Introdução: A fibromialgia é uma síndrome complexa que envolve componentes sensorial-discriminativo, afetivo-motivacional, cognitivo-avaliativo e social. O modelo fisiopatológico mais aceito atualmente engloba mecanismos centrais de modulação e amplificação da dor juntamente com a sensibilização periférica. Além da dor, déficits de memória e atenção são encontrados em cerca de 50-80% destes pacientes, os quais podem aumentar a vulnerabilidade a novos sintomas e prejudicar o enfrentamento da doença. Terapias atuais buscam contra- regular esse processo mal adaptativo, entretanto com relativo sucesso terapêutico. Diante disso, são necessárias novas possibilidades terapêuticas para tratar esses déficits cognitivos, bem como para um melhor entendimento da fisiopatologia. O desenvolvimento deste estudo originou dois artigos, os quais constituem esta tese. Estudo I Objetivos: Avaliar as mudanças neurofisiológicas intra e entre grupos induzidas pela estimulação transcraniana de corrente continua (ETCC) combinada a um treino da memória de trabalho nos sinais eletrofisiológicos das pacientes com fibromialgia. Métodos: Foi realizado um estudo piloto com 14 pacientes com idade ente 18 e 65 anos com diagnóstico de FM de acordo com os critérios da colégio Americano de Reumatológia 2010, alocadas aleatoriamente em dois grupos de intervenção: ETCC-ativa combinada com treino de memória de trabalho (MT) (n=5;2 participantes excluídas por dados inconsistentes) e ETCC-sham combinada com treino de MT (n=7). A intervenção consistiu em oito sessões de ETCC-ativa aplicadas sobre o córtex pré-frontal dorsolateral esquerdo (CPFDLE), na intensidade de 2mA durante 20 min. Avaliou-se pré e pós-intervenção o sinal eletrofisiológico através do eletroencefalograma (EEG), percepção do nível da dor, pensamento catastrófico sobre a dor, sintomas de ansiedade e de depressão. Resultados: Observou-se uma mudança estatisticamente significativa na área sob a curva (AUC) da amplitude da onda do P300, um componente de potencial relacionado aevento (ERP), na condição ETCC-sham + treino de MT comparada à linha de base, no canal Pz (p=0.016). Esta diferença não foi observada para o grupo ETCC-ativa + treino de MT. No entanto, houve reduções significativas nos níveis de dor, ansiedade, depressão e catastrofismo após o tratamento com ETCC-ativa. Além disso, os níveis de dor após o tratamento correlacionaram-se inversamente com a AUC da onda do P300, independente do grupo de tratamento, o que indica que quanto maior este sinal eletrofisiológico menor o nível de dor. Conclusões: Estes resultados indicam que o tratamento ativo pode contra-regular a hiperexcitabilidade das redes neurais envolvidas no processamento da dor em pacientes com FM e reduzir a dor e outros sintomas clínicos correlatos Estudo II Objetivos: Foi avaliado se a combinação da ETCC-ativa combinada a um treino de memória de trabalho poderiam produzir um efeito de maior magnitude comparada a ETCC-sham combinada a um treino de memória de trabalho no desempenho da memória episódica, de curto e longo prazo. Métodos: Neste ensaio clínico randomizado participaram 40 pacientes com idade ente 18 e 65 anos com diagnóstico de FM de acordo com os critério do Colégio Americano de Reumatologia 2010, dividas randomicamente em dois grupos: ETCC-ativo combinada a um treino de memória (n=19;1participante foi excluída porque quebrou a perna ) e ou ETCC-sham combinada a um treino de memória de trabalho (n=20). A ETCC consistiu em oito sessões de estimulação aplicadas sobre o córtex pré-frontal dorsolateral esquerdo (DLPFC), na intensidade de 2mA durante 20 min. Avaliou-se pré e pós o desempenho da memória episódica imediata e tardia, fluência verbal, memória de trabalho e o nível do fator neurotrófico derivado do cérebro (BDNF). Resultados: Observou-se que a ETCC-ativa combinada a um treino de memória de trabalho melhorou de forma significativa (p=0,02) o desempenho da memória de curto prazo no teste de Rey A1-A5(desfecho primário), considerando a média (17,30) e desvio padrão (15,01) do delta (Δ), quando comparado ao grupo sham Assim como, melhorou de forma significativa o desempenho no teste de fluência verbal ortográfica (p=0,02) e semântica (p=0,03), considerando as médias (23,46 e 14,08) e desvio dos Δ (27,94 e 23,78) respectivamente. Esses dados significativos foram encontrados quando controlado pelo índice ajustado do BDNF e anos de estudo. O efeito do tratamento ativo sobre a memória de curto prazo foi dependente dos níveis de fator neurotrófico do cérebro basal para o teste de Rey A1-A5, no entanto, os níveis séricos desta neurotrofina não se correlacionaram com o desempenho nos testes de fluência verbal. Conclusões estudo: Este estudo mostrou que o efeito da ETCC-ativa combinada a um treino de memória de trabalho melhorou a função de redes envolvidas na memória de curto prazo e fluência verbal. Também sugerem que o efeito da ETCC-ativa combinada a um treino de memória de trabalho, nos testes de memória de curto prazo, são dependentes das condições de plasticidade do sistema na linha de base. / ABSTRACT Introduction: Fibromyalgia is a complex syndrome that involves sensory-discriminative, affective-motivational, cognitive-evaluative, and social components. The most accepted pathophysiological model currently focuses on central mechanisms of modulation and amplification of pain together with peripheral sensitization. In addition to pain, memory and attention deficits are found in about 50-80% of these patients, which can increase vulnerability and impair the search for resources to cope with the disease. The current therapies of fibromyalgia seek against regular this maladaptive process, however with relative therapeutic success. Due to this, new therapeutic possibilities are necessary to treat these cognitive deficits as well as the better understanding of the pathophysiology. The development of this study originated two articles which constitute this thesis. Study I Objectives: We evaluated intra and intergroup neurophysiological changes induced by transcranial direct-current stimulation (tDCS) combined with work memory training in the electrophysiological signs of patients with fibromyalgia. Methods: A pilot study was conducted with 14 patients aged 18 and 65 years with FM diagnosis according to the criteria of the American College of Rheumatology 2010, divided randomly into two groups: tDCS-active combined with a work memory training(WM) (n = 5; 2 participants excluded for inconsistent data) and tDCS-sham combined with a WM training (n = 7). The tDCS consisted of eight stimulation sessions applied on the left dorsolateral prefrontal cortex (DLPFC), at 2mA intensity for 20 min. The electrophysiological signal through electroencephalogram (EEG), perception of pain level, catastrophic thinking about pain, anxiety and depression symptoms were evaluated before and after intervention. Results: A statistically significant change was observed in the area under the curve (AUC) of the P300 wave amplitude as a measure of the event-related potential (ERP) in the sham -tDCS combined with a work-memory training compared to the baseline, in the Pz channel (p = 0.016), however, this difference in effect was not observed for active-tDCS combined with work-memory training. However, there were significant reductions in levels of pain, anxiety, depression and catastrophism after treatment with active-tDCS. In addition, pain levels after treatment correlated inversely with P300 wave AUC, regardless of treatment group, indicating that the higher this electrophysiological signal the lower the level of pain. Conclusions: These results indicate that active treatment may counter-regulate the hyperexcitability of neural networks involved in pain management in patients with FM and reduce pain and other related clinical symptoms. Study II Objectives: We assessed whether the combination of active -tDCS combined with a working memory training could produce a comparative magnitude greater effect sham- tDCS combined with a working memory training in the performance in episodic memory performance, short and long term. Methods: In this randomized clinical trial, 40 patients aged 18 to 65 years with FM diagnosis according to the criteria of the American College of Rheumatology 2010 were randomly divided into two groups: Active-tDCS combined with a memory training (n = 19; 1 participant was excluded because broke their leg) and or sham-tDCS combined with a working memory training (n = 20). The tDCS consisted of eight stimulation sessions applied on the left dorsolateral prefrontal cortex (DLPFC), at 2 mA intensity for 20 min. Episodic memory performance, verbal fluency, working memory and the level of brain-derived neurotrophic factor (BDNF) were evaluated before and after treatment. Results: It was observed that the Active-tDCS combined with a working memory training improved significantly (p = 0.02) the performance of the short term memory test in the delta (Δ) Rey A1-A5 (primary outcome), considering the mean (17.30) and standard deviation (15.01) compared to the sham group. As well as, it significantly improved performance in the Δ orthographic fluency test (p = 0.02) and semantics (p = 0.03), considering the means (23.46 and 14.08) and standard deviation (27. 94 and 23.78) respectively. These significant data were found when controlled by the adjusted BDNF index and years of study. The effect of active treatment on short-term memory was dependent on basal levels BDNF for the Rey A1-A5 test, however, serum levels of this neurotrophin did not correlate with performance on verbal fluency tests. Conclusions: This study showed that the effect of active- tDCS combined with a working memory training improved the function of networks involved in short-term memory and verbal fluency. They also suggest that the effect of active- tDCS combined with a working memory training in short-term memory tests are dependent on baseline system plasticity conditions.

Identifying targets in cluttered scenes is critical for our interactions in complex environments. Our visual system is challenged to both detect elusive targets that we may want to avoid or chase and discriminate between targets that are highly similar. These tasks require our visual system to become an expert at detecting distinctive features that help us differentiate between indistinguishable targets. As the human brain is trained on this type of visual tasks, we observe changes in its function that correspond to improved performance. We use functional brain imaging, to measure learning-dependent modulations of brain activation and investigate the processes that mediate functional brain plasticity. I propose that dissociable brain mechanisms are engaged when detecting targets in clutter vs. discriminating between highly similar targets: for the former, background clutter needs to be suppressed for the target to be recognised, whereas for the latter, neurons are tuned to respond to fine differences. Although GABAergic inhibition is known to suppress redundant neuronal populations and tune neuronal representations, its role in visual learning remains largely unexplored. Here, I propose that GABAergic inhibition plays an important role in visual plasticity through training on these tasks. The purpose of my PhD is to investigate the inhibitory mechanisms that mediate visual perceptual learning; in particular, learning to detect patterns in visual clutter and discriminate between highly similar patterns. I show that BOLD signals as measured by functional Magnetic Resonance Imaging (fMRI) do not differentiate between the two proposed mechanisms. In contrast, Magnetic Resonance Spectroscopy (MRS) provides strong evidence for the distinct involvement of GABAergic inhibition in visual plasticity. Further, my findings show GABA changes during the time-course of learning providing evidence for a distinct role of GABA in learning-dependent plasticity across different brain regions involved in visual learning. Finally, I test the causal link between inhibitory contributions and visual plasticity using a brain stimulation intervention that perturbs the excitation-inhibition balance in the visual cortex and facilitates learning.

Spreading depression (SD) is a slow propagating wave of depolarization that can spread throughout the cortex in the event of brain injury or any general energy failure of the brain. Massive cellular depolarization causes enormous ionic and water shifts and silences synaptic transmission in the affected tissue. Large amounts of energy are required to restore ionic gradients and are not always met. When these energetic demands are not met, brain tissue damage can occur. The exact mechanism behind initiation and propagation of SD are unknown, but a general model is known. It may be possible to prevent or delay the onset of SD using non-invasive electromagnetic techniques. Transcranial magnetic stimulation (TMS), electrical stimulation (ES), and transcranial direct coupled stimulation (tDCS) could be used to decrease neuronal excitability in different ways. In theory, any technique that can reduce cortical excitability could suppress SD initiating or propagating.

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A estimulação transcraniana com corrente contínua (ETCC) vem sendo utilizada na reabilitação de diversas patologias que envolvem a disfunção do sistema sensitiva. Apesar disso, a opção para tratamento de parestesias do ramo mandibular nunca foi empregada. Este estudo piloto teve como objetivo avaliar os efeitos da ETCC em pacientes com queixa de parestesia em ramos do nervo mandibular. Seis pacientes com parestesia referida na topografia do ramo alveolar inferior (uni ou bilateral), com sintomas iniciados após cirurgia bucomaxilofacial, receberam 10 sessões de ETCC (2 mA, 20 min). A avaliação sensitiva composta pelo teste de sensibilidade tátil com o estesiômetro Semmes-Weinstein e pelo teste térmico com solução spray -50° C foi realizada previamente ao tratamento e após a quinta e a décima estimulação, em 24 pontos na topografia de inervação do ramo em estudo. Houve melhora significativa na sensibilidade no teste tátil nas regiões hipoestésicas, com a terceira avaliação significativamente diferente da primeira (p-valor= 0,0015), mas não diferente da segunda (p-valor=0,1932). No teste térmico os participantes reconheceram mais pontos gelados com o passar das avaliações (p-valor=0,05). A aplicação de ETCC pareceu melhorar a sensibilidade tátil e térmica, assim como alívio das parestesias decorrentes de cirurgia bucomaxilofacial. / Transcranial direct current stimulation (tDCS) has been used in the rehabilitation of various diseases that involve dysfunction of the sensory system. However, the option for treating the mandibular branch paresthesia has not been already employed. This pilot study aimed to evaluate the effects of tDCS in patients with paresthesia in branches of the mandibular nerve. Six patients had paresthesia of inferior alveolar nerve (unilateral or bilateral) and symptoms that began after maxillofacial surgery. They received 10 sessions of tDCS (2 mA, 20 min). The sensory evaluation was conducted prior to the treatment, after the fifth and after the tenth application in 24 points in the branch innervation of topography study. The evaluation was composed by tactile sensitivity test with the Semmes-Weinstein esthesiometer and thermal test with spray solution -50 ° C. There was significant improvement in the sensitivity during the tactile test in hypoesthesia regions, with the third evaluation significantly different from the first (p-value = 0.0015), but not different from the second evaluation (p-value = 0.1932). In the thermal test, the participants recognized a larger number of cold areas in the course of ratings (p-value = 0.05). The use of tDCS seemed to improve the tactile and thermal sensitivity of paresthesia, as well as the relief of paresthesias caused by oral and maxillofacial surgery.

Introdução: Fibromialgia (FM) é uma síndrome que acomete entre 1-6% da população, com maior frequência em mulheres. Costuma cursar com dor crônica, alterações de sono, sintomas depressivos e prejuízo de memória. Seu impacto na vida das pacientes está relacionado às limitações para atividades da vida diária, incluindo as funções executivas. A disfunção das redes neurais envolvidas no sistema de excitabilidade e de inibição tem repercussões cognitivas que comprometem a atenção e o desempenho de atividades laborais. A dor é o sintoma que governa esta síndrome e é capaz de afetar a capacidade atencional de pacientes com FM e prejudicar realizações cotidianas. No entanto, pouco se conhece sobre as vias e os processos envolvidos nesse conjunto de sintomas. Faz-se necessário, portanto, compreender esses processos e buscar estratégias terapêuticas com efeito nesses mecanismos. Dentre os tratamentos, pode-se citar a estimulação transcraniana de corrente continua (ETCC), intervenção com feito modulador da atividade neuronal, cujo potencial beneficio tem sido demonstrado na FM. A integração do efeito excitatório da ETCC ao efeito inibitório das tarefas neurocogntivas em áreas envolvidas no processamento afetivo-motivacional, incluindo a dor crônica, não foi profundamente explorada. O objetivo do presente estudo foi comparar o efeito da ETCC-ativa (a) com ETCC-sham (s) combinada a tarefa neurocognitva inibitória (Go- noGo Task) na dor e capacidade atencional de pacientes com FM. Métodos: Foram selecionadas pacientes com diagnóstico de FM de acordo com o American College of Rheumatology (ACR) 2010. A amostra foi composta por 40 pacientes, subdivididas em dois grupos- ETCC-a ou ETCC-s- num ensaio clínico do tipo cruzado, duas sessões com intervalo de sete dias entre uma intervenção e outra. A estimulação ETCC foi anódica pré-frontal dorsolateral (DLPFC) de 1 mA por 20 minutos. As intervenções utilizadas foram Go- noGo Task (GNG), Attention Network Task (ANT) e ETCC. Resultados: Houve significativa diferença entre os grupos ETCC-a e ETCC-s nos resultados de ANT. ETCC-a combinada a tarefa GNG foi capaz de potencializar a rede de atenção executiva e amenizar a sensação de dor. Em ANT os dados relacionados à orientação foram -14,63 de diferença média, com 95% intervalo de confiança (IC) (de -18,89 a -0,37). Quanto à execução, foi verificada média de 21.00 com 95% de IC (4.11 a 37.89). Em relação ao alerta não houve diferença, apresentando a média de -3,17; com 95% de IC (-3,17 a 4,88). Pacientes com maior nível de catastrofização e dor apresentaram diminuição da atenção executiva em comparação com os demais pacientes do estudo. Conclusão: Os efeitos sobre a rede neuronal induzida por uma tarefa inibitória combinada com ETCC-a apresentou maior desempenho na execução atencional e redução da dor. / Introduction: Fibromyalgia (FM) is a syndrome that affects 1-6% of the population, mostly women. It usually courses with chronic pain, sleep disturbance, symptoms of depression and memory loss. Its impact on the female patients’ life is related to the limitations in everyday activities, including executive functions. The dysfunction of the neural networks involved in the excitability and inhibition systems has cognitive repercussions that compromise attention and the performance of work-related activities. Pain is the symptom that rules this syndrome and can affect the attentional capacity of patients with FM and impair daily achievements. However, little is known about the pathways and the processes involved in this set of symptoms. It is, therefore, necessary to understand these processes and look for therapeutic strategies that have an effect on these mechanisms. Among these treatments we can mention Transcranial direct current stimulation (tDCS) an intervention with a modulating effect of neuronal activity, whose potential benefit has been demonstrated in FM. The integration of the excitatory effect of tDCS on the inhibitory effect of neurocognitive tasks in areas involved in the affective-motivational processing, including chronic pain, has not been profoundly explored. The purpose of the present study was to compare the effect of active tDCS(a) with sham tDCS(s) combining the inhibitory neurocognitive task (Go- noGo Task) in pain and in the attentional capacity of patients with FM. Methods: Patients with a diagnosis of FM according to the American College of Rheumatology (ACR) 2010 were selected. The sample was composed by 40 patients, subdivided into two groups - tDCS-a or tDCS-s - in a clinical assay of the cross-matched type, two sessions with a seven-day interval between one intervention and another. The tDCS stimulation was anodyne (DLPFC) of 1mA for 20 minutes. The interventions used were Go- noGo Task (GNG), Attention Network Task (ANT) and tDCS. Results: There was a significant difference betweeen the tDCS-a and tDCS-s groups in the ANT results. tDCS-a combined with the GNG task was able to potentiate the network of executive attention and attenuate the feeling of pain. In ANT the data related to orientation were -14.63 of mean difference, with a 95% confidence interval (CI) (from -18.89 to -0.37). As to execution, a mean of 21.00 was found with 95% CI (4.11 to 37.89). As to the alert, there was no difference, and the mean was -3.17; with 95% CI (-3.17 to 4.88). Patients with a higher level of catastrophization and pain presented reduced executive attention compared to the other patients in the study. Conclusion: The effects on the neuronal network induced by an inhibtory task combined with tDCS-a presented a greater performance in attentional execution and pain reduction.

The primary aim of this thesis is to investigate the physiological effects of transcranial direct current stimulation (tDCS) as applied to the primary motor cortex (M1). This research was largely motivated by the need to understand the basic physiological changes of tDCS, in order to evaluate its use as a potential tool in recovery after stroke, as well as its more general applicability as a tool to modulate plasticity. The experiments in this thesis assess the ability of tDCS to modulate the primary motor cortex in healthy controls. The effects of tDCS on cortical GABA and motor resting state functional connectivity were measured with magnetic resonance spectroscopy (MRS) and resting functional MRI (fMRI). Anodal stimulation reduced GABA concentration and increased functional connectivity in the stimulated M1. Testing these changes within the same individuals demonstrated that the magnitude of changes do not correlate across subjects. Novel evidence on the timecourse of GABA change demonstrated that the reduction in GABA is most prominent in the 30-minute period after stimulation. To determine whether the tDCS-induced modulations in inhibition is restricted to the stimulated hemisphere or whether inhibitory changes could be observed in the nonstimulated M1, or in the interhemispheric connections between the M1s, transcranial magnetic stimulation (TMS) was used to measure intracortical inhibition in each M1 and interhemispheric inhibition and facilitation in the contralateral M1. There were no polarity-specifc effects on intracortical inhibition within either M1, and no changes in interhemispheric excitability from the stimulated to non-stimulated M1. Development of a two-voxel MRS method at ultra high field (7 Tesla) allowed for concurrent measurements of cortical neurotransmitters from both M1s with excellent spectral quality and GABA quantifcation. This method was used to demonstrate the timecourse of tDCS-induced changes in neurochemicals concurrently from both M1s. Anodal stimulation reduced GABA in both the anode-targeted and non-stimulated M1. Cathodal stimulation decreased GABA and glutamate in the non-stimulated M1, with no concurrent changes in the cathode-targeted M1. Bilateral stimulation reduced glutamate in both M1 with no change in GABA.