Yes / Human neuropsychological and neuroimaging studies have raised the possibility that different attributes of optic flow stimuli, namely radial direction and the position of the focus of expansion (FOE), are processed within separate cortical areas. In the human brain, visual areas V5/MT+ and V3A have been proposed as integral to the analysis of these different attributes of optic flow stimuli. In order to establish direct causal relationships between neural activity in V5/MT+ and V3A and the perception of radial motion direction and FOE position, we used Transcranial Magnetic Stimulation (TMS) to disrupt cortical activity in these areas whilst participants performed behavioural tasks dependent on these different aspects of optic flow stimuli. The cortical regions of interest were identified in seven human participants using standard fMRI retinotopic mapping techniques and functional localisers. TMS to area V3A was found to disrupt FOE positional judgements, but not radial direction discrimination, whilst the application of TMS to an anterior sub-division of hV5/MT+, MST/TO-2, produced the reverse effects, disrupting radial direction discrimination but eliciting no effect on the FOE positional judgement task. This double dissociation demonstrates that FOE position and radial direction of optic flow stimuli are signalled independently by neural activity in areas hV5/MT+ and V3A. / This work was funded by the BBSRC (grant B/N003012/1).

This dissertation examines the use of repetitive transcranial magnetic stimulation (rTMS) as a monotherapy as well as in combination with sensorimotor training technologies to improve the lives of individuals living with chronic pain. rTMS has the potential to promote analgesia and, when combined with technology to promote movement, is anticipated to have even greater effects that diminish pain intensity and improve function. Four experiments are included in the dissertation. Experiment 1 explores the use of rTMS in an individual living with neuropathic pain following spinal cord injury (SCI). Experiment 2 combines rTMS with hand sensorimotor training in a case report in complex regional pain syndrome (CRPS). Experiment 3 explores the effects of rTMS in an open label feasibility study in CRPS. Experiment 4 combines rTMS with augmented reality sensorimotor training (ARST) in a sham-controlled feasibility study in chronic neck pain (CNP). Of specific focus in this dissertation is the development of technologies that promote movement and can be implemented immediately following rTMS, to potentially enhance analgesia and function in chronic pain. Two separate sensorimotor training technologies were developed during this dissertation. The first technology is discussed in Chapter 2, involved hand sensorimotor training which used nerve stimulation to cue goal directed movements of the right-hand digits performed on a custom-built hand device. The second discussed in Chapter 4, used augmented reality to present virtual objects in a user’s environment to complete goal directed cervical movements. The latter technology has been filed as intellectual property with McMaster University. Further, this dissertation emphasizes rigorous interventional periods of rTMS with or without adjunct technology, to enhance patient outcomes. Therefore, the focus is on feasibility aspects of trial design to ensure that the intensive intervention and methodologies used in this dissertation are feasible to be tested in larger samples. Overall, in Chapter 2 and 4 this dissertation has shown that rTMS may be effective at reducing neuropathic pain and CRPS, with certain pain phenotypes exhibiting greater propensity for change. In addition, in Chapter 3, rTMS combined with hand sensorimotor training is effective at reducing pain, allodynia, and improving physical function in a patient with CRPS of the upper limb. Lastly, in Chapter 5, rTMS with ARST is effective at reducing pain, neck disability, and increasing physical function in CNP. Interestingly, the data obtained to date suggest that the effects observed in CNP may be associated with ARST and not rTMS per se. In addition, this dissertation illustrates that chronic pain interventions delivered three to five times per week for four to nine weeks is feasible however, long term follow-ups may be challenging in certain pain populations. Last, these studies have demonstrated that rTMS combined with adjunct therapies are tolerated in pain populations and demonstrate effective reductions in pain, creating an opportunity to explore their effects in large scale trials. / Dissertation / Doctor of Philosophy (PhD) / This thesis investigates the use of a non-invasive form of brain stimulation known as repetitive transcranial magnetic stimulation (rTMS) to treat symptoms of chronic pain. Although research shows rTMS is a promising method to treat pain, there are many people who do not respond to rTMS treatment. Also, for individuals who do respond to rTMS, it is unclear how much benefit is received from rTMS and for how long the benefits persist following rTMS. The effects of rTMS on chronic pain may be improved by using new protocols for rTMS delivery and by combining rTMS with other forms of therapy. Chronic pain is associated with changes in how the brain processes sensory information and uses that information to control movement, a process known as sensorimotor integration. Part of this thesis is focused on developing new technologies that target and improve sensorimotor integration that can be paired with rTMS. rTMS may enhance the brain’s ability to adapt and learn from training, a process known as neuroplasticity. By pairing rTMS with sensorimotor training, rTMS may optimize how the brain can adapt and potentially benefit from sensorimotor training. The overall goal of this thesis is to assess the feasibility and preliminary effectiveness of new, rigorous protocols for rTMS delivery, as well as its combination with new sensorimotor training technology. This thesis focuses on three chronic pain conditions, neuropathic pain, complex regional pain syndrome, and chronic neck pain. Ultimately, this thesis will be used to inform larger studies to further test the effects of these novel protocols and technologies on chronic pain. This thesis is intended to advance the field of non-invasive brain stimulation and provide new methods to optimize the delivery of rTMS to improve the lives of people living with chronic pain.

Movement training modulates the excitability in several cortical and subcortical areas. Compared to training with a single arm, movement training with both arms yields a greater increase in motor related cortical regions. A short-term session of bimanual training (BMT) enhances cortical activity of motor preparation and execution areas in both hemispheres. The underlying neural mechanisms for this increased activation with BMT are unclear, but may involve interhemispheric connections between homologous primary motor cortex (M1) representations and input from motor preparatory areas (i.e. dorsal premotor cortex (PMd)). Also, it is unclear how selective up-regulation or down-regulation of specific motor-related areas may contribute to changes in M1 excitability when combined with BMT. The work in this thesis investigated modulation of M1 excitability in terms of in-phase versus anti-phase BMT (Study #1), potentially up-regulating the left dorsal premotor cortex (lPMd) via iTBS before BMT (Study #2), theoretically down-regulating contralateral (right) M1 homologous representation before BMT (Study #3), and finally the potential intracortical and interhemispheric cortical adaptations in M1 bilaterally due to the same interventions as Study #2 (Study #4). For Study #1, it was hypothesized that in-phase BMT would lead to an increased excitability in M1. For Studies #2-4, it was hypothesized that modulation of motor-related areas would cause an increase in the excitability of left M1, and this modulation would be greater when combined with BMT. Study #1 found that in-phase, and not anti-phase BMT, lead to increase M1 excitability. Study #2 found that iTBS to lPMd followed by BMT caused a unique increase in M1 excitability, in terms of increased spatial extent and global MEP amplitude. Study #3 found that the combination of cTBS to right M1 with BMT caused greater excitability enhancements than either intervention alone. Finally, Study #4 found distinct modulations of cortical excitability within and across M1 bilaterally due to BMT, iTBS to lPMd and the combination of these interventions that involved long-interval inhibitory circuitry asymmetrically. Overall, this current work found that the modulation of remote cortical areas to M1 (i.e. lPMd and contralateral M1) in combination with movement training led to unique, and at times greater, excitability enhancements of M1 which could be advantageous in enhancing short-term plasticity in damaged M1.

Introduction: Memory is a complex cognitive process formerly linked to mechanisms of brain plasticity that can be estimated in the left dorsolateral prefrontal cortex (DLPFC) using transcranial magnetic stimulation and electroencephalography (TMS-EEG). Also, cortical thickness in the DLPFC may be a potential proxy measure of brain plasticity as previous literature reports a link between better memory and thicker cortex. However, the link between brain plasticity and memory performance as well as DLPFC thickness remains to be clarified. Methods: Intermittent theta burst stimulation (iTBS) probed plasticity-like mechanisms in the left DLPFC in 17 cognitively healthy participants. TMS-EEG recordings were performed before and after sham and active iTBS to quantify plasticity via transcranial magnetic stimulation-evoked potentials (TEPs). Composite memory scores for each domain (verbal episodic, visual episodic and working memory) were obtained using the Cambridge Neuropsychological Test Automated Battery. Anatomical T1 images were acquired by magnetic resonance imaging and processed by open-source software (CIVET) and the Automated Anatomical Labeling atlas to extract cortical thickness of the DLPFC. All statistical analyses (linear mixed model, Tukey's post hoc test and Pearson's correlations) were completed in R Studio. Results: iTBS resulted in increased TEP amplitude P30 (F= 5.239, p = 0.029), as shown by a significant interaction between condition (iTBS, sham) and time (pre- and post-condition). Specifically, Tukey's post hoc test revealed that the P30 increase was near trending significant post-iTBS compared to pre-iTBS for the active condition (p = 0.166) but not for the sham condition (p = 0.294). A trending significant relationship was observed between the magnitude of P30 change post-iTBS and thicker left DLPFC (r = 0.488; p = 0.108). Lastly, no significant relationships between P30 change and memory performance were observed. Conclusion: These preliminary findings suggest there could be a relationship between increased capacity for brain plasticity and a thicker left DLPFC. To further investigate these relationships, we plan to recruit additional cognitively healthy participants. Our preliminary findings support the foundation for future clinical studies in which DLPFC thickness could be explored as a predictive factor for response to plasticity-targeting iTBS treatment.

The present work introduces a synthesis of neocerebellar state estimation and feedforward control with multi-level language processing. The approach combines insights from clinical, imaging, and modelling work on the cerebellum with psycholinguistic and historical linguistic research. It finally provides the first experimental attempts towards the empirical validation of this synthesis, employing transcranial magnetic stimulation. A neuroanatomical locus traditionally seen as limited to lower sensorimotor functions, the cerebellum has, over the last decades, emerged as a widely accepted foundation of feedforward control and state estimation. Its cytoarchitectural homogeneity and diverse connectivity with virtually all parts of the central nervous system strongly support the idea of a uniform, domain-general cerebellar computation. Its reciprocal connectivity with language-related cortical areas suggests that this uniform cerebellar computation is also applied in language processing. Insight into the latter, however, remains an elusive desideratum; instead, research on cerebellar language functions is predominantly involved in the frontal cortical-like deficits (e.g. aphasias) seldom induced by cerebellar impairment. At the same time, reflections on cerebellar computations in language processing remain at most speculative, given the lack of discourse between cerebellar neuroscientists and psycholinguists. On the other hand, the fortunate contingency of the recent accommodation of these computations in psycholinguistic models provides the foundations for satisfying the desideratum above. The thesis thus formulates a neurolinguistic model whereby multi-level, predictive, associative linguistic operations are acquired and performed in neocerebello-cortical circuits, and are adaptively combined with cortico-cortical categorical processes. A broad range of psycholinguistic phenomena, involving, among others, "pragmatic normalization", "verbal/semantic illusions", associative priming, and phoneme restoration, are discussed in the light of recent findings on neocerebellar cognitive functions, and provide a rich research agenda for the experimental validation of the proposal. The hypothesis is then taken further, examining grammaticalization changes in the light of neocerebellar linguistic contributions. Despite a) the broad acceptance of routinization and automatization processes as the domain-general core of grammaticalization, b) the growing psycholinguistic research on routinized processing, and c) the evidence on neural circuits involved in automatization processes (crucially involving the cerebellum), interdisciplinary discourse remains strikingly poor. Based on the above, a synthesis is developed, whereby grammaticalization changes are introduced in routinized dialogical interaction as the result of maximized involvement of associative neocerebello-cortical processes. The thesis then turns to the first steps taken towards the verification of the hypothesis at hand. In view of the large methodological limitations of clinical research on cerebellar cognitive functions, the transcranial magnetic stimulation apparatus is employed instead, producing the very first linguistic experiments involving cerebellar stimulation. Despite the considerable technical difficulties met, neocerebellar loci are shown to be selectively involved in formal- and semantic-associative computations, with far-reaching consequences for neurolinguistic models of sentence processing. In particular, stimulation of the neocerebellar vermis is found to selectively enhance formal-associative priming in native speakers of English, and to disrupt, rather selectively, semantic-categorical priming in native speakers of Modern Greek, as well as to disrupt the practice-induced facilitation in processing repeatedly associated letter strings. Finally, stimulation of the right neocerebellar Crus I is found to enhance, quite selectively, semantic-associative priming in native speakers of English, while stimulation of the right neocerebellar vermis is shown to disrupt semantic priming altogether. The results are finally discussed in the light of a future research agenda overcoming the technical limitations met here.

<p>Making decisions is fundamental to everything we do, yet it can be impaired in various disorders and conditions. While research into the neural basis of decision-making has flourished in recent years, many questions remain about how decisions are instantiated in the brain. Here we explored how primates make abstract decisions and decisions in social contexts, as well as one way to non-invasively modulate the brain circuits underlying decision-making. We used rhesus macaques as our model organism. First we probed numerical decision-making, a form of abstract decision-making. We demonstrated that monkeys are able to compare discrete ratios, choosing an array with a greater ratio of positive to negative stimuli, even when this array does not have a greater absolute number of positive stimuli. Monkeys’ performance in this task adhered to Weber’s law, indicating that monkeys—like humans—treat proportions as analog magnitudes. Next we showed that monkeys’ ordinal decisions are influenced by spatial associations; when trained to select the fourth stimulus from the bottom in a vertical array, they subsequently selected the fourth stimulus from the left—and not from the right—in a horizontal array. In other words, they begin enumerating from one side of space and not the other, mirroring the human tendency to associate numbers with space. These and other studies confirmed that monkeys’ numerical decision-making follows similar patterns to that of humans, making them a good model for investigations of the neurobiological basis of numerical decision-making. </p><p>We sought to develop a system for exploring the neuronal basis of the cognitive and behavioral effects observed following transcranial magnetic stimulation, a relatively new, non-invasive method of brain stimulation that may be used to treat clinical disorders. We completed a set of pilot studies applying offline low-frequency repetitive transcranial magnetic stimulation to the macaque posterior parietal cortex, which has been implicated in numerical processing, while subjects performed a numerical comparison and control color comparison task, and while electrophysiological activity was recorded from the stimulated region of cortex. We found tentative evidence in one paradigm that stimulation did selectively impair performance in the number task, causally implicating the posterior parietal cortex in numerical decisions. In another paradigm, however, we manipulated the subject’s reaching behavior but not her number or color comparison performance. We also found that stimulation produced variable changes in neuronal firing and local field potentials. Together these findings lay the groundwork for detailed investigations into how different parameters of transcranial magnetic stimulation can interact with cortical architecture to produce various cognitive and behavioral changes.</p><p>Finally, we explored how monkeys decide how to behave in competitive social interactions. In a zero-sum computer game in which two monkeys played as a shooter or a goalie during a hockey-like “penalty shot” scenario, we found that shooters developed complex movement trajectories so as to conceal their intentions from the goalies. Additionally, we found that neurons in the dorsolateral and dorsomedial prefrontal cortex played a role in generating this “deceptive” behavior. We conclude that these regions of prefrontal cortex form part of a circuit that guides decisions to make an individual less predictable to an opponent.</p> / Dissertation

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.