Increasingly, virtual reality therapy (VRT) technologies are being used to augment pediatric rehabilitation. The mechanisms underlying success/failure of VRTs are not well understood. This thesis proposed an innovative 3-phase framework for evaluating VRT technologies with respect to neuroplasticity based on results of a scoping review of 21 studies. A case study was undertaken to demonstrate use of the framework to design and evaluate ‘Musical Steps’, a VRT technology aimed at promoting heel contact in toe-walking children. 5 therapists and 4 children were engaged in this study. The system accurately detected 88%(SD=7%) of heel contacts and was rated positively in usability testing (phase 1). Feasibility studies indicated that, while enjoyable, children did not understand the feedback provided and hence, heel contact was not increased (phase 2). These findings will direct future reiterations prior to evaluating clinical impact (phase 3). The proposed framework may enhance design and translation of therapeutically relevant VRTs.

Nikotin gilt als die Abhängigkeit verursachende Komponente im Zigarettenrauch. Zudem hat Nikotin einen Einfluss auf die Ausbildung von lang anhaltenden kortikalen Erregbarkeitsveränderungen. Diese als neuroplastisch bezeichneten Veränderungen gelten als neurophysiologische Grundlage von Lern- und Gedächtnisprozessen. Die kognitiven Fähigkeiten sind bei Rauchern im Nikotinentzug reduziert und bessern sich erst nach Nikotingabe wieder. Auch Nichtraucher zeigen verbesserte kognitive Leistungen nach Nikotingabe. Im Rahmen dieser Arbeit sollte untersucht werden, in welchem Maße nikotinerge Acetylcholin-Rezeptoren bei der Induktion von inhibitorischen kortikalen Erregbarkeitsveränderungen im menschlichen Gehirn eine Rolle spielen. Daher führten wir Versuche mit dem für diese Rezeptoren spezifischen Liganden Nikotin durch. Wir untersuchten den Einfluss von schnell anflutendem Nikotin in Form von Nasenspray und eines kontinuierlich hohen Nikotinspiegels in Form eines Nikotinpflasters auf inhibitorische kortikale Erregbarkeitsveränderungen bei Rauchern und Nichtrauchern. Für die Auslösung fokaler inhibitorischer Erregbarkeitsveränderungen verwendeten wir die gepaarte assoziative Stimulation (PAS). Mittels transkranieller Magnetstimulation wurden die kortikalen Exzitabilitätsveränderungen über die Änderung der MEP-Amplituden im Musculus abductor digiti minimi erfasst. Ohne Nikotin hatten sowohl Nichtraucher als auch Raucher die Fähigkeit zur Ausbildung von inhibitorischen kortikalen Erregbarkeitsveränderungen, wobei diese bei Rauchern im Nikotinentzug deutlich schlechter ausgeprägt waren als bei Nichtrauchern. Bei Nichtrauchern wurden die inhibitorischen Nacheffekte der PAS durch Nikotin aufgehoben bzw. vermindert, während sie bei Rauchern initial kürzer anhielten, später jedoch erneut auftraten. Unsere Ergebnisse zeigen, dass Nikotin eine wichtige Rolle bei der Ausbildung von inhibitorischen kortikalen Erregbarkeitsveränderungen spielt. Da diese als neuroplastisch bezeichneten Veränderungen als neurophysiologisches Korrelat für Lernvorgänge und Gedächtnis angesehen werden, lässt sich ein hierdurch vermittelter Einfluss von Nikotinabhängigkeit und Nikotinentzug auf kognitive Prozesse annehmen. Zudem nimmt Nikotin einen bedeutsamen Einfluss auf die durch zerebrale Stimulationsprotokolle wie die PAS ausgelösten Effekte.

No description available.

Conventional functional electrical stimulation (FES) therapy, if provided shortly after an incomplete spinal cord injury, is able to help an individual to restore voluntary hand function. This is thought to occur through the induction of neuroplasticity. However, conventional FES therapy employs a push-button-based control scheme, which does not fully require the recipient to generate volitional movements. The first study in this thesis therefore sought to determine, in an early proof-of-concept test with able-bodied participants, whether control strategies which are triggered by volitional activity (including an electroencephalography-based brain-machine interface (BMI-FES) and an electromyogram-based control scheme (EMG-FES)) might provide greater benefits to hand function. The results offer relatively weak evidence to suggest that BMI-FES, and especially EMG-FES, were able to induce greater neuroplasticity than conventional treatments in the corticospinal tract leading to the hands, but that this did not immediately translate to more functional improvements such as maximum grip force. ii The second study in this thesis focussed on spinal associative stimulation (SAS), which involves paired stimulation pulses at both the head (via transcranial magnetic stimulation), and the wrist (via peripheral nerve stimulation). The purpose of this, as with the first study, was to induce neuroplasticity and upregulate the corticospinal tract leading to the hands. While limited research has suggested that it is possible to produce neuroplasticity through SAS, all such studies have provided stimulation at a fixed frequency of 0.1 or 0.2 Hz. The present study therefore sought to compare the effectiveness of a typical 0.1 Hz paradigm with a 1 Hz paradigm, and a paradigm which provided stimulation in 5 Hz “bursts”. None of the paradigms were able to successfully induce neuroplasticity in a consistent manner. The increased variability in this study as compared to the previous one, despite the nearly identical assessment methodology, suggests that responses to the SAS treatment may have been highly individual. This serves to highlight a potential limitation of the treatment, which is that its effectiveness may not be universal, but rather dependent on each specific recipient. This may be a challenge faced by SAS should it continue to be tested as a novel therapy.

One of the most common risk factors for stroke is diabetes. Diabetics are 2 to 4 times more likely to have a stroke and are also significantly more likely to show poor functional recovery. In order to determine why diabetes is associated with poor stroke recovery, we tested the hypotheses that diabetes either exacerbates initial stroke damage, or inhibits neuronal circuit plasticity in surviving brain regions that is crucial for successful recovery. Type 1 diabetes was chemically induced in mice four weeks before receiving a targeted photothrombotic stroke in the right forelimb somatosensory cortex to model a chronic diabetic condition. Following stroke, a subset of diabetic mice were treated with insulin to determine if controlling blood glucose levels could improve stroke recovery. Consistent with previous studies, one behavioural test revealed a progressive improvement in sensory function of the forepaw in non-diabetic mice after stroke. By contrast, diabetic mice treated with and without insulin showed persistent deficits in sensori-motor forepaw function. To determine whether these different patterns of stroke recovery correlated with changes in functional brain activation, forepaw evoked responses in the somatosensory cortex were imaged using voltage sensitive dyes at 1 and 14 weeks after stroke. In both diabetic and non-diabetic mice that did not have a stroke, brief mechanical stimulation of the forepaw evoked a robust and near simultaneous depolarization in the primary (FLS1) and secondary somatosensory (FLS2) cortex. One week after stroke, forepaw-evoked responses had not been remapped in the peri-infarct cortex in both diabetic and non-diabetic mice. Fourteen weeks after stroke, forepaw evoked responses in non-diabetic mice re-emerged in the peri-infarct cortex whereas diabetic mice showed very little activation, reminiscent of the 1 week recovery group. Moreover, controlling hyperglycemia using insulin therapy failed to restore sensory evoked responses in the peri-infarct cortex. In addition to these differences in peri-infarct responsiveness, we discovered that stroke was associated with increased responsiveness in FLS2 of non-diabetic, but not diabetic or insulin treated mice. To determine the importance of FLS2 in stroke recovery, we silenced the FLS2 cortex and found that it re-instated behavioural impairments in stroke recovered mice, significantly more so than naïve mice that still had a functioning FLS1. Collectively, these results indicate that both diabetes and the secondary somatosensory cortex play an important role in determining the extent of functional recovery after ischemic cortical stroke. Furthermore, the fact that insulin therapy after stroke did not normalize functional recovery, suggests that prolonged hyperglycemia (before stroke) may induce pathological changes in the brain’s circulation or nervous system that cannot be easily reversed. / Graduate

Deafferented cortical visual areas exhibit topographical plasticity such that their constituent neural populations adapt to the loss of sensory input through the expansion and eventual remapping of receptive fields to new regions of space. Such representational plasticity is most compelling in the long-term (months or years) but begins within seconds of retinal deafferentation (short-term plasticity). The neural mechanism proposed to underlie topographical plasticity is one of disinhibition whereby long-range horizontal inputs are "unmasked" by a reduction in local inhibitory drive. In this dissertation, four experiments investigated the neural mechanisms of short-term visual plasticity and disinhibition in humans using a combination of psychophysics and event-related potentials (ERPs). Short-term visual plasticity was induced using a stimulus-induced analog of retinal deafferentation known as an artifical scotoma. Artificial scotomas provide a useful paradigm for the study of short-term plasticity as they induce disinhibition but are temporary and reversible. Experiment 1 measured contrast response functions from within the boundaries of an artificial scotoma and evaluated them relative to a sham control condition. Changes in the contrast response function suggest that disinhibition can be conceived of in terms of two dependent but separable processes: receptive field expansion and unrestricted neural gain. A two-process model of disinhibition is proposed. A complementary ERP study (Experiment 2) recorded visual evoked potentials elicited by probes appearing within the boundaries of an artificial scotoma. Results revealed a neural correlate of disinhibition consistent with origins in striate and extrastriate visual areas. Experiment 3 and 4 were exploratory examinations of the representation of space surrounding an artificial scotoma and revealed a neural correlate of invading activity from normal cortex. Together, the results of these four studies strengthen the understanding of the neural mechanisms that underlie short-term plasticity and provide a conceptual framework for their evaluation.

Introdução: Estimulação transcraniana com corrente contínua (ETCC) é um método não invasivo de estimulação cerebral que modifica o potencial de repouso da membrana neuronal através de uma corrente elétrica de baixa intensidade. Trata-se de uma técnica neuromodulatória aplicável ao contexto terapêutico de disfunções do sistema nervoso implicados na fisiopatologia da dor e transtornos neuropsiquiátricos, com baixo custo, mínimos efeitos adversos e fácil aplicação. A ETCC tem se mostrado eficaz no tratamento de dores crônicas incluindo a fibromialgia (FM) em curto prazo. Seu uso se sustenta na melhor compreensão dos mecanismos fisiopatológicos dessa síndrome, os quais incluem processos de desinibição em nível cortical e infracortical, demonstrado por medidas neurofisiológicas como facilitação e desinibição, assim como redução da potência dos sistemas modulatórios descendentes da dor, além de alterações nas vias nociceptivas periféricas, como as fibras nervosas finas. No entanto, essa alteração isolada não foi previamente associada à disfunção no sistema de modulação descendente da dor (SMDD), observado na FM. As áreas de aplicação da ETCC dependem do objetivo terapêutico. O córtex motor primário (M1) é o alvo mais estudado e com maior contingente de evidências para o tratamento da dor e reabilitação motora, enquanto o córtex pré-frontal dorsolateral esquerdo (DLPFC) tem sido eficaz na depressão e melhora dos componentes psicoafetivos dos pacientes com dor crônica. Seu principal limitador prático é a necessidade de ir ao centro de atendimento durante dias consecutivos, pois o efeito terapêutico sustentado da ETCC necessita repetição das sessões Objetivos: Esta tese está constituída por dois estudos. O primeiro objetiva examinar se a disfunção de fibras finas que ocorre em pacientes com FM está ligada a um mau funcionamento do sistema modulador descendente da dor. No segundo, o objetivo é avaliar a eficácia do uso em longo prazo da ETCC em nível domiciliar na FM, com o objetivo de facilitar o uso e permitir a disponibilização desta técnica a pacientes do Sistema Único de Saúde. Estudo I: No primeiro estudo avaliamos se a disfunção de fibras nervosas finas periféricas está ligada a um mau funcionamento do sistema modulador descendente da dor (SMD) na FM. Métodos: Foi realizado um estudo exploratório no qual 41 mulheres com FM e 28 voluntárias saudáveis foram submetidas a testes psicofísicos que avaliaram a função de fibras sensitivas envolvidas na nocicepção. O teste quantitativo sensorial (QST) foi utilizado para medir o limiar perceptivo térmico (HTT), o limiar de dor térmica (HPT) e o limiar de tolerância à dor térmica (HPTo), bem como avaliar a mudança na Escala Numérica de Dor (NPS0-10) durante uma tarefa de modulação da dor condicionada (CPM-task). A algometria foi utilizada para determinar o limiar de pressão de dor (PPT). Escalas para avaliação de catastrofização, ansiedade, depressão e distúrbios do sono também foram aplicadas. O fator neurotrófico derivado do cérebro (BDNF) foi medido como um marcador de neuroplasticidade. Realizamos modelos de regressão linear multivariada por grupo (saudáveis e FM) para estudar a relação entre a função do SMD e sua relação com as medidas psicofísicas. Resultados: As amostras diferiram em seu perfil psicológico, e nas medidas psicofísicas, o grupo e pacientes com FM apresentou menor sensibilidade e limiares de dor. Na FM, mas não nos saudáveis, os modelos de regressão revelaram que o HTT estava relacionado ao BDNF e ao CPM-Task (Hotelling's Trace = 1,80, P<0,001, poder=0,94, R2=0,64). HTT foi correlacionado positivamente com a CPM-task (B = 0,98, P= 0,004, Partial-ƞ2=0,25), e ao HPT (B=1,61, P=0,008, parcial -ƞ2= 0,21). No entanto PPT não foi correlacionado com o HTT. Na FM a relação do BDNF com CPM-Task teve uma relação negativa (B=-0,04, P=0,043, parcial-ƞ2=0,12) e a HPT foi diretamente proporcional (B= - 0,08, P=0,03, parcial-ƞ2 = 0,14). O BDNF não influenciou no modelo. E os efeitos adversos relatados foram maiores no grupo ativo (17,8%) em comparação com o grupo sham (6,6%). Conclusão: A disfunção sensorial periférica está associada positivamente à disfunção do sistema modulatório descendente da dor e aos níveis séricos de BDNF na FM, o que não ocorre em indivíduos saudáveis. Estudo II: O segundo estudo teve como objetivo avaliar a eficácia do uso domiciliar de 60 sessões da ETCC-ativa e ETCC-simulada aplicadas sobre a área DLPFC esquerda, nas pacientes com diagnóstico de FM. Métodos: Foi realizado um ensaio clínico randomizado, duplo cego, em paralelo, controlado com ETCC-simulada em 20 mulheres com diagnóstico de fibromialgia. A estimulação foi realizada durante cinco dias consecutivos na semana, durante 30 min, com a intensidade de 2 mA, por 12 semanas, totalizando 60 sessões. As pacientes receberam treinamento para uso do equipamento especialmente desenvolvido para uso domiciliar e mantinham contato com o pesquisador responsável por meio de mensagem de texto diariamente. Os efeitos foram medidos por meio da escala visual de dor (EAV) durante o curso de 12 semanas de tratamento, bem como o uso de analgésicos e possíveis eventos adversos, diariamente. Foram avaliados os níveis de depressão, catastrofismo e capacidade funcional para tarefas diárias, QST para verificar limiar de dor e tolerância ao calor, PPT e dosagem dos níveis séricos de BDNF no início, após 30 sessões e no final do tratamento. Um modelo linear misto com efeitos fixos foi usado para comparar mudanças nos escores de dor na EAV ao longo do tratamento. Resultados: A ETCC ativa domiciliar reduziu os escores de dor pela EAV (p<0.001) quando comparado ao sham, com uma redução média de dor de 64% (p<0.001). Além disso, ETCC ativa reduziu significativamente a incapacidade relacionada a dor [B-PCP:S escore total (p=0.023);-ƞ2=0.61]. Também reduziu os escores nas medidas clínicas de depressão, catastrofismo e qualidade do sono [BDI-II, PCS e PSQI (p<0.05)]. No entanto, ETCC ativa aumentou os escores na algometria (PPT) e tolerância térmica (HPTo) (p<0.01). O BDNF não influenciou no modelo. Os efeitos adversos relatados foram maiores no grupo ativo (17,8%) em comparação com o grupo sham (6,6%). Conclusão: A ETCC para uso domiciliar mostrou-se segura e eficaz na redução da dor, incapacidade relacionada a dor, sintomas depressivos e catastróficos e redução do uso de analgésicos. O conjunto de dados desta tese sugere que em pacientes fibromiálgicas, o nível de disfunção do sistema modulador descendente da dor está relacionado ao nível de disfunção de fibras nervosas finas periféricas envolvidas na nocicepção. Além disso, a ETCC de longo prazo em fibromiálgicas foi eficaz na melhora dos sintomas disfuncionais relacionados à dor crônica e se mostrou adequada para uso domiciliar. / Introduction: Transcranial direct current stimulation (tDCS) is a noninvasive method of brain stimulation that modifies the resting potential of the neuronal membrane through a low intensity electrical current. It is a neuromodulatory technique to the therapeutic context of dysfunctions of the nervous system implicit in physiotherapy and neuropsychological disorders, with low cost, adverse effects and easy application. tDCS has been effective without a chronic fight process, including fibromyalgia (FM), in which the processes of disinhibition are cortical and infracortical, demonstrated by neurophysiological as intracortical facilitation and desinhibition, as well as reduction of the power of the systems descending pain modulators. In addition, studies have shown a severity of inhibition of central positive correlation with BDNF (Brain Derived Neurotrophic Factor) levels and seems to have some relation to the peripheral nociceptive pathways, as the areas of application of the stimulation depend on the primary motor cortex (M1) is the most studied target and the largest contingent of selection for the treatment of pain and motor reaction, while the dorsolateral prefrontal cortex (DLPFC) was effective in the treatment of depression and psychoaffective components in cases of patients with the chronic condition. Although tDCS has been successful in treating FM, its main limiter is a need for the service center for consecutive days as it has cumulative effect. In fact, the erasure of the sessions guaranteed the therapeutic effect of the ETCC. The application of measures on consecutive days motivated the study of its value when applied at the household level, in order to allow the large-scale treatment technique to be adopted in the Unified Health System. This is proved by two studies. The first objective is to examine whether a fine-fiber dysfunction that occurs in patients with FM is linked to an operation of the pain-modulating system. Neuropathy of long nerve fibers has been implicated by a descriptor of pain, neurophysiological and psychophysiological neurophysiology, as well as skin biopsy studies. However, this comparison was not associated with dysfunction in the descending pain system (DPMS) not on FM. Objective did the study explore the association of dysfunction of small fibers with the DPMS and other substitutes for nociceptive changes in FM. In the second, the term is a measure of long-term use of ETCC at household level in FM Study I: In this first study evaluating the presence of nerve and peripheral fiber failure, it is linked to the functioning of the descending pain modulator system (DPMS) in FM Methods: It was performed an exploratory study with 41 FM women and 28 healthy volunteers whose were evaluated in psychophysical tests that evaluated a function of sensory fibers involved in nociception. The quantitative sensory test (QST) was used to measure the Heat thermal threshold (HTT), the heat pain threshold (HPT) and the thermal pain tolerance (HPTo), as well as the numerical scale of pain (NPS0 -10 ) over a task of modulation of conditioned pain (CPM-task). Algometry was used to determine the pain pressure threshold (PPT). Scales for evaluation of catastrophic, anxiety, depression and sleep disorders were also applied. Brain-derived neurotrophic factor (BDNF) was measured as a marker of neuroplasticity. Multivariate linear regression models by group (health and FM) for a relationship between a descending modulatory system function and its relationship with psychophysical measures. Results: The samples differed in their psychological profile, and in the psychophysical measures, the group and the patients with FM had lower sensitivity and pain thresholds. At FM, regression models revealed that HTT was related to BDNF and CPM-Task (Hotelling's Trace = 1.80, P <0.001, power = 0.94, R2 = 0.64). HTT was positively correlated with a CPM task (B = 0.98, P = 0.004, partial-ƞ2 = 0.25), and HPT (B = 1.61, P = 0.008, partial -ƞ2 = 0.21) . However PPT was not correlated with HTT. In FM, the relationship of BDNF with CPM, a negative relation was found (B = -0.04, P = 0.043, partial- = 2 = 0.12) and HPT was proportionally (B = -0.08, P = 0.03, partial-ƞ2 = 0.14). BDNF did not influence the model. And the adverse effects reported were higher in the active group (17.8%) compared to the sham group (6.6%). Conclusion: Peripheral sensory dysfunction is positively associated with the modulating dysfunction of BDNF levels in FM, which does not occur in isolated individuals. Study II: The second study had the purpose of evaluating the home use of 60 sessions of atDCS and s-tDCS on a left DLPFC area in patients with FM. Methods: A randomized, double-blind, parallel-sham controlled study in 20 women with FM. Stimulation was performed for five consecutive days in the week for 30 min at the intensity of 2 mA for 12 weeks, totaling 60 sessions. Patients were trained to use equipment specially designed for home use and maintained contact with the researcher responsible through daily text message. The effects were measured through visual pain scale (VAS) daily during the course of 12 weeks of treatment, as well as the use of analgesics and possible adverse events daily. The levels of depression, catastrophism and disability for daily tasks were assessed. The QST was used to check pain threshold and tolerance to heat, an algometry was used to check pressure pain threshold (PPT) and blood collection was performed to evaluate serum BDNF levels at baseline, after 30 sessions and at the end of treatment. A Mixed Linear Model with fixed effects was used to compare changes in pain scores in VAS throughout the treatment. Results: Home-based tDCS reduced dairy pain VAS scores (p<0.001), with cumulative mean pain drop of 64% (p<0.001). Furthermore, active home-based tDCS reduced significantly disability due to pain [B-PCP:S total scores (p=0.023; partial-ƞ2=0.61]. And also reduced scores in clinical measures like depression scores, catastrophizing pain scores and sleep quality scores [BDI-II and PCS (p<0.05), PSQI (p<0.05)]. However, active homebased tDCS enhance scores in algometry (PPT) and heat pain tolerance (HPTo) (p<0.01). Conclusion: Home-based anodal tDCS applied over the DLPFC in FM had a baseline neuroplasticity-dependent reduction effect on pain. In addition, it improved the disability due to pain, depressive symptoms and pain catastrophizing. It reduced the analgesic use and increased pressure and heat pain tolerance.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Fatty acids (FA) are constituents of neuronal phospholipid membranes, where they are essential for the development and functioning of the brain. During the peak of neuronal growth, occurring during the last week of gestation and lactation, there is a rapid accumulation of long-chain polyunsaturated FA (LC-PUFAs), which are synthesized from a physiologically appropriate supply of essential fatty acids (EFA) for normal fetal and neonatal development , ensuring the development of neurological functions. During the last decades, there occurred changes in dietary habits in Western countries, mainly with increased consumption of trans fatty acids (TFA) and omega-6 (n-6) at the expense of consumption of omega-3 (n-3). These changes may increase oxidative damage and alter neuronal neuroplasticity, thereby facilitating the development of neuropsychiatric diseases such as bipolar disorder (BD). Through a model of amphetamine-induced mania in rats, we evaluated comparatively the influence of daily supplementation of different fats since pre-conception until weaning of 1st and 2nd generation litters on behavioral parameters in conjunction with biochemical changes in brain regions. Three groups of female Wistar rats were supplemented (3g/kg; p.o. per day) from one week before conception through pregnancy and breast-feeding with fish oil (FO, rich in n-3 PUFA), soybean oil (SO; rich in PUFA n-6) or hydrogenated vegetable fat (HVF; rich in TFA). During weaning, pups of both sexes were kept under the original supplementation until 90 days of age. While male offspring were included in the study of the 1st generation, females were mated and maintained in the same supplementation, thus obtaining animals of the 2nd generation, which were used in the 2nd study and divided into 3 experiments. In the study of the 1st generation at 90 days of age, one half of each supplementation group was treated with a daily dose of amphetamine (AMPH 4mg/kg, ip) or saline (control) for 14 days, when they were subjected to behavioral tests and biochemical assessments in the cortex, striatum and hippocampus. HVF supplementation was associated with TFA incorporation in the three structures, increased AMPH-induced locomotor activity, and increased oxidative damage. Since FO supplementation increased DHA percentage and decreased the n6/n3 ratio in the three regions analyzed, it may have improved membrane fluidity and reduced oxidative stress in such animals. Adult male rats born from the 2nd generation were also exposed to an animal model of mania induced by amphetamine and used in two different experiments. In the first experiment, animals were evaluated for memory behavior and biochemical and molecular analysis in the hippocampus, in which these parameters were decreased by HVF supplementation and improved by FO supplementation. In the second experiment, animals were evaluated regarding hyperactivity and biochemical and molecular analyses in the cortex, where again HVF supplementation was associated with loss in some parameters. In a third experiment we evaluated the influence of trans fat supplementation in rats exposed to the same mania animal model and the response to lithium (a mood stabilizing drug) treatment in 1st and 2nd generation animals. Lithium was able to reverse all AMPH-induced effects. Taken together, our findings suggest that the increased consumption of processed foods, which are rich in trans fat, may be related to an increased incidence of neuropsychiatric conditions. Conversely, a balanced diet, which includes omega-3 sources , reduces susceptibility to developing such conditions, possibly by changing the composition of the neuronal phospholipid membrane. / Ácidos graxos (AG) são fosfolipídeos constituintes das membranas neuronais onde são fundamentais para o desenvolvimento e funcionamento do cérebro. Durante o pico do crescimento neuronal, o qual ocorre durante a última semana de gestação e período de aleitamento, há um rápido acúmulo de AG poliinsaturados de cadeia longa (AGPI-CL) para o desenvolvimento fetal e neonatal normal, garantindo o desenvolvimento de suas funções neurológicas. Durante as últimas décadas foram observadas mudanças nos hábitos alimentares, principalmente em países ocidentais, devido ao aumento do consumo de AG trans e ômega-6 (n-6) em detrimento do consumo de AG ômega-3 (n-3). Estas mudanças podem favorecer o desenvolvimento de processos oxidativos e alterar a neuroplasticidade neuronal, facilitando assim o desenvolvimento de doenças neuropsiquiátricas, e dentre estas, o transtorno bipolar (TB). Através de um modelo animal de mania induzido por anfetamina, avaliamos comparativamente a influência da suplementação diária de óleos ou gordura desde o período pré-concepcional até o desmame das ninhadas em regiões cerebrais dos filhotes de 1ª e de 2ª geração. Três grupos de ratas Wistar foram suplementadas diariamente (3g/kg/v.o.) desde uma semana antes da concepção, durante a gestação e aleitamento com óleo de peixe (OP, rico em AGPI n-3); óleo de soja (rico em AGPI n-6) ou gordura vegetal hidrogenada (GVH; rica em AGT). No período de desmame, filhotes de ambos os sexos foram mantidos sob a mesma suplementação original até 90 dias de idade. Enquanto os filhotes machos foram incluídos no estudo da 1ª geração, as fêmeas foram separadas e acasaladas nas mesmas condições de suplementação já descritas, obtendo-se assim, animais adultos de 2ª geração, os quais foram incluídos no 2º estudo e divididos em 3 experimentos. No estudo de 1ª geração, aos 90 dias de idade, metade de cada suplementação foi tratada com uma dose diária de anfetamina (4mg/Kg, ip) ou solução salina (controle), durante 14 dias, quando foram submetidos aos testes comportamentais e avaliações bioquímicas no córtex, estriado e hipocampo. A suplementação com GVH favoreceu a incorporação de AGT nas três estruturas cerebrais descritas, aumentou a atividade locomotora induzida por ANF e aumentou os danos oxidativos. Já a suplementação com OP permitiu um aumento da porcentagem de DHA, diminuindo a razão AGPI n6/n3 nas três regiões avaliadas, o que pode ter contribuído para uma maior fluidez das membranas neurais e menor incidência de danos oxidativos. Ratos machos adultos da 2ª geração foram também expostos ao modelo animal de mania induzido por anfetamina, sendo porém separados em dois experimentos distintos: no primeiro experimento, além de avaliações comportamentais relacionadas à memória, marcadores do status oxidativo e análises moleculares foram feitas no hipocampo, sendo observado um prejuízo destes parâmetros no grupo suplementado com GVH, enquanto o grupo OP mostrou efeitos benéficos. No segundo experimento, além do comportamento locomotor, análises bioquímicas e moleculares foram feitas no córtex, quando novamente, a suplementação com GVH mostrou efeitos deletérios. No terceiro experimento avaliamos a influência da suplementação de gordura trans em animais de 1ª e 2ª geração sobre o mesmo modelo animal de mania e a resposta farmacológica ao carbonato de lítio (droga estabilizadora do humor), quando observamos que o lítio foi capaz de reverter todos efeitos induzidos pela ANF. Tomados em conjunto, os dados apresentados nesta tese sugerem que o consumo aumentado de alimentos industrializados, os quais são ricos em grodura trans, podem estar envolvidos no aumento da incidência de doenças neuropsiquiátricas. Contrariamente, uma alimentação balanceada, a qual inclui fontes de omega-3, reduz a suscetibilidade para o desenvolvimento de tais condições, em decorrência das possíveis alterações na composição fosfolipídica das membranas neurais.

Introdução: Estimulação transcraniana com corrente contínua (ETCC) é um método não invasivo de estimulação cerebral que modifica o potencial de repouso da membrana neuronal através de uma corrente elétrica de baixa intensidade. Trata-se de uma técnica neuromodulatória aplicável ao contexto terapêutico de disfunções do sistema nervoso implicados na fisiopatologia da dor e transtornos neuropsiquiátricos, com baixo custo, mínimos efeitos adversos e fácil aplicação. A ETCC tem se mostrado eficaz no tratamento de dores crônicas incluindo a fibromialgia (FM) em curto prazo. Seu uso se sustenta na melhor compreensão dos mecanismos fisiopatológicos dessa síndrome, os quais incluem processos de desinibição em nível cortical e infracortical, demonstrado por medidas neurofisiológicas como facilitação e desinibição, assim como redução da potência dos sistemas modulatórios descendentes da dor, além de alterações nas vias nociceptivas periféricas, como as fibras nervosas finas. No entanto, essa alteração isolada não foi previamente associada à disfunção no sistema de modulação descendente da dor (SMDD), observado na FM. As áreas de aplicação da ETCC dependem do objetivo terapêutico. O córtex motor primário (M1) é o alvo mais estudado e com maior contingente de evidências para o tratamento da dor e reabilitação motora, enquanto o córtex pré-frontal dorsolateral esquerdo (DLPFC) tem sido eficaz na depressão e melhora dos componentes psicoafetivos dos pacientes com dor crônica. Seu principal limitador prático é a necessidade de ir ao centro de atendimento durante dias consecutivos, pois o efeito terapêutico sustentado da ETCC necessita repetição das sessões Objetivos: Esta tese está constituída por dois estudos. O primeiro objetiva examinar se a disfunção de fibras finas que ocorre em pacientes com FM está ligada a um mau funcionamento do sistema modulador descendente da dor. No segundo, o objetivo é avaliar a eficácia do uso em longo prazo da ETCC em nível domiciliar na FM, com o objetivo de facilitar o uso e permitir a disponibilização desta técnica a pacientes do Sistema Único de Saúde. Estudo I: No primeiro estudo avaliamos se a disfunção de fibras nervosas finas periféricas está ligada a um mau funcionamento do sistema modulador descendente da dor (SMD) na FM. Métodos: Foi realizado um estudo exploratório no qual 41 mulheres com FM e 28 voluntárias saudáveis foram submetidas a testes psicofísicos que avaliaram a função de fibras sensitivas envolvidas na nocicepção. O teste quantitativo sensorial (QST) foi utilizado para medir o limiar perceptivo térmico (HTT), o limiar de dor térmica (HPT) e o limiar de tolerância à dor térmica (HPTo), bem como avaliar a mudança na Escala Numérica de Dor (NPS0-10) durante uma tarefa de modulação da dor condicionada (CPM-task). A algometria foi utilizada para determinar o limiar de pressão de dor (PPT). Escalas para avaliação de catastrofização, ansiedade, depressão e distúrbios do sono também foram aplicadas. O fator neurotrófico derivado do cérebro (BDNF) foi medido como um marcador de neuroplasticidade. Realizamos modelos de regressão linear multivariada por grupo (saudáveis e FM) para estudar a relação entre a função do SMD e sua relação com as medidas psicofísicas. Resultados: As amostras diferiram em seu perfil psicológico, e nas medidas psicofísicas, o grupo e pacientes com FM apresentou menor sensibilidade e limiares de dor. Na FM, mas não nos saudáveis, os modelos de regressão revelaram que o HTT estava relacionado ao BDNF e ao CPM-Task (Hotelling's Trace = 1,80, P<0,001, poder=0,94, R2=0,64). HTT foi correlacionado positivamente com a CPM-task (B = 0,98, P= 0,004, Partial-ƞ2=0,25), e ao HPT (B=1,61, P=0,008, parcial -ƞ2= 0,21). No entanto PPT não foi correlacionado com o HTT. Na FM a relação do BDNF com CPM-Task teve uma relação negativa (B=-0,04, P=0,043, parcial-ƞ2=0,12) e a HPT foi diretamente proporcional (B= - 0,08, P=0,03, parcial-ƞ2 = 0,14). O BDNF não influenciou no modelo. E os efeitos adversos relatados foram maiores no grupo ativo (17,8%) em comparação com o grupo sham (6,6%). Conclusão: A disfunção sensorial periférica está associada positivamente à disfunção do sistema modulatório descendente da dor e aos níveis séricos de BDNF na FM, o que não ocorre em indivíduos saudáveis. Estudo II: O segundo estudo teve como objetivo avaliar a eficácia do uso domiciliar de 60 sessões da ETCC-ativa e ETCC-simulada aplicadas sobre a área DLPFC esquerda, nas pacientes com diagnóstico de FM. Métodos: Foi realizado um ensaio clínico randomizado, duplo cego, em paralelo, controlado com ETCC-simulada em 20 mulheres com diagnóstico de fibromialgia. A estimulação foi realizada durante cinco dias consecutivos na semana, durante 30 min, com a intensidade de 2 mA, por 12 semanas, totalizando 60 sessões. As pacientes receberam treinamento para uso do equipamento especialmente desenvolvido para uso domiciliar e mantinham contato com o pesquisador responsável por meio de mensagem de texto diariamente. Os efeitos foram medidos por meio da escala visual de dor (EAV) durante o curso de 12 semanas de tratamento, bem como o uso de analgésicos e possíveis eventos adversos, diariamente. Foram avaliados os níveis de depressão, catastrofismo e capacidade funcional para tarefas diárias, QST para verificar limiar de dor e tolerância ao calor, PPT e dosagem dos níveis séricos de BDNF no início, após 30 sessões e no final do tratamento. Um modelo linear misto com efeitos fixos foi usado para comparar mudanças nos escores de dor na EAV ao longo do tratamento. Resultados: A ETCC ativa domiciliar reduziu os escores de dor pela EAV (p<0.001) quando comparado ao sham, com uma redução média de dor de 64% (p<0.001). Além disso, ETCC ativa reduziu significativamente a incapacidade relacionada a dor [B-PCP:S escore total (p=0.023);-ƞ2=0.61]. Também reduziu os escores nas medidas clínicas de depressão, catastrofismo e qualidade do sono [BDI-II, PCS e PSQI (p<0.05)]. No entanto, ETCC ativa aumentou os escores na algometria (PPT) e tolerância térmica (HPTo) (p<0.01). O BDNF não influenciou no modelo. Os efeitos adversos relatados foram maiores no grupo ativo (17,8%) em comparação com o grupo sham (6,6%). Conclusão: A ETCC para uso domiciliar mostrou-se segura e eficaz na redução da dor, incapacidade relacionada a dor, sintomas depressivos e catastróficos e redução do uso de analgésicos. O conjunto de dados desta tese sugere que em pacientes fibromiálgicas, o nível de disfunção do sistema modulador descendente da dor está relacionado ao nível de disfunção de fibras nervosas finas periféricas envolvidas na nocicepção. Além disso, a ETCC de longo prazo em fibromiálgicas foi eficaz na melhora dos sintomas disfuncionais relacionados à dor crônica e se mostrou adequada para uso domiciliar. / Introduction: Transcranial direct current stimulation (tDCS) is a noninvasive method of brain stimulation that modifies the resting potential of the neuronal membrane through a low intensity electrical current. It is a neuromodulatory technique to the therapeutic context of dysfunctions of the nervous system implicit in physiotherapy and neuropsychological disorders, with low cost, adverse effects and easy application. tDCS has been effective without a chronic fight process, including fibromyalgia (FM), in which the processes of disinhibition are cortical and infracortical, demonstrated by neurophysiological as intracortical facilitation and desinhibition, as well as reduction of the power of the systems descending pain modulators. In addition, studies have shown a severity of inhibition of central positive correlation with BDNF (Brain Derived Neurotrophic Factor) levels and seems to have some relation to the peripheral nociceptive pathways, as the areas of application of the stimulation depend on the primary motor cortex (M1) is the most studied target and the largest contingent of selection for the treatment of pain and motor reaction, while the dorsolateral prefrontal cortex (DLPFC) was effective in the treatment of depression and psychoaffective components in cases of patients with the chronic condition. Although tDCS has been successful in treating FM, its main limiter is a need for the service center for consecutive days as it has cumulative effect. In fact, the erasure of the sessions guaranteed the therapeutic effect of the ETCC. The application of measures on consecutive days motivated the study of its value when applied at the household level, in order to allow the large-scale treatment technique to be adopted in the Unified Health System. This is proved by two studies. The first objective is to examine whether a fine-fiber dysfunction that occurs in patients with FM is linked to an operation of the pain-modulating system. Neuropathy of long nerve fibers has been implicated by a descriptor of pain, neurophysiological and psychophysiological neurophysiology, as well as skin biopsy studies. However, this comparison was not associated with dysfunction in the descending pain system (DPMS) not on FM. Objective did the study explore the association of dysfunction of small fibers with the DPMS and other substitutes for nociceptive changes in FM. In the second, the term is a measure of long-term use of ETCC at household level in FM Study I: In this first study evaluating the presence of nerve and peripheral fiber failure, it is linked to the functioning of the descending pain modulator system (DPMS) in FM Methods: It was performed an exploratory study with 41 FM women and 28 healthy volunteers whose were evaluated in psychophysical tests that evaluated a function of sensory fibers involved in nociception. The quantitative sensory test (QST) was used to measure the Heat thermal threshold (HTT), the heat pain threshold (HPT) and the thermal pain tolerance (HPTo), as well as the numerical scale of pain (NPS0 -10 ) over a task of modulation of conditioned pain (CPM-task). Algometry was used to determine the pain pressure threshold (PPT). Scales for evaluation of catastrophic, anxiety, depression and sleep disorders were also applied. Brain-derived neurotrophic factor (BDNF) was measured as a marker of neuroplasticity. Multivariate linear regression models by group (health and FM) for a relationship between a descending modulatory system function and its relationship with psychophysical measures. Results: The samples differed in their psychological profile, and in the psychophysical measures, the group and the patients with FM had lower sensitivity and pain thresholds. At FM, regression models revealed that HTT was related to BDNF and CPM-Task (Hotelling's Trace = 1.80, P <0.001, power = 0.94, R2 = 0.64). HTT was positively correlated with a CPM task (B = 0.98, P = 0.004, partial-ƞ2 = 0.25), and HPT (B = 1.61, P = 0.008, partial -ƞ2 = 0.21) . However PPT was not correlated with HTT. In FM, the relationship of BDNF with CPM, a negative relation was found (B = -0.04, P = 0.043, partial- = 2 = 0.12) and HPT was proportionally (B = -0.08, P = 0.03, partial-ƞ2 = 0.14). BDNF did not influence the model. And the adverse effects reported were higher in the active group (17.8%) compared to the sham group (6.6%). Conclusion: Peripheral sensory dysfunction is positively associated with the modulating dysfunction of BDNF levels in FM, which does not occur in isolated individuals. Study II: The second study had the purpose of evaluating the home use of 60 sessions of atDCS and s-tDCS on a left DLPFC area in patients with FM. Methods: A randomized, double-blind, parallel-sham controlled study in 20 women with FM. Stimulation was performed for five consecutive days in the week for 30 min at the intensity of 2 mA for 12 weeks, totaling 60 sessions. Patients were trained to use equipment specially designed for home use and maintained contact with the researcher responsible through daily text message. The effects were measured through visual pain scale (VAS) daily during the course of 12 weeks of treatment, as well as the use of analgesics and possible adverse events daily. The levels of depression, catastrophism and disability for daily tasks were assessed. The QST was used to check pain threshold and tolerance to heat, an algometry was used to check pressure pain threshold (PPT) and blood collection was performed to evaluate serum BDNF levels at baseline, after 30 sessions and at the end of treatment. A Mixed Linear Model with fixed effects was used to compare changes in pain scores in VAS throughout the treatment. Results: Home-based tDCS reduced dairy pain VAS scores (p<0.001), with cumulative mean pain drop of 64% (p<0.001). Furthermore, active home-based tDCS reduced significantly disability due to pain [B-PCP:S total scores (p=0.023; partial-ƞ2=0.61]. And also reduced scores in clinical measures like depression scores, catastrophizing pain scores and sleep quality scores [BDI-II and PCS (p<0.05), PSQI (p<0.05)]. However, active homebased tDCS enhance scores in algometry (PPT) and heat pain tolerance (HPTo) (p<0.01). Conclusion: Home-based anodal tDCS applied over the DLPFC in FM had a baseline neuroplasticity-dependent reduction effect on pain. In addition, it improved the disability due to pain, depressive symptoms and pain catastrophizing. It reduced the analgesic use and increased pressure and heat pain tolerance.

Está estabelecido na literatura de neurociência que ocorrem transformações no encéfalo de animais, devido à neuroplasticidade; estas podem ser potencializadas de acordo com os ambientes nos quais o indivíduo interage, assim como o tipo de interação estabelecida por este. Na literatura, a aplicação do conceito de ambiente enriquecido para a prática experimental mostra resultados favoráveis e significativos na aprendizagem e desenvolvimento de animais. Neste estudo, buscou-se ampliar o conceito de ambiente enriquecido para o ambiente educacional de um centro de ciência. Investigar a interação de alunos do 5º ano da rede pública de ensino, em ambiente educacional de oficinas de construção de brinquedos oferecidas, no Centro de ciência Sabina: Escola Parque do Conhecimento (Santo André, SP), e possíveis aproximações com o conceito de ambiente educacional enriquecido, proposto neste estudo, constitui o objeto deste trabalho. Nesta investigação buscou-se destacar os componentes ambientais que influem no desempenho e na interação dos alunos durante as oficinas. A investigação, de natureza qualitativa, foi inspirada na metodologia de Estudo de Caso do tipo Etnográfico Aplicado à Educação, que indica a imersão do pesquisador no campo investigado para apreensão de relações e significados dos sujeitos, apenas realizada após longa permanência do pesquisador em campo. Foram utilizados como instrumentos entrevistas, gravação em áudio e em vídeo e adotado o diário de campo para registro das observações. Os dados mostraram incorporação de elementos conceituais de fenômenos observados durante a execução das oficinas, assim como busca ativa de explicação para compreensão desses fenômenos físicos identificados durante a interação dos alunos com os brinquedos. Por meio deste estudo, identificou-se a necessidade de considerar os ambientes educacionais em perspectiva integral, em seus componentes físico-estruturais e humanos. Em ambiente educacional, as aquisições por parte dos alunos não se restringem ao ensino e aprendizagem de conteúdos, mas também se realizam na mudança de atitudes e crenças, compreensão de fenômenos e aspectos do cotidiano, entendimento estético, identidade etc. Foi observado que alunos rotulados no ambiente escolar como aluno com distúrbios; com dificuldades de aprendizagem e ou comprometimento, no ambiente das oficinas de construção de brinquedos apresentaram desempenho e envolvimento tão bom ou melhor quanto os dos alunos considerados normais. O estudo destacou o papel do mediador e do professor como essencial na atividade, como parte dos elementos enriquecedores do ambiente de aprendizagem, em que sua expectativa em relação ao desempenho dos alunos, sua concepção de ensino e de aprendizagem e orientações oferecidas aos alunos influem significativamente no ambiente, condução da atividade e desempenho dos alunos. Desta forma, observamos que o ambiente de construção de brinquedos possui elementos que propiciam a aprendizagem, a interação e desenvolvimento dos alunos / It is well established in the literature of Neuroscience that transformations occur in the brain of animals due to neuroplasticity, these can be potentiated according to the environments in which the individual interacts, as well as the type and quality of interaction established by the individual. In the literature, the application of the concept of enriched environment for the experimental practice shows favorable and significant results in learning and development of animals. In this study, we sought to extend the concept of an enriched environment for the educational environment of a science center. To investigate the interaction of students in the 5th year of public school in the educational environment of workshops to build toys that are offered at the Centro de Ciência Sabina: Escola Parque do Conhecimento (Santo André, SP), and possible approaches to the concept of enriched educational environment, proposed in this study are the objective of this research. In this study we sought to investigate the environmental components that influence the performance and interaction of students during the workshops. The research, qualitative in nature, was inspired by the methodology of case study Ethnographic Applied to Education type which indicates the immersion of the researcher in the investigated field for seizure of relationships and meanings of the subjects performed only after long enough residence of the researcher in the field. Interviews, audio and video recording were used as instruments along with the field diary to record observations. The data showed incorporation of elements of the conceptual phenomena worked during the workshops, as well as an active search for an explanation for understanding these identified physical phenomena during the students\' interaction with the proposed toys. Through this study, we identified the need to consider the educational environments in a comprehensive perspective on their physical-structural and human components. In the educational environment, acquisitions of knowledge by students are not restricted to teaching and learning contents, but also take place by changing attitudes and beliefs, understanding of the phenomena and aspects of everyday life, aesthetic understanding, identity, etc. It was also observed that students labeled at school as a student with learning problems, in the environment of the workshops to build toys showed involvement and performance as good or better as the students originally considered normal. The study highlighted the role of the mediators and the teacher as essential in the activity as part of the elements enriching the learning environment, in which their expectations regarding the performance of the students, their conception of teaching and learning and guidance offered to pupils significantly affect the environment, conducting the activity and performance of students. Thus, we observed that the environment of building toys might have physical and human elements to promote learning and students interaction and so it might be considered as enriched environment