Résumé : Introduction: La douleur chronique et les problèmes de sommeil ont un impact significatif sur la qualité de vie. La prévalence de ces deux conditions augmente substantiellement avec l’âge. L’objectif de cette étude était d’évaluer la faisabilité d’une étude randomisée, contrôlée par placebo et de recueillir des données sur l’efficacité de la stimulation transcrânienne par courant direct (tDCS) pour réduire la douleur et améliorer le sommeil chez des aînés souffrant de douleur chronique d’origines musculo-squelettique. Méthodes: Quatorze patients souffrant de douleur chronique et de problèmes de sommeil ont reçu cinq séances quotidiennes consécutives de tDCS anodique appliquée au cortex moteur primaire (2 mA, 20 minutes) ou cinq séances de tDCS simulée de manière randomisée. L’intensité de la douleur était mesurée avec une échelle visuelle analogue et les paramètres de sommeil avec l’actigraphie. Pendant toute la durée de l’étude, des journaux de bord de douleur et de sommeil étaient aussi utilisés afin de mesurer l'effet de la tDCS sur la douleur et le sommeil du quotidien des participants. Résultats: Les résultats indiquent que la tDCS réelle engendre une analgésie de 59 %, alors que la tDCS simulée ne réduit pas la douleur (p < 0,05). Par contre, aucun changement n’a été observé au niveau des paramètres de sommeil (tous les p ≥ 0,18). Conclusion: Il appert que cinq séances de tDCS anodique appliquée au niveau du cortex moteur primaire seraient efficaces pour réduire la douleur des aînés souffrant de douleur chronique, mais pas pour améliorer leur sommeil. De futures études seront nécessaires afin de déterminer si d’autres paramètres de stimulation pourraient avoir un impact sur le sommeil et si ces résultats peuvent être reproduits en utilisant un plus grand nombre de patients. / Abstract : Introduction: Chronic pain and sleep problems have a significant impact on quality of life. The prevalence of these two conditions increases substantially with age. The objective of this study was to assess the feasibility of conducting a randomized sham-controlled trial and to collect preliminary data on the efficacy of transcranial direct current stimulation (tDCS) for reducing pain and improving sleep in older adults suffering from chronic musculoskeletal pain. Methods: Fourteen patients with chronic pain and sleep problems were randomized to receive five consecutive daily sessions of anodal tDCS applied to the primary motor cortex (2 mA, 20 minutes) or five sessions of sham tDCS. Pain intensity was measured with a visual analogue scale, and sleep parameters with actigraphy. Throughout the study, pain and sleep logbook were also used to measure the effect of tDCS on daily pain and sleep. Results: Our results indicate that the real tDCS causes greater pain relief than sham tDCS (59 % vs -19 %; p <0.05). By cons, no change was observed in sleep parameters (all p ≥ 0.18). Conclusion: Five sessions of anodal tDCS applied to the motor cortex seem to be effective to reduce pain in elderly individuals suffering of chronic pain, but not to improve their sleep. Future studies are needed to determine whether other stimulation parameters could have an impact on sleep and whether these results can be replicated using a larger number of patients.

Introdução: O hálux valgo é uma importante causa de dor e desconforto e acomete 28% dos adultos e 37% dos idosos, com predominância na população feminina. Para atingir a cura desta deformidade, faz-se necessário o tratamento cirúrgico, cuja principal razão é o tratamento da incapacidade relacionada à dor (IRD). No entanto, um ano após a cirurgia de hálux valgo, dor crônica moderada a grave persiste em 21% em repouso e 43% durante a caminhada. Esta resposta anormal faz parte dos sintomas que constitui a síndrome de sensibilização central (SSC), a qual é decorrente de um processo de neuroplasticidade mal adaptativa. Pacientes sensibilizados, não só têm uma maior propensão a desenvolver dor persistente pós-operatória como também experenciam uma dor pós-operatória mais intensa em comparação com pacientes não sensibilizados, devido à amplificação da resposta a estímulos nociceptivos e disfunção dos sistemas inibitórios. Relacionadas ao processo de alterações neuroplásticas, encontramos proteínas tais como o fator neurotrófico derivado do cérebro (BDNF). Esta neurotrofina participa do processo de LTP, mecanismo de neuroplasticidade que sustenta o processo de memória dolorosa. O aumento de BDNF incrementa a LTP, enquanto que a redução de seus níveis atenua este fenômeno. Portanto, a relação de níveis de BDNF com a severidade da doença pode confirmar a influência sistêmica desse biomarcador em estados de dor sustentada. A fim de alterar a neuroplasticidade mal adaptativa induzida pela dor a longo prazo, a estimulação transcraniana por corrente contínua (ETCC), uma técnica não invasiva, que visa à modulação do sistema nervoso central para controle da dor, pode se tornar uma opção terapêutica. No entanto, ainda não foi explorado o efeito da ETCC aplicada no período pré-operatório com intuito de melhorar o controle da dor pós-operatória de pacientes sensibilizadas e melhorar a reabilitação pós-operatória dessas pacientes. Neste estudo optou-se pelo uso da ETCC pelo seu potencial de contra regular as alterações ETCC pré-operatória comparada ao ETCC-sham no controle da dor e reabilitação em pacientes com artralgia da 1ªAMF submetidas a tratamento cirúrgico de hálux valgo. Método: Ensaio clínico, randomizado, duplo-cego, em paralelo, controlado com sham que incluiu 40 pacientes do sexo feminino, entre 18 e 70 anos, candidatas a tratamento cirúrgico de hálux valgo sob técnica combinada de Chevron e Akin por artralgia da 1ªAMF. As pacientes foram randomizadas e divididas em dois grupos que receberam duas sessões de 20 minutos de ETCC-ativa(a) ou ETCC-sham(s) no período pré-operatório. A estimulação foi feita por corrente contínua de 2mA através do eletrodo anodal sobre o córtex motor primário (M1) e o catodal sobre a área supraorbital contralateral. Os desfechos avaliados foram: escores de dor na EAV(0-10), consumo analgésico, IRD avaliada pela B-PCP:S, função do sistema modulador descendente da dor, avaliada pelo teste CPM e os níveis séricos e liquóricos de BDNF. Resultados: O grupo ETCC-a apresentou escores mais baixos na escala Análogo Visual de Dor [EAV(0-10)] em repouso e durante a caminhada (P <0,001). Em repouso, a diferença entre os dois grupos foi de 2,13cm (95% IC = 1,59 a 2,68), enquanto durante a caminhada foi de 1,67cm (IC 95% = 1,05 a 2,28). O grupo ETCC-a, quando comparado ao grupo ETCC-s mostrou menor necessidade de doses analgésicas diárias com média de 1,37 (0,63) contra 1,81 (0,64) doses respectivamente (P <0,001). A ETCC ativa também obteve maior melhora da IRD que a ETCC sham, conforme demostrado pela maior redução na Brazilian Profile of Chronic Pain: Screen (B-PCP:S) (diferença média de 9,41 pontos, IC95% = 0,63 a 18,21) e ainda, aumentou a função do sistema modulador descendente da dor durante o teste da modulação condicionada de dor (CPM) com um tamanho de efeito médio. O aumento da função desse sistema representa a reversão das alterações neuroplásticas mal adaptativas promovidas pela dor crônica. Conclusão: Duas sessões de ETCC anódica aplicadas sobre M1 no pré-operatório melhorou a dor pós-operatória, como demonstrado pela redução dos escores de dor, consumo de analgésicos e IRD. Além disso, sugere-se que os efeitos da ETCC pré-operatória nestes desfechos envolvem a melhora da função dos sistemas moduladores descendentes da dor e mecanismos de neuroplasticidade conforme mensurados pelo BDNF. / Introduction: Hallux valgus, is an important cause of feet pain and discomfort and affects 28% of adults and 37% of elderly, predominantly in female population. To achieve the deformity heal, surgical treatment is needed, which main goal is to treat incapacity related to pain (IRP). However, one year after hallux valgus surgical treatment, moderate to severe chronic pain persists in 21% during rest and 43% during walking. This abnormal response is part of the symptoms that constitute central sensitization syndrome (CSS), which is due to a maladaptive neuroplasticity process. Sensitized patients, not only are more likely to develop postoperative persistent pain, but also experience more intense postoperative pain comparing to non-sensitized patients, due to the amplification of nociceptive inputs and inhibitory systems disfunction. Related to neuroplasticy process, proteins such as brain neurotrophic factor (BDNF) are found. This neurotrophin participates in the LTP process, a mechanism of neuroplasticity that sustains the process of pain memory. The increase of BDNF increases the LTP, while the reduction of its levels attenuates this phenomenon. Therefore, the relationship of BDNF levels with disease severity may confirm the systemic influence of this biomarker on sustained pain states. In order to alter long-term pain-induced maladaptive neuroplasticity, transcranial direct current stimulation (tDCS), a non-invasive technique, which aims for the central nervous system modulation for pain control, may become a therapeutic option for postoperative pain. However, the effect of tDCS applied in the preoperative period has not been explored yet with the intent of improving the postoperative pain control in sensitized patients, neither in postoperative rehabilitation. In this study, it was chosen to use tDCS due to its potential to counter-regulate the maladaptive neuroplastic alterations associated to chronic pain. Objective: to evaluate the effect of preoperative tDCS compared to tDCS-sham in the pain control and in the rehabilitation of patients with arthralgia of the first metatarsalfalangeal articulation submitted to hallux valgus surgical correction. Method: it is a randomized, double-blinded, placebo-sham controlled clinical trial, which includes 40 female patients, between 18 and 70 years old, candidates to hallux valgus surgical treatment by combined Chevron + Akin osteotomy due to arthralgia of the first metatarsalfalangeal articulation. The patients were randomized and divided into two groups that were treated with two tDCS or tDCS-sham sessions of 20 minutes each in preoperative period. The stimulation was done by 2mA continuous current through the anodal electrode on the primary motor cortex (M1) and the catodal on the contralateral supraorbital area. The outcomes were: VAS(0-10) scores, analgesic consumption, DRP assessed by the B-PCP: S, the function of the descending pain modulator system, assessed by the CPM test and the serum and CSF levels of BDNF. Results: a-tDCS group showed lower scores on Visual Analogue Scale [VAS(0-10)] at rest and during walking (P<0.001). At rest, the difference between both groups was 2.13cm (95%CI=1.59 to 2.68) while during walking was 1.67cm (95%CI=1.05 to 2.28). The a-tDCS group, when compared to s-tDCS, showed reduced need of daily analgesic intake from 1.37 (0.63) to 1.81 (0.64) mean doses, respectively (P<0.001). Active tDCS improved the DRP, as demonstrated by a greater reduction in the Brazilian Profile of Chronic Pain: Screen (B-PCP:S) (mean difference of 9.41 points, 95%CI=0.63 to 18.21) and also increased the function of descending pain modulatory system (DPMS) during conditioned pain modulation (CPM-task), with a medium size effect. The increased function of this system represents the reversal of maladaptive neuroplastic changes promoted by chronic pain. Conclusion: Two preoperative anodic tDCS sessions applied over M1 improved postoperative pain, as demonstrated by reduction in the pain scores, analgesic consumption and DRP. In addition, these results suggest that the effects of preoperative tDCS on these outcomes involved improving the function of pain modulation systems and neuroplasticity mechanisms as measured by BDNF.

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.

The reticular-activating hypofrontality model of acute exercise (RAH) predicts exercise-induced hypoactivity in frontal cortex which mediates executive function. Connors Continuous Performance Test (CCPT) was used to investigate changes in executive function during- and post treadmill running in healthy volunteers (n=30, 15 male). In a randomized order, subjects performed the CCPT at rest, during low- (LI; 63% maximal heart rate; MHR) and moderate intensity (MI; 75% MHR). Separately, subjects then performed isocalorifically matched exercise bouts of LI, MI and high intensity interval training (HIT) consisting of 4x4 min with 90% MHR and 3 min recovery at 60-70% MHR. Repeated measures ANOVAs revealed main effects of exercise intensity for reaction time RT during- (p≤0.001) and post exercise (p≤0.0001). Subsequent analyses showed an overall increase of RT during exercise compared to rest (p≤0.005). RT decreased significantly from rest to post exercise levels in an exercise intensity dependent, linear fashion (p≤0.0001). Commission errors showed a non significant linear trend to increase both during (p=0.057), and post exercise (p=0.052) as a function of intensity. In a follow up study, we sought to relate observed exercise effects to frontal cortex activity through the use of transcranial direct current stimulation (tDCS) (n=4) and transcranial magnetic stimulation (TMS) over the dorsolateral prefrontal cortex (DLPFC). Prior to TMS stimulation cortical excitability was estimated post running through motor-evoked potentials (MEP) elicited from the primary motor cortex (M1) induced by single burst TMS and measured in the first dorsal interosseous (FDI) muscle using electromyography. At rest, inhibitory cathodal tDCS with left DLPFC cathode and right supraorbital anode led to improved reaction time and increased amount of commission errors, whereas anodal stimulatory tDCS in the immediate post exercise period was unable to recover the post exercise effect. Continuous theta burst stimulation over the left DLPFC post running further impaired inhibitory control and facilitated reaction time. Different findings during- and after- exercise suggests that potential contributing mechanisms such as computational and metabolic factors may be differentially active during these respective conditions. Furthermore, the fact that an inhibitory TMS protocol pronounced the post running effects even more and that we were able to mimic the reported RAH effects at rest with inhibitory frontal tDCS, but observed different patterns during exercise, suggests that the latter state cannot be fully explained by reducing activity in the left frontal cortex alone. Failure to modify the after exercise effect with stimulatory tDCS also supports an interplay of different factors and might emphasize the strong, robust effects of exercise that cannot simply be attenuated by current application. Increases in MEP post running for 35min paired with the observed performance decrements imply an excited state of M1 and might serve as an explanatory cross-link to central fatigue suggesting that a hypofrontal state might enhance the motor cortical drive to activate muscles.

Introdução: O hálux valgo é uma importante causa de dor e desconforto e acomete 28% dos adultos e 37% dos idosos, com predominância na população feminina. Para atingir a cura desta deformidade, faz-se necessário o tratamento cirúrgico, cuja principal razão é o tratamento da incapacidade relacionada à dor (IRD). No entanto, um ano após a cirurgia de hálux valgo, dor crônica moderada a grave persiste em 21% em repouso e 43% durante a caminhada. Esta resposta anormal faz parte dos sintomas que constitui a síndrome de sensibilização central (SSC), a qual é decorrente de um processo de neuroplasticidade mal adaptativa. Pacientes sensibilizados, não só têm uma maior propensão a desenvolver dor persistente pós-operatória como também experenciam uma dor pós-operatória mais intensa em comparação com pacientes não sensibilizados, devido à amplificação da resposta a estímulos nociceptivos e disfunção dos sistemas inibitórios. Relacionadas ao processo de alterações neuroplásticas, encontramos proteínas tais como o fator neurotrófico derivado do cérebro (BDNF). Esta neurotrofina participa do processo de LTP, mecanismo de neuroplasticidade que sustenta o processo de memória dolorosa. O aumento de BDNF incrementa a LTP, enquanto que a redução de seus níveis atenua este fenômeno. Portanto, a relação de níveis de BDNF com a severidade da doença pode confirmar a influência sistêmica desse biomarcador em estados de dor sustentada. A fim de alterar a neuroplasticidade mal adaptativa induzida pela dor a longo prazo, a estimulação transcraniana por corrente contínua (ETCC), uma técnica não invasiva, que visa à modulação do sistema nervoso central para controle da dor, pode se tornar uma opção terapêutica. No entanto, ainda não foi explorado o efeito da ETCC aplicada no período pré-operatório com intuito de melhorar o controle da dor pós-operatória de pacientes sensibilizadas e melhorar a reabilitação pós-operatória dessas pacientes. Neste estudo optou-se pelo uso da ETCC pelo seu potencial de contra regular as alterações ETCC pré-operatória comparada ao ETCC-sham no controle da dor e reabilitação em pacientes com artralgia da 1ªAMF submetidas a tratamento cirúrgico de hálux valgo. Método: Ensaio clínico, randomizado, duplo-cego, em paralelo, controlado com sham que incluiu 40 pacientes do sexo feminino, entre 18 e 70 anos, candidatas a tratamento cirúrgico de hálux valgo sob técnica combinada de Chevron e Akin por artralgia da 1ªAMF. As pacientes foram randomizadas e divididas em dois grupos que receberam duas sessões de 20 minutos de ETCC-ativa(a) ou ETCC-sham(s) no período pré-operatório. A estimulação foi feita por corrente contínua de 2mA através do eletrodo anodal sobre o córtex motor primário (M1) e o catodal sobre a área supraorbital contralateral. Os desfechos avaliados foram: escores de dor na EAV(0-10), consumo analgésico, IRD avaliada pela B-PCP:S, função do sistema modulador descendente da dor, avaliada pelo teste CPM e os níveis séricos e liquóricos de BDNF. Resultados: O grupo ETCC-a apresentou escores mais baixos na escala Análogo Visual de Dor [EAV(0-10)] em repouso e durante a caminhada (P <0,001). Em repouso, a diferença entre os dois grupos foi de 2,13cm (95% IC = 1,59 a 2,68), enquanto durante a caminhada foi de 1,67cm (IC 95% = 1,05 a 2,28). O grupo ETCC-a, quando comparado ao grupo ETCC-s mostrou menor necessidade de doses analgésicas diárias com média de 1,37 (0,63) contra 1,81 (0,64) doses respectivamente (P <0,001). A ETCC ativa também obteve maior melhora da IRD que a ETCC sham, conforme demostrado pela maior redução na Brazilian Profile of Chronic Pain: Screen (B-PCP:S) (diferença média de 9,41 pontos, IC95% = 0,63 a 18,21) e ainda, aumentou a função do sistema modulador descendente da dor durante o teste da modulação condicionada de dor (CPM) com um tamanho de efeito médio. O aumento da função desse sistema representa a reversão das alterações neuroplásticas mal adaptativas promovidas pela dor crônica. Conclusão: Duas sessões de ETCC anódica aplicadas sobre M1 no pré-operatório melhorou a dor pós-operatória, como demonstrado pela redução dos escores de dor, consumo de analgésicos e IRD. Além disso, sugere-se que os efeitos da ETCC pré-operatória nestes desfechos envolvem a melhora da função dos sistemas moduladores descendentes da dor e mecanismos de neuroplasticidade conforme mensurados pelo BDNF. / Introduction: Hallux valgus, is an important cause of feet pain and discomfort and affects 28% of adults and 37% of elderly, predominantly in female population. To achieve the deformity heal, surgical treatment is needed, which main goal is to treat incapacity related to pain (IRP). However, one year after hallux valgus surgical treatment, moderate to severe chronic pain persists in 21% during rest and 43% during walking. This abnormal response is part of the symptoms that constitute central sensitization syndrome (CSS), which is due to a maladaptive neuroplasticity process. Sensitized patients, not only are more likely to develop postoperative persistent pain, but also experience more intense postoperative pain comparing to non-sensitized patients, due to the amplification of nociceptive inputs and inhibitory systems disfunction. Related to neuroplasticy process, proteins such as brain neurotrophic factor (BDNF) are found. This neurotrophin participates in the LTP process, a mechanism of neuroplasticity that sustains the process of pain memory. The increase of BDNF increases the LTP, while the reduction of its levels attenuates this phenomenon. Therefore, the relationship of BDNF levels with disease severity may confirm the systemic influence of this biomarker on sustained pain states. In order to alter long-term pain-induced maladaptive neuroplasticity, transcranial direct current stimulation (tDCS), a non-invasive technique, which aims for the central nervous system modulation for pain control, may become a therapeutic option for postoperative pain. However, the effect of tDCS applied in the preoperative period has not been explored yet with the intent of improving the postoperative pain control in sensitized patients, neither in postoperative rehabilitation. In this study, it was chosen to use tDCS due to its potential to counter-regulate the maladaptive neuroplastic alterations associated to chronic pain. Objective: to evaluate the effect of preoperative tDCS compared to tDCS-sham in the pain control and in the rehabilitation of patients with arthralgia of the first metatarsalfalangeal articulation submitted to hallux valgus surgical correction. Method: it is a randomized, double-blinded, placebo-sham controlled clinical trial, which includes 40 female patients, between 18 and 70 years old, candidates to hallux valgus surgical treatment by combined Chevron + Akin osteotomy due to arthralgia of the first metatarsalfalangeal articulation. The patients were randomized and divided into two groups that were treated with two tDCS or tDCS-sham sessions of 20 minutes each in preoperative period. The stimulation was done by 2mA continuous current through the anodal electrode on the primary motor cortex (M1) and the catodal on the contralateral supraorbital area. The outcomes were: VAS(0-10) scores, analgesic consumption, DRP assessed by the B-PCP: S, the function of the descending pain modulator system, assessed by the CPM test and the serum and CSF levels of BDNF. Results: a-tDCS group showed lower scores on Visual Analogue Scale [VAS(0-10)] at rest and during walking (P<0.001). At rest, the difference between both groups was 2.13cm (95%CI=1.59 to 2.68) while during walking was 1.67cm (95%CI=1.05 to 2.28). The a-tDCS group, when compared to s-tDCS, showed reduced need of daily analgesic intake from 1.37 (0.63) to 1.81 (0.64) mean doses, respectively (P<0.001). Active tDCS improved the DRP, as demonstrated by a greater reduction in the Brazilian Profile of Chronic Pain: Screen (B-PCP:S) (mean difference of 9.41 points, 95%CI=0.63 to 18.21) and also increased the function of descending pain modulatory system (DPMS) during conditioned pain modulation (CPM-task), with a medium size effect. The increased function of this system represents the reversal of maladaptive neuroplastic changes promoted by chronic pain. Conclusion: Two preoperative anodic tDCS sessions applied over M1 improved postoperative pain, as demonstrated by reduction in the pain scores, analgesic consumption and DRP. In addition, these results suggest that the effects of preoperative tDCS on these outcomes involved improving the function of pain modulation systems and neuroplasticity mechanisms as measured by BDNF.

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.

Introdução: O hálux valgo é uma importante causa de dor e desconforto e acomete 28% dos adultos e 37% dos idosos, com predominância na população feminina. Para atingir a cura desta deformidade, faz-se necessário o tratamento cirúrgico, cuja principal razão é o tratamento da incapacidade relacionada à dor (IRD). No entanto, um ano após a cirurgia de hálux valgo, dor crônica moderada a grave persiste em 21% em repouso e 43% durante a caminhada. Esta resposta anormal faz parte dos sintomas que constitui a síndrome de sensibilização central (SSC), a qual é decorrente de um processo de neuroplasticidade mal adaptativa. Pacientes sensibilizados, não só têm uma maior propensão a desenvolver dor persistente pós-operatória como também experenciam uma dor pós-operatória mais intensa em comparação com pacientes não sensibilizados, devido à amplificação da resposta a estímulos nociceptivos e disfunção dos sistemas inibitórios. Relacionadas ao processo de alterações neuroplásticas, encontramos proteínas tais como o fator neurotrófico derivado do cérebro (BDNF). Esta neurotrofina participa do processo de LTP, mecanismo de neuroplasticidade que sustenta o processo de memória dolorosa. O aumento de BDNF incrementa a LTP, enquanto que a redução de seus níveis atenua este fenômeno. Portanto, a relação de níveis de BDNF com a severidade da doença pode confirmar a influência sistêmica desse biomarcador em estados de dor sustentada. A fim de alterar a neuroplasticidade mal adaptativa induzida pela dor a longo prazo, a estimulação transcraniana por corrente contínua (ETCC), uma técnica não invasiva, que visa à modulação do sistema nervoso central para controle da dor, pode se tornar uma opção terapêutica. No entanto, ainda não foi explorado o efeito da ETCC aplicada no período pré-operatório com intuito de melhorar o controle da dor pós-operatória de pacientes sensibilizadas e melhorar a reabilitação pós-operatória dessas pacientes. Neste estudo optou-se pelo uso da ETCC pelo seu potencial de contra regular as alterações ETCC pré-operatória comparada ao ETCC-sham no controle da dor e reabilitação em pacientes com artralgia da 1ªAMF submetidas a tratamento cirúrgico de hálux valgo. Método: Ensaio clínico, randomizado, duplo-cego, em paralelo, controlado com sham que incluiu 40 pacientes do sexo feminino, entre 18 e 70 anos, candidatas a tratamento cirúrgico de hálux valgo sob técnica combinada de Chevron e Akin por artralgia da 1ªAMF. As pacientes foram randomizadas e divididas em dois grupos que receberam duas sessões de 20 minutos de ETCC-ativa(a) ou ETCC-sham(s) no período pré-operatório. A estimulação foi feita por corrente contínua de 2mA através do eletrodo anodal sobre o córtex motor primário (M1) e o catodal sobre a área supraorbital contralateral. Os desfechos avaliados foram: escores de dor na EAV(0-10), consumo analgésico, IRD avaliada pela B-PCP:S, função do sistema modulador descendente da dor, avaliada pelo teste CPM e os níveis séricos e liquóricos de BDNF. Resultados: O grupo ETCC-a apresentou escores mais baixos na escala Análogo Visual de Dor [EAV(0-10)] em repouso e durante a caminhada (P <0,001). Em repouso, a diferença entre os dois grupos foi de 2,13cm (95% IC = 1,59 a 2,68), enquanto durante a caminhada foi de 1,67cm (IC 95% = 1,05 a 2,28). O grupo ETCC-a, quando comparado ao grupo ETCC-s mostrou menor necessidade de doses analgésicas diárias com média de 1,37 (0,63) contra 1,81 (0,64) doses respectivamente (P <0,001). A ETCC ativa também obteve maior melhora da IRD que a ETCC sham, conforme demostrado pela maior redução na Brazilian Profile of Chronic Pain: Screen (B-PCP:S) (diferença média de 9,41 pontos, IC95% = 0,63 a 18,21) e ainda, aumentou a função do sistema modulador descendente da dor durante o teste da modulação condicionada de dor (CPM) com um tamanho de efeito médio. O aumento da função desse sistema representa a reversão das alterações neuroplásticas mal adaptativas promovidas pela dor crônica. Conclusão: Duas sessões de ETCC anódica aplicadas sobre M1 no pré-operatório melhorou a dor pós-operatória, como demonstrado pela redução dos escores de dor, consumo de analgésicos e IRD. Além disso, sugere-se que os efeitos da ETCC pré-operatória nestes desfechos envolvem a melhora da função dos sistemas moduladores descendentes da dor e mecanismos de neuroplasticidade conforme mensurados pelo BDNF. / Introduction: Hallux valgus, is an important cause of feet pain and discomfort and affects 28% of adults and 37% of elderly, predominantly in female population. To achieve the deformity heal, surgical treatment is needed, which main goal is to treat incapacity related to pain (IRP). However, one year after hallux valgus surgical treatment, moderate to severe chronic pain persists in 21% during rest and 43% during walking. This abnormal response is part of the symptoms that constitute central sensitization syndrome (CSS), which is due to a maladaptive neuroplasticity process. Sensitized patients, not only are more likely to develop postoperative persistent pain, but also experience more intense postoperative pain comparing to non-sensitized patients, due to the amplification of nociceptive inputs and inhibitory systems disfunction. Related to neuroplasticy process, proteins such as brain neurotrophic factor (BDNF) are found. This neurotrophin participates in the LTP process, a mechanism of neuroplasticity that sustains the process of pain memory. The increase of BDNF increases the LTP, while the reduction of its levels attenuates this phenomenon. Therefore, the relationship of BDNF levels with disease severity may confirm the systemic influence of this biomarker on sustained pain states. In order to alter long-term pain-induced maladaptive neuroplasticity, transcranial direct current stimulation (tDCS), a non-invasive technique, which aims for the central nervous system modulation for pain control, may become a therapeutic option for postoperative pain. However, the effect of tDCS applied in the preoperative period has not been explored yet with the intent of improving the postoperative pain control in sensitized patients, neither in postoperative rehabilitation. In this study, it was chosen to use tDCS due to its potential to counter-regulate the maladaptive neuroplastic alterations associated to chronic pain. Objective: to evaluate the effect of preoperative tDCS compared to tDCS-sham in the pain control and in the rehabilitation of patients with arthralgia of the first metatarsalfalangeal articulation submitted to hallux valgus surgical correction. Method: it is a randomized, double-blinded, placebo-sham controlled clinical trial, which includes 40 female patients, between 18 and 70 years old, candidates to hallux valgus surgical treatment by combined Chevron + Akin osteotomy due to arthralgia of the first metatarsalfalangeal articulation. The patients were randomized and divided into two groups that were treated with two tDCS or tDCS-sham sessions of 20 minutes each in preoperative period. The stimulation was done by 2mA continuous current through the anodal electrode on the primary motor cortex (M1) and the catodal on the contralateral supraorbital area. The outcomes were: VAS(0-10) scores, analgesic consumption, DRP assessed by the B-PCP: S, the function of the descending pain modulator system, assessed by the CPM test and the serum and CSF levels of BDNF. Results: a-tDCS group showed lower scores on Visual Analogue Scale [VAS(0-10)] at rest and during walking (P<0.001). At rest, the difference between both groups was 2.13cm (95%CI=1.59 to 2.68) while during walking was 1.67cm (95%CI=1.05 to 2.28). The a-tDCS group, when compared to s-tDCS, showed reduced need of daily analgesic intake from 1.37 (0.63) to 1.81 (0.64) mean doses, respectively (P<0.001). Active tDCS improved the DRP, as demonstrated by a greater reduction in the Brazilian Profile of Chronic Pain: Screen (B-PCP:S) (mean difference of 9.41 points, 95%CI=0.63 to 18.21) and also increased the function of descending pain modulatory system (DPMS) during conditioned pain modulation (CPM-task), with a medium size effect. The increased function of this system represents the reversal of maladaptive neuroplastic changes promoted by chronic pain. Conclusion: Two preoperative anodic tDCS sessions applied over M1 improved postoperative pain, as demonstrated by reduction in the pain scores, analgesic consumption and DRP. In addition, these results suggest that the effects of preoperative tDCS on these outcomes involved improving the function of pain modulation systems and neuroplasticity mechanisms as measured by BDNF.

Made available in DSpace on 2016-03-15T19:39:47Z (GMT). No. of bitstreams: 1 Patricia Aparecida Dall Agnol.pdf: 1818404 bytes, checksum: b31cf0df83e4242783a4c903b8811770 (MD5) Previous issue date: 2011-08-12 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The integrity of the sensory system is important to the development of human skills. Notwithstanding, after the loss of one or more systems, the nervous system ability of adapting itself to the new condition is variably due to type and age of loss and other factors involved on the learning of new skills, as in neural plasticity for example. Nevertheless, such adoption is possible once the remaining systems, linked to compensatory mechanisms, supply the retention of sensory loss information. Several studies have pursued neural substrates understanding towards sensorial lost in the face of sensory loss. This paper had as primary goal unravel tDCS influence on somatosensory cortex over the two points and textures discrimination tests submitted to sighted and blind subjects and verify its possible neuromodulatory effects. The results have showed that Anodic tDCS applied to the left somatosensory field produced benefits on two points discrimination performance and texture discrimination. Cathodic tDCS, by its turn, had harmful effects on texture discrimination performance in early blind and sighted subjects. It was found that tDCS has the ability of neuromodulating the excitability of somatosensorial cortex over the tactile discrimination. By taking such findings into consideration, it is possible to conclude that anodic and cathodic tDCS have considerable different effects on early blind and sighted subjects regarding their tactile perception, when applied on primary somatosensory cortex. Inasmuch as anodic tDCS has improved tactile performance, sooner may be possible that, with further researches, such tool may aid sensory loss and disturb treatments or even strengthen Braille reading for blind subjects. / A integridade do sistema sensorial é importante para o desenvolvimento das habilidades humanas. Entretanto, com a perda de um ou mais sentidos, a capacidade do sistema nervoso em adaptar-se a nova condição é variável devido ao tipo e idade de perda e outros fatores envolvidos na aprendizagem de novas habilidades, como na plasticidade neural. Todavia, essa adaptação é possível uma vez que os sentidos remanescentes associados a mecanismos compensatórios suprem a retenção da informação do sentido perdido. Muitos estudos buscam a compreensão dos substratos neurais diante da perda sensorial. Dessa forma, este estudo teve por objetivo investigar a influência da Estimulação Transcraniana por Corrente Contínua (ETCC) aplicada no Córtex Somatossensorial Primário (CS1), de indivíduos com visão preservada e de deficientes visuais, durante os testes de discriminação de dois pontos e de discriminação de texturas. Os resultados mostraram que a ETCC anódica aplicada no CS1 produziu efeito benéfico no desempenho da discriminação de dois pontos e da discriminação de textura. Já a ETCC catódica teve efeito prejudicial no desempenho da discriminação de texturas em deficientes visuais congênitos e indivíduos com visão. Esses resultados são atribuídos à capacidade que a ETCC tem em neuromodular a excitabilidade cortical do córtex somatossensorial. Por fim, concluímos que a aplicação da ETCC anódica e catódica no CS1 têm efeitos significativos na percepção tátil em deficientes visuais congênitos e indivíduos com visão durante as tarefas realizadas no presente estudo. Nesse sentido, pesquisas subsequentes com essa ferramenta poderão auxiliar em tratamentos de distúrbios e de perdas sensoriais ou mesmo potencializar a aprendizagem de deficientes visuais na leitura Braille.

Ma thèse est consacrée à l’étude des réseaux neuronaux spinaux impliqués dans la motricité chez l’Homme est comprend deux chapitres. Des travaux récents effectués sur la moelle épinière du rat ont mis en évidence qu’au cours du développement chez les mammifères, les synapses GABAergiques et glycinergiques sont tout d’abord excitatrices avant de devenir inhibitrices et qu’une section de la moelle épinière ne permet pas cette transformation. Cette transition développementale semble due à l’action d’un transporteur transmembranaire (KCC2) au cours de développement qui diminue après section de la moelle épinière. La diminution de l’expression du KCC2 dépolarise l’action du GABA et de la glycine, ce qui conduit donc à une réduction de l'efficacité de synapse inhibitrice. Le but de ce projet est d’explorer si chez l’Homme une section traumatique de la moelle épinière qui prive les neurones inhibiteurs de leur contrôle suprasegmentaire a pour conséquence de modifier leur comportement synaptique, voire de les ramener à un fonctionnement « immature », c’est-à-dire de transformer des synapses inhibitrices en synapses facilitatrices. Pour tester cette hypothèse, nous avons étudié l’effet sur des synapses inhibitrices de la moelle épinière d’une prise per os de furosémide, un antagoniste de KCC2, et comparé ses effets chez des sujets sains et chez des patients porteurs d’une section de la moelle épinière. L’étude sur les sujets sains suggère que le furosémide (40 mg) a pour effet une réduction du fonctionnement des synapses inhibitrices. Cet effet du furosémide sur les synapses inhibitrices semble être réduit chez des patients. Les résultats obtenus chez les sujets sains indiquent que furosémide administré per os à des dose largement utilisé en clinique humain modifie sélectivement le fonctionnement des synapses inhibitrices et permet donc de disposer d’un mesure non-invasive de fonctionnement intrinsèque de la synapse inhibitrice. Les résultats préliminaires obtenus chez les patients porteurs d’une section de la moelle épinière suggèrent une réduction de l’efficacité de synapses inhibitrices qui probablement contribue à la spasticité. La stimulation électrique transcrânienne de courant continu encore appelée « transcranial direct current stimulation (tDCS) » par les anglo-saxons, a connu un essor considérable et constitue aujourd’hui une technique de référence pour moduler l’excitabilité du cortex chez l’Homme. En 2009, Roche et al. ont montré dans notre laboratoire, que la tDCS anodale appliquée sur l’hémisphère contralateral pouvait également modifier l’excitabilité des réseaux neuronaux spinaux (i.e. l’inhibition réciproque au niveau du poignet) enregistrée sur le côté dominant chez les sujets sains. L’existence de projection corticale ipsilatérale sur les réseaux neuronaux spinaux de la moelle épinière et leurs éventuelles modifications après lésion cortico-sous-corticale reste très controversée. Dans ce projet, nous avons testé les effets de la tDCS ipsi- et contralarérale du cortex non-lésé sur l’inhibition réciproque chez des patients AVC. La tDCS ipsilatérale n’induit pas de modifications de l’inhibition réciproque chez les sujets sains. Des résultats similaires enregistrés sur le membre supérieur lésé ont été observés chez des patients AVC, mais ces résultats mériteraient d’être confortés avec un plus grand nombre de sujets. La tDCS contralatérale chez les sujets sains n’induit pas de modifications de l’inhibition réciproque enregistrées sur le membre supérieur non-dominant. Ce résultat est différent de celui observé sur le membre supérieur dominant par Roche et al. (2009). Ce contrôle asymétrique sur l'inhibition réciproque est argument en faveur de l'hypothèse que l'inhibition inter-hémisphérique (IHI) entre les deux cortex moteurs est asymétrique. L’IHI à partir de l'hémisphère «dominant» est probablement plus importante. / My thesis is devoted to the study of the spinal circuitry involved in motor functions using non-invasive electrophysiological methods in humans. It comprises two research projects.Studies in animals have shown that during neural development, GABAergic and glycinergic neurons are first excitatory, and then become inhibitory during maturation. This developmental transition is mainly due to the activation of co-transporter KCC2 at the mature state. A down-regulation of KCC2 was reported after spinal cord transection in the rat that leads to the depolarising (excitatory) action of GABA and glycine and thus results in a reduction of inhibitory synaptic efficiency. The aim of this project was to explore if spinal cord injury (SCI) in human reverses the pattern of GABAergic and glycinergic neurons back towards the immature state (primarily excitatory). To test this hypothesis, we studied the effects of furosemide (a KCC2 antagonist) on spinal inhibitory synaptic function, and compared the results obtained in healthy subjects and SCI patients. Results in healthy subjects suggest that furosemide (40 mg, orally-administrated) induces a reduction of inhibitory synapse functions. This effect of furosemide on inhibitory synapses seems to be reduced in SCI patients. Our results suggest that furosemide has the potential to test functions of inhibitory synapses in humans. The difference of furosemide effects on spinal inhibitory synapse excitability in healthy subjects and SCI patients favours the hypothesis of a decrease in inhibitory neuronal activity induced by down-regulation of KCC2 after SCI in humans that likely contributes to spasticity. Transcranial direct current stimulation (tDCS) has emerged as a method for exploring cortex excitability in humans. Roche et al. (2009) have shown in our laboratory that using anodal tDCS over contralateral motor cortex can also induce changes in spinal network excitability (i.e. reciprocal inhibition between forearm muscles) in the dominant limb in healthy subjects. It is unknown whether motor activity from the unaffected cerebral hemisphere could be employed after semi-brain damage in patients with hemiplegia. Moreover, little is known about the non-affected limb if it always functions like 'normal' after unilateral stroke. In this project, the ipsi- and contralateral corticospinal controls on reciprocal inhibition between forearm muscles were explored using anodal tDCS applied over the unaffected motor cortex of stroke patients and then compared to the results obtained in healthy subjects. Ipsilateral tDCS induces no change in reciprocal inhibition in healthy subjects. Similar results recorded on the affected upper limb are observed in stoke patients. However a larger number of patients is required to confirm the results. Contralateral anodal tDCS in healthy subjects shows no changes of reciprocal inhibition recorded in the non-dominant upper limb. This result is different from that observed in the dominant upper limb by Roche et al. (2009). This asymmetrical control on reciprocal inhibition would favour the hypothesis that the inter-hemispheric inhibition (IHI) between both motor cortices is asymmetric, with prominent IHI projections originating in the “dominant” left hemisphere. Contralateral anodal tDCS of the unaffected motor cortex induces a strong decrease in reciprocal inhibition in non-affected upper limb in stoke patients.This is different from that observed in both dominant and non-dominant upper limb in healthy subjects suggesting that the pathophysiological changes after unilateral stroke would probably not occur only on the hemiparesis side, but may also the non-affected side. A larger number of patients is still required to confirm the results.

The effects of cranial electrotherapy stimulation (CES) on human EEG and brain current density were evaluated by quantitative electroencephalography (qEEG) and low resolution brain electromagnetic tomography (LORETA). A total of 72 research subjects were provided with a single session of CES, 38 were provided with 0.5 Hz CES while 34 were provided with 100 Hz CES. The qEEG paired t-tests revealed that in both frequencies of CES there was a significant (.05) increase in alpha relative power with concomitant decreases in delta and beta relative power. The 0.5 Hz CES decreased a wider frequency range of delta activity, while the 100 Hz CES decreased a wider frequency range of beta activity; suggesting some difference may exist in the EEG response to different frequencies of CES. The changes found in qEEG relative power were consistent with the affective and cognitive effects of CES reported in the literature, such as increased relaxation and decreased anxiety. Statistically significant changes for qEEG values other than relative power, such as coherence, amplitude asymmetry, phase lag and power ratios were also found. The LORETA paired t-tests found statistically significant (.05) increases in cortical and subcortical theta and alpha frequency current density with concomitant decreases in delta and beta current density. The effects of CES on current density varied by frequency, but did not show a differential in response based on proximity to the contacts, or structures within the brain. Statistically significant changes in current density were found in all 2394 gray matter voxels represented by LORETA, indicating a whole brain response to the CES stimulus. The qEEG and LORETA findings revealed that a single 20-minute session of CES does have a significant effect on the cortical and subcortical activity of the human brain resulting in activity consistent with decreased anxiety and increased relaxation.