In the first part of this thesis, motivated by the development of deep brain stimulation for Parkinson's disease, we consider the problem of reducing the synchrony of a neuronal population via a closed-loop electrical stimulation. This, under the constraints that only the mean membrane voltage of the ensemble is measured and that only one stimulation signal is available (mean-field feedback). The neuronal population is modeled as a network of interconnected Landau-Stuart oscillators controlled by a linear single-input single-output feedback device. Based on the associated phase dynamics, we analyze existence and robustness of phase-locked solutions, modeling the pathological state, and derive necessary conditions for an effective desynchronization via mean-field feedback. Sufficient conditions are then derived for two control objectives: neuronal inhibition and desynchronization. Our analysis suggests that, depending on the strength of feedback gain, a proportional mean-field feedback can either block the collective oscillation (neuronal inhibition) or desynchronize the ensemble.In the second part, we explore two possible ways to analyze related problems on more biologically sound models. In the first, the neuronal population is modeled as the interconnection of nonlinear input-output operators and neuronal synchronization is analyzed within a recently developed input-output approach. In the second, excitability and synchronizability properties of neurons are analyzed via the underlying bifurcations. Based on the theory of normal forms, a novel reduced model is derived to capture the behavior of a large class of neurons remaining unexplained in other existing reduced models.

A major challenge in the field of neuroscience is to link behavior with specific neuronal circuitries and cellular events. One way of facing this challenge is to identify unique cellular markers and thus have the ability to, through various mouse genetics tools, mimic, manipulate and control various aspects of neuronal activity to decipher their correlation to behavior. The Vesicular Glutamate Transporter 2 (VGLUT2) packages glutamate into presynaptic vesicles for axonal terminal release. In this thesis, VGLUT2 was used to specifically target cell populations within the basal ganglia of mice with the purpose of investigating its connectivity, function and involvement in behavior. The motor and limbic loops of the basal ganglia are important for processing of voluntary movement and emotions. During such physiological events, dopamine plays a central role in modulating the activity of these systems. The brain reward system is mainly formed by dopamine projections from the ventral tegmental area (VTA) to the ventral striatum. Certain dopamine neurons within the VTA exhibit the ability to co-release dopamine and glutamate. In paper I, glutamate and dopamine co-release was targeted and our results demonstrate that the absence of VGLUT2 in dopamine neurons leads to perturbations of reward consumption and reward-associated memory, probably due to reduced DA release observed in the striatum as detected by in vivo chronoamperometry. In papers II and IV, VGLUT2 in a specific subpopulation within the subthalamic nucleus (STN) was identified and targeted. Based on the described role of the STN in movement control, we hypothesized that the mice would be hyperlocomotive. As shown in paper II, this was indeed the case. In paper IV, a putative reward-related phenotype was approached and we could show reduced operant-self administration of sugar and altered dopamine release levels suggesting a role for the STN in reward processes. In paper III, we investigated and identified age- and sex-dimorphisms in dopamine kinetics in the dorsal striatum of one of the most commonly used mouse lines worldwide, the C57/Bl6J. Our results point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J strain as model for neurological and neuropsychiatric disorders.

About 50 million people worldwide suffer from epilepsy and one third of them have seizures that are refractory to medication. In the past few decades, deep brain stimulation (DBS) has been explored by researchers and physicians as a promising way to control and treat epileptic seizures. To make the DBS therapy more efficient and effective, the feedback loop for titrating therapy is required. It means the implantable DBS devices should be smart enough to sense the brain signals and then adjust the stimulation parameters adaptively. This research proposes a signal-sensing channel configurable to various neural applications, which is a vital part for a future closed-loop epileptic seizure stimulation system. This doctoral study has two main contributions, 1) a micropower low-noise neural front-end circuit, and 2) a low-power configurable neural recording system for both neural action-potential (AP) and fast-ripple (FR) signals. The neural front end consists of a preamplifier followed by a bandpass filter (BPF). This design focuses on improving the noise-power efficiency of the preamplifier and the power/pole merit of the BPF at ultra-low power consumption. In measurement, the preamplifier exhibits 39.6-dB DC gain, 0.8 Hz to 5.2 kHz of bandwidth (BW), 5.86-μVrms input-referred noise in AP mode, while showing 39.4-dB DC gain, 0.36 Hz to 1.3 kHz of BW, 3.07-μVrms noise in FR mode. The preamplifier achieves noise efficiency factor (NEF) of 2.93 and 3.09 for AP and FR modes, respectively. The preamplifier power consumption is 2.4 μW from 2.8 V for both modes. The 6th-order follow-the-leader feedback elliptic BPF passes FR signals and provides -110 dB/decade attenuation to out-of-band interferers. It consumes 2.1 μW from 2.8 V (or 0.35 μW/pole) and is one of the most power-efficient high-order active filters reported to date. The complete front-end circuit achieves a mid-band gain of 38.5 dB, a BW from 250 to 486 Hz, and a total input-referred noise of 2.48 μVrms while consuming 4.5 μW from the 2.8 V power supply. The front-end NEF achieved is 7.6. The power efficiency of the complete front-end is 0.75 μW/pole. The chip is implemented in a standard 0.6-μm CMOS process with a die area of 0.45 mm^2. The neural recording system incorporates the front-end circuit and a sigma-delta analog-to-digital converter (ADC). The ADC has scalable BW and power consumption for digitizing both AP and FR signals captured by the front end. Various design techniques are applied to the improvement of power and area efficiency for the ADC. At 77-dB dynamic range (DR), the ADC has a peak SNR and SNDR of 75.9 dB and 67 dB, respectively, while consuming 2.75-mW power in AP mode. It achieves 78-dB DR, 76.2-dB peak SNR, 73.2-dB peak SNDR, and 588-μW power consumption in FR mode. Both analog and digital power supply voltages are 2.8 V. The chip is fabricated in a standard 0.6-μm CMOS process. The die size is 11.25 mm^2. The proposed circuits can be extended to a multi-channel system, with the ADC shared by all channels, as the sensing part of a future closed-loop DBS system for the treatment of intractable epilepsy.

La compréhension des mécanismes physiologiques et physiopathologiques du contrôle la locomotion et de ses troubles, constitue un enjeu majeur de la recherche biomédicale, pour améliorer la qualité et l'espérance de vie des patients atteints de la maladie de Parkinson. A partir de données expérimentales, la stimulation cérébrale profonde de la formation réticulée mésencéphalique (FRM), incluant les noyaux pédonculopontins et cunéiformes, a été proposée en 2005 comme nouvelle stratégie thérapeutique pour traiter le freezing de la marche. Cependant, au regard de résultats cliniques très hétérogènes, de nombreuses interrogations se posent concernant les connaissances anatomiques et fonctionnelles de la FRM, marquées notamment par un nombre limité de données expérimentales chez le primate non-humain. Cette étude s'inscrit dans une approche translationnelle associant des données cliniques et pré-cliniques. Dans un premier temps, un modèle de locomotion bipède chez le primate non-humain a été développé puis validé à partir de données cinématiques. Une approche IRM multi-séquences a été développée pour permettre un suivi longitudinal du protocole et la construction d'un atlas du tronc cérébral de Macaca fascicularis. Un mapping électrophysiologique de la FRM a ensuite été réalisé chez deux primates éveillés, qui a permis de mettre en évidence pour la première fois, des activités neuronales qui répondaient à la locomotion, confirmant ainsi l'existence d'une région locomotrice mésencéphalique chez le primate. Après intoxication au MPTP, seule une modification du pattern de décharge des neurones de la FRM a été observée, ainsi que des arguments en faveur d'un dysfonctionnement de l'activité de certains neurones de la FRM durant le blocage du pas. Enfin, des enregistrements électrophysiologiques durant des phases de locomotion puis d'endormissement naturel, suggèrent une double implication de populations neuronales dans le contrôle de la locomotion et du niveau de vigilance. La réalisation d'un nouveau système de coordonnées adapté au tronc cérébral humain a permis de réaliser une étude de corrélations anatomo-cliniques des effets de la stimulation cérébrale profonde du noyau pédonculopontin et de proposer une cible probabiliste pour l'implantation d'électrodes dans la FRM pour traiter le freezing de la marche dans le contexte parkinsonien. / The comprehension of the physiological and pathophysiological mechanisms involved in the control of locomotion and gait troubles remains a major challenge for biomedical research in order to improve quality and expectancy of life in parkinsonian patient. On the basis of experimental data, deep brain stimulation of the mesencephalic reticular formation (MRF), including the pedunculopontine and cuneiform nuclei, was proposed in 2005 as a new target to treat freezing of gait. However, regarding the heterogeneity of the clinical results, different questions now raise concerning the lack of anatomical and functional data of the MRF especially in non-human primate. The present study falls within a translational approach using clinical and pre-clinical data. First, a non-human primate model of bipedal locomotion was developed and validated on the basis of kinematic data. Multi-sequences MRI methodology was developed, allowing a longitudinal monitoring of the primate protocol and to construct a brainstem atlas of Macaca fascicularis. Then, an electrophysiological mapping of the MRF was performed in two behaving primates during rest and locomotion periods. For the first time, neurons within the MRF were found to respond to locomotion confirming the existence of a mesencephalic locomotor region in primate. After MPTP intoxication, only changes in neuronal discharge pattern were observed and arguments in favor of a misfunctioning of some MRF neurons during gait blockage. Finally, electrophysiological recordings during locomotion and natural transition from wakefulness to sleep suggest a dual function of some MRF neurons in the control of locomotion and arousal. The development of a new coordinate system adapted to human brainstem anatomy allowed to perform an anatomo-clinical evaluation of deep brain stimulation of the pedunculopontine nucleus and to provide a probabilist target for electrode implantation in the MRF to treat freezing of gait in the parkinsonian context.

Made available in DSpace on 2014-12-17T15:28:52Z (GMT). No. of bitstreams: 1 KellySF_DISSERT.pdf: 3939064 bytes, checksum: 5be69492fa857ba043776a01195d92b4 (MD5) Previous issue date: 2012-09-21 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Crises epil?pticas s?o eventos parox?sticos do sistema nervoso central (SNC) caracterizadas por uma descarga el?trica neuronal anormal, com ou sem perda de consci?ncia e com sintomas cl?nicos variados. Nas epilepsias do lobo temporal as crises tem in?cio focal, em estruturas do sistema l?mbico. Dados cl?nicos e experimentais mostram que essas regi?es apresentam morte neuronal (esclerose hipocampal), reorganiza??o sin?ptica (brotamento aberrante das fibras musgosas) e gliose reativa, sendo esses marcadores biol?gicos da zona epileptog?nica. Registros extracelulares mostram que al?m das altera??es anat?micas mencionadas acima, a zona epileptog?nica tamb?m apresenta oscila??es de alta frequ?ncia patol?gicas (pOAF). As pOAF s?o oscila??es transientes (50 100 ms de dura??o), de baixa amplitude (200 &#956;V - 1.5 mV) e de frequ?ncias vari?veis (80 800 Hz). A rela??o entre essas oscila??es e a g?nese das crises espont?neas ainda ? desconhecida. O objetivo do presente trabalho foi avaliar os efeitos da estimula??o el?trica intracerebral (EIC) nas pOAF e frequ?ncia de crises espont?neas de animais cronicamente epil?pticos (modelo da epilepsia do lobo temporal). Atualmente, a EIC ? utilizada no tratamento de dist?rbios do movimento (e.g., doen?a de Parkinson) e em alguns casos de dor cr?nica, e experimentalmente, no tratamento das epilepsias de dif?cil controle. A hip?tese de trabalho dessa disserta??o ? de que a indu??o de depress?o de longa dura??o por EIC, ao reduzir a excitabilidade neuronal local, modular? as pOAF, bem como a frequ?ncia de crises espont?neas. Para isso, comparamos as caracter?sticas espectrais das pOAF e a frequ?ncia de crises espont?neas antes e depois de um protocolo de 12 horas de estimula??o el?trica de baixa frequ?ncia (0,2 Hz) aplicado na via perforante. De fato, esse protocolo reduziu a amplitude do potencial de a??o coletivo registrado no giro denteado (GD) do hipocampo dorsal em 45% (amplitude m?dia da primeira e da ?ltima hora de estimula??o: 7,3 ? 3,0 mV e 4,1 ? 1,5 mV, respectivamente; p<0,05; teste t). O monitoramento cont?nuo do potencial de campo local, realizado no GD e em CA3 simultaneamente, mostrou que o protocolo de estimula??o empregado foi eficaz em (i) aumentar a dura??o (64,6 ? 9,3 ms vs. 70,5 ? 11,5 ms) e reduzir (ii) a entropia (3,72 ? 0,28 vs. 3,58 ? 0,30), (iii) o ?ndice pOAF (0,20 ? 0,08 vs. 0,15 ? 0,07) e (iv) o modo espectral (237,5 ? 15,8 Hz vs. 228,7 ? 15,2 Hz) das pOAF (valores do GD, expressos como m?dia ? desvio-padr?o, para os per?odos pr? e p?s estimula??o respectivamente; p<0,05; teste t). Ainda, este protocolo reduziu significativamente a frequ?ncia de crises espont?neas (1,8 ? 0,4 vs. 1,0 ? 0,3 crises/hora; pr? e p?s estimula??o, respectivamente; p<0,05; teste t). Curiosamente, observamos um aumento na dura??o m?dia das crises espont?neas ap?s o t?rmino do protocolo (39,7 ? 6,0 vs. 51,6 ? 12,5 s; pr? e p?s estimula??o respectivamente; p<0,05; teste t). Estes resultados sugerem que a redu??o da excitabilidade neuronal, por meio de protocolos de estimula??o el?trica, altera o perfil espectral das pOAF. Esse efeito foi acompanhado de redu??o na frequ?ncia de crises espont?neas. Apesar de preliminar, o presente trabalho contribui para o refinamento de terapias baseadas em EIC para indiv?duos com epilepsia

Dystonia is a neurological syndrome characterized by the involuntary contraction of opposing muscles, causing twisting movements or abnormal postures (modified by Fahn, 1987). Writer's cramp is the most common form of task-specific focal dystonia. In the first study, patients with writer's cramp were evaluated for differences in cortical activation during movements likely to induce cramps (complex movements) and movements which rarely lead to dystonia (simple movements). Although complex patient movements during fMRI were never associated with dystonic cramps, they exhibited abnormally decreased cortical activity. This was not observed in simple movements and was unrelated to the character of handwriting or the presence/absence of visual feedback. Our results support the theory of dualistic sensorimotor system behavior in writer's cramp. As the somatosensory system is believed to be affected in focal dystonia, we focused on modulation of the primary somatosensory cortex (SI) induced by repetitive transcranial magnetic stimulation (rTMS) in the second study, in order to improve writer's cramp. In conclusion, 1 Hz rTMS of the SI cortex can improve manifestations of writer's cramp while increasing cortical activity in both hemispheres. Handwriting as well as subjective assessment improved in most...

Les effets de la stimulation électrique sur la dynamique des systèmes neuronaux épileptiques sont encore méconnus. L'objectif principal de cette thèse est de progresser dans la compréhension des effets attendus en fonction des paramètres de stimulation. Dans la première partie du manuscrit, un modèle mésoscopique (population neuronale) de la boucle thalamocorticale est proposé pour étudier en détails les effets de stimulation indirecte (thalamique), avec une attention particulière sur la fréquence. Des signaux EEG intracérébraux acquis chez un patient souffrant d'épilepsie pharmaco-résistante ont d'abord été analysés selon une approche temps-fréquence (algorithme de type Matching Pursuit). Les caractéristiques extraites ont ensuite été utilisées pour identifier les paramètres du modèle proposé en utilisant une approche exhaustive (minimisation de la distance entre signaux simulés et réels). Enfin, le comportement dynamique du modèle a été étudié en fonction de la fréquence du signal de stimulation. Les résultats montrent que le modèle reproduit fidèlement les signaux observés ainsi que la relation non linéaire entre la fréquence de stimulation et ses effets sur l'activité épileptique. Ainsi, dans le modèle, la stimulation à basse fréquence (SBF ; fs <20 Hz) , et la stimulation à haute fréquence (SHF ; fs > 60 Hz) permettent d'abolir les dynamiques épileptiques, alors que la stimulation à fréquence intermédiaire (SFI; 20 < fs < 60 Hz) n'ont pas d'effet , comme observé cliniquement. De plus, le modèle a permis d'identifier des mécanismes cellulaires et de réseau impliqués dans les effets modulateurs de la stimulation. La deuxième partie du manuscrit porte sur les effets polarisants de la stimulation directe en courant continu (CC) de la zone épileptogène dans le contexte de l'épilepsie mésiale du lobe temporal (EMLT). Un modèle biomathématique bien connu de la région hippocampique CA1 a été adapté pour cette étude. Deux modifications sont été intégrées au modèle, 1) une représentation physiologique de l'occurrence des décharges paroxystiques hippocampiques (DPH) basée sur une identification de leurs statistiques d'occurrence basée sur des données expérimentales (modèle in vivo d'EMLT)et 2) une représentation électrophysiologiquement plausible de la stimulation prenant en compte l'interface électrode-électrolyte. L'analyse de la sortie du modèle en fonction de la polarité de stimulation, a montré qu'une réduction (resp. augmentation) significative des DPH (en durée et en fréquence) sous stimulation anodale (resp. cathodole). Un protocole expérimental a ensuite été proposé et utilisé afin de valider les prédictions du modèle. / The effects of electrical stimulation on the dynamics of epileptic neural systems are still unknown. The main objective of this thesis is to progress the understanding of the expected effects as a function of stimulation parameters. In the first part of the manuscript, a mesoscopic model (neural population) of the thalamocortical loop is proposed to study in details the effects of indirect stimulation (thalamic), with a particular attention to stimulation frequency. Intracerebral EEG signals acquired from a patient with drug-resistant epilepsy were first analyzed using a time-frequency approach (Matching Pursuit algorithm). The extracted features were then used to optimize the parameters of the proposed model using a Brute-Force approach (minimizing the distance between simulated and real signals). Finally, the dynamical behavior of the model was studied as a function of the frequency of the stimulation input. The results showed that the model reproduces the real signals as well as the nonlinear relationship between the frequency of stimulation and its effects on epileptic dynamics. Thus, in the model, low-frequency stimulation (LFS; fs <20 Hz) and high-frequency stimulation (HFS; fs > 60 Hz) suppress epileptic dynamics, whereas intermediate-frequency stimulation (IFS; 20 < fs <60 Hz) has no effect, as observed clinically. In addition, the model was used to identify the cellular and network mechanisms involved in the modulatory effects of stimulation. The second part of the manuscript addresses the polarizing effects of direct current (DC) stimulation of the epileptogenic zone in the context of the mesial temporal lobe epilepsy (MTLE). A well-known computational model of the hippocampal CA1 region was adapted for this study. Two modifications were added to the model: 1) a physiological representation of the occurrence of hippocampal paroxysmal discharges (HPD) based on the statistical identification of their occurrence in experimental data (in vivo model of MTLE) and 2) an electrophysiologically plausible representation of the stimulation inputs taking into account the electrode-electrolyte interface. The analysis of the model output as a function of the polarity of stimulation, showed a significant reduction (resp. increase) of HPDs (duration and frequency) in anodal stimulation (resp. cathodol). An experimental protocol was then proposed and used to validate the model predictions.

Background: Eating disorders are psychiatric illnesses whose treatment is difficult and usually the classic procedures fail. Recently, the number of researches in neuromodulatory methods has increased. I present an overview of basic stimulation methods, their use in the treatment of anorexia nervosa (AN), bulimia nervosa and binge-eating and the results of our study focused on the treatment of AN by transcranial direct current stimulation (tDCS). Methods: It was a randomized, double-blind, sham-controlled trial. Forty-three inpatients with AN were divided to receive either active (n=22) or sham (n=21) tDCS over the left DLPFC (anode F3/cathode Fp2, 2mA for 30 minutes). All patients filled the Eating Disorder Examination Questionnaire (EDE-Q) and Zung depression scale (ZUNG), we measured them the thermal pain threshold, the objective dissatisfaction with their own body by Anamorfic program and evaluated BMI before the first and after the last tDCS. Follow-up was after 2 and 4 weeks. It was evaluated using ANOVA and OPLS model. Results: Compared to sham tDCS, active tDCS improved self-evaluation based on one's body shape (p < 0,05) and significantly decreased the need of excessive control over calorie intake (p < 0,05) in 4-week follow-up (questions 4 and 23 in EDE-Q). Question 21 in EDE-Q was more...

La maladie de Parkinson est caractérisée par la manifestation de symptômes moteursprincipalement dus à la dégénérescence du système dopaminergique. Malgré l'accent mis surles déficits moteurs, la maladie de Parkinson est également caractérisée par des symptômesnon moteurs, incluant l'anxiété et la dépression, qui sont sous-étudiés et de ce fait pas bientraités. Alors que certaines études cliniques ont suggéré que l'anxiété et la dépressionpourraient être associées à la dégénérescence des neurones dopaminergiques, d'autres ontsuggéré l'implication de la dégénérescence des neurones noradrénergiques etsérotoninergiques dans les troubles observés mais également dans les effets induits par laLévodopa et la stimulation cérébrale profonde du noyau sous-thalamique.Dans un premier temps, nous avons étudié le rôle respectif de la dopamine, de lanoradrénaline et de la sérotonine dans la manifestation des déficits parkinsoniens moteurs etnon moteurs chez le rat. L’ensemble de nos résultats démontre que malgré l’importance dusystème dopaminergique, la perturbation des trois systèmes monoaminergiques joue un rôleimportant à la fois dans la manifestation des troubles moteurs et non moteurs.Nous avons également étudier l’impact des monoamines sur l’efficacité des traitementsantiparkinsoniens, à savoir, la Lévodopa et la stimulation cérébrale profonde du noyau sousthalamique,sur les troubles observés. Nos résultats montrent que la déplétion combinée dessystèmes monoaminergiques peut altérer l’efficacité de la Lévodopa ainsi que de lastimulation cérébrale profonde sur certains troubles. Ces résultats peuvent expliquer lemanque d’efficacité des traitements antiparkinsoniens chez certains patients et la difficulté àtraiter tous les symptômes.Pour finir, nous avons voulu mettre en évidence le lien entre le noyau sous-thalamique,structure excitatrice des ganglions de la base et les troubles moteurs, ainsi que l’amygdalebasolatérale et l’habénula latérale, structures impliquées dans les comportements émotionnels,et les troubles non moteurs. Nous avons mis en évidence le parallèle existant entre lesmodifications du mode de décharge des neurones du NST et les troubles moteurs, leschangements de l’amygdale basolatérale et les troubles anxieux ainsi que ceux de l’habénulalatérale et les troubles dépressifs.Les résultats de ces travaux de thèse ont donc permis d’apporter de nouvelles évidences surl’implication des trois systèmes monoaminergiques dans la physiopathologie et la thérapie dela maladie de Parkinson. / Parkinson’s disease is characterized by the manifestation of motor symptoms mostlyassociated with the degeneration of dopaminergic neurons. While Parkinson’s disease is oftenfocused on motor deficits, the disease is also characterized by non-motor deficits, includinganxiety and depression, which are under studied and consequently are not well treated.Whereas some clinical studies suggested that anxiety and depression could be linked to thedegeneration of dopaminergic neurons, others suggested the involvement of norepinephrineand serotonin in the observed symptoms and also in the efficacy of Levodopa and deep brainstimulation of the subthalamic nucleus.In a first time, we investigated the respective role of the neuronal degeneration of dopamine,noradrenaline and serotonin in the manifestation of motor and non-motor parkinsonian-likedisorders in the rat. Our results demonstrate that despite the importance of the dopaminergicsystem, the disturbances in the three-monoaminergic systems play a key role in themanifestation of motor and non-motor deficits.In a second time, we studied the impact of monoamine depletions on the efficacy ofantiparkinsonian treatments, the Levodopa and deep brain stimulation of the subthalamicnucleus. Our results showed that the combined depletions could deteriorate the efficacy of theLevodopa and of the deep brain stimulation on some deficits. Together, these results canexplain the lack of efficacy of the antiparkinsonian treatments in some patients and thedifficulty to treat all the symptoms.Finally, we investigated the link between the subthalamic nucleus, which is an excitatorystructure of the basal ganglia, and the motor deficits, as well as the involvement of thebasolateral amygdala and the lateral habenula in emotional control of the behavior, and nonmotordeficits. We showed the parallel between changes in the neuronal activity of thesubthalamic nucleus and the motor deficits, of the basolateral amygdala and anxiety and ofthe lateral habenula and depression.Results from this thesis provide new evidences on the involvement of the threemonoaminergicsystems in the pathophysiology and the therapy of Parkinson’s disease.

Dystonia is a neurological syndrome characterized by the involuntary contraction of opposing muscles, causing twisting movements or abnormal postures (modified by Fahn, 1987). Writer's cramp is the most common form of task-specific focal dystonia. In the first study, patients with writer's cramp were evaluated for differences in cortical activation during movements likely to induce cramps (complex movements) and movements which rarely lead to dystonia (simple movements). Although complex patient movements during fMRI were never associated with dystonic cramps, they exhibited abnormally decreased cortical activity. This was not observed in simple movements and was unrelated to the character of handwriting or the presence/absence of visual feedback. Our results support the theory of dualistic sensorimotor system behavior in writer's cramp. As the somatosensory system is believed to be affected in focal dystonia, we focused on modulation of the primary somatosensory cortex (SI) induced by repetitive transcranial magnetic stimulation (rTMS) in the second study, in order to improve writer's cramp. In conclusion, 1 Hz rTMS of the SI cortex can improve manifestations of writer's cramp while increasing cortical activity in both hemispheres. Handwriting as well as subjective assessment improved in most...