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: Há evidências de modulação da excitabilidade do córtex motor por informações cerebelares, em animais e humanos. O objetivo deste estudo foi comparar a assimetria inter-hemisférica de excitabilidade cortical entre indivíduos com infarto cerebelar na fase crônica e controles saudáveis, através de estimulação magnética transcraniana. MÉTODOS: Foram incluídos sete indivíduos com infarto cerebelar (> 4 meses pós-infarto) e sete controles saudáveis. Cada participante foi submetido a uma sessão de estimulação magnética transcraniana do córtex motor no hemisfério direito e no hemisfério esquerdo, para a realização de medidas de excitabilidade e a determinação de assimetrias entre os hemisférios cerebrais. Os seguintes parâmetros de excitabilidade cortical foram avaliados: limiar motor de repouso, facilitação intracortical, inibição intracortical, relação entre amplitudes de potenciais evocados motores e amplitudes de ondas M, com intensidade de estimulação correspondendo ao limiar motor de repouso, a 130% do limiar motor de repouso, e a 100% da capacidade máxima do estimulador. RESULTADOS: Houve diferença significante na assimetria inter-hemisférica da inibição intracortical entre os grupos (teste de Mann-Whitney, p=0,048). Em todos os indivíduos com infartos cerebelares, a inibição intracortical foi menor no córtex motor primário contralateral ao infarto cerebelar, em comparação ao córtex motor ipsilateral. Houve ainda correlação significante entre o tempo de ocorrência do infarto cerebelar e a assimetria da inibição intracortical (r=0,91, p=0,004). Os demais parâmetros avaliados não apresentaram diferença significante entre os dois hemisférios em ambos os grupos. CONCLUSÕES: Estes resultados indicam que, em indivíduos com infarto cerebelar na fase crônica, ocorre desinibição do córtex motor contralateral. Avaliados em conjunto com estudos realizados em indivíduos com infartos cerebelares na fase subaguda, apoiam a hipótese de que alterações na inibição intracortical passam por modificações dinâmicas em diversas fases após um infarto cerebelar / INTRODUCTION: There is evidence of modulation of excitability of the motor cortex by cerebellar and somatosensory input in animals and humans. The goal of this study was to compare the inter-hemispheric asymmetry of cortical excitability in humans with cerebellar infarcts and healthy controls. METHODS: In order to evaluate inter-hemispheric asymmetry, seven individuals with cerebellar infarcts (> 4 months post-infarct) and seven healthy subjects were evaluated. There were no significant differences in age or gender between the groups. Each participant was submitted to one session of transcranial magnetic stimulation of the motor cortex of the right and left hemispheres, to determine asymmetries in excitability between the cerebral hemispheres. The following parameters of cortical excitability were evaluated: resting motor threshold, intracortical facilitation, intracortical inhibition, the relationship between motor evoked potential amplitudes and M-wave amplitudes. Three stimulation intensities were used: resting motor threshold, 130% of the resting motor threshold, and the stimulator\'s maximum output. RESULTS: There was a significant difference in inter-hemispheric asymmetry of intracortical inhibition between the groups (Mann-Whitney test, p=0.048). For all individuals with cerebellar infarcts, intracortical inhibition was lower in the primary motor cortex contralateral to the cerebellar infarction, compared to the ipsilateral motor cortex. There was also a significant correlation between the time elapsed since the cerebellar infarction and asymmetry of intracortical inhibition (r=0.91, p=0.004). The other variables evaluated were not significantly different between the two hemispheres in either group. CONCLUSIONS: These results indicate that disinhibition of the contralateral motor cortex occurs in individuals with chronic cerebellar infarcts. Taken together with studies performed in individuals with cerebellar infarcts in the subacute phase, these results support the hypothesis that changes in intracortical inhibition undergo dynamic changes over time, after a cerebellar infarct

Em pacientes com esquizofrenia, sintomas obsessivo-compulsivos (SOC) são associados com taxas mais baixas de qualidade de vida e polifarmácia. Não há estudos controlados anteriores testando a eficácia da estimulação magnética transcraniana repetitiva (EMTr) para o tratamento de SOC nesta população. Este trabalho examinou os efeitos terapêuticos da EMTr aplicadas à Área Motora Suplementar (1 Hz, 20 min, 20 sessões) em SOC e sintomas gerais em pacientes com esquizofrenia ou transtorno esquizoafetivo, e se esta intervenção pode produzir alterações nos níveis plasmáticos do fator neurotrófico derivado do cérebro (BDNF). Inicialmente, foi realizado um relato de três casos, com o objetivo de fornecer uma evidência inicial de eficácia. Dois dos três pacientes que participaram apresentaram redução da Escala de Sintomas Obsessivo-Compulsivos de Yale-Brown (Y-BOCS), com retorno aos valores iniciais 4 semanas após o término do tratamento. Foi realizado então um estudo duplo-cego randomizado controlado por placebo para confirmação dos efeitos terapêuticos. EMTr ativa e placebo foram entregues para 12 pacientes (6 em cada grupo). Os escores da Escala de Sintomas Obsessivo-Compulsivos de Yale-Brown (Y-BOCS) e da Escala Breve de Avaliação Psiquiátrica (BPRS), bem como os níveis de BDNF, foram avaliados antes, depois, e 4 semanas após as intervenções. A EMTr não alterou significativamente os resultados após o tratamento e no follow-up (Y-BOCS: Χ2 = 3,172; p = 0,205; BPRS: X2 = 1.629; p = 0,443; BDNF: X2 = 2.930; p = 0,231). Parece haver uma tendência para a melhoria da pontuação BPRS 4 semanas após o tratamento no grupo ativo comparando com placebo (d de Cohen = 0,875, com 32,9% de poder estatístico). Não foram relatados efeitos colaterais. São necessários estudos futuros com amostras maiores. / In patients with schizophrenia, obsessive-compulsive symptoms (OCS) are associated with lower rates of quality of life and polypharmacy. No previous controlled studies have tested the efficacy of repetitive transcranial magnetic stimulation (rTMS) on the treatment of OCS in this population. The present study examined the therapeutic effects of rTMS applied to the supplementary motor area (1 Hz, 20 min, 20 sessions) on OCS and general symptoms in patients with schizophrenia or schizoaffective disorder, and whether this intervention can produce changes in plasma levels of brain-derived neurotrophic factor (BDNF). Initially, there was a report of three cases with the aim of providing initial evidence of efficacy. Two patients showed a reduction on the Yale-Brown Obsessive-Compulsive Symptoms Scale (Y-BOCS) scores, with return to baseline 4 weeks after completion of treatment. Then, a double-blind randomized controlled trial was conducted. Active and sham rTMS were delivered to 12 patients (6 on each group). Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Brief Psychiatric Rating Scale (BPRS) scores, as well as BDNF levels, were assessed before, after, and 4 weeks after treatment. rTMS did not significantly change the outcomes after treatment and on the follow-up (Y-BOCS: Wald’s Χ2=3.172; p=0.205; BPRS: X2=1.629; p=0.443; BDNF: X2=2.930; p=0.231). There seemed to be a trend towards improvement of BPRS scores 4 weeks after rTMS treatment comparing with sham (Cohen’s d=0.875, with 32.9% statistical power). No side effects were reported. Future studies with larger sample sizes are needed.

O AVC está entre a principais causas de mortalidade e disfuncionalidade no mundo. A recuperação da função motora pós-AVC é normalmente incompleta; uma vez que as terapias atuais tem impacto limitado na promoção da plasticidade cerebral. Novas abordagens que podem intensificar a plasticidade cerebral têm sido estudadas para melhorar a reabilitação motora pós- AVC, entre eles a fluoxetina e a estimulação magnética transcraniana (EMTr) alcançaram resultados promissores. Portanto, nós conduzimos um ensaio clínico exploratório randomizado, duplo-cego, placebo controlado, avaliando os efeitos da combinação da EMTr em baixa frequência com a fluoxetina para aumentar a função motora do membro superior em pacientes com AVC. Vinte e sete pacientes hemiplégicos secundários a AVC isquêmico que apresentaram o evento nos últimos 2 anos foram randomizados em três grupos: EMTr ativa + fluoxetina, sham EMTr + fluoxetina e placebo (sham EMTr + fluoxetina placebo). Os participantes receberem 18 sessões (10 sessões diárias seguidas de 8 sessões semanais) de EMTr a 1 Hz sobre o córtex motor primário (M1) do hemisfério não afetado, combinadas com 90 dias de fluoxetina (20 mg/dia). As escalas de Jebsen Taylor (JTHF) e Fugl-Myer (FMA) foram utilizadas. Além disso, desfechos secundários incluíram questionário de segurança e comportamentais. Nossos resultados demonstraram melhora significativa na FMA e JTHF após o tratamento nos três grupos. Após ajustar para o tempo desde o evento isquêmico houve um aumento significativo na melhora da função motora de acordo com o JTHF no grupo que combinou EMTr ativa + fluoxetina quando comparados os grupos placebo ou fluoxetina exclusivamente. Essa análise mostrou uma melhora menos significativa na função motora no grupo fluoxetina quando comparada com o grupo placebo quando avaliada pelo JTHF (p=0.038) e pelo FMA (p=0.039), sugerindo um efeito potencialmente prejudicial da medicação ativa quando comparada com o placebo. Por fim, observamos que os desfechos de humor, função cognitiva e a segurança não foram significativos. A combinação da EMTr com a fluoxetina demonstrou melhoras significativas na função motora pós-AVC quando comparada com placebo, a terapia exclusiva com fluoxetina parece causar um efeito negativo / Stroke is among the leading causes of mortality and disability worldwide. Post stroke recovery of motor function is usually incomplete; these poor effects are believed to be due to the limited impact of current therapies in promoting brain plasticity. Novel approaches that can enhance brain plasticity have been studied to improve motor rehabilitation after stroke, among them fluoxetine and repetitive transcranial magnetic stimulation (rTMS) yielded promising results. Therefore, we conducted a randomized, double-blinded, sham-controlled, exploratory trial evaluating the effects of the combination of low-frequency rTMS and fluoxetine to increase upper limb motor function in stroke patients. Twenty-seven hemiplegic ischemic stroke patients within 2 years post event were randomized into three groups: active rTMS+fluoxetine, sham rTMS+fluoxetine, or placebo (sham rTMS+ placebo fluoxetine). Participants received 18 sessions (10 daily sessions followed by 8 weekly sessions) of 1Hz rTMS applied over the primary motor cortex (M1) over the unaffected hemisphere combined with 90 days of fluoxetine (20 mg/day). A blinded rater assessed motor function as indexed by Jebsen Taylor hand function (JTHF) and Fugl-Myer (FMA) scales. Additional secondary outcomes included safety and behavioral questionnaires. Our results showed a significant improvement in FMA and JTHF post treatment in all three groups. After adjusting for time since stroke there was a significantly larger improvement in motor function as indexed by JTHF seen in the combined active rTMS+fluoxetine group when compared to placebo and fluoxetine only groups. Additionally, this analysis showed significant less improvement in motor function in the fluoxetine group when compared to placebo group as indexed by JTHF (p=0.038) and FMA (p=0.039); consequently, suggesting a potential detrimental effect of the active medication when compared to placebo. Lastly, we observed that mood, cognitive performance and safety outcomes were not significantly. Despite establishing that the combination of TMS and fluoxetine leads to higher/greater improvements in motor function post stroke when compared to placebo, solely therapy with fluoxetine seemed to lead to a negative effect and thus it is plausible to believe that the benefit observed in the combined group is more likely due to the effects of TMS intervention

Neurological disorders require varying types and degrees of treatments depending on the symptoms and underlying causes of the disease. Patients suffering from medication-refractory symptoms often undergo further treatment in the form of brain stimulation, e.g. electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), or transcranial magnetic stimulation (TMS). These treatments are popular and have been shown to relieve various symptoms for patients with neurological conditions. However, the underlying effects of the stimulation, and subsequently the causes of symptom-relief, are not very well understood. In particular, TMS is a non-invasive brain stimulation therapy which uses time-varying magnetic fields to induce electric fields on the conductive parts of the brain. TMS has been FDA-approved for treatment of major depressive disorder for patients refractory to medication, as well as symptoms of migraine. Studies have shown that TMS has relieved severe depressive symptoms, although researchers believe that it is the deeper regions of the brain which are responsible for symptom relief. Many experts theorize that cortical stimulation such as TMS causes brain signals to propagate from the cortex to these deep brain regions, after which the synapses of the excited neurons are changed in such a way as to cause plasticity. It has also been widely observed that stimulation of the cortex causes signal firing at the deeper regions of the brain. However, the particular mechanisms behind TMS-caused signal propagation are unknown and understudied. Due to the non-invasive nature of TMS, this is an area in which investigation can be of significant benefit to the clinical community. We posit that a deeper understanding of this phenomenon may allow clinicians to explore the use of TMS for treatment of various other neurological symptoms and conditions. This thesis project seeks to investigate the various effects of TMS in the human brain, with respect to brain tissue stimulation as well as the cellular effects at the level of neurons. We present novel models of motor neuron circuitry and fiber tracts that will aid in the development of deep brain stimulation modalities using non-invasive treatment paradigms.

The human central nervous system (CNS) is capable of significant architectural and physiological reorganization in response to environmental stimuli. Novel sensorimotor experiences stimulate neuronal networks to modify their intrinsic excitability and spatial connectivity within and between CNS structures. Early learning-induced adaptations in the primary motor cortex are thought to serve as a priming stimulus for long term CNS reorganization underlying long-lasting changes in motor skill. Recent animal and human studies suggest that whole body exercise and core temperature elevation as systemic stressors also recruit activity-dependent processes that prime the motor cortex, cerebellum, and hippocampus to process sensorimotor stimuli from the environment, enhancing overall CNS learning and performance. A primary goal of rehabilitation specialists is to evaluate and design activity-based intervention strategies that induce or enhance beneficial neuroplastic processes across the lifespan. As such, an investgation of the influence of physical, non-pharmacological interventions on cortical excitability, motor learning, and cognitive function provide the central theme of this dissertation. The first study investigated the effects of a visually-guided motor learning task on motor cortex excitability at rest and during voluntary activation measured via transcranical magnetic stimulation (TMS). Motor learning significantly increased resting cortical excitability that was not accompanied by changes in excitability as a function of voluntary muscle activation. The cortical silent period, a measure of inhibition, increased after learning and was associated with the magnitude of learning at low activation. These findings suggest that separate excitatory and inhibitory mechanisms may influence motor output as a function of learning success. The following studies investigated the influence of systemic whole-body thermal stress on motor cortex excitability, motor learning and cognitive performance. We established the reliability of a novel TMS cortical mapping procedure to study neurophysiological responses after whole-body heat stress. Heat stress significantly potentiated motor cortex excitability, though acute motor learning and cognitive test performance did not differ between subjects receiving heat stress and control subjects. Future research is needed to delineate the potential of whole body heat stress as a therapeutic modality to influence central nervous system plasticity and performance.

This thesis describes a series of experiments to investigate the effect of thermal stimulation on corticospinal excitability using transcranial magnetic stimulation (TMS). Experiment I showed that innocuous cooling or warming of a single digit, produced short-lasting and mixed patterns of modulation only during actual thermal stimulation, with the inhibition being the most common pattern observed. In line with this finding, cooling stimulation applied to a larger area (i.e. multi-digits) produced variable but more sustained modulation in motor evoked potential (MEP) amplitude in the post-cooling phase (Exp II). Notably, the responses to cooling in terms of either suppressed or enhanced corticospinal excitability tended to be fairly consistent in a given individual with repeated applications. When examining possible sources of the observed variable MEP modulation, we found that individual characteristics such as age, sex and changes in skin temperature had no major influences. We hypothesized that the variability of responses might be related to individual differences in the excitability of intra-cortical circuits involved in sensorimotor integration. To test this hypothesis, we performed Experiment III using conditioning TMS paradigms. This experiment revealed that TMS markers of sensorimotor integration (SAI and SAF levels) were good predictors of individual variations in cooling-induced modulation in corticospinal excitability. This provided evidence supporting the role of SAI and SAF as markers to predict individual’s response to focal thermal stimulation. The identification of such predictors could enhance the therapeutic applicability of this form of stimulation in neurorehabilitation. Collectively, these findings advance our understanding of the neurophysiological basis of thermal stimulation and shed light on the development of a more rational application of neurofacilitation techniques based on afferent stimulation in clinical populations, such as stroke survivors.

No description available.

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.

<p>Neuroimaging and neurophysiology techniques were used to study some aspects of cortical sensory and motor system reorganisation in patients in the chronic phase after stroke. Using Diffusion Tensor Imaging, we found that the degree of white matter integrity of the corticofugal tracts (CFT) was positively related to grip strength. Structural changes of the CFT were also associated with functional changes in the corticospinal pathways, measured using Transcranial Magnetic Stimulation. This suggests that structural and functional integrity of the CFT is essential for upper limb function after stroke.</p><p>Using functional magnetic resonance imaging (fMRI), to measure brain activity during slow and fast passive hand movements, we found that velocity-dependent brain activity correlated positively with neural contribution to passive movement resistance in the hand in ipsilateral primary sensory (S1) and motor (M1) cortex in both patients and controls. This suggests a cortical involvement in the hyperactive reflex response of flexor muscles upon fast passive stretch.</p><p>Effects of a four week passive-active movement training programme were evaluated in chronic stroke patients. The group improved in range of motion and upper limb function after the training. The patients also reported improvements in a variety of daily tasks requiring the use of the affected upper limb. </p><p>Finally, we used fMRI to explore if brain activity during passive hand movement is related to time after stroke, and if such activity can be affected with intense training. In patients, reduced activity over time was found in supplementary motor area (SMA), contralateral M1 and prefrontal and parietal association areas along with ipsilateral cerebellum. After training, brain activity increased in SMA, ipsilateral S1 and intraparietal sulcus, and contralateral cerebellum in parallel with functional improvements of the upper limb. The findings suggest a use-dependent modification of cortical activation patterns in the affected hand after stroke. </p>