A Fibromialgia (FM) é uma síndrome que se caracteriza por dor crônica difusa, fadiga, transtornos do sono e alterações de humor. Embora sua fisiopatologia não esteja totalmente elucidada, o processo neurobiológico parece envolver alterações do córtex sensitivo e motor e de suas conexões com estruturas subcorticais que constituem a neuromatriz da dor, assim como alterações neuropáticas periféricas. Sabe-se que o aumento do cálcio intracelular acima de certo limiar, pode ser parte do processo dependente de atividade que leva à sensibilização central, por aumento do influxo de cálcio por meio de canais NMDA, AMPA, canais dependentes de voltagem, e por liberação de reservas intracelular microssomais. A sensibilização central pode ser também interpretada como um processo de plasticidade mal-adaptativa que sustenta circuitos da dor e de seus correlatos. Por tanto, o córtex sensitivo e motor tem sido alvo diagnóstico e terapêutico para o estudo e tratamento da dor crônica. Dentre as múltiplas estratégias farmacológicas tem sido preconizado o uso da pregabalina, aprovado pela Food and Drug Administration (FDA) dos EUA para uso no tratamento de fibromialgia em 2007. A pregabalina age inibindo os canais de cálcio pré sinápticos dependentes de voltagem por se ligar à proteína auxiliar alfa-2-delta. In vitro, este fármaco reduz a liberação de neurotransmissores cálcio-dependentes incluindo glutamato, norepinefrina, calcitonina e substância P, estes neurotransmissores têm sido associados à sensibilização do sistema nervoso. Portanto, considerando o potencial neuromodulador da pregabalina baseado no seu mecanismo de ação, é um fármaco atrativo para avaliar o papel da modulação do córtex sensitivo e motor na fisiopatolgia da FM. No entanto, para que se avance no conhecimento do efeito dos fármacos na função encefálica, necessitamos utilizar recursos de neuroimagem que sejam exequíveis em contextos diversos, e que permitam mensurar o efeito dos fármacos dinamicamente. Dentre os recursos de imagem existe a Functional Near Infrared Spectroscopy (fNIRS) que permite avaliar ativação cortical por meio da mudança no consumo local de oxigênio que acompanha o disparo neuronal regional, mensurado pelas mudanças na concetração da oxi- e desoxi-hemoglobina. Com estas considerações, hipotetizamos que a modulação farmacológica induzida pela pregabalina poderia ser mensurada, clinicamente por meio de testes psicofísicos da dor (que avaliam vias nociceptivas associadas a termoreceptores e barorreceptores) e à nível de neuroimagem por meio do fNIRS. Por se tratar de um mesmo sistema com potencial de ser avaliado de forma virtualmente simultânea, hipotetizamos também que existirá uma associação entre as modulações clínicas (testes psicofísicos) e neurológicas (fNIRS do córtex sensitivo e motor primários). Desta forma, neste estudo avaliou-se o efeito de pregabalina (150 mg) em dose única em fibromiálgicas e controles saudáveis. Em ambos os grupos a pregabalina foi comparada ao placebo, num desenho de estudo randomizado, duplo-cego, cruzado. Avaliou-se o efeito das intervenções, intra e inter-grupos, na ativação cortical de maneira indireta, pela concetração da oxi-hemoglobina durante testes psicofísicos da dor por meio meio do Quantitative Sensory Testing (QST) e algometria de pressão, que foram comparados com a ativação cortical durante uma tarefa motora de percussão dos dedos da mão (left hand finger tapping). Foram estudadas mulheres com idade entre 18 e 65 anos, 17 fibromiálgicas e 10 controles saudáveis. Os parâmetros do QST foram avaliados uma hora após dose única de 150 mg de pregabalina. Resultados: Na linha de base, as fibromiálgicas apresentaram alterações no QST sugestivas de lesão de fibras finas: o limiar de detecção de calor (HDT, do inglês Heat Detection Threshold) foi maior que nas controles (35,53 ºC ± 3,22 vs. 33,33 ºC ± 0,85; p<0,05), enquanto o limiar de dor por pressão (PPT, do inglês Pain Pressure Threshold) foi menor (2,44 kg/cm2 ± 1,08 vs. 4,32 kg/cm2 ± 1,45; P<0,01). Não foram observadas diferenças nos outros componentes do QST, nem mudanças com a pregabalina. Quando comparados com as saudáveis, nas fibromiálgicas o HDT, limiar de dor por calor (HPT) e a tolerância ao calor (HT) evocaram activação nos giros frontal médio, precentral e póscentral, porém, de menor amplitude do que as controles. Depois da administração da pregabalina, aumentou a ativação em responsta ao HDT, mas não teve correlação com o valor do limiar. Já o HPT mostrou se correlacionar de forma inversa com a ativação nos giros frontal superior (rs=-0,552, p=0,033) e precentral (rs=-0,545, p=0,036) na linha de base e após pregabalina (rs=-0,52, p=0,047). A HT também apresentou uma correlação inversa com os giros frontal superior (rs=-0,645, p=0,032) e precentral (rs=-0,655, p=0,029), mas neste caso, esta correlação desapareceu após ter recebido pregabalina. A ativação cortical pelo PPT não detectou diferenças entre fibromiálgicas e controles. Conclusões: O perfil nos testes psicofísicos nas pacientes apresenta correlação com sua ativação cortical. As alterações nos testes sugerem alterações de fibras finas nociceptivas, o que é explicado por um componente de neuropatia periférica, que na fibromialgia é acompanhado por diminuição da ativação em áreas sensitivas e motoras, e aumento da ativação em áreas associadas com processamento cognitivo da dor, cuja atividade foi elevada com a pregabalina. Quando comparadas às controles, nas fibromiálgicas a HT recrutou mais áreas associada ao processamento cognitivo da dor, o que fortalece a hipótese a favor da existência do componente de sensibilização central na fibromialgia. Desta forma, estes achados reforçam a provável coexistência de alterações periféricas e centrais na fisiopatologia da fibromialgia. / Fibromyalgia is a syndrome characterized by presenting chronic diffuse pain, fatigue, mood and sleep disturbances. Although its pathophysiology has not been totally elucidated yet, the neurobiological processes seems to involve funciontal alterations of the sensorimotor cortex and its conections with subcortical structures (related to the pain neuronal matrix), and also, with quantitative and qualitative alterations in fine sensitive fibers from the peripheral nervous system. It is known that increased intracellular calcium above certain threshold might be part of a process activity-dependant that leads to central sensitization, due to elevated calcium influx through NMDA and AMPA channels, as well as voltage-dependent channels, and also due to relase of intracellular microsomal reserves. Central sensitization can also be interpreted as a maladaptive plasticity that sustains pain circuits and its correlated. Thus, the sensorimotor cortex has been a diagnostic and therapeutic target for the study and treatment of chronic pain. Among the multiple pharmacological strategies, the use of pregabalin has been recommended and approved by the Food and Drug Administration (FDA) of the United States of America for treatment of patients with fibromyalgia since 2007. Pregabalin acts by inhibiting voltage-dependant pre-synaptic calcium channels by binding to the auxiliary protein alfa-2-delta. In vitro, this drug reduces the liberation of neurottransmissors that depend on calcium, and that include glutamate, norepinephrine, calcitonin and P-substance. All the latter mentioned neurotransmitters are associated with the central nervou system sensitization. Thus, considering its potential as neuronal modulation, taking into accout tis mechanisms of action, the pregabalin is an appealing drug to study the role of the modulation fo the sensorimotor cortex in the pathophysiology of fibromyalgia. Nevertheless, to incrase the knowledge about the effect of drugs on the cortical function, we need to use feasible neuroimaging resources able to be applied in diverse contexts, and that allow to measure the effect of the drugs in real time. Among the neuroimaging resources, there is the Functional Near Infrared Spectroscopy (fNIRS), which allows to assess cortical activation estimating the uptake of regional oxygen, that accompanies local neuronal firing. The fNIRS measures changes in the concentration of oxy and desoxy hemoglobin. Given these considerations, we hypothezise that the pharmacological modulation induced by pregabalin could be measured, clinically through psychophysical pain testing, and at the neuroimaging level using fNIRS. Given that it is about the same system with the potential to be assessed in complementary and virtually simultaneous ways, we also hypothesize that there still could exist an association between the clinical modulation (psychophysical tests) and cortical sensorimotor activation (assessed by fNIRS). In this way, this study appraised the effect of a single dose of pregabalin (150 mg) in the cortical activation and psicophysical pain testing in fibromyalgic and in healthy subjects. In both groups, pregabalin was compared to placebo, in a randomized, double-blinded, cross-over trial design. We assessed the effect of pregabalin, within and between-groups, on the cortical activity in an indirect way via the changes in oxy-hemoglobin upon heat and pressure stimuliation inside a protocol of QST, and also compared the psychophysical pain tests results with the performance during a Left Hand Fingertapping Task. We studied women aging 18 to 65, 17 of them with fibromyalgia and 10 healthy controls. QST parameters were assessed one hour after a single dose of 150 mg of pregabalin. Results: At baseline, patients with fibromyalgia presented QST alterations suggestive of fine nerve fibers lesion: baseline HDT was higher in fibromyalgia (35.53±3.22 vs. 33.33±0.85, P<0.05), while PPT was lower (2.44±1.08 vs. 4.32±1.45, P<0.01) than healthy volunteers, but did not change with pregabalin. When compared to healthy subjects, HDT, HPT, and HT evoked smaller activation in the middle frontal, pre- and post-central gyri in fibromyalgia, that increased after pregabalin (only for HDT-induced activation), but that was not correlated to the HDT. HPT was inversely correlated to the activation in the superior frontal (rs=-0.552, p=0.033) and precentral gyri (rs=-0.545, p=0.036), remaining unchanged after pregabalin (rs=-0.52, p=0.047). HT was inversely correlated to the middle frontal (rs=-0.645, p=0.032) and precentral gyri activation (rs=-0.655, p=0.029), but was no longer correlated after pregabalin. PPT cortical activation did not differ between fibromyalgia and healthy volunteers. Conclusions: The psychophysical pain testing profile in fibromyalgia has a cortical correlate. Alterations in tests for small fibers support its probable peripheral neuropathic component, and was accompanied by decreased activation in sensorimotor areas but increased in pain-related cognitive processing cortexes, and whose activity is increased by pregabalin. Also, upon HT fibromyalgia patients recruited more areas related to pain cognitive processing, which could favor the hypothesis of a component of central sensitization in fibromyalgia, and which was poorly modulated by pregabalin. Taken together, these findings support the co-existence of both, peripheral and central alterations in fibromyalgia.

This study aims to shed light on how and when mechanisms of the human brain evolved to support complex cognition and language. The field of evolutionary cognitive archaeology asserts that prehistoric technologies, as products of past cognition in action, are informative of the minimum cognitive and linguistic abilities that hominins needed to possess for their production. Previous researchers attempted to reconstruct the neural correlates of two Early Stone Age (ESA) tool industries, the 2.6 million-year-old Oldowan industry and the 0.7 million-year-old late Acheulian industry, by using positron emission tomography (PET) to observe the functional activation occurring in the brains of trained and expert stone knappers after making these different tool types. Because of evidence for overlap between the knapping and language circuits of the brain and increased anterior frontal activity during Acheulian tool production, these researchers argued that their results 1) indicate increased cognitive demands for late Acheulian tool production relative to Oldowan tool production and 2) support a technological origin for language, meaning that certain language functions co-opted the neural substrate and functions that were already established for toolmaking and tool use. Because of the motion limiting aspects of PET, however, these studies were unable to record the hemodynamic response of naturalistic stone knapping in real-time. They also were unable to observe the functional activation associated with the earliest stage of learning, which is likely to differ from late stage learning or expertise. Furthermore, any conclusion regarding a technological origin for language is problematic if it relies on data obtained from participants who learned to knap with verbal instruction. To test these two claims, this dissertation utilized a neuroimaging technique called functional near-infrared spectroscopy (fNIRS) to explore the neural correlates of real-time, naturalistic Oldowan and Acheulian stone knapping at three different points in learning. Participants in the study were separated into two groups to learn ESA knapping skills. Both groups watched the same video tutorials that depicted an expert’s hands as he made stone tools, but those in the verbal group heard spoken instructions, while those in the nonverbal group watched a version with the sound turned off. Functional brain images were reconstructed from the digitized landmarks of each participant’s head and from the optical data. An analysis of variance (ANOVA) revealed a clearer distinction between the neural processes of Oldowan and Acheulian tool manufacturing tasks than has previously been demonstrated. Only the Acheulian task recruited a frontotemporal working memory network. Selection for individuals with increased working memory capacities, which would have allowed them to make increasingly complex tools to gain access to novel dietary items, may have spurred the evolution of larger brain size in the genus Homo during the early Pleistocene. The results also demonstrated that the presence or absence of language during training dictated which higher-order cognitive areas of the brain become engaged and at what point in training. Thus, the results of previous neuroarchaeological studies reflect a very specific condition of stone knapping skill acquisition that involves linguistic instruction, which may not be analogous to how skills were transmitted during the ESA. Finally, evidence of overlap between left hemisphere language and stone knapping circuits among the participants in the nonverbal group lends additional support for the technological origin for language hypothesis.

Functional Near Infrared Spectroscopy (fNIRS) is a safe, low-cost, non-invasive opti-cal technique to monitor focal changes in brain activity using neurovascular coupling and measurements of local tissue oxygenation, i.e., changes in concentrations of oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (HbR)[42]. This thesis utilizes two fNIRS approaches to measure hemodynamic changes associated with functional stimulation of the human auditory cortex. The first approach, single-distance continuous wave NIRS (CW-NIRS) utilizes relatively simple instrumentation and the Modified-Beer Lambert (MBL) law to estimate activation induced changes in tissue oxygenation (∆CHbO and ∆CHbR)[17]. The second more complex approach, frequency domain NIRS (FD-NIRS), employs a photon diffusion model of light propagation through tissue to measure both baseline (CHbO and CHbR), and stimulus induced changes in oxygenated and deoxygenated hemoglobin[10]. FD-NIRS is more quantitative, but requires measurements at multiple light source-detector separations and thus its use in measuring focal changes in cerebral hemodynamics have been limited. A commercial FD-NIRS instrument was used to measure the cerebral hemodynamics from the right auditory cortex of 9 adults (21 ± 35 years) with normal hearing, while presented with two types of auditory stimuli: a 1000 Hz Pure tone, and Broad band noise. Measured optical intensities were analyzed using both MBL and photon diffusion approaches. Oxygenated hemoglobin was found to increase by 0.351 ± 0.116 µM and 0.060 ± 0.084 µM for Pure tone and Broad band noise stimuli, when analyzed by the MBL method at the ‘best’ source-detector separation. On average (across all sources), MBL analysis estimated an increase in CHbO of 0.100±0.075 µM and 0.099±0.084 µM respectively for Pure tone and Broad band noise stimulation. In contrast, the frequency domain analysis method estimated CHbO to increase by −0.401 ± 0.384 µM and −0.031 ± 0.358 µM for Pure tone and Broad band noise stimulation respectively. These results suggest that although more quantitative, multi-distance FD-NIRS may underestimate focal changes in cerebral hemodynamics that occur due to functional activation. Potential reasons for this discrepancy, including the partial volume effect, are discussed.

Induktion präfrontaler Dysfunktion bei gesunden Probanden durch inhibitorische TMS: Eine NIRS-Messung / Induction of a prefrontal dysfunction on healthy subjects with inhibitory TMS: a near-infrared spectroscopy (NIRS) study

The ability to control one’s behaviour is a fundamental cognitive function subserved by the prefrontal cortex (PFC). Whereas the neural basis of inhibitory control is reasonably well-established, the possible influence of individual differences in personality on cortical activity associated with this ability remains largely unexplored. The present study obtained self-report ratings of Five-Factor Model personality traits from 42 healthy adults while hemodynamic oxygenation in the PFC was recorded during a Go/No-Go task. Results indicated that Neuroticism, Agreeableness and Openness to Experience were associated with attenuated activity in the lateral PFC, a region critical for emotion regulation and behavioural control, whereas Extraversion and Conscientiousness were associated with greater activation in these regions. Activity within the medial PFC, an area linked to task engagement and self-monitoring, shared a positive association with Agreeableness. These findings provide important insights into how neural systems supporting inhibitory control may be affected by individual differences in personality.

The ability to control one’s behaviour is a fundamental cognitive function subserved by the prefrontal cortex (PFC). Whereas the neural basis of inhibitory control is reasonably well-established, the possible influence of individual differences in personality on cortical activity associated with this ability remains largely unexplored. The present study obtained self-report ratings of Five-Factor Model personality traits from 42 healthy adults while hemodynamic oxygenation in the PFC was recorded during a Go/No-Go task. Results indicated that Neuroticism, Agreeableness and Openness to Experience were associated with attenuated activity in the lateral PFC, a region critical for emotion regulation and behavioural control, whereas Extraversion and Conscientiousness were associated with greater activation in these regions. Activity within the medial PFC, an area linked to task engagement and self-monitoring, shared a positive association with Agreeableness. These findings provide important insights into how neural systems supporting inhibitory control may be affected by individual differences in personality.

Introduktion: Silversplints til personer med hypermobil Ehlers-Danlos syndrom er blevet udbredt i Danmark, men der findes ingen dokumenteret evidens for fingerortoserne til denne målgruppe. Hypermobilitet gør simple greb krævende og indikerer, at personer med EDS bruger væsentligt mere mental opmærksomhed på simple håndbevægelser sammenlignet med raske personer. Formål: Formålet med studiet var at undersøge effekten af silversplints til personer med EDS og hypermobilitet målt på henholdsvis håndfunktion og den mentale arbejdsbyrde præfrontalt. Metode: 5 deltagere med EDS samt 5 matchede kontrolpersoner blev rekrutteret. Den relative koncentration af O2Hb og HHb præfrontalt blev målt med fNIRS under Box and Block testen samt 3 øvrige modificerede håndfunktionstest. Målinger af deltagerne med EDS blev foretaget under to konditioner; uden og med silversplints. Resultat: fNIRS målingerne viste en signifikant reducering af den relative O2Hb koncentration og en tilsvarende signifikant øgning af den relative HHb koncentration ved anvendelsen af silversplints kontra ingen ortoser. Box and Block testen viste en signifikant forskel ved de to konditioner, og mens skrivetesten demonstrerede en signifikant forskel mellem deltagerne med EDS og kontrolgruppen. Konklusion: Silversplints reducerer den mentale arbejdsbyrde ved personer med EDS.

A Fibromialgia (FM) é uma síndrome que se caracteriza por dor crônica difusa, fadiga, transtornos do sono e alterações de humor. Embora sua fisiopatologia não esteja totalmente elucidada, o processo neurobiológico parece envolver alterações do córtex sensitivo e motor e de suas conexões com estruturas subcorticais que constituem a neuromatriz da dor, assim como alterações neuropáticas periféricas. Sabe-se que o aumento do cálcio intracelular acima de certo limiar, pode ser parte do processo dependente de atividade que leva à sensibilização central, por aumento do influxo de cálcio por meio de canais NMDA, AMPA, canais dependentes de voltagem, e por liberação de reservas intracelular microssomais. A sensibilização central pode ser também interpretada como um processo de plasticidade mal-adaptativa que sustenta circuitos da dor e de seus correlatos. Por tanto, o córtex sensitivo e motor tem sido alvo diagnóstico e terapêutico para o estudo e tratamento da dor crônica. Dentre as múltiplas estratégias farmacológicas tem sido preconizado o uso da pregabalina, aprovado pela Food and Drug Administration (FDA) dos EUA para uso no tratamento de fibromialgia em 2007. A pregabalina age inibindo os canais de cálcio pré sinápticos dependentes de voltagem por se ligar à proteína auxiliar alfa-2-delta. In vitro, este fármaco reduz a liberação de neurotransmissores cálcio-dependentes incluindo glutamato, norepinefrina, calcitonina e substância P, estes neurotransmissores têm sido associados à sensibilização do sistema nervoso. Portanto, considerando o potencial neuromodulador da pregabalina baseado no seu mecanismo de ação, é um fármaco atrativo para avaliar o papel da modulação do córtex sensitivo e motor na fisiopatolgia da FM. No entanto, para que se avance no conhecimento do efeito dos fármacos na função encefálica, necessitamos utilizar recursos de neuroimagem que sejam exequíveis em contextos diversos, e que permitam mensurar o efeito dos fármacos dinamicamente. Dentre os recursos de imagem existe a Functional Near Infrared Spectroscopy (fNIRS) que permite avaliar ativação cortical por meio da mudança no consumo local de oxigênio que acompanha o disparo neuronal regional, mensurado pelas mudanças na concetração da oxi- e desoxi-hemoglobina. Com estas considerações, hipotetizamos que a modulação farmacológica induzida pela pregabalina poderia ser mensurada, clinicamente por meio de testes psicofísicos da dor (que avaliam vias nociceptivas associadas a termoreceptores e barorreceptores) e à nível de neuroimagem por meio do fNIRS. Por se tratar de um mesmo sistema com potencial de ser avaliado de forma virtualmente simultânea, hipotetizamos também que existirá uma associação entre as modulações clínicas (testes psicofísicos) e neurológicas (fNIRS do córtex sensitivo e motor primários). Desta forma, neste estudo avaliou-se o efeito de pregabalina (150 mg) em dose única em fibromiálgicas e controles saudáveis. Em ambos os grupos a pregabalina foi comparada ao placebo, num desenho de estudo randomizado, duplo-cego, cruzado. Avaliou-se o efeito das intervenções, intra e inter-grupos, na ativação cortical de maneira indireta, pela concetração da oxi-hemoglobina durante testes psicofísicos da dor por meio meio do Quantitative Sensory Testing (QST) e algometria de pressão, que foram comparados com a ativação cortical durante uma tarefa motora de percussão dos dedos da mão (left hand finger tapping). Foram estudadas mulheres com idade entre 18 e 65 anos, 17 fibromiálgicas e 10 controles saudáveis. Os parâmetros do QST foram avaliados uma hora após dose única de 150 mg de pregabalina. Resultados: Na linha de base, as fibromiálgicas apresentaram alterações no QST sugestivas de lesão de fibras finas: o limiar de detecção de calor (HDT, do inglês Heat Detection Threshold) foi maior que nas controles (35,53 ºC ± 3,22 vs. 33,33 ºC ± 0,85; p<0,05), enquanto o limiar de dor por pressão (PPT, do inglês Pain Pressure Threshold) foi menor (2,44 kg/cm2 ± 1,08 vs. 4,32 kg/cm2 ± 1,45; P<0,01). Não foram observadas diferenças nos outros componentes do QST, nem mudanças com a pregabalina. Quando comparados com as saudáveis, nas fibromiálgicas o HDT, limiar de dor por calor (HPT) e a tolerância ao calor (HT) evocaram activação nos giros frontal médio, precentral e póscentral, porém, de menor amplitude do que as controles. Depois da administração da pregabalina, aumentou a ativação em responsta ao HDT, mas não teve correlação com o valor do limiar. Já o HPT mostrou se correlacionar de forma inversa com a ativação nos giros frontal superior (rs=-0,552, p=0,033) e precentral (rs=-0,545, p=0,036) na linha de base e após pregabalina (rs=-0,52, p=0,047). A HT também apresentou uma correlação inversa com os giros frontal superior (rs=-0,645, p=0,032) e precentral (rs=-0,655, p=0,029), mas neste caso, esta correlação desapareceu após ter recebido pregabalina. A ativação cortical pelo PPT não detectou diferenças entre fibromiálgicas e controles. Conclusões: O perfil nos testes psicofísicos nas pacientes apresenta correlação com sua ativação cortical. As alterações nos testes sugerem alterações de fibras finas nociceptivas, o que é explicado por um componente de neuropatia periférica, que na fibromialgia é acompanhado por diminuição da ativação em áreas sensitivas e motoras, e aumento da ativação em áreas associadas com processamento cognitivo da dor, cuja atividade foi elevada com a pregabalina. Quando comparadas às controles, nas fibromiálgicas a HT recrutou mais áreas associada ao processamento cognitivo da dor, o que fortalece a hipótese a favor da existência do componente de sensibilização central na fibromialgia. Desta forma, estes achados reforçam a provável coexistência de alterações periféricas e centrais na fisiopatologia da fibromialgia. / Fibromyalgia is a syndrome characterized by presenting chronic diffuse pain, fatigue, mood and sleep disturbances. Although its pathophysiology has not been totally elucidated yet, the neurobiological processes seems to involve funciontal alterations of the sensorimotor cortex and its conections with subcortical structures (related to the pain neuronal matrix), and also, with quantitative and qualitative alterations in fine sensitive fibers from the peripheral nervous system. It is known that increased intracellular calcium above certain threshold might be part of a process activity-dependant that leads to central sensitization, due to elevated calcium influx through NMDA and AMPA channels, as well as voltage-dependent channels, and also due to relase of intracellular microsomal reserves. Central sensitization can also be interpreted as a maladaptive plasticity that sustains pain circuits and its correlated. Thus, the sensorimotor cortex has been a diagnostic and therapeutic target for the study and treatment of chronic pain. Among the multiple pharmacological strategies, the use of pregabalin has been recommended and approved by the Food and Drug Administration (FDA) of the United States of America for treatment of patients with fibromyalgia since 2007. Pregabalin acts by inhibiting voltage-dependant pre-synaptic calcium channels by binding to the auxiliary protein alfa-2-delta. In vitro, this drug reduces the liberation of neurottransmissors that depend on calcium, and that include glutamate, norepinephrine, calcitonin and P-substance. All the latter mentioned neurotransmitters are associated with the central nervou system sensitization. Thus, considering its potential as neuronal modulation, taking into accout tis mechanisms of action, the pregabalin is an appealing drug to study the role of the modulation fo the sensorimotor cortex in the pathophysiology of fibromyalgia. Nevertheless, to incrase the knowledge about the effect of drugs on the cortical function, we need to use feasible neuroimaging resources able to be applied in diverse contexts, and that allow to measure the effect of the drugs in real time. Among the neuroimaging resources, there is the Functional Near Infrared Spectroscopy (fNIRS), which allows to assess cortical activation estimating the uptake of regional oxygen, that accompanies local neuronal firing. The fNIRS measures changes in the concentration of oxy and desoxy hemoglobin. Given these considerations, we hypothezise that the pharmacological modulation induced by pregabalin could be measured, clinically through psychophysical pain testing, and at the neuroimaging level using fNIRS. Given that it is about the same system with the potential to be assessed in complementary and virtually simultaneous ways, we also hypothesize that there still could exist an association between the clinical modulation (psychophysical tests) and cortical sensorimotor activation (assessed by fNIRS). In this way, this study appraised the effect of a single dose of pregabalin (150 mg) in the cortical activation and psicophysical pain testing in fibromyalgic and in healthy subjects. In both groups, pregabalin was compared to placebo, in a randomized, double-blinded, cross-over trial design. We assessed the effect of pregabalin, within and between-groups, on the cortical activity in an indirect way via the changes in oxy-hemoglobin upon heat and pressure stimuliation inside a protocol of QST, and also compared the psychophysical pain tests results with the performance during a Left Hand Fingertapping Task. We studied women aging 18 to 65, 17 of them with fibromyalgia and 10 healthy controls. QST parameters were assessed one hour after a single dose of 150 mg of pregabalin. Results: At baseline, patients with fibromyalgia presented QST alterations suggestive of fine nerve fibers lesion: baseline HDT was higher in fibromyalgia (35.53±3.22 vs. 33.33±0.85, P<0.05), while PPT was lower (2.44±1.08 vs. 4.32±1.45, P<0.01) than healthy volunteers, but did not change with pregabalin. When compared to healthy subjects, HDT, HPT, and HT evoked smaller activation in the middle frontal, pre- and post-central gyri in fibromyalgia, that increased after pregabalin (only for HDT-induced activation), but that was not correlated to the HDT. HPT was inversely correlated to the activation in the superior frontal (rs=-0.552, p=0.033) and precentral gyri (rs=-0.545, p=0.036), remaining unchanged after pregabalin (rs=-0.52, p=0.047). HT was inversely correlated to the middle frontal (rs=-0.645, p=0.032) and precentral gyri activation (rs=-0.655, p=0.029), but was no longer correlated after pregabalin. PPT cortical activation did not differ between fibromyalgia and healthy volunteers. Conclusions: The psychophysical pain testing profile in fibromyalgia has a cortical correlate. Alterations in tests for small fibers support its probable peripheral neuropathic component, and was accompanied by decreased activation in sensorimotor areas but increased in pain-related cognitive processing cortexes, and whose activity is increased by pregabalin. Also, upon HT fibromyalgia patients recruited more areas related to pain cognitive processing, which could favor the hypothesis of a component of central sensitization in fibromyalgia, and which was poorly modulated by pregabalin. Taken together, these findings support the co-existence of both, peripheral and central alterations in fibromyalgia.

A Fibromialgia (FM) é uma síndrome que se caracteriza por dor crônica difusa, fadiga, transtornos do sono e alterações de humor. Embora sua fisiopatologia não esteja totalmente elucidada, o processo neurobiológico parece envolver alterações do córtex sensitivo e motor e de suas conexões com estruturas subcorticais que constituem a neuromatriz da dor, assim como alterações neuropáticas periféricas. Sabe-se que o aumento do cálcio intracelular acima de certo limiar, pode ser parte do processo dependente de atividade que leva à sensibilização central, por aumento do influxo de cálcio por meio de canais NMDA, AMPA, canais dependentes de voltagem, e por liberação de reservas intracelular microssomais. A sensibilização central pode ser também interpretada como um processo de plasticidade mal-adaptativa que sustenta circuitos da dor e de seus correlatos. Por tanto, o córtex sensitivo e motor tem sido alvo diagnóstico e terapêutico para o estudo e tratamento da dor crônica. Dentre as múltiplas estratégias farmacológicas tem sido preconizado o uso da pregabalina, aprovado pela Food and Drug Administration (FDA) dos EUA para uso no tratamento de fibromialgia em 2007. A pregabalina age inibindo os canais de cálcio pré sinápticos dependentes de voltagem por se ligar à proteína auxiliar alfa-2-delta. In vitro, este fármaco reduz a liberação de neurotransmissores cálcio-dependentes incluindo glutamato, norepinefrina, calcitonina e substância P, estes neurotransmissores têm sido associados à sensibilização do sistema nervoso. Portanto, considerando o potencial neuromodulador da pregabalina baseado no seu mecanismo de ação, é um fármaco atrativo para avaliar o papel da modulação do córtex sensitivo e motor na fisiopatolgia da FM. No entanto, para que se avance no conhecimento do efeito dos fármacos na função encefálica, necessitamos utilizar recursos de neuroimagem que sejam exequíveis em contextos diversos, e que permitam mensurar o efeito dos fármacos dinamicamente. Dentre os recursos de imagem existe a Functional Near Infrared Spectroscopy (fNIRS) que permite avaliar ativação cortical por meio da mudança no consumo local de oxigênio que acompanha o disparo neuronal regional, mensurado pelas mudanças na concetração da oxi- e desoxi-hemoglobina. Com estas considerações, hipotetizamos que a modulação farmacológica induzida pela pregabalina poderia ser mensurada, clinicamente por meio de testes psicofísicos da dor (que avaliam vias nociceptivas associadas a termoreceptores e barorreceptores) e à nível de neuroimagem por meio do fNIRS. Por se tratar de um mesmo sistema com potencial de ser avaliado de forma virtualmente simultânea, hipotetizamos também que existirá uma associação entre as modulações clínicas (testes psicofísicos) e neurológicas (fNIRS do córtex sensitivo e motor primários). Desta forma, neste estudo avaliou-se o efeito de pregabalina (150 mg) em dose única em fibromiálgicas e controles saudáveis. Em ambos os grupos a pregabalina foi comparada ao placebo, num desenho de estudo randomizado, duplo-cego, cruzado. Avaliou-se o efeito das intervenções, intra e inter-grupos, na ativação cortical de maneira indireta, pela concetração da oxi-hemoglobina durante testes psicofísicos da dor por meio meio do Quantitative Sensory Testing (QST) e algometria de pressão, que foram comparados com a ativação cortical durante uma tarefa motora de percussão dos dedos da mão (left hand finger tapping). Foram estudadas mulheres com idade entre 18 e 65 anos, 17 fibromiálgicas e 10 controles saudáveis. Os parâmetros do QST foram avaliados uma hora após dose única de 150 mg de pregabalina. Resultados: Na linha de base, as fibromiálgicas apresentaram alterações no QST sugestivas de lesão de fibras finas: o limiar de detecção de calor (HDT, do inglês Heat Detection Threshold) foi maior que nas controles (35,53 ºC ± 3,22 vs. 33,33 ºC ± 0,85; p<0,05), enquanto o limiar de dor por pressão (PPT, do inglês Pain Pressure Threshold) foi menor (2,44 kg/cm2 ± 1,08 vs. 4,32 kg/cm2 ± 1,45; P<0,01). Não foram observadas diferenças nos outros componentes do QST, nem mudanças com a pregabalina. Quando comparados com as saudáveis, nas fibromiálgicas o HDT, limiar de dor por calor (HPT) e a tolerância ao calor (HT) evocaram activação nos giros frontal médio, precentral e póscentral, porém, de menor amplitude do que as controles. Depois da administração da pregabalina, aumentou a ativação em responsta ao HDT, mas não teve correlação com o valor do limiar. Já o HPT mostrou se correlacionar de forma inversa com a ativação nos giros frontal superior (rs=-0,552, p=0,033) e precentral (rs=-0,545, p=0,036) na linha de base e após pregabalina (rs=-0,52, p=0,047). A HT também apresentou uma correlação inversa com os giros frontal superior (rs=-0,645, p=0,032) e precentral (rs=-0,655, p=0,029), mas neste caso, esta correlação desapareceu após ter recebido pregabalina. A ativação cortical pelo PPT não detectou diferenças entre fibromiálgicas e controles. Conclusões: O perfil nos testes psicofísicos nas pacientes apresenta correlação com sua ativação cortical. As alterações nos testes sugerem alterações de fibras finas nociceptivas, o que é explicado por um componente de neuropatia periférica, que na fibromialgia é acompanhado por diminuição da ativação em áreas sensitivas e motoras, e aumento da ativação em áreas associadas com processamento cognitivo da dor, cuja atividade foi elevada com a pregabalina. Quando comparadas às controles, nas fibromiálgicas a HT recrutou mais áreas associada ao processamento cognitivo da dor, o que fortalece a hipótese a favor da existência do componente de sensibilização central na fibromialgia. Desta forma, estes achados reforçam a provável coexistência de alterações periféricas e centrais na fisiopatologia da fibromialgia. / Fibromyalgia is a syndrome characterized by presenting chronic diffuse pain, fatigue, mood and sleep disturbances. Although its pathophysiology has not been totally elucidated yet, the neurobiological processes seems to involve funciontal alterations of the sensorimotor cortex and its conections with subcortical structures (related to the pain neuronal matrix), and also, with quantitative and qualitative alterations in fine sensitive fibers from the peripheral nervous system. It is known that increased intracellular calcium above certain threshold might be part of a process activity-dependant that leads to central sensitization, due to elevated calcium influx through NMDA and AMPA channels, as well as voltage-dependent channels, and also due to relase of intracellular microsomal reserves. Central sensitization can also be interpreted as a maladaptive plasticity that sustains pain circuits and its correlated. Thus, the sensorimotor cortex has been a diagnostic and therapeutic target for the study and treatment of chronic pain. Among the multiple pharmacological strategies, the use of pregabalin has been recommended and approved by the Food and Drug Administration (FDA) of the United States of America for treatment of patients with fibromyalgia since 2007. Pregabalin acts by inhibiting voltage-dependant pre-synaptic calcium channels by binding to the auxiliary protein alfa-2-delta. In vitro, this drug reduces the liberation of neurottransmissors that depend on calcium, and that include glutamate, norepinephrine, calcitonin and P-substance. All the latter mentioned neurotransmitters are associated with the central nervou system sensitization. Thus, considering its potential as neuronal modulation, taking into accout tis mechanisms of action, the pregabalin is an appealing drug to study the role of the modulation fo the sensorimotor cortex in the pathophysiology of fibromyalgia. Nevertheless, to incrase the knowledge about the effect of drugs on the cortical function, we need to use feasible neuroimaging resources able to be applied in diverse contexts, and that allow to measure the effect of the drugs in real time. Among the neuroimaging resources, there is the Functional Near Infrared Spectroscopy (fNIRS), which allows to assess cortical activation estimating the uptake of regional oxygen, that accompanies local neuronal firing. The fNIRS measures changes in the concentration of oxy and desoxy hemoglobin. Given these considerations, we hypothezise that the pharmacological modulation induced by pregabalin could be measured, clinically through psychophysical pain testing, and at the neuroimaging level using fNIRS. Given that it is about the same system with the potential to be assessed in complementary and virtually simultaneous ways, we also hypothesize that there still could exist an association between the clinical modulation (psychophysical tests) and cortical sensorimotor activation (assessed by fNIRS). In this way, this study appraised the effect of a single dose of pregabalin (150 mg) in the cortical activation and psicophysical pain testing in fibromyalgic and in healthy subjects. In both groups, pregabalin was compared to placebo, in a randomized, double-blinded, cross-over trial design. We assessed the effect of pregabalin, within and between-groups, on the cortical activity in an indirect way via the changes in oxy-hemoglobin upon heat and pressure stimuliation inside a protocol of QST, and also compared the psychophysical pain tests results with the performance during a Left Hand Fingertapping Task. We studied women aging 18 to 65, 17 of them with fibromyalgia and 10 healthy controls. QST parameters were assessed one hour after a single dose of 150 mg of pregabalin. Results: At baseline, patients with fibromyalgia presented QST alterations suggestive of fine nerve fibers lesion: baseline HDT was higher in fibromyalgia (35.53±3.22 vs. 33.33±0.85, P<0.05), while PPT was lower (2.44±1.08 vs. 4.32±1.45, P<0.01) than healthy volunteers, but did not change with pregabalin. When compared to healthy subjects, HDT, HPT, and HT evoked smaller activation in the middle frontal, pre- and post-central gyri in fibromyalgia, that increased after pregabalin (only for HDT-induced activation), but that was not correlated to the HDT. HPT was inversely correlated to the activation in the superior frontal (rs=-0.552, p=0.033) and precentral gyri (rs=-0.545, p=0.036), remaining unchanged after pregabalin (rs=-0.52, p=0.047). HT was inversely correlated to the middle frontal (rs=-0.645, p=0.032) and precentral gyri activation (rs=-0.655, p=0.029), but was no longer correlated after pregabalin. PPT cortical activation did not differ between fibromyalgia and healthy volunteers. Conclusions: The psychophysical pain testing profile in fibromyalgia has a cortical correlate. Alterations in tests for small fibers support its probable peripheral neuropathic component, and was accompanied by decreased activation in sensorimotor areas but increased in pain-related cognitive processing cortexes, and whose activity is increased by pregabalin. Also, upon HT fibromyalgia patients recruited more areas related to pain cognitive processing, which could favor the hypothesis of a component of central sensitization in fibromyalgia, and which was poorly modulated by pregabalin. Taken together, these findings support the co-existence of both, peripheral and central alterations in fibromyalgia.

Der moderne Leistungs- und Wettkampfsport verfolgt das anspruchsvolle Ziel, die Effizienz von Trainingsprozessen zu steigern und damit die motorische Leistungsfä-higkeit von SportlerInnen zu optimieren. In diesem Zusammenhang kommt dem zentralen Nervensystem eine entscheidende Bedeutung zu, da das Gehirn als Initia-tor jeglicher Willkürbewegungen gilt, indem es neuronale Impulse erzeugt, welche die Ausführung von Bewegungen steuern. Aktuellen neurowissenschaftlichen Untersu-chungen zufolge führen körperliche Aktivität im Allgemeinen und motorisches Lernen sowie regelmäßiges Training im Speziellen zu permanenten funktionellen und struk-turellen Anpassungen des Gehirns (Neuroplastizität). Darüber hinaus konnten bei SportlerInnen neuronale Expertise-Effekte nachgewiesen werden, die sich sowohl in einer angepassten Hirnmorphologie als auch in einer erhöhten Effizienz der neurona-len Verarbeitung manifestieren. Die Rolle des Gehirns und insbesondere motorisch relevanter Hirnareale bei der Ausführung einfacher und/oder komplexer (sportartspe-zifischer) Bewegungen sowie der Einfluss des Gehirns auf die motorische Leistungs-fähigkeit sind bisher jedoch nur unzureichend erforscht. Das Ziel der vorliegenden kumulativen Dissertation war daher unter Anwendung mo-dernster nicht-invasiver Bildgebungs- und Stimulationsverfahren in einem sportbezo-genen Kontext gegenwärtige Forschungslücken zu schließen. Dazu wurden zwei Studien durchgeführt, in denen neuronale Besonderheiten bei SportlerInnen im Ver-gleich zu Nicht-SportlerInnen untersucht wurden. Mit Hilfe der funktionellen Nahinfra-rotspektroskopie (fNIRS) konnte gezeigt werden, dass (1) die Hirnaktivität in Abhän-gigkeit zur Intensität während einer Radsportbelastung zunimmt, was darauf hindeu-tet, dass eine erhöhte Rekrutierung von Muskelfasern ein höheres Maß an neurona-len Ressourcen erfordert. In einer weiteren Studie wurde gezeigt, dass (2) die Erhö-hung der Erregbarkeit in motorisch relevanten Hirnarealen mittels transkranieller Gleichstromstimulation (tDCS) nicht per se zu positiven Effekten auf Verhaltensebe-ne führt, dass jedoch (3) bestimmte Parameter einer motorischen Leistung selektiv moduliert und optimiert werden können. Zusammenfassend unterstreichen die vorliegenden Ergebnisse das Potential nicht-invasiver Bildgebungs- und Stimulationsverfahren in einem sportbezogenen Kontext und tragen neue Erkenntnisse zu einem innovativen Forschungsgebiet bei. Die sys-tematische Anwendung dieser Methoden eröffnet neue Perspektiven in der zukünfti-gen Sportwissenschaft, um Trainingsergebnisse zu diagnostizieren, zu steigern und die motorische Leistungsfähigkeit von SportlerInnen zu optimieren. Dennoch bleiben einige Fragen bezüglich der zugrundeliegenden Mechanismen und möglichen Erklä-rungsansätzen noch unbeantwortet und müssen daher adressiert werden, um das gesamte Potential des Gehirns im Sport nutzen zu können. / Modern competitive and elite sports pursue the challenging goal of increasing the efficiency of training processes and thereby optimizing motor performance in ath-letes. In this context, the central nervous system is of crucial importance, since the brain is considered the initiator of any voluntary movements by generating neural impulses that control the execution of movements. According to current neuroscien-tific research, physical activity in general and motor learning and regular training in particular lead to permanent functional and structural brain adaptations (neuroplastic-ity). Moreover, neuronal expertise effects have been demonstrated in athletes, which are manifested both in adapted brain morphology and in increased efficiency of neu-ronal processing. However, the role of the brain and more specifically of motor-related brain areas during the execution of simple and/or complex (sport-specific) movements as well as the brain’s influence on motor performance still need to be clarified. Hence, the aim of the present cumulative dissertation was to apply state-of-the-art non-invasive brain imaging and stimulation techniques in a sports-related context focusing on current research gaps. Therefore, two studies were conducted to inves-tigate neuronal particularities in athletes compared to non-athletes. Using functional near-infrared spectroscopy (fNIRS), it has been demonstrated that (1) brain activa-tion increases as a function of intensity during a cycling exercise, indicating that in-creased recruitment of muscle fibers requires a higher level of neuronal resources. In a further study, it has been shown that (2) the increase of excitability in motor-related brain areas by means of transcranial direct current stimulation (tDCS) does not per se translate into positive effects on a behavioral level, but that (3) certain parameters of motor performance can be selectively modulated and optimized. In summary, the present findings underline the potential of non-invasive brain imag-ing and stimulation techniques in a sports-related context and contribute novel knowledge to an innovative research field. The systematic application of these meth-ods provides new perspectives in future sports science in order to diagnose and in-crease training outcomes and optimize motor performance in athletes. However, several questions with regards to underlying mechanisms and potential explanations still remain elusive and need to be addressed to use the brain's entire potential in sports.