No description available.

Type 1 diabetes (T1D) is a chronic disease that is due to the dysregulation of glucose in the blood when insulin is not made endogenously. Patients rely on a combination of exogenic insulin, medications, blood glucose monitoring, and healthy lifestyle activities such as dietary control and exercise to manage their blood glucose levels. T1D typically begins its onset during childhood or adolescence, where it may also affect the development of executive function (EF) processes which are also relevant for self-regulation, or goal-directed behavior. This in turn may affect individuals’ adherence to their T1D management regimens, which can result in severe short- and long-term complications. Despite evidence for the plasticity of EF during childhood, previous research has not frequently focused on EF or self-regulation (SR) as a possible mechanism for improving health outcomes in adolescents with T1D. This study focused on the dosage of EF training and its possible effects on both cognitive and health outcomes for 47 adolescents (M= 15.4, SD =1.45) with T1D undergoing a larger adherence intervention. EF was measured by the Digit Span and Go/No-Go tests, while composite measures of T1D treatment adherence were aggregated via separate parent and adolescent reports. It was hypothesized that both cognitive measures and treatment adherence would have a dose-dependent relationship with n-back training. However, no association was found between training dosage and EF outcomes or treatment adherence. The study’s limitations include a relatively small sample size along with low participant compliance for the EF training. It also might be that the relationship between EF, SR, and health behaviors is more nuanced than previously suggested and that there are a variety of reasons why dosage of training was not linked to differential outcomes. As such, further investigation is required to better understand this relationship in the search for effective interventions for health behavior. / M.S. / Adolescents with Type 1 Diabetes often demonstrate difficulty following their diabetes management plans. One potential reason for these challenges may be that their self-regulation (the ability to intentionally direct their behavior towards a goal) is still developing. This study examined whether there was a dose-response relationship between a cognitive intervention aimed at increasing cognition/self-regulation as well as adherence to diabetes management regimens. The sample included 47 adolescents whose mean age was 15 years. Overall, no effect of dosage of cognitive training was observed on the adolescents' cognitive performance or diabetes management adherence. Reasons for this finding include the study's small sample size, low participation in the cognitive training, or a more nuanced relationship between self-regulation and health behavior.

<p>Children with sickle cell disease (SCD) have a high risk of neurocognitive impairment. No known research, however, has examined the impact of neurocognitive functioning on quality of life in this pediatric population. In addition, limited research has examined neurocognitive interventions for these children. In light of these gaps, two studies were undertaken to (a) examine the relationship between cognitive functioning and quality of life in a sample of children with SCD and (b) investigate the feasibility and preliminary efficacy of a computerized working memory training program in this population. Forty-five youth (ages 8-16) with SCD and a caregiver were recruited for the first study. Participants completed measures of cognitive ability, quality of life, and psychosocial functioning. Results indicated that cognitive ability significantly predicted child- and parent-reported quality of life among youth with SCD. In turn, a randomized-controlled trial of a computerized working memory program was undertaken. Eighteen youth with SCD and a caregiver enrolled in this study, and were randomized to a waitlist control or the working memory training condition. Data pertaining to cognitive functioning, psychosocial functioning, and disease characteristics were obtained from participants. The results of this study indicated a high degree of acceptance for this intervention but poor feasibility in practice. Factors related to feasibility were identified. Implications and future directions are discussed.</p> / Dissertation

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

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

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

Background: Methamphetamine (MA) abuse is a global crisis that exacerbates sociopolitico-economic burdens in South Africa. MA use is associated with a myriad of neural abnormalities of structure and function, with associated neurocognitive deficits, particularly executive function (EF). Working memory (WM) training has been identified as a potential adjunct to treatment of substance use disorder (SUD) to improve EF in the hope of reducing relapse rates. Neuroimaging suggests MA alters intrinsic resting state functional connectivity (rsFC), and this may contribute to neuropsychological deficits observed in methamphetamine use disorder (MUD). Methods: This nested study analysed data described in Brooks et al. (2016), in which WM training was used as an adjunct to inpatient treatment of MUD. Healthy controls (HC, N = 25) were compared to two MUD groups, one receiving treatment as usual (TAU, N = 17), and one receiving additional cognitive training (CT, N = 24) in the form of a modified version of the ‘N-back' task (C-Ya). This task was also used to assess WMA in the neural scanner, using conditions of 0-back and 1-back across groups. The current research explored these data in a novel manner through examining rsFC. Hypotheses: It was predicted that: 1) HC and MUD participants would differ on measures of WMA, but WMA would improve in MA groups at follow-up compared to baseline and this would be augmented in the CT group; 2) rsFC networks of neural regions supporting WM would be predictive of ability to perform well and improve on WM tasks; and 3) MA groups would display heightened rsFC activity within and between resting state neural networks of the default mode network (DMN) and canonical cognitive control networks (CCNs). Results: Significant differences were observed between HC and MA groups in race and level of education, but not on WMA as tested in the scanner. The CT group, who completed WMA 3-back conditions, demonstrated significant improvement on this task post- intervention. Exploratory regression models showed the WM rsFC network did not demonstrate significant relationships with any clinical, demographic, or WM variables when controlling for multiple comparisons. Heightened connectivity within and between the DMN and CCNs was observed in the MUD compared to the HC group, which provided support for hypothesis 3. Exploratory multivariate regression models demonstrated race, age, education, duration of drug use, and an interaction of group and abstinence may impact rsFC in these networks. Post-hoc analyses identified pairwise network combinations affected by these variables. Conclusions: Despite limitations of this small study, it offers tentative preliminary insights into the largely unexplored field of rsFC in MA populations. This study supports limited research demonstrating hyperconnectivity within and between CCNs and DMN of MA users. This study also offers support for recent research suggesting that easier conditions of the Nback task may not reliably test all aspects of WM function. Exploratory analyses of covariates potentially affecting rsFC provide a platform for directions of future research.

The study seeks to bring together literature on decision-making, the effects of work-related demands and stress, and individual differences in trait anxiety on near and far transfer effects of emotional working memory training (eWM). A sample of 31 students and working participants underwent emotional working memory training through an adaptive dual n-back method or a placebo face match training task for 14 days. Pre- and post-training measures were taken of a near transfer task, digit span, medium transfer measure of executive control, emotional Stroop, and a far transfer task of decision-making under uncertainty, the Iowa Gambling Task (IGT). In line with previous studies, eWM was expected to show gains in transfer task performance between pre- and post-training, and, especially for those scoring high on trait anxiety and workplace measures of stress demands (taken from COPSOQ), for whom there is more scope for improvement in emotional regulation. Gains in emotional Stroop specifically were further expected to show support for the effects of eWM training on emotional well-being in addition to decision-making. Results fell short of replicating previous work on transfer gains, though interference effects in Stroop did lessen in the eWM training group. Relationships between work demands, anxiety, stress and performance in the training itself, reinforce previous research showing that work stress and anxiety lead to cognitive failures, highlighting the importance of intervention studies in the organizational field, but they were not linked to benefits of the training. Resource and methodological limitations of the current study are considered, especially those involved in conducting pre-post designs and cognitive testing online.

Deficits in working memory (WM) functions represent one of the main causes of limited participation in daily life and impaired recovery after brain injury. Based on promising research in clinically healthy individuals, which suggest that repetitive training may improve WM performance and other related cognitive functions, this thesis aimed at exploring the potential and limits of WM training in clinical populations. Existing research on WM training and relevant neuropsychological outcomes were examined with a special focus on individuals with acquired brain injury by means of a meta-analysis (study I). The findings indicated relevant impact of WM training on both behavioral performance and disease-related symptom reduction. To determine the primary outcome variable for the evaluation studies, the Corsi Block-Tapping Task was reviewed (study II). Due to the lack of an appropriate theory-based intervention tailored for the needs of individuals with low WM capacity, the program 'WOME' was developed (study III). Three randomized, double-blind, placebo-controlled trials were carried out to evaluate the efficacy of the new intervention and to provide valuable recommendations for its application in clinical practice (study IV, V and VI). Significant improvements in the trained tasks, moderate to large transfer effects in overall WM performance, and related benefits in daily life were demonstrated. The effects were short-termed with very limited evidence supporting transfer to other cognitive functions. In accordance with the results of the meta-analysis (study I), the number of sessions was identified as an important modulator of efficacy by comparing different training intensities and training tasks. The specific content, in contrast, seemed to be less relevant. Mediation analyses revealed that inter-individual differences influence the successful application of the intervention, in particular initial WM capacity. Implications for clinical application and WM training research are discussed.:1. Introduction 1.1. Definition of the working memory system 1.2. Functional neuroanatomy of working memory 1.3. Functional relevance of working memory 1.4. Training of working memory functions 1.5. Objectives of the current thesis 2. Experimental work 2.1. Study I: Can impaired working memory functioning be improved by training? A meta-analysis with a special focus on brain injured patients 2.2. Study II: „Was misst eigentlich die Blockspanne?“ — Der Gold-Standard im Fokus. 2.3. Study III: WOME working memory training — A new intervention for individuals with low WM capacity 2.4. Study IV: WOME: Theory-based working memory training — A placebo-controlled, double-blind evaluation in older adults 2.5. Study V: Effects of working memory training in patients with acquired brain injury: a double-blind randomized controlled trial. 2.6. Study VI: The effect of high vs. low intensity neuropsychological treatment on working memory in patients with acquired brain injury. 3. General discussion 3.1. Summary of the empirical findings 3.2. Implications for clinical practice 3.2.1. Benefits and limits of working memory training 3.2.2. The importance of training dose and its practical implementation 3.2.3. The influence of inter-individual differences on training efficacy 3.3. Implications for working memory training research 3.4. Critical comments and directions for future research 3.5. Conclusion 4. References 5. Summary 6. Zusammenfassung Appendices List of abbreviations List of Tables List of Figures Supplemental material Curriculum vitae List of publications Selbstständigkeitserklärung

The overall aim of this thesis was to explore the role of different assessment tools and training regimens in assessment and remediation for children with special educational needs in school. A central purpose of assessment explored was that it should inform remediation, teaching and instruction. The concepts of working memory, complex executive function and metacognitive strategy training for children with special educational needs were specifically explored in relation to this purpose of assessment. Complex executive function refers to planning and metacognitive ability, that many children with special educational needs struggle with, and which they are expected to handle in learning during school day. Of particular interest in the thesis was the contrast between working memory and complex executive function and how these concepts inform assessment and remediation practices. In this context, special attention was given to mathematical learning difficulties. The thesis was based on four studies (I‑IV). Study I explored the prevalence of different assessment tools, and dilemmas and challenges as perceived by assessment professionals, teachers and parents, in the work with children with special educational needs in Europe. In Study II, a metacognitive strategy training framework was developed as a training regimen, guided by research on complex executive function, and applied on working memory training. Effects of working memory training were compared between the two training regimens, with and without metacognitive strategy training, and also the overall effect of working memory training on cognitive functioning and the school related skills of reading, writing and arithmetic. In Study III, different types of measures of working memory and their predictive capacities in relation to mathematics achievement in national curriculum assessments were explored, as well as the effects of working memory training on mathematics achievement. In Study IV the role of working memory and complex executive function in identifying risk for mathematical learning difficulties in children with special educational needs was explored. The results from Study I suggested that assessment and remediation practices can contribute to a deficiency‑oriented outlook on children with special educational needs. In contrast parents and teachers in Sweden also reported that assessment could help them to better understand the needs of the child. Results from studies II-IV showed that only the use of a metacognitive strategy training regimen targeting complex executive function resulted in improvements following working memory training. The results also indicated that working memory training strongly predicted mathematical performance in national curriculum assessments of mathematics in school, and that a more complex change measure of working memory was a better predictor than simple working memory measures in this regard. Finally, the results also showed that complex executive function, defined as planning ability, was a better predictor than simple working memory in the assessment of risk for mathematical learning difficulties. The results from the studies were discussed in relation to the purpose of assessment to inform remediation, teaching and instruction for children with special educational needs. It was concluded that, in addition to working memory, as complex executive function – planning and metacognitive ability - seems to be an important cognitive function related to learning, this should be addressed both in the assessment of children with special educational needs as well as in the remediation when designing training regimens and interventions for children with special educational needs in general, and children at risk for mathematic learning difficulties in particular. It was also highlighted that in remediation, the role of the teacher as a mediator of metacognition and complex executive function seems vital. / Det övergripande syftet med avhandlingen var att undersöka den roll som olika utredningsverktyg och begrepp spelar i utformandet av utrednings‑ och stödinsatser för barn i behov av stöd i skolan. Ett centralt syfte med utredningar som utforskades är att de ska bidra med kunskaper vid utformande av stödinsatser och undervisning. I relation till detta syfte utforskades specifikt begreppen arbetsminne, komplex exekutiv funktion och metakognitiv strategiträning för barn i behov av stöd. Komplex exekutiv funktion syftar till planerings- och metakognitiv förmåga, något som många barn i behov av stöd upplevs ha svårigheter med, och som de förväntas kunna hantera i lärandet i skolans vardag. Av särskilt intresse i avhandlingen var kontrasten mellan arbetsminne och komplex exekutiv funktion och hur dessa begrepp bidrar till en förståelse i utformandet av utrednings- och stödinsatser. I detta sammanhang uppmärksammades särskilt matematiksvårigheter hos barn i behov av stöd. Avhandlingen bygger på fyra studier (I-IV). I Studie I undersöktes förekomsten av olika utredningsverktyg, samt utredares, lärares och föräldrars uppfattningar av dilemman och utmaningar i arbetet kring barn i behov av stöd, i Europa. I Studie II utformades ett koncept för metakognitiv strategiträning med utgångspunkt från forskning kring komplex exekutiv funktion och tillämpades i arbetsminnesträning. Effekten av arbetsminnesträning med och utan metakognitiv strategiträning jämfördes, liksom effekten av arbetsminnesträning på kognitiva funktioner och skolrelaterade färdigheter inom läsning, skrivning och aritmetik. I Studie III undersöktes olika mått på arbetsminne, och deras prediktiva kapacitet i relation till matematisk förmåga mätt genom nationella prov i matematik, samt effekten av arbetsminnesträning på matematisk förmåga. I Studie IV undersöktes vilken roll arbetsminne och komplex exekutiv funktion har i identifiering av barn i behov av stöd i riskzon för matematiksvårigheter. Resultaten från Studie I visade att utrednings- och stödinsatser kunde bidra till att förstärka ett brist-orienterat synsätt på barn i behov av stöd. I kontrast till detta, delgav lärare och föräldrar i Sverige att utredningar kunde hjälpa dem att förstå barnets behov på ett bättre sätt. Resultaten från studie II-IV visade att enbart den metakognitiva träningen, fokuserad på komplex exekutiv funktion, bidrog till förbättringar efter arbetsminnesträning. Resultatet indikerade också att arbetsminnesträning predicerar matematisk prestation i nationella prov i matematik, och att ett mer komplext arbetsminnesmått var en bättre prediktor än enklare arbetsminnesmått. Slutligen visade resultaten också att komplex exekutiv funktion i form av planeringsförmåga var en bättre prediktor än enkelt arbetsminnesmått vid utredning av risk för matematiksvårigheter. Resultaten från studierna diskuterades i relation till syftet med utredning: att bidra med kunskaper vid utformande av extra anpassningar, särskilt stöd och undervisning för barn i behov av stöd. Eftersom komplex exekutiv funktion –planerings- och metakognitiv förmåga - verkar vara en viktig kognitiv funktion i lärandet, bör man ta hänsyn till detta både i utrednings- och stödinsatser kring barn i behov av stöd generellt, och särskilt kring barn i riskzon för matematiksvårigheter. Det belystes också att i stödinsatser är lärarens roll som mediator av metakognition och komplex exekutiv funktion viktig. / <p>Vid tidpunkten för disputationen var följande delarbeten opublicerade: delarbete 3 (inskickat), delarbete 4 (inskickat)</p><p>At the time of the doctoral defence the following papers were unpublished: paper 3 (submitted), paper 4 (submitted)</p>