Chronic non-specific low back pain (CNSLBP) is a widespread but poorly understood condition that places a substantial burden on the sufferer, health services and the wider economy. Existing approaches to management do not demonstrate impressive levels of effectiveness. There is growing evidence that CNSLBP is associated with significant alterations in central nervous system (CNS) structure and function, suggesting a possible role for the brain in the aetiology of the condition, and presenting a case for novel therapies which aim to treat CNSLBP by affecting brain function. One such potential therapeutic approach is non-invasive brain stimulation (NIBS). Following a literature review discussing the epidemiology and management of low back pain, the evidence for altered CNS function and the potential role of brain stimulation in CNSLBP and chronic pain generally this thesis includes 3 original scientific studies: (i) A Cochrane systematic review of the effectiveness of NIBS techniques for the treatment of chronic pain; (ii) A randomised double-blind exploratory study of transcranial direct current stimulation of the motor cortex in the treatment of CNSLBP; (iii) Is blinding to the stimulation condition maintained in trials comparing 2mA tDCS with sham stimulation? A randomised cross-over study. Results: There is limited existing evidence that some forms of NIBS may have a beneficial effect on chronic pain, though caution is warranted. Exploratory data from study 2 is not suggestive that tDCS to the motor cortex is effective for treating CNSLBP. Commonly used sham controls in trials of tDCS do not ensure adequate blinding, and so introduce a potential source of bias to the existing evidence base. Conclusion: Further research is required to establish the value of NIBS as a treatment for chronic pain and CNSLBP. Future research in tDCS will need to develop and employ fully validated sham controls to ensure adequate blinding. NIBS cannot currently be recommended for the treatment of CNSLBP.

Chronic pain is a major health problem that affects approximately 20% of the adult population, but only 60% of its patients find success in managing their condition. As an alternative therapeutic tool, transcranial direct current stimulation (tDCS) has appeared promising in recent literature, with several papers using the left dorsolateral prefrontal cortex (L-DLPFC) as the stimulation target due to its inherent role in pain modulation. However, the underlying mechanisms of this treatment have never been directly investigated. The thesis intends to explore this question through the application of a combination of tDCS, functional and structural imaging, and an ongoing pain model. The first study investigated the task-free effects of L-DLPFC tDCS by using concurrent arterial spin labeling (ASL) perfusion imaging. Anodal (excitatory) tDCS was associated with an increase in regional cerebral blood flow (rCBF) of L-DLPFC, while cathodal (inhibitory) tDCS was related to a relative decrease. Regions connected to L-DLPFC, such as thalamus and primary somatosensory cortex, also experienced significant perfusion changes. Further analyses found modulations of L-DLPFC–thalamic functional correlations, which was particularly relevant due to the importance of the thalamus in antinociceptive processing. To understand pain neuromodulation, a robust ongoing pain model was required to serve as a platform for the investigation. Thus, electrical, thermal, and capsaicin stimuli were tested in a series of studies. The former two did not produce an ongoing pain sensation, thus failing to replicate a chronic pain experience on healthy volunteers. However, topical application of capsaicin appeared to induce such a response, which entailed a pain intensity rating between 5 and 7 on a 0-10 visual analogue scale for at least 30 minutes. Careful screening ensued to select capsaicin responders from the cohort, who served as the research volunteers for the remainder of the thesis. Combining these two studies, rCBF changes associated with tDCS-induced pain neuromodulation were then directly investigated with concurrent ASL and the above capsaicin model. Behavioral measurements suggested a significant reduction in pain intensity for the anodal tDCS condition over the sham tDCS condition, which corroborated the results from previous pain-tDCS studies. Modulations of L-DLPFC and thalamic rCBF continued to be observed with anodal tDCS. In addition, the activity of the posterior insula, an indicator of ongoing pain intensity, was higher for the sham tDCS condition than for the anodal tDCS condition. The final study explored the importance of L-DLPFC–thalamic connection in pain modulation with diffusion tensor imaging (DTI). Probability tractography and tract-based spatial statistics (TBSS) were used to extract the mean fractional anisotropy (FA) of the tract. As hypothesized, the mean FA values within this tract positively correlated with the pain intensity changes, which indicated that individuals with stronger structural connection enjoyed greater alleviation from L-DLPFC tDCS. As a whole, the above studies suggest that the clinical efficacy of L-DLPFC tDCS in pain treatment may arise from the resulting top-down modulation of the thalamus. Further studies on chronic pain patients may offer further verification of the mechanism that has been proposed in this thesis.

This thesis investigated transcranial direct current stimulation (tDCS) as applied to the motor system, and its ability to modulate underlying cortical processes and resultant motor behaviours. Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) were employed to assess the extent to which tDCS induces quantifiable changes in neural structure and function in controls and stroke patients. Modifications in the connectivity of intrinsic functional networks following tDCS application were examined using resting state fMRI. Polarity-specific changes were found: cathodal (inhibitory) tDCS increased the strength of the default mode network and increased functional coupling between major nodes within the motor network. No significant effects were found following anodal (excitatory) tDCS. Although anodal tDCS elicited only subtle changes in resting activity, it is known to produce robust modifications of behaviour. Single and paired-pulse TMS were used to investigate the neurophysiological underpinnings of these changes. Consistent with the theory of homeostatic plasticity, anodal tDCS applied prior to task performance increased GABAA-mediated cortical inhibition and worsened behaviour. The specificity of these changes suggests a central role for the mechanism of surround inhibition. A longitudinal clinical trial in chronic stroke patients was conducted to determine the utility of tDCS as an adjunct in motor rehabilitation. Serial MRI scans revealed that, when combined with motor training, anodal tDCS increased functional activity and grey matter in primarily ipsilesional motor areas. These brain changes were correlated with behavioural improvements in the stroke-affected upper limb. The laterality of connectivity at baseline, as measured by resting state activity and corticospinal tract integrity, was predictive of response to the rehabilitation program, particularly in those stroke patients who received tDCS. Asymmetry favouring the contralesional hemisphere predicted greater behavioural gains. Such results underscore the importance of re-normalisation of structure and functional activity toward the lesioned hemisphere in stroke rehabilitation.

Introdução: Climatério é definido como o período de tempo onde ocorre a mudança de vida reprodutiva para não reprodutiva, com extensão de duração variável. Durante esse período e após o estabelecimento da menopausa, é comum o surgimento de diversos sintomas que expressam o esgotamento dos folículos ovarianos. Dentre os sintomas, o mais comumente relatado pelas mulheres são os sintomas vasomotores ou fogachos. Além da Terapia de Reposição Hormonal (TRH), outras medicações como os Inibidores Seletivos da Recaptação da Serotonina (ISRS) têm sido empregadas na tentativa de melhorá-los. Justificativa: TRH não pode ser aplicado a todas as mulheres com sintomas. As medicações não hormonais, apesar de apresentarem melhores respostas que placebo, ainda demonstram pouco impacto clínico na redução dos sintomas vasomotores. Esta lacuna permite avaliar outras alternativas terapêuticas, como a Estimulação Transcraniana por Corrente Direta (ou tDCS, do inglês transcranial direct current stimulation). O racional para estudar o efeito desta técnica neste contexto, é o seu possível efeito modulatório autonômico. O que reforça a escolha desta técnica é o fato de ter eficácia demonstrada em outras patologias como depressão, dor, doença Parkinson dentre outras. A tDCS é um método de neuromodulação transcraniana não invasivo, que se baseia na aplicação de correntes contínuas de baixa intensidade, através de eletrodos colocados sobre o escalpo, de forma simples e indolor. Objetivo: Avaliar o efeito da tDCS (tratamento ativo) comparada ao tDCS-sham (placebo) nos sintomas vasomotores de mulheres na pós- menopausa como objetivo primário; e como objetivo secundário, seus efeitos na qualidade de vida. Método: Ensaio Clínico Randomizado realizado em 30 pacientes pós-menopáusicas com queixa de pelo menos 05 episódios de fogachos/dia. Participantes foram selecionadas no ambulatório de Climatério do Serviço de Ginecologia e Obstetrícia do Hospital de Clínicas de Porto Alegre e via chamamento de jornal. Estas foram randomizadas para um dos grupos: tDCS ou placebo-sham. A intervenção consistiu na aplicação de sessões diárias de estimulação com corrente elétrica de 02 mili Ampere, pelo período de 10 dias consecutivos, à exceção dos finais de semana. Por uma semana anterior à intervenção e por 30 dias após, as participantes registravam o número e intensidade dos fogachos ao dia. Responderam ao Women´s Health Questionaire (WHQ) antes e ao termino da intervenção. Resultados: A média de fogachos/dia se comportou de forma semelhante nos dois grupos havendo uma redução do número de fogachos nas três primeiras semanas após intervenção com retorno ao basal a partir da quarta semana pós-aplicação. No grupo tDCS, se observou uma tendência a uma transferência dos fogachos intensos para leves sugerindo uma melhora clínica. Os resultados, apesar de não apresentarem significância estatística, reforçam a ideia de ampliar a investigação, com maior número de pacientes e com maior tempo de duração além do caráter inovador da pesquisa. / Introduction: Menopause is defined as a period where there is a change from the reproductive stage to a nonreproductive phase, with variable duration. During this period and following the establishment of menopause, there is usually an onset of several symptoms indicating the depletion of ovarian follicles. Among the symptoms, the ones that are more frequently reported by women are vasomotor symptoms or hot flashes. In addition to Hormone Replacement Therapy (HRT), other medications such as Selective Serotonin Reuptake Inhibitors (SSRIs) have been employed to treat them. Justification: HRT may not be applied to all women with symptoms. Non-hormonal medications, despite having better responses than placebo, have still shown little clinical impact on the reduction of vasomotor symptoms. This gap allows other therapeutic alternatives to be considered, such as Transcranial Direct Current Stimulation (tDCS). The rationale for studying the effect of this technique in this context is its possible autonomic modulatory effect. What reinforces the choice of this technique is the efficacy which it has demonstrated in other disorders such as depression, pain, Parkinson's disease, among others. tDCS is a non-invasive transcranial neuromodulation method based on the application of continuous low-intensity currents through electrodes placed to the scalp, in a simple and painless way. Goal: To evaluate the effect of tDCS (active treatment) compared to tDCS-sham (placebo) on vasomotor symptoms in postmenopausal women as a primary endpoint and its effects on quality of life as a secondary endpoint. Method: Randomized Clinical Trial conducted in 30 postmenopausal patients complaining of at least five episodes of hot flashes per day. Participants were selected at the Gynecology and Obstetrics Service Menopause Outpatient Clinic, Hospital de Clínicas de Porto Alegre and via a newspaper call. These were randomized to one of the groups: tDCS or placebo-sham. The intervention consisted of daily sessions in which stimulation was applied with an electric current of 02 milliamperes for 10 consecutive days, except on weekends. Participants recorded the number and intensity of hot flashes per day for one week before and for 30 days after the intervention. They answered the Women’s Health Questionnaire (WHQ) before and after the intervention completion. Results: The mean of hot flashes/day behaved in a similar way in both groups, and there was a reduction in hot flashes in the first three weeks following the intervention with a return to baseline starting in the fourth week after the administration. In the tDCS group, a trend towards a conversion of intensive hot flashes into mild ones was noted, which suggested a clinical improvement. The results, despite not showing statistical significance, supported the idea of extending the investigation with a larger number of patients and longer duration, in addition to the innovating nature of the research.

With increasing life expectancy and global population of older adults, preserving cog- nitive function throughout life represents a growing priority. Numerous approaches to cognitive enhancement exist, but few have scientific merit. Among the most preva- lent – and commercialized – approaches are cognitive training (“brain training”) and non-invasive brain stimulation through electric currents applied at the surface of the scalp. The present dissertation describes a collection of work contextualizing the appeal of these cognitive enhancement methods and addressing some of the most pervasive limitations of research in this field thus far. One largely ignored issue in cognitive intervention research pertains to people’s expectations of programs and their relationship with intervention outcomes. In a series of initial studies, we developed and validated the Expectation Assessment Scale (EAS), a tool created to measure as well as prime expectations of outcomes in the context of cognitive enhancement interventions. In our first two studies, we probed expectations of cognitive training or non-invasive brain stimulation in over 1,000 young, middle-aged, and older adults. Ratings on the EAS suggested that older adults may have particularly high expectations of cognitive training, but that expectations can be primed to increase or decrease – at least in hypothetical scenarios. We used these data to assess the psychometric properties of the EAS with item-response theory, and confirmed its internal consistency. Next, we incorporated the EAS into two cognitive enhancement trials, one in- vestigating a computerized cognitive training intervention in nearly 100 older adults and another examining non-invasive brain stimulation in nearly 100 young adults. Both trials had a double-blind balanced-placebo design in which participants were assigned to the intervention or control condition, and then subdivided to receive ei- ther high or low expectation priming (i.e., primed to have high or low expectations of the program’s effectiveness). Although expectation ratings replicated our previous findings, results from these trials suggest little, if any, effect of either expectations or the intervention on performance outcomes. We nevertheless found that participants enjoyed their assigned program and that those who received high expectation prim- ing tended to report a more positive experience. Our findings put into question the effectiveness of such interventions and support the need for more rigorous trials of cognitive enhancement.

Tinnitus is the perception of sound in the absence of an actual sound stimulus. Recent developments have shifted the focus to the central nervous system and the neural correlate of tinnitus. Broadly, tinnitus involves cortical map rearrangement, pathological neural synchrony, and increased spontaneous firing rates. Various cortical regions, such as Heschl’s gyrus in the auditory cortex, have been found to be associated with different aspects of tinnitus, such as perception and loudness. I propose a cortical stimulation mapping study of Heschl’s gyrus using a depth and subdural electrode montage to conduct electrocorticography. This study would provide high-resolution data on abnormal frequency band oscillations characteristic of tinnitus and pinpoint regions where they occur. The validity of the neural synchrony model would also be tested in this study.

It is well established that cathodal transcranial direct current stimulation (tDCS) can decrease the excitability of the primary motor cortex (M1) in humans. Despite the cortical inhibition caused by cathodal tDCS, it remains unknown how this intervention alters unrestrained dynamic reaching movements qualitatively. Accordingly, we designed this study to examine how cathodal tDCS impacts unrestrained dynamic reaching as measured by qualitative kinematic features and electromyography (EMG). Ten young, healthy adult subjects were recruited to participate in a two day protocol involving repetitively reaching to two different targets (large and small) both before and following cathodal tDCS applied over the contralateral M1 during one session and before and following sham tDCS over the same brain region during another session. We discovered that cathodal tDCS was not able to alter the kinematic features of reaching in these subjects but did degrade the EMG performance, specifically by increasing the amount of co-contraction between muscle pairs. Because co-contraction is an indicator of relatively unskilled performance, these results seem to indicate that cathodal tDCS of M1 preferentially disrupts the learning or execution of highly coordinated muscle firing patterns during dynamic reaching. This work adds to the growing body of knowledge about how tDCS applied over M1 affects our movements. Moreover, it leads us to believe that tDCS can be utilized to assist in rehabilitation of patient populations who suffer from neurological dysfunctions but EMG assessments may need to be included in order to more effectively assess the patient performance.

An important aspect of cognitive neuroscience is to localise specific brain regions involved in cognitive tasks, and to determine the mediating brain processes. There are several investigative approaches towards this, but amongst them, only transcranial magnetic stimulation (TMS) is able to interfere with the brain in such a way as to show the critical involvement of a brain region in a particular behaviour. TMS can be applied in normal subjects during the performance of a cognitive task and the resulting disruption of activity in the targeted brain region leads to an alteration in, or suspension of, behaviour consequent upon that brain activity. More recently, another brain stimulation technique has emerged that may also be able to contribute to the investigation of human cognition. Transcranial direct current stimulation (tDCS) applies a weak direct current to a targeted brain region, modulating cortical excitability and thereby altering the behavioural output. tDCS may be able to provide information that complements TMS and other investigative techniques by modulating behaviour in a way that depends on the role the brain region is carrying out in the task. This thesis describes a series of experiments in which TMS and tDCS were applied to two well-studied cognitive behaviours, working memory (WM) and mental rotation (MR). WM is the temporary retention of information that can be manipulated in order to guide behaviour. The most popular psychological model of WM proposes a multi-modal central executive (CE) that acts upon information stored in dedicated buffers (Baddeley, 1986). The dorsolateral prefrontal cortex (DLPFC) is a strong candidate as a key CE node (D'Esposito & Postle, 2000; Petrides, 2000b; Smith & Jonides, 1997; Stuss & Knight, 2002). MR is a visuo-cognitive process by which an image can be mentally modified into an orientation other than the one in which it is displayed (Corballis & McLaren, 1984). The area centred around the intraparietal sulcus is a brain key region for MR (Alivisatos & Petrides, 1996; Harris et al., 2000; Jordan et al., 2001). The work presented in this thesis examines the roles of the DLPFC and posterior parietal cortex (PPC) in WM and MR, respectively, and also highlights some of the methodological issues that are necessary to consider in order to produce reliable virtual lesions. The studies were carried out in young healthy volunteers, and were approved by the institutional ethics committee. In one study, repetitive TMS (rTMS) was shown to disrupt the manipulation of verbal information held in WM when administered over the right DLPFC, a result which supports a process-based segregation of the human prefrontal cortex for WM. Low- and high-frequency rTMS did not disrupt performance on another popular test of executive processing, n-back, a result which suggests that specific stimulation and task conditions must be met in order to produce virtual lesions, but also questions the critical importance of recruitment of the DLPFC for a running span task. rTMS applied to the right PPC replicated results from a previous TMS investigation, supporting the critical role this region in the rotation of images (Harris & Miniussi, 2003). When the left PPC was stimulated, impairment was produced only for the rotation of inverted stimuli. A role for the left PPC in the rotation of objects-as-a-whole is proposed based on these findings. The use of tDCS in the investigation of WM and MR is amongst the first to be described. Stimulation of the left DLPFC led to decreased performance accuracy on a verbal WM task in a polarity-specific manner. The pattern of results produced supports the role of the DLPFC as a node of a CE. tDCS over the left DLPFC did not modulate n-back task performance, a result which supports the TMS results that the involvement of the left DLPFC is not critical to the successful performance of the n-back task, although methodological issues remain of concern in relation to this conclusion. MR was not affected by tDCS applied to the right PPC and this result is most likely a direct demonstration of the importance of electrode montage. In conclusion, these studies show that rTMS and tDCS can be usefully applied to create virtual cortical lesions or modulate cortical excitability during the performance of cognitive tasks in humans, and can play an important role in investigating cognitive neuropsychological models. More widespread use of these techniques to complement lesion studies and functional neuroimaging is recommended.

Anodal transcranial direct current stimulation (tDCS) is an intervention which is thought to enhance motor learning in healthy and stroke-injured states, when applied adjunctively during skill learning. We set out to investigate whether anodal tDCS might enhance functional rehabilitation from incomplete tetraplegic SCI. To address current limitations in the measurement of task-dependent skill, a novel integrated skill training and measurement task, the Motor Skill Rehabilitation Task (MSRT) was designed and developed. Measures of performance from this task delivered the functional measure of spatial motor skill learning, Task Productivity Rate (TPR). TPR was analysed and validated as a univariate dependent outcome, which is of potential importance to the future development of clinical measures measuring goal-directed motor skills. The MSRT was included alongside conventional behavioural measures in a repeated-measures RCT pilot study, the first to investigate the effect of anodal tDCS on rehabilitation of motor skill from chronic spinal cord injury. Adjunctive application of anodal tDCS had a statistically significant benefit upon retention of skill in the incomplete spinal cord injured population, but only when the independent factor of sensory acuity was included in the analysis. Differences between the development of task-dependent skill and generic dexterity over time suggested that spatial skill development was subject to an interaction of short-term and lasting effects. A larger study in healthy persons further investigated these phenomena, also applying Transcranial Magnetic Stimulation (TMS)–evoked measurements to investigate intervention-dependent effects upon the excitability of projections between the primary motor cortex and muscles involved in the prehension task. The findings revealed that active tDCS did not enhance skill learning at 7 days beyond the training period, but did significantly alter the development of motor skill following a period of learning and subsequent skill consolidation which was associated with underlying perturbation of motor control strategy. Significant and divergent patterns of cortical plasticity were evoked in projections to muscles necessary for reaching and grasping. The main findings of this thesis do not support anodal tDCS as an effective adjunctive means of enhancing spatial motor skill in rehabilitation from incomplete tetraplegic SCI. If applied in patient populations, the clinical benefits of anodal tDCS may be contingent both on the nature of the sensorimotor deficit affecting upper limb function and the spatial demands of the behavioural task. The findings of this project serve to inform further research in relation to the effect of anodal tDCS on the brain and behavioural outcomes, the potential for efficacy in target patient groups and the sensitivity of outcome measures to spatial and temporal dimensions of practical motor skills.

Introdução: Climatério, ou transição menopáusica, é definido como o período onde ocorre a mudança de vida reprodutiva para não reprodutiva, com extensão de duração variável. Durante esse período, e após o estabelecimento da menopausa, é comum o surgimento de diversos sintomas que expressam o esgotamento dos folículos ovarianos; sendo os sintomas vasomotores, ou fogachos, os mais comumente relatados pelas mulheres. Atualmente, Terapia Hormonal, bem como os Inibidores Seletivos da Recaptação da Serotonina, têm sido empregadas na tentativa de melhorar estes sintomas. As medicações não hormonais, apesar de apresentarem melhores respostas que placebo, ainda demonstram pouco impacto clínico na redução dos sintomas vasomotores. Esta lacuna permite avaliar outras alternativas terapêuticas, como a Estimulação Transcraniana por Corrente Direta (ou tDCS, do inglês transcranial direct current stimulation). Objetivo: avaliar a diminuição no número de episódios de sintomas vasomotores em pacientes tratadas com aplicação de tDCS e placebo-sham, além de testar os efeitos do tDCS sobre o processo de neuroplasticidade, através da medida sérica de BDNF. Métodos: foram selecionadas nove pacientes pós-menopausicas com queixa de ao menos 5 episódios diários de sintomas vasomotores. Estas pacientes foram randomizadas para um dos grupos, tDCS (tratamento ativo) ou placebo-sham. O tratamento consistiu na aplicação de sessões diárias de estimulação com corrente elétrica de 02 mili Ampere, pelo período de dez dias consecutivos. Após uma semana e um mês de tratamento, as pacientes registravam o número de fogachos ao dia, e respondiam ao Women´s Health Questionaire (WHQ). No primeiro e no último dia de tratamento, foram coletadas amostras sanguíneas para dosagem de BDNF. Resultados: comparando o número médio de sintomas vasomotores (fogachos) ao dia, durante o período de sete dias, não houve diferença significativa entre os dois grupos, assim como nos níveis de BDNF e no WHQ. Conclusão: no momento, não podemos descartar o uso de tDCS no tratamento dos sintomas vasomotores, em virtude de pequeno número de pacientes avaliadas nesta pesquisa. Será mantido o acompanhamento das pacientes avaliadas até esse momento, e o tratamento será aplicado em novas mulheres com sintomas vasomotores. / Background: Climacteric or Menopausal Transition is defined as the time period where there is a change to non-reproductive reproductive life, with extension of variable length. During this period, and after the establishment of Menopause and non-functioning ovarian, the appearance of various symptoms that express the depletion of ovarian follicles is common; among these symptoms, the most frequently reported by women are vasomotor symptoms or hot flashes. In addition to hormonal therapy, other medications have been employed in an attempt to improve these symptoms; although they present better results than placebo, yet have little clinical impact in reducing vasomotor symptoms. Therefore, this gap allows the evaluation of alternative therapies, such as Transcranial Direct Current Stimulation (tDCS). Objective: evaluate the decrease in the number of episodes of vasomotor symptoms in patients treated with tDCS and placebo –sham, beyond testing the effects of tDCS on the neuroplasticity process through measurement of serum BDNF. Methods: nine post-menopausal women with at least 5 episodes of hot flashes/day were selected. These patients were randomized to one of the groups, tDCS (active treatment) or placebo-sham. The treatment consisted in daily application sessions of stimulation with electrical current of 02 mA, for ten consecutive days. After one week and one month of treatment, patients recorded the number of hot flashes per day, and answered the Women's Health Questionnaire (WHQ). In the first and in the last day of treatment, blood samples were collected for measurement of BDNF. Results: Comparing the average number of vasomotor symptoms (hot flashes) per day during the period of seven days, there was no significant difference between the two groups, and there were no differences in the levels of BDNF and WHQ. Conclusion: we can not rule out the use of tDCS in the treatment of vasomotor symptoms, because of the small number of patients evaluated in this study. Monitoring of these patients will be kept, and treatment will be applied to other women with vasomotor symptoms.