can be reliably measured by TMS across different sessions. The current study contributes to the literature suggesting that SICF is important for motor control. Further, this understanding of the role of SICF in the healthy brain could provide avenues for future research to examine SICF in people with movement or neurological disorders affecting motor control.

no<br>To investigate the underlying nature of the effects of transcranial magnetic stimulation (TMS) on speed perception, we applied repetitive TMS (rTMS) to human V5/MT+ following adaptation to either fast- (20 deg/s) or slow (4 deg/s)-moving grating stimuli. The adapting stimuli induced changes in the perceived speed of a standard reference stimulus moving at 10 deg/s. In the absence of rTMS, adaptation to the slower stimulus led to an increase in perceived speed of the reference, whilst adaptation to the faster stimulus produced a reduction in perceived speed. These induced changes in speed perception can be modelled by a ratio-taking operation of the outputs of two temporally tuned mechanisms that decay exponentially over time. When rTMS was applied to V5/MT+ following adaptation, the perceived speed of the reference stimulus was reduced, irrespective of whether adaptation had been to the faster- or slower-moving stimulus. The fact that rTMS after adaptation always reduces perceived speed, independent of which temporal mechanism has undergone adaptation, suggests that rTMS does not selectively facilitate activity of adapted neurons but instead leads to suppression of neural function. The results highlight the fact that potentially different effects are generated by TMS on adapted neuronal populations depending upon whether or not they are responding to visual stimuli.<br>BBSRC

A Neuronavegação é uma técnica de visualização computacional da localização de instrumentos em relação às estruturas neuronais. A estimulação magnética transcraniana (EMT) é uma ferramenta para estimulação cerebral não-invasiva, que tem sido utilizada em aplicações clínicas, para o tratamento de algumas patologias, e também em pesquisas. Entretanto, a EMT é uma técnica altamente dependente de parâmetros como o posicionamento e orientação da bobina de estimulação em relação às estruturas neuronais. Para auxiliar no posicionamento da bobina, uma combinação entre neuronavegação e EMT é utilizada, chamada de EMTnavegada (EMTn). Essa técnica permite o monitoramento em tempo real da bobina de EMT em relação às neuroimagens. Porém, a utilização da EMTn ainda é pouco explorada, tanto na pesquisa quanto no ambiente clínico, devido ao alto custo, exigência da imagem de ressonância magnética, complexidade e baixa portabilidade dos sistemas de EMTn comerciais. O neuronavegador de código aberto e livre, InVesalius Navigator, vem sendo desenvolvido para ajudar a suprir essa necessidade. Assim, o objetivo desta dissertação foi desenvolver ferramentas para o sistema de neuronavegação InVesalius Navigator. As funcionalidades adicionadas foram: i) suporte para três tipos de rastreadores espaciais; ii) sincronização da EMT com o neuronavegador; iii) guia para o reposicionamento da bobina. Além disso, com intuito de contornar a necessidade de utilizar a imagem de ressonância magnética foram realizados estudos para a substituição por uma imagem padrão. Na parte de desenvolvimento, experimentos de caracterização foram realizados para validação das ferramentas. O sistema de neuronavegação apresentou-se intuitivo e de fácil portabilidade. Além disso, a precisão obtida foi semelhante à de sistemas comerciais. Os erros de localização foram inferiores a 3 mm, considerados aceitáveis para aplicações clínicas. Na segunda parte, procedimentos que não exigem extrema precisão, como a localização e digitalização do hotspot, a variabilidade foi considerada aceitável. Portanto, a utilização da imagem média mostrou-se uma possível alternativa para as imagens de ressonância magnética.<br>Neuronavigation is a computer image-guided technique to locate surgical instruments related to brain structures. The transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method, it has been used for clinical purposes, treating neurological disorders, and also for research purpose, studying cortical brain function. However, the use of TMS is highly dependent on coil position and orientation related to brain structures. The navigated TMS (nTMS) is a combined technique of neuronavigation system and TMS, this technique allows tracking TMS coil by image guidance. Yet, nTMS is not widely used, either in research and in the clinical environment, due to the high cost, magnetic resonance imaging requirement, complexity, and low portability of commercial TMS systems. Thus, the aim of this dissertation was to develop tools for the neuronavigator system InVesalius Navigator, such as: i) support for three types of spatial trackers; ii) synchronization of the TMS with the neuronavigator; iii) guide for coil repositioning. In addition, in order to overcome the magnetic resonance imaging requirement, studies were made to replace it with a standard brain image. In the development part, characterization experiments were done to validate the new functionalities. Therefore, the accuracy obtained was similar to commercial systems. Localization errors were less than 3 mm considered acceptable for clinical applications. In the second part, for procedures that do not require extreme accuracy, such as the location and scanning of the hotspot, the variability was considered acceptable. Therefore, the use of the standard brain image was a possible alternative for magnetic resonance imaging.

Recently separate control systems for postural and movement control have been found in primates. Dystonia is a hyperkinetic movement disorder and its cause it not well understood. We have observed that dystonia patients have preserved fine movement control, but difficulty maintaining the appropriate and sustained posture that supports these movements. Postural control requires multiple modalities of sensory input such as cutaneous, proprioceptive, vestibular and visual stimuli. Through clinical observation, dystonia is improved by sensory alteration. Sensorimotor integration dysfunction has been observed in dystonia patients using multiple methods of study, such as neuroimaging and neurophysiological studies. This thesis investigates if dystonia is secondary to abnormalities in postural control rather than movement control mechanisms, using transcranial magnetic stimulation (TMS) and surface electromyography (EMG). In order to understand how to interpret neurophysiological data collected from focal cervical dystonia patients, we analysed the clinical characteristics and demographics of focal cervical dystonia and writer’s cramp patients. We also compared our findings to the results from a larger cohort which was derived from Dystonia Coalition study, an international collaborative study, in which our participants contributed. Cervical dystonia patients are more likely to have associated tremor and a geste antagoniste than writer’s cramp patients, whereas task-specificity is more common in writer’s cramp. Cervical dystonia severity and pain scale had a strong positive correlation with cortical silent period, whereas the writer’s cramp severity scale had a strong negative correlation with cortical silent period. The differences in clinical characteristics and neurophysiological findings between focal cervical dystonia and writer’s cramp patients reflect differences in pathophysiology and neurophysiological studies of focal dystonia need to analyse dystonia subtypes separately. The differences in muscle activity generation and co-contraction of agonist and antagonist muscle groups were analysed in normal controls and focal dystonia patients during comparable movement and postural control tasks. It was hypothesized that during a postural control task, there would be an increase in agonist and antagonist co-contraction, which is a known neurophysiological correlate in dystonia. Using surface EMG, we found no increase in agonist/antagonist co-contraction during posture maintenance in dystonia patients, contrary to our hypothesis. However, during a non-dystonia inducing task, there was exaggerated compensatory postural muscle activity during the movement phase of voluntary wrist extension in both cervical dystonia and writer’s cramp patients. In order to explore differences in the behaviour of the motor cortex during postural versus movement control in healthy participants, transcranial magnetic stimulation was used to measure cortical excitability and inhibition. A novel paradigm was developed where participants performed a comparable postural and movement control task of finger extension during measurement of cortical excitability and inhibition. It was shown that motor cortical inhibition was reduced during the movement compared with posture control task. This novel paradigm was then used to explore the behaviour of the motor cortex during the postural versus movement control task in patients with focal dystonia. It was hypothesized that dystonia patients would show greater differences when compared with healthy participants in the postural versus movement control task. Contrary to our hypothesis, there was no difference between either cervical dystonia or writer’s cramp patients when compared with normal participants in the behaviour of the motor cortex during either the postural or movement control tasks. Both dystonia and healthy participants showed similar levels of reduced motor cortical inhibition during the movement compared with posture control task. It is concluded that patients with cervical dystonia and writer’s cramp show differences in their clinical characteristics and the relationship of their clinical measures of disease severity with cortical inhibition, as reflected in the cortical silent period. However, the behaviour of their motor cortex was similar to healthy participants in a postural versus movement control task. This suggests that the fundamental defect in motor control in dystonia might not be a specific disorder of control of postural muscle activity, but instead lies elsewhere. Additional studies using different paradigms of postural versus movement control would be of interest to confirm the findings of this thesis, as would additional studies using different techniques of studying brain behaviour during these different movement paradigms such as functional imaging studies. Future studies should segregate different forms of focal dystonia which might have different underlying pathophysiology.

To increase understanding into the specific networks involved in the pathophysiology of different types of epilepsy, we proposed extensive neurophysiological studies. First, we studied patients with photosensitive epilepsy since they represent a “model” of system epilepsy. Then, we focused on patients with focal (FE) and generalized epilepsies (GE) to unravel the neurophysiological basis of seizure generalization. Finally, we explored the motor cortex plasticity in juvenile myoclonic epilepsy (JME), the most common subtype of GE in adults. We used the paired transcranial magnetic stimulation (paired-TMS) to investigate the time related changes in functional connectivity between visual and primary motor cortex in healthy subjects and in patients with photosensitivity to study the visuomotor integration. We also studied the interhemispheric connection involved in seizure generalization in FE and GE; to explore the motor cortex synaptic plasticity in patients with JME we used the paired associative stimulation.The findings support a physiologically relevant visuomotor functional connectivity, which likely contributes to visuomotor integration. Substantial physiologic changes in this network underlie the photosensitivity, which may justify the origin of epileptic motor phenomena (i.e. myoclonus). We found significant differences in the interhemispheric connection of drug-treated patients with FE and those with IGE. Whilst interhemispheric inhibition changes would not be crucial for the IGE pathophysiology, they may represent one key factor for the contralateral spread of focal discharges, and seizure generalization. As to the patients with JME, we provided evidence of a defective long term potentiation-like plasticity, which may be primarily involved in the pathogenesis of myoclonus. In conclusion, we documented substantial changes in the epileptogenic networks involved in different types of epilepsy.

Neurological disorders require varying types and degrees of treatments depending on the symptoms and underlying causes of the disease. Patients suffering from medication-refractory symptoms often undergo further treatment in the form of brain stimulation, e.g. electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), or transcranial magnetic stimulation (TMS). These treatments are popular and have been shown to relieve various symptoms for patients with neurological conditions. However, the underlying effects of the stimulation, and subsequently the causes of symptom-relief, are not very well understood. In particular, TMS is a non-invasive brain stimulation therapy which uses time-varying magnetic fields to induce electric fields on the conductive parts of the brain. TMS has been FDA-approved for treatment of major depressive disorder for patients refractory to medication, as well as symptoms of migraine. Studies have shown that TMS has relieved severe depressive symptoms, although researchers believe that it is the deeper regions of the brain which are responsible for symptom relief. Many experts theorize that cortical stimulation such as TMS causes brain signals to propagate from the cortex to these deep brain regions, after which the synapses of the excited neurons are changed in such a way as to cause plasticity. It has also been widely observed that stimulation of the cortex causes signal firing at the deeper regions of the brain. However, the particular mechanisms behind TMS-caused signal propagation are unknown and understudied. Due to the non-invasive nature of TMS, this is an area in which investigation can be of significant benefit to the clinical community. We posit that a deeper understanding of this phenomenon may allow clinicians to explore the use of TMS for treatment of various other neurological symptoms and conditions. This thesis project seeks to investigate the various effects of TMS in the human brain, with respect to brain tissue stimulation as well as the cellular effects at the level of neurons. We present novel models of motor neuron circuitry and fiber tracts that will aid in the development of deep brain stimulation modalities using non-invasive treatment paradigms.

The aims of the experiments in this thesis were to describe and further understand changes that occur in patients with heart failure after exercise. The first chapter outlines the pathophysiology of heart failure and why the motor system, from the central nervous system to the muscles, may be important in the generation of symptoms and possibly the generation of the syndrome. It also lays qut the hypotheses that guided the work in this thesis. Chapter two explains the methodologies used. Chapters three and four describe the impact of exhaustive cycle exercise on respiratory muscle and quadriceps muscle function of patients with congestive heart failure (CHF). In chapter three, 12 patients and 13 control subjects were studied. Diaphragm contractility as determined by the twitch transdiaphragmatic pressure did not fall significantly. There was no evidence of low frequency diaphragm fatigue. In chapter four, 10 patients and 10 control subjects were studied. There was significant evidence of low frequency quadriceps fatigue after exercise, which was slightly, but not significantly, more marked in the normal subjects. Having studied the principal muscles of breathing and cycling, I went on to consider the impact of heart failure on the central nervous system. Transcranial magnetic stimulation (TMS) is a technique that is well established for studying cortical excitability and a small number of studies have documented changes in motor cortical excitability after exercise. Two��?���· studies on healthy volunteers are described in chapter five which not only confirmed that we could successfully induce these changes at lower workloads (more comparable to the workloads that subjects with CHF might be expected to attain), but also suggested that the changes induced were more related to total body work done, rather than the work of an individual muscle group. Building on these��?���· studies I went on to study the impact of exhaustive cycle exercise on patients with 9HF. 10 patients and 10 healthy age-matched control subjects were studied. The data suggested that, by some measures, central fatigue was not induced and that changes in cortical excitability, although present, were less marked in those with CHF compared to control Subjects. Pot~ntial reasons for this are explored. The final chapter brings together the' findings and suggests. future avenues for research. A number of appendices are attached; inclUding the' custom-written software to analyse exercise tolerance tests and the work of breathing, the two papers published so far from this work and an abstract presented at the European Society of Cardiology in 2005.

The issue of the laterality of control during unimanual and bimanual coordination was addressed in this thesis. Two tasks were used throughout: a repetitive discrete response task (finger tapping) and a continuous task (circle-drawing). Different mechanisms have been implicated in the temporal control of repetitive discrete movements and continuous movements. The tasks also differ in the degree of spatiotemporal coordination required which might have important implications in the question of laterality of control. The first section of the thesis examined between-hand differences in the dynamics of performance during unimanual and bimanual coordination. During tapping, the dominant hand was faster and less temporally variable than the nondominant hand. During circle drawing the dominant hand was faster, more accurate, less temporally and spatially variable, and produced smoother trajectories than the nondominant hand. During bimanual coordination, several of these asymmetries were attenuated: the rate of movement of the two hands became equivalent (the hands became temporally coupled), the asymmetry in temporal variability during tapping was reduced, and the asymmetry in trajectory smoothness during circle drawing was reduced. The second section of the thesis examined the effects of disrupting motor processes with transcranial magnetic stimulation (TMS) over the left or right primary motor cortex (M1) on the ongoing performance of the hands. In the first study, TMS over left or right M1 during unimanual tapping caused large disruptions to tapping with the contralateral hand but had little effect on the ipsilateral hand. In contrast, for a subset of trials during bimanual tapping, two lateralized effects of stimulation were seen: the effect of TMS on the contralateral hand was greater after stimulation over left M1 than after stimulation over right M1, and prolonged changes in inter-tap interval were observed in the left hand regardless of the side of stimulation. In the second study, TMS over left M1 during circle drawing decreased the accuracy of drawing with both the contralateral and ipsilateral hand, whereas TMS over right M1 decreased accuracy of drawing only with the contralateral hand. This lateralized effect was not limited to the bimanual case, but was also apparent during unimanual drawing. The final chapter addressed issues in bimanual motor control after unilateral stroke. Performance of the affected limb was examined during unimanual and bimanual coordination in a group of stroke patients with varying levels of impairment. The results indicated an improvement in the performance of the affected limb for some patients with mild to moderate, but not severe upper limb motor deficits during bimanual movement. The improvements were limited to the patients who showed evidence of temporal coupling between the hands. These findings support the hypothesis that the dominant motor cortex has a role in the control of both hands during bimanual coordination. In addition, the dominant hemisphere appears to play a role in controlling both hands during unimanual movements which require a greater degree of spatiotemporal coordination. The final study suggests that temporal coupling between the limbs is crucial for the facilitation of performance of the affected limb during bimanual coordination, which has both theoretical and practical implications.

Action observation interventions have been shown to contribute to improvements in motor performance and (re)learning. This thesis examined the effect of manipulating action observation variables on corticospinal excitability (CSE) using transcranial magnetic stimulation (TMS), with the aim of informing interventions for motor (re)learning. Eye-tracking and interview techniques were employed in combination with TMS to provide novel explorations for how screen position, visual context, and emotional valence influence CSE, visual attention, and individual experience during action observation. The Pilot Experiment (Chapter 5) tested the appropriateness of both single- and paired-pulse TMS techniques during action observation. Results determined that single-pulse TMS was appropriate for the subsequent experiments included in this thesis. Experiment 1 (Chapter 6) investigated the effect of screen position during action observation on CSE. The results demonstrated greater CSE during action observation on a horizontal, compared to a vertical, screen position, but only once each individual's viewing preference had been taken into account. Experiment 2 (Chapter 7) investigated the effect of congruent and incongruent contexts on CSE. The results indicated that congruent context during action observation facilitates CSE more than control conditions in contrast to an incongruent visual context. Experiment 3 (Chapter 8) explored the effect of each participant's most preferred, least preferred, and neutral preference food items involved in an observed reach and grasp action on CSE. The results showed no significant differences between the control condition and observing a reach and grasp of each participant's personalised least preferred and neutral preference food items. Significant inhibition of CSE was shown during observation of a reach and grasp of each participant's most preferred food item. The three main experiments in this thesis provide novel contributions to action observation literature by incorporating eye-tracking and interview techniques in combination with TMS to better determine the nature of CSE modulation. Taken together, these findings directly inform both future research and practice in motor (re)learning by highlighting the importance of meaning and context during action observation.

Recovery of upper limb function after stroke is associated with reorganisation of cortical motor control, but the mechanisms underlying this process in humans remain unclear. We used Transcranial Magnetic Stimulation (TMS) to probe the natural history of neurophysiological reorganisation acutely and chronically after stroke. We then investigated the use of repetitive TMS as an intervention to interact with learning-associated physiological changes, aiming to enhance the rate at which healthy subjects and patients after stroke learn a novel motor task. Physiological measures acquired longitudinally after stroke revealed an immediate shift from intracortical inhibition towards facilitation in both hemispheres. Correlations of intracortical excitability measures with clinical scores emerged by 3 months, suggesting that disinhibition provides access to remote cortical networks which become clinically relevant during this period. A subsequent experiment used paired coil TMS, and concurrent TMS during functional Magnetic Resonance Imaging, to study cortico-cortical interactions after stroke. The contralesional dorsal premotor cortex showed disinhibition in its interaction with the ipsilesional motor cortex and greater motor state-dependent influence on this region in more impaired patients, suggesting a constructive interhemispheric interaction with the affected hemisphere. In healthy subjects the facilitatory effect of Theta Burst Stimulation (TBS) on cortical excitability was enhanced and prolonged by nicotine, but not by levodopa or dextroamphetamine. Using a thumb movement task, TBS successfully enhanced subsequent motor learning but this effect was blocked by nicotine. TBS increased motor variability, which correlated with learning, and also increased the directional dispersion of evoked thumb movements. This suggests a constructive role for motor output variability in this training paradigm. In chronic stroke, either TBS or levodopa accelerated training in a similar task but without improving final performance. Levodopa alone was associated with overnight consolidation. This work supports a potential role for physiological and/or pharmacological interventions as adjuncts to post-stroke therapy.

The thesis designs, constructs, and tests an electrically small dipole antenna probe for the measurement of electric field distributions induced by a transcranial magnetic stimulation (TMS) coil. Its unique features include high spatial resolution, large frequency band from 100 Hz to 300 kHz, efficient feedline isolation via a printed Dyson balun, and accurate mitigation of noise. Prior work in this area is thoroughly reviewed. The proposed probe design is realized in hardware; implementation details and design tradeoffs are described. Test data is presented for the measurement of a CW capacitor electric field, demonstrating the probe’s ability to properly measure conservative electric fields caused by a charge distribution. Test data is also presented for the measurement of a CW solenoidal electric field, demonstrating the probe’s ability to measure non-conservative solenoidal electric fields caused by Faraday’s law of induction. Those are the primary fields for the transcranial magnetic stimulation. Advantages and disadvantages of this probing system versus those of prior works are discussed. Further refinement steps necessary for the development of this probe as a valuable TMS instrument are discussed.

Previous research and current models have proposed that the right temporoparietal junction (rTPJ) is crucially involved in the control and distinction of shared representations of action. Hitherto, this assumption has mainly been based on neuroimaging work ( (Spengler, von Cramon, & Brass, 2009); (Spengler, von Cramon, & Brass, 2010)) We tested this hypothesis, that the rTPJ is causally involved in managing shared representations by using repetitive transcranial magnetic stimulation in an offline paradigm to disrupt neural activity in this region. Using a simple imitation-inhibition task we showed that stimulation of the rTPJ led to increased reaction times when participants had to control automatic imitation of a perceived hand movement, as they had to concurrently plan and execute an opposite movement. Our study provides the first empirical evidence that the rTPJ is necessary for managing and navigating within a shared representational system. These results may also have important implications for future theorizing about the role of the TPJ region in controlling shared representations also in other domains, such as somatosensation or emotional experiences.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-04-20T13:29:35Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação_Lorena Melo.pdf: 5009694 bytes, checksum: 8c547ec6fe15f072172ade3743762b9f (MD5)<br>Made available in DSpace on 2017-04-20T13:29:35Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação_Lorena Melo.pdf: 5009694 bytes, checksum: 8c547ec6fe15f072172ade3743762b9f (MD5) Previous issue date: 2016-07-12<br>CAPES<br>A presente dissertação apresenta dois estudos com o intuito de avançar no conhecimento das repercussões das estimulações cerebelares no aprendizado motor e equilíbrio de indivíduos saudáveis. O estudo 1 se propôs a investigar os efeitos polaridade-dependentes da estimulação transcraniana por corrente contínua cerebelar (ETCCc) no equilíbrio de indivíduos saudáveis. O estudo 2, verificou os efeitos da ETCCc e da estimulação magnética transcraniana repetitiva cerebelar (EMTr-c) no aprendizado motor de saudáveis. No primeiro estudo, 15 voluntárias saudáveis e destras foram submetidas a três sessões de ETCCc (anódica, catódica e sham) no hemisfério cerebelar direito em ordem contrabalanceada. Em cada sessão, o equilíbrio estático e dinâmico foi avaliado pela ferramenta Biodex Balance System antes e após cada estimulação, através dos testes Athlete Single Leg Stability e Limits of Stability. Os resultados apontaram para uma piora no equilíbrio estático após a ETCCc catódica, avaliado pelo Athlete Single Leg Stability do membro inferior esquerdo em comparação com os valores basais (p=0,01) e com a ETCCc sham (p=0,04). Dessa forma, é possível afirmar que a ETCCc catódica foi capaz de interferir no equilíbrio estático de indivíduos saudáveis. O segundo estudo foi realizado com 18 voluntários destros, submetidos a seis sessões em ordem contrabalanceada. As sessões consistiram na aplicação dos seguintes protocolos sobre o hemisfério cerebelar esquerdo: (i) ETCCc anódica; (ii) ETCCc catódica; (iii) ETCCc sham; (iv) EMTr-c 10 Hz; (v) EMTr-c 1 Hz e (vi) EMTr-c sham. O aprendizado motor online (durante a estimulação) e offline (após a estimulação) foi avaliado através do teste de reação serial (aquisição e evocação) e teste de escrita (duração total e precisão do movimento), respectivamente. Foi observado que para o aprendizado motor online, as EMTr-c 1 Hz (p=0,018) e 10 Hz (p=0,010) e ETCCc catódica (p=0,001) foram capazes de alterar a aquisição, enquanto que todas as estimulações (p<0,05), com exceção da anódica (p=0,126), foram capazes de interferir na evocação da sequência aprendida. Em relação ao aprendizado motor offline, houve redução da duração total da escrita para todas as condições de estimulação (p<0,05). Para a precisão do movimento, houve melhora apenas para as condições: ETCCc anódica (p=0,003), EMTr-c 1 Hz (p=0,006) e 10 Hz (p=0,014). Portanto, a EMTr-c parece melhorar o aprendizado motor independente da frequência de estimulação e do momento da execução da tarefa (online ou offline). Por outro lado, o efeito da ETCCc mostra-se polaridade-dependente, visto que apenas a ETCCc anódica melhorou o aprendizado offline e a catódica apresentou melhores resultados para o aprendizado online.<br>This dissertation comprises two studies in order to understand the effects of cerebellar stimulations on motor learning and postural balance of healthy individuals. The first experiment (study 1) aimed to investigate the polarity-dependent effects of cerebellar transcranial direct current stimulation (ctDCS) on postural balance in healthy volunteers. The second experiment (study 2) aimed to evaluate ctDCS and cerebellar repetitive transcranial magnetic stimulation (c-rTMS) effects on motor learning in healthy individuals. In the first study, 15 righ-handed healthy volunteers were submitted to three ctDCS sessions (anodal, cathodal and sham) in a counterbalanced order. In each session, static and dynamic balance were evaluated by the Biodex Balance System before and after each stimulation through the Athlete Single Leg Stability and Limits of Stability tests. It was found a worsening static balance after cathodal ctDCS, assessed by Left Athlete Single Leg Stability test when compared to baseline (p=0.01) and sham stimulation (p=0.04). Thus, it is reasonable to assume that cathodal ctDCS was able to interfere on static balance in healthy individuals. The second experiment (study 2) was performed with 18 righthanded volunteers submitted to six session in a counterbalanced order. In each session, the left cerebellar hemisphere was modulated by the following protocols: (i) Anodal ctDCS; (ii) Cathodal ctDCS; (iii) Sham ctDCS; (iv) 10 Hz c-rTMS; (v) 1 Hz crTMS and (vi) Sham c-rTMS. Motor learning was evaluated during (online) or after (offline) stimulation protocols by the serial reaction test (acquisition and evoking phases) and handwriting test (duration and movement precision), respectively. It was observed that for online motor learning, 1 Hz c-rTMS (p=0.018) and 10 Hz (p=0.010) and also cathodal ctDCS (p=0.001), were able to interfere on acquisition phase. All stimulations (p<0.05) except for anodal ctDCS (p=0.126) were able to interfere when the learned sequence was evoked. Regarding offline motor learning, results revealed a reduction of duration for all stimulation conditions. However, for movement precision it was found an improvement for anodal ctDCS (p=0.003), 1 Hz c-rTMS (p=0.006) and 10 Hz c-rTMS (p=0.014). Therefore, c-rTMS seems to improve motor learning independently of stimulation frequency and time (online or offline). On the other hand, ctDCS effects were polarity-dependent since anodal ctDCS was capable to modulate offline learning, while cathodal ctDCS showed better results for online motor learning performance.