Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Introdução: A Distonia Cervical (DC) é o tipo mais comum de distonia focal primária e atualmente o tratamento padrão ouro consiste na aplicação periódica de toxina botulínica nos músculos afetados. Considerando que cada formulação de toxina botulínica é farmacologicamente distinta, nesta pesquisa foi realizada a comparação de dois tipos de toxina botulínica tipo A (TBA) disponíveis no Brasil: Dysport® (Abobotulinumtoxin A) e Prosigne® (Lanzhou botulinum toxin type A). Metodologia: Foi conduzido um estudo prospectivo, randomizado e duplo cego com dois braços em uso de substância ativa, Dysport® e Prosigne®. Foram recrutados 34 pacientes do ambulatório de toxina botulínica (ATXB) do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP) de maio de 2010 a junho de 2011, foram incluídos apenas pacientes com diagnóstico de distonia cervical idiopática. Cada indivíduo foi acompanhado por um período de 13 meses, sendo que nesse período foram submetidos a 5 aplicações de TBA com intervalo de 3 meses entre cada procedimento. Como instrumento para aferir a melhora dos movimentos involuntários, aplicamos a Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), escala completa com subescalas de gravidade, incapacidade e dor, antes da primeira aplicação e um mês após, e antes da última aplicação e um mês após. Após cada aplicação os pacientes foram submetidos à entrevista estruturada para aplicação da escala de melhora global Clinician Interview-Based Impression of Change (CIBIC) e colher dados sobre tempo de duração do efeito benéfico da toxina e efeitos colaterais apresentados. Para análise estatística foram utilizados o teste t para amostras pareadas, o teste não-paramétrico de Mann-Whitnney, o teste não paramétrico de Friedman e o teste do qui quadrado. Resultados: Foram recrutados 14 indivíduos para o grupo Dysport® e 20 indivíduos para o grupo Prosigne®, a média de idade foi de 57,21 anos no primeiro grupo e 51,95 no segundo (p = 0,239). Após a primeira aplicação houve uma redução média nos valores da TWSTRS de 12,78 pontos no grupo sendo tratado com Dysport® e 9,98 pontos no grupo sendo tratado com Prosigne® (p = 0,38). Após a última aplicação a redução desses valores foi de 11,87 pontos no primeiro grupo e 11,35 no segundo (p = 0,86). Em relação à escala CIBIC a grande maioria dos pacientes referiu algum grau de melhora após as aplicações, sem diferença estatística entre os dois braços do estudo. Também não houve diferença estatística entre os grupos em relação ao tempo de duração da melhora após aplicações. Disfagia foi o efeito colateral mais comum, ocorrendo em 27,27 % das aplicações, seguido por dor local e fraqueza muscular. Não houve diferença significativa entre os grupos em relação à incidência de efeitos colaterais. Conclusão: Nossos dados mostram que as toxinas botulínicas Dysport® e Prosigne® tem perfil de eficácia similar para o tratamento da distonia cervical idiopática. Além disso, ambas as toxinas são equivalentes em relação à segurança e tolerabilidade. / Introduction: Cervical dystonia (CD) is the most frequent type of primary focal dystonia and treatment with botulinum toxin is currently the gold standard. Considering that each botulinum toxin brand is pharmacologically distinct, in this paper we compared two botulinum toxins available in Brazil: Abobotulinumtoxin A (Dysport®) and Lanzhou botulinum toxin type A (Prosigne®). Methodology: We conducted a prospective, randomized, double blind trial with one group being treated with Dysport® and the other Prosigne®. We recruited 34 patientes from Ribeirao Preto Medical Schools (HCFMRP) botulinum toxin clinic (ATXB) from may 2010 to june 2011, only patients with idiopathic CD were included in the trial. Each individual was followed during a 13 month period, during which 5 TBA injection sessions were conducted with 3 month intervals between them. To assess objective improvement we used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), full scale and severity, disability and pain subscales, before and after the first and fifth treatment sessions. After each treatment session we assessed improvement with the Clinician Interview Based Impression of Change (CIBIC) scale and asked about side effects and duration of improvement. For statistical analysis we used the following tests: t test for paired samples, Mann-Whitneys non parametrical test, Friedmans non parametrical test and qui square test. Results: Fourteen patients were randomized to receive Dysport® and twenty to receive Prosigne®. Mean age in Dysport® group was 57.21 years and in Prosigne® group was 51.95 (p = 0.23). After first injection, mean TWSTRS values reduced 12.78 points in Dysport® group and 9.98 in Prosigne® group (p = 0.38). After last injection the reduction in TWSTRS values was 11.87 points for Dysport® and 11.35 points for Prosigne® (p = 0.86). CIBIC scores showed that the majority of patients reported some level of improvement after injections without statistical differences between groups. Dysphagia was the commonest adverse effect, occurring after 27.27 % of all injections, followed by local pain and muscle weakness. Once again there were no statistical difference between groups regarding adverse effects. Conclusion: Our data showed similar efficacy and safety profiles when comparing both toxins, Dysport® and Prosigne®.

Os objetivos deste estudo foram: caracterizar, comparar e correlacionar, em indivíduos com distonia laríngea, antes e após 30 e 120 dias da aplicação da toxina botulínica tipo A no músculo tireoaritenoideo unilateralmente, os parâmetros vocais perceptivo-auditivos e visuais e o impacto vocal na qualidade de vida. Participaram do estudo 16 indivíduos com diagnóstico de distonia laríngea, sendo 11 de gênero feminino e cinco de gênero masculino, com idade média de 57 anos e dois meses, sendo que 68,75% deles apresentaram tremor vocal associado. Todos foram submetidos à aplicação da toxina botulínica tipo A (Dysport®), no músculo tireoaritenoideo unilateralmente, guiado por eletromiografia, gravação do sinal vocal e preenchimento do protocolo de qualidade de vida, Índice de Desvantagem Vocal, antes da injeção da toxina botulínica, no primeiro retorno de seguimento, em média, após 36 dias, e no segundo retorno, coincidente com o dia da nova aplicação de toxina botulínica, que foi em média, 137 dias. Os resultados para análise perceptivo-auditiva e visual de sinais e sintomas vocais, realizada por dois juízes especialistas em voz, revelou, na comparação entre a pré-aplicação e o primeiro retorno, diminuição da severidade da oscilação de intensidade, quebras de voz (sonoridade) e tremor vocal (p=0,002), portanto sem alterações no segundo retorno. No grau de severidade da qualidade da voz, voz tensa-estrangulada, rugosidade, soprosidade e astenia não foram observadas alterações nos três tempos. Para esta análise, notou-se concordância excelente e muito boa (0,71 a 0,99) intrajuízes. Na comparação entre a pré-aplicação e o primeiro retorno, para o Índice de desvantagem vocal, verificou-se diminuição dos valores para o escore total (p=0,039) e para o domínio emocional (p=0,035). Quanto à comparação entre a pré-aplicação e segundo o retorno, houve redução significativa para o domínio funcional (p=0,03) unicamente. De modo que, entre a análise perceptivo-auditiva e visual, do grau de severidade da qualidade vocal e o escore total do índice de desvantagem vocal, evidenciou-se correlação moderada na pré-aplicação e segundo retorno e fraca no primeiro retorno. Portanto, concluiu-se que o tratamento com toxina botulínica para os indivíduos com distonia laríngea mostrou-se eficiente na diminuição de sinais e sintomas vocais, bem como no impacto vocal na qualidade de vida, gerando mudanças na função fonatória e facilitando a comunicação após 30 dias da aplicação, com retorno dos sintomas vocais para a maioria dos indivíduos após 120 dias. / The purpose of this study was to characterize, compare, and correlate the laryngeal dystonia in individuals before, after 30, and 120 days after the application of botulinum toxin type A in the unilateral thyroarytenoid muscle the perceptual vocal and visual parameters and the vocal impact in quality of life. 16 individuals with diagnosed laryngeal dystonia participated in the study, 11 being of the female gender and five of the male gender, with an average age of 57 years and two months, being that 68.75% of individuals having presented associated vocal tremor. All individuals were subjected to: the application of botulinum toxin type A (Dysport®) via electromyography in the unilateral thyroarytenoid muscle, a recording of the vocal sound waves, filling out a survey about his/her quality of life and an Voice Handicap Index (VHI) before the botulinum toxin injection, in the first follow-up on average 36 days after, and in the second follow-up concurrent with the new botulinum toxin application visit, which was on average after 137 days. The results for the perceptual auditory and visual analysis of vocal sound waves and symptoms, conducted by two adjudicating voice specialists, revealed in the comparison between the pre-application and the first follow-up a decrease in the severity of the oscillation intensity, voice breaks (sonority), and vocal tremor (p=0.002), however, revealed no changes in the second follow-up. During the three visits, no changes were observed in grading the severity of voice quality in tense-strangled voice, roughness, breathiness and asthenia. For this analysis, a very good and excellent agreement between the adjudicators was noted (0.71 to 0.99). Comparing the pre-application and the first follow-up, for the index of vocal disability, a decrease in the values of total score (p=0.039) and of emotional mastery (p=0.035) was observed, whereas comparing the pre-application and the second follow-up, there was a significant decrease only for functional mastery (p=0.03). In this way, between perceptual auditory and visual analysis, grading the severity of vocal quality and the total score of the Voice Handicap Index, a moderate correlation was evident in the pre-application and second follow-up and a faint correlation was evident in the first follow-up. Therefore, it can be concluded that the treatment with botulinum toxin for individuals with laryngeal distonia who participated in this study proved effective in the decrease of symptoms, as well as in a vocal impact of quality of life which created changes in the phonatory function and facilitated communication after 30 days of the application, with a return of vocal symptoms for the majority of individuals after 120 days.

A distonia é uma síndrome que consiste de contrações musculares involuntárias que resultam em movimentos distorcidos e repetitivos e/ou posturas anormais. O tratamento pode ser por farmacoterapia, com drogas anticolinérgicas ou com a injeção de toxina botulínica no grupo de músculos afetados. O objetivo do trabalho foi avaliar a deglutição nos pacientes com distonia laríngea, antes e após o tratamento com a toxina botulínica. Nossa hipótese foi que a toxina botulínica modificaria a deglutição dos pacientes com distonia laríngea. Foram avaliados 17 indivíduos adultos, acima de 18 anos de idade, com diagnóstico clínico de distonia laríngea antes e após o tratamento com o uso de toxina botulínica do tipo A, e 20 indivíduos adultos saudáveis como controles. Os participantes foram submetidos à anamnese fonoaudiológica e avaliação videofluoroscópica da deglutição. Os pacientes com distonia foram avaliados antes e 30 dias após a injeção de toxina botulínica, guiada por eletromiografia. Na videofluoroscopia foram avaliadas 6 deglutições de 5mL, sendo 3 na consistência líquida (sulfato de bário 100%, e 3 na consistência pastosa (3g do espessante alimentar ThickenUp Clear, em 50 mL de sulfato de bário (100%) oferecidas em uma colher. A ordem das deglutições foi aleatória. Foram estudadas as fases oral e faríngea da deglutição, com registro de 30 quadros por segundo. Os pacientes com distonia laríngea apresentaram aumento de resíduos na região oral e em valécula e maior número de deglutições. Os pacientes apresentaram tempo de trânsito faríngeo (TTF) menor do que os controles (p<0,01), para os bolos nas consistências líquida e pastosa. O TTF foi menor após aplicação do que antes da aplicação da toxina botulínica, quando da deglutição do bolo pastoso. Portanto, concluiu-se que os pacientes com distonia laríngea, comparado a controles, têm trânsito mais rápido pela faringe, aumento de resíduos na região oral e em valécula e maior número de deglutições para o mesmo volume.Trinta dias após a aplicação da toxina botulínica foi observado diminuição da duração do trânsito pela faringe, com o bolo pastoso, e resposta tardia do movimento do osso hióide em relação à chegada do bolo na faringe. / Dystonia is a syndrome consisting of involuntary muscle contractions that result in distorted and repetitive movements and/or abnormal postures. Treatment may be by pharmacotherapy with anticholinergic drugs or with the injection of botulinum toxin in the affected muscle group. The aim of this study was to evaluate swallowing in patients with dystonia before and after treatment with botulinum toxin. Our hypothesis was that botulinum toxin modify the swallowing of patients with spastic dystonia. Seventeen adult subjects over the age of 18 years with clinically diagnosed dystonia were evaluated before and after treatment with botulinum toxin type A and compared to 20 healthy adults as controls. Participants underwent phonologic anamnesis and videofluoroscopy assessment of swallowing. Patients with dystonia were assessed before and 30 days after injection of botulinum toxin, guided by electromyography. In fluoroscopy, 6 swallows were evaluated of 5ml: 3 in a liquid consistency (100% barium sulfate) and 3 in a pasty consistency (3g of food thickener, ThickenUp Clear) in 50 mL of 100% barium sulfate, offered on a spoon. The oral and pharyngeal phases of swallowing were studied from swallows of random order, with registration of 30 frames per second. Patients with dystonia showed an increase of residue in the oral region and vallecula and greater number of multiple swallows. Patients had less pharyngeal transit time (PTT) than controls (p<0.01) for boluses of liquid and pasty consistencies. PTT was lower after the application of botulinum toxin than before with the swallowing of a pasty bolus. It was concluded that patients with dystonia, compared to controls, have more rapid transit through the pharynx, increased residues in the oral region and vallecula and a greater number of swallows for the same volume. Thirty days after the botulinum toxin, it was observed a shorter pharyngeal transit time with paste bolus, and delayed hyoid movement response to bolus presence in pharynx.

INTRODUÇÃO: Apesar da terapia com toxina botulínica ser o tratamento de escolha para a distonia cervical, admite-se que um tratamento multidisciplinar, agregando a fisioterapia ao tratamento com toxina botulínica, poderia acrescentar maiores benefícios aos pacientes com distonia cervical; sendo assim, o objetivo primário deste estudo foi avaliar o efeito da associação da toxina botulínica a um protocolo de fisioterapia na gravidade da distonia cervical, incapacidade e dor; e o objetivo secundário foi avaliar o efeito desta associação na qualidade de vida de pacientes com distonia cervical. MÉTODOS: Participaram deste estudo controlado aberto quarenta de setenta pacientes com distonia cervical, tratados no Ambulatório de Distúrbios do Movimento do Departamento de Neurologia da Faculdade de Medicina do Hospital das Clínicas da Universidade de São Paulo. Antes de serem submetidos à aplicação da toxina botulínica, os pacientes foram avaliados por um médico da equipe, e esperava-se que neste dia os pacientes estivessem sem a ação da medicação. Todos os pacientes avaliados foram convidados a participar do programa de fisioterapia, e conforme a disponibilidade de aderir ao programa dos mesmos, chegou-se ao número de vinte pacientes em G1 (fisioterapia e toxina botulínica) e vinte pacientes em G2 (toxina botulínica), sendo esta amostra de conveniência. Para G2, foram escolhidos os primeiros vinte pacientes consecutivos que não poderiam aderir ao programa fisioterapêutico. Os pacientes de G1 e G2 foram reavaliados após quarenta e cinco dias. As escalas utilizadas foram a Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) e a Short-Form Health Survey (SF-36). Foi proposto um novo modelo de tratamento para pacientes com distonia cervical que seriam submetidos a um protocolo fisioterapêutico, baseado em três principais abordagens: aprendizagem motora, cinesioterapia e estimulação elétrica funcional na musculatura antagonista ao padrão distônico. Os pacientes de G1 foram tratados por um período de quatro semanas, a frequência era diária (cinco vezes por semana) e a duração da sessão em média uma hora e quinze minutos. RESULTADOS: As características demográficas iniciais dos indivíduos não diferiram significativamente entre os dois grupos tratados, em apenas um dos itens avaliados (tempo de tratamento) houve diferença entre grupos no momento inicial. Os resultados dos tratamentos na qualidade de vida foram avaliados pela escala SF-36, esta dividida em dois grandes domínios: aspectos físicos e aspectos emocionais. Em relação aos aspectos físicos, G1 apresentou melhora significativa comparando-se antes e depois do tratamento (intragrupo) em três subdomínios: capacidade funcional, limitação por aspectos físicos e dor; em G2 não houve melhora significativa em nenhum dos quatro subdomínios. Houve também uma diferença entre G1 e G2 depois dos tratamentos (entre grupos) em dois subdomínios: limitação por aspectos físicos e dor. Em relação aos aspectos emocionais, em G1, houve melhora significativa nos seguintes subdomínios depois do tratamento (intragrupo): vitalidade, aspectos sociais e saúde mental. Houve também uma diferença entre G1 e G2 depois dos tratamentos (entre grupos) em dois subdomínios: vitalidade e saúde mental. Não houve melhora em G2 nos subdomínios dos aspectos emocionais. A avaliação das características e gravidade da distonia cervical, medida pela TWSTRS, demonstrou melhora significativa de G1 e G2 após os tratamentos que foram submetidos (intra grupos) em duas subescalas: gravidade (I) e incapacidade (II). Na subescala de dor (III), apenas G1 apresentou melhora intragrupo após o tratamento a que foi submetido; houve também, neste mesmo subdomínio, diferença significativa entre G1 e G2 depois dos tratamentos, entre grupos. CONCLUSÕES: O presente estudo avaliou possibilidade de que a utilização da toxina botulínica, junto a um protocolo de fisioterapia facilmente reprodutível, poderia agregar melhoras em sintomas como gravidade da doença, incapacidade, dor e qualidade de vida de uma população de indivíduos com distonia cervical, e os resultados obtidos permitiram negar as hipóteses nulas. Novas pesquisas são necessárias para confirmar esses achados e solidificar a reabilitação neurológica como um tratamento eficaz no manejo da distonia cervical / INTRODUCTION: Despite the fact that therapy with botulinum toxin is considered the best treatment for cervical dystonia, it is assumed that a multidisciplinary treatment, adding physical therapy to the botulinum toxin treatment could provide additional gains to patients with cervical dystonia. The primary objective of this study was to evaluate the effect of the combination of botulinum toxin and physical therapy on severity of cervical dystonia, disability and pain. The secondary objective was to evaluate the effect of this combination on the quality of life in patients with cervical dystonia. METHODS: forty patients of seventy with cervical dystonia from the Ambulatório de Distúrbios do Movimento do Departamento de Neurologia da Faculdade de Medicina do Hospital das Clínicas da Universidade de São Paulo attended this open- controlled study. Before receiving an application of botulinum toxin, the patients were evaluated by a neurologist and it was assumed that patients were not under any effect of the medication (botulinum toxin). All patients were asked to participate in a physical therapy program, and according to the patients availability to join the program, we reached the number of twenty patients in G1 (physical therapy and botulinum toxin) and in G2 (botulinum toxin only), the first twenty consecutive patients who couldnt participate in the physical therapy program were chosen. This was a convenience sample. Patients of G1 and G2 were revaluated after forty five days, and the evaluation scales used was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Short-Form Health Survey (SF-36). A new model of physical therapy treatment was applied to patients with cervical dystonia, and it was based on three main approaches: motor learning, kinesiotherapy and functional electrical stimulation on the antagonist muscles of the dystonic pattern. The patients in G1 were treated daily for a period of four weeks, and each session lasted one hour and fifteen minutes. RESULTS: The demographic characteristics of individuals didnt differ significantly between two treated groups, but there was a difference between groups in the initial moment (baseline) in only one feature evaluated (time of treatment). The SF-36 scale was used to evaluate the results of the treatments for quality of life, and was divided into two big domains: physical and emotional aspects. When analyzing physical aspects, G1 showed a significant improvement when comparing before and after the proposed treatment (inside group) in three subdomains: physical functioning, role-physical and body pain; in G2 there was no improvement in any of the four subdomains. A difference between G1 and G2, after the treatments (between groups), was also seen in two subdomains: role-physical and body pain. In relation to emotional aspects, in G1, after the treatment (intra-group), there was a significantly improvement in vitality, social functioning and mental health. There was also a difference between G1 and G2 after the treatment (between groups) in two subdomains: vitality and mental health. There was no improvement in G2 in any domains of the social aspects. Severity of cervical dystonia showed a significant improvement of G1 and G2 after treatments (intra-group) in two subdomains: severity (I) and disability (II). In subscale pain (III), only patients of G1 showed a significant improvement intra-group after the treatment; in this subdomain there was also a significant difference between groups after the treatments (G1 and G2). CONCLUSIONS: The present study showed that botulinum toxin, combined with an easily reproducible physical therapy protocol, could improve symptoms like severity of cervical dystonia, disability, pain and quality of life, in a population of individuals with cervical dystonia, and these results makes it possible to deny the null hypothesis. Other studies are needed to confirm these findings and solidify neurologic rehabilitation as an effective cervical dystonia treatment approach

Introdução: A distonia cervical (DC) é a distonia focal mais comum no mundo, cujas manifestações clínicas e consequências vão muito além dos movimentos involuntários cervicais. A doença causa significativo impacto sobre a vida profissional e social dos indivíduos acometidos, com acentuado comprometimento da qualidade de vida, além de dor cervical. Uma avaliação clínica completa é necessária para um manejo adequado desta enfermidade. Não há, no Brasil, escala validada que permita uma avaliação holística dos pacientes portadores de DC. A escala Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) é um instrumento de avaliação conhecido em todo o mundo, tendo sido utilizado em inúmeros estudos de avaliação de DC, e sua validação é o objetivo deste estudo. Casuística e métodos: A adaptação transcultural foi realizada segundo critérios já publicados. Após o pré-teste com 30 pacientes, observou-se que a escala era de difícil entendimento para pessoas com escolaridade abaixo de 8 anos, e a escala foi novamente submetida a um processo de adaptação, com modificações sugeridas por juízes, produzindo a escala adaptada. A validação do instrumento seguiu orientações padrão: comparação com instrumento de medida de qualidade de vida (WHOQOL-Bref); realização de teste-reteste por meio de três avaliações separadas entre si por 2 semanas; cálculo do alfa de Cronbach para os itens da escala; medida do coeficiente de correlação intraclasse e intervalo de confiança de 95%; e cálculo dos gráficos de concordância/dispersão de BlandAltman. Resultados: A escala final foi de fácil entendimento por pessoas de todos os níveis educacionais. A consistência interna foi boa a excelente (0,599 para o domínio Intensidade, 0,860 para o domínio Incapacidade, e 0,878 para o domínio Dor). Houve boa correlação com a escala padrão e concordância entre examinadores. A confiabilidade e reprodutibilidade da escala, conforme cálculo do ICC e IC95%, alcançaram níveis aceitáveis. Os gráficos de Bland-Altman produziram dados dispersos de forma aleatória, sugerindo ausência de tendência nas avaliações. Conclusão: A versão em Português da TWSTRS é válida para a avaliação de pacientes brasileiros portadores de DC possui boa consistência interna e apresenta boa reprodutibilidade entre examinadores / Background: Cervical dystonia (CD) is the most common focal dystonia, its clinical picture and outcome going far beyond the involuntary muscle contractions. This illness has a significant impact over the social and professional lives of affected individuals, leading to severe compromise of quality of life (QoL), and cervical pain. A complete clinical assessment is of utmost importance to an adequate management of this disease. There is no validated clinical tool in Brazil devised to a holistic evaluation of CD patients. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) is a world famous scale used in several studies of CD evaluation, and its validation is the objective of this study. Patients and methods: The transcultural adaptation was performed according to published criteria. After the initial pre-test with 30 patients, it was observed that patients with schooling under 8 years could not understand the whole scale, and the tool underwent a new adaptation process after modifications suggested by the judges, producing the adapted scale. The validation followed standard methods: comparison with a QoL instrument (WHOQOL-Bref); test-retest with three examinations 2-weeks apart from each other; Cronbach\'s ? calculation of the items of the scale; intraclass correlation coefficient (CCI) and 95% confidence interval (95%CI) determination; and production of the Bland-Altman graphs. Results: The final version of the scale was easy to understand by all patients examined. The internal consistency was good to excellent (0.599 for domain Intensity, 0.860 for the domain Disability, and 0.878 for domain Pain). There was a good correlation between the adapted scale and the QoL instrument and good concordance between examiners. The reliability and reproducibility according to CCI and 95% CI reached acceptable values. The Bland-Altman graphs displayed randomly dispersed data, suggesting no tendency in the evaluations. Conclusions: The Portuguese version of the TWSTRS is valid for evaluation of Brazilian CD patients, has good internal consistency, and is reproducible between examiners

Bakgrund: Cervikal dystoni är en neurologisk sjukdom som drabbar nackmuskulaturen med muskelsammandragningar som kan resultera i felställningar, smärta och tremor. Behandlingen består i dagsläget av injektioner med Botulinumtoxin och fysioterapi. Syfte: Syftet med denna studie var att undersöka den självrapporterade nivån av fysisk aktivitet och sambandet mellan fysisk aktivitet och smärta hos personer med cervikal dystoni. Metod: Detta var en icke experimentell tvärsnittstudie med 273 medlemmar i Svensk dystoniförening som deltagare. Insamling av data skedde via en enkät.  Den fysiska aktivitetsnivån mättes med IPAQ-sf och smärta med NRS. Resultat: Gruppen placerades i kategori två enligt International Physical Activity Questionnaire´s (IPAQ) riktlinjer med ett medianvärde på 925,5 MET-minuter vilket innebär måttligt aktiva. I gruppen uppnådde 34,05% de allmänna rekommendationerna för fysisk aktivitet uppsatta av WHO. Det förelåg ingen skillnad mellan män och kvinnor vad gäller fysisk aktivitetsnivå och en låg icke signifikant korrelation mellan smärta och fysisk aktivitetsnivå. Konklusion: För fysioterapeuter är det bra att ha i beaktning att personer med cervikal dystoni är mindre fysisk aktiva och behandlingen bör utformas efter individen för bästa möjliga behandling. Liknande studier med andra datainsamlingsmetoder behövs för att säkerställa resultatet. / Background: Cervical dystonia is a neurological disease which effects the muscles of the neck with muscle contractions that could lead to malalignments, pain and tremor. Todays treatment consists of injections with botulinum toxin and physical therapy. Aim: The purpose of this study was to examine the self-reported level of physical activity and the correlation between physical activity and pain among people with cervical dystonia. Method: This was a nonexperimental cross-sectional study with 273 members of Svensk dystoniförening as participants. Collection of data was gathered thru a questionnaire. The level of physical activity was measured with IPAQ-sf and level of pain with NRS. Results: The result showed that the group was placed in category two according to the International Physical Activity Questionnaire´s (IPAQ) guidelines with a median of 925,5 MET-minutes which means moderately active. Within the group 34,05% reached the current recommendations for physical activity stated by WHO. There was no difference between men and women as to level of physical activity (p=0,39, p=0,36), and a low insignificant correlation between pain and level of physical activity (r=-0,15). Conclusion: Similar studies with other data collection methods is needed to ensure a possible result. For physiotherapists, it is good to keep in mind that people with cervical dystonia are less physical active and that the treatment should be designed for the individual for the best possible result.

Syfte: Att undersöka vilka faktorer personer med cervikal dystoni (CD) anser underlättar respektive hindrar deras möjlighet till fysisk aktivitet.  Design och metod: Explorativ och deskriptiv design. Kvalitativ innehållsanalys och kvantitativ frekvensberäkning av svar på två öppna frågor i en enkät (n=144). Utifrån graden av upplevt aktivitetshinder på grund av CD gjordes även uppdelning i subgrupper. Resultat: Sju kategorier (och 28 subkategorier) underlättande faktorer framkom.  De tre största var ”Rörlig i vardagen”, ”Psykiska faktorer” och ”Nytta av hjälpmedel”. Vid större grad av aktivitetshinder angavs ”Nytta av hjälpmedel” oftare än ”Psykiska faktorer”. Vid mindre grad av aktivitetshinder utgjorde istället ”Psykiska faktorer” största kategorin följt av ”Rörlig i vardagen” och ”Träningsrelaterade faktorer”. Åtta kategorier (och 24 subkategorier) hindrande faktorer framkom. De tre största var ”Nackrelaterade besvär”, ”Psykiska begränsningar” och ”Andra fysiska besvär”. Vid större grad av aktivitetshinder angavs ”Nackrelaterade besvär” mest frekvent, följt av ”Andra fysiska besvär” och ”Begränsningar i vardaglig fysisk aktivitet”. Vid mindre grad av aktivitetshinder angavs istället oftast ”Psykiska begränsningar” följt av ”Nackrelaterade besvär” och ”Andra fysiska besvär”. Konklusion: För att optimera möjligheten till fysisk aktivitet hos personer med CD bör fysioterapiinsatser förutom fokus på reducering av sjukdomsrelaterade besvär även inkludera ett evidensbaserat beteendemedicinskt förhållningssätt. Insatserna bör påbörjas i ett tidigt skede av sjukdomen. / Purpose: To investigate the self-perceived facilitators and barriers to physical activity among people with cervical dystonia (CD). Design and method: Explorative and descriptive design. Qualitative content analysis and quantitative frequency analysis of two open-ended questions in a survey (n= 144). Subgroups based on self-perceived CD-related limitations in activity were also formed. Result: Seven categories (and 28 subcategories) facilitators emerged. The three most commonly reported were “Motion in everyday life”, “Psychological factors” and “Supportive aid”. Patients with major activity limitation mentioned more frequent “Supportive aid” than” Psychological factors”. Among patients with minor activity limitation “Psychological factors” was the largest category followed by “Motion in everyday live” and “Exercise-related factors”. Eight categories (and 24 subcategories) barriers emerged. The three most commonly reported were “Neck-related problems”, “Psychological limitations” and “Other physical disabilities”. People with major activity limitation most frequent experienced “Neck-related problems” followed by “Other physical disabilities” and “Limitations in everyday physical activities”, while “Psychological limitations” was most frequent mentioned by patients with minor activity limitation, followed by “Neck-related problems” and “Other physical disabilities”. Conclusion: To optimize the possibility for people with CD to be physical active, physical therapy interventions should not only focus on reducing disease-related complications but also incorporate an evidence-based behavioral medicine approach. Interventions should begin at an early stage of the disease.

L'adaptation motrice permet d'ajuster la sortie motrice en réponse à des perturbations de l'environnement. Au début de l'adaptation, un processus stratégique conscient appelé recalibration a lieu. Ce processus implique le cervelet et le cortex pariétal postérieur. Il permet de réduire les erreurs motrices en se basant sur le retour sensoriel. Les patients dystoniques ont des altérations du traitement de l'information somatosensorielle. Nous avons fait l'hypothèse que cela devait entrainer des anomalies d'adaptation au cours de la phase de recalibration. En utilisant l'imagerie par résonnance magnétique (IRMf) et la magnétoencéphalographie (MEG), nous avons enregistré l'activité cérébrale chez des patients ayant une crampe de l'écrivain et chez des volontaires sains, alors qu'ils réalisaient une tâche de pointage avec ou sans perturbation visuelle associée. L'étude en IRMf a révélé l'implication d'un réseau cérébello-pariétal postérieur dans la détection des erreurs motrices. Ce réseau était hypoactif chez les patients qui compensaient en recrutant un réseau alternatif plus cognitif mettant en jeu la mémoire visuo-spatiale et la représentation cognitive de la main. La MEG nous a permis d'analyser la dynamique temporelle des activations et de montrer en particulier que la préparation du mouvement est déjà anormale chez les patients; de réaliser une analyse fréquentielle de la communication cérébello-corticale. Cette analyse a révélé un défaut de cohérence dans la bande gamma, entre le cervelet et le cortex moteur et prémoteur ainsi qu'avec le cortex pariétal postérieur. L'ensemble de nos résultats suggère un désordre constitutionnel de ce réseau dans la dystonie. / Dystonia is a movement disorder characterized by prolonged muscle contractions causing involuntary repetitive twisting movements and abnormal postures. Motor adaptation shapes the motor output according to the changes in the environment. At its early stage, motor adaptation involves a strategic conscious process called “recalibration” that minimizes the perturbation and reduces the motor error based on online integration of sensory feedback. Sensorimotor processing is impaired in dystonia and we hypothesized that this may lead to deficits of the “recalibration” phase during motor adaptation. We used magnetoencephalography (MEG) and functional magnetic resonance imagery (fMRI) to record brain activation in patients with writer’s cramp and healthy volunteers using a classical rotation learning task. The fMRI study revealed that the cerebello-parietal network was directly implicated in motor error detection. In writer’s cramp, this network was underactivacted and patients relied more on cognitive networks based on visuospatial memory and cognitive representations of the hand. With MEG, (1) we reconstructed the temporal dynamic of activations in the cerebello-parietal network and demonstrated abnormal movement preparation in writer’s cramp patients; (2) we realized a spectral analysis of the cerebello-parietal communication. This analysis revealed decreased gamma coherence between the cerebellum, and the premotor and motor cortices and with posterior parietal cortex. All of our data suggest an underlying disorder of this network in dystonia.

La dystonie est une pathologie du contrôle du mouvement caractérisée par des contractions musculaires involontaires. Les causes génétiques de cette pathologie sont multiples. J’ai créé des bases de données locus spécifiques colligeant l’ensemble des diversités alléliques disponible pour 16 gènes de dystonie. L’objectif de ce travail est d’aider au diagnostic de cette pathologie et, à plus long terme et lorsque les données le permettent, d’établir des corrélations génotypes-phénotypes. Cela a été le cas pour le gène THAP1 (définissant la forme DYT6) pour lequel nous avons décrits plusieurs corrélations. J'ai recherché la mutation causale dans plusieurs familles par séquençage d'exome. Cela a permis d’identifier une famille porteuse d’une mutation prédite pathogène dans le gène ANO3 (DYT23). Une autre famille est porteuse d’une mutation dans un site d’épissage du gène ATP1A3 (DYT12) entrainant la rétention totale de l'intron 17. Pour une autres famille, un gène candidat a été identifié : ADD2 qui code l'adducine beta. Plusieurs résultats expérimentaux ont été obtenus. Tout d’abord j'ai observé des différences au niveau du cytosquelette d’actine. En effet la surexpression de la protéine sauvage provoque un comportement anormal de l’actine au niveau des fibres de stress. Par ailleurs des études de d’apprentissage par association dans un modèle C. elegans KO ADD2 ont montré un défaut de mémorisation à long-terme. Mes travaux de thèse ont permis d'approfondir les connaissances quant à la contribution de chaque gène déjà connu dans les dystonies, ainsi que d'élargir l'hétérogénéité génétique caractéristique de cette pathologie par l'identification d'un nouveau gène candidat. / Dystonia is a movement control disorder characterized by involuntary muscle contractions. The genetic causes of this disease are multiple. I have created databases " loci-specific " collecting all allelic diversity available in the literature for 16 dystonia genes. The goal of this work is to to assist in the diagnosis of this disease and in the longer term, when there are sufficient data, to establish genotype-phenotype correlations. This was the case for the THAP1 gene (responsible for DYT6 dystonia) for which we have described several correlations.I searched for the disease gene in several families using exome sequencing. I identified a pathogenic mutation in the predicted gene ANO3 (DYT23) carried by one family. Another family carries a mutation in a splice site of ATP1A3 (DYT12) resulting in the total retention of intron 17. In another family a candidate gene was identified: ADD2 gene, coding beta adducin. Several functional results were obtained. First, overexpression of wild type and mutated ADD2 enabled to view differences in the actin cytoskeleton. Indeed the overexpression of the wild type protein causes abnormal behavior of actin at the level of stress fibers and at the plasma membrane. Besides, learning by association studies in a Caenorhabditis elegans model KO for ADD2 gene have shown a long-term default memory compared to the wild type. This confirms the involvement of the protein in neuronal plasticity. My thesis work led to further knowledge about the contribution of each gene already known in dystonia , as well as broaden the genetic heterogeneity characteristic of this disease by identifying a new candidate gene.