Hemispatial neglect, is a major cause of post-stroke disability and poor functional recovery. Hence, identifying sensitive methods to assess and rehabilitate neglect is important. Chapters 3 and 4 focused on development of novel assessment techniques for representational neglect. The 'Shopping Mall' and 'Clock Cueing' tasks improved upon previous tests and were useful in identifying dissociations in representational neglect based on type of stimuli (topological, non-topological) and time of assessment (pre-stroke, post-stroke) in chronic stroke patients. Chapters 5 and 6 investigated the efficacy of offline inhibitory repetitive Transcranial Magnetic Stimulation (rTMS) in producing short (<1 month) and long term (>6 months) changes in visual neglect behaviour. Overall, the findings from these chapters were limited due to lack of sufficient power. After controlling for the effect of baseline performance, the Intervention group's Activities of Daily Living scores significantly improved in the short-term post rTMS, as compared to the Control group. The fMRI task attempted to recruit attention-based top down modulation of sensory activity. It revealed relative hypoactivation of the right occipital lobe in the four left neglect patients tested, both pre and post rTMS, when compared to elderly controls. Chapter 7 explored cognitive predictors of spatial and object neglect in the sub-acute stage after controlling for demographic and stroke related factors, using multivariate blocked logistic regressions. Cognitive performance indicative of spatial attention and selective attention to local features predicted both spatial and object neglect. In addition, coding of spatial relations between features also predicted spatial neglect. Suggestions for combining neglect rehabilitation techniques to target these cognitive processes are discussed. Overall, this thesis provides novel methods to improve representational neglect assessment and highlights the importance of ancillary cognitive domains in contributing to both representational and visual neglect. The rTMS research provides study design-related insights to incorporate in future studies with larger patient samples.

Introdução: Níveis elevados de ansiedade têm sido associados com intensidade e comportamento da dor em pacientes com dores aguda e crônica. Foi observado, em indíviduos com síndrome dolorosa miofascial (SDM), que o estresse e a ansiedade aumentam a predisposição para o desenvolvimento de pontos-gatilhos miofasciais. Adicionalmente a isto, existe a tendência do indivíduo experimentar emoções negativas em situações de estresse (neuroticismo), característica de personalidade associada ao traço de personalidade, que pode influenciar negativamente na experiência de dor. Indivíduos com alta ansiedade-traço são geralmente hipersensíveis a estímulos e psicologicamente mais reativos. É concebível supôr a coexistência de alteração na excitabilidade cortical, entre dor crônica e ansiedade nestes pacientes. Para melhorar a compreensão dos mecanismos centrais relacionados à ansiedade e à dor crônica, avaliou-se os parâmetros de excitabilidade cortical, usando estimulação magnética transcraniana (EMT), pulso único e pareado. Nossa hipótese é que a excitabilidade corticoespinhal seja modulada pela ansiedade favorecendo a perda de influxo inibitório descendente. Objetivos: O presente estudo teve como objetivo responder a três perguntas relacionadas à síndrome dolorosa miofascial (SDM): 1) A excitabilidade do córtex motor está relacionada com a ansiedade-traço? 2) A ansiedade-traço modula alterações da excitabilidade corticoespinhal, após dor evocada pelo Quantitative Sensory Testing (QST)? 3) A ansiedade-traço prevê resposta à dor evocada pelo QST, se receber simultaneamente um estímulo heterotópico [Conditioned Pain Modulation (CPM)]? Pacientes e métodos: Foram incluídas mulheres com SDM (n = 47) e controles saudáveis (n = 11), com idade entre 19 e 65 anos. A excitabilidade do córtex motor foi avaliada pela EMT, e a ansiedade foi avaliada com base no Inventário de Ansiedade Traço-Estado (IDATE). A incapacidade relacionada à dor foi avaliada pelo perfil da escala de dor crônica para a população brasileira (B:PCP:S), e as medidas psicofísicas da dor foram medidas pelo QST e CPM. Resultados: Nas pacientes, a ansiedade-traço foi positivamente correlacionada com a facilitação intracortical (FIC) no baseline e após a dor evocada pelo QST (β = 0,05 e β = 0,04, respectivamente) e negativamente relacionada com o período de silêncio cortical (PSC) no baseline e após a dor evocada pelo QST (β = -1,17 e β = -1,23, respectivamente) (P <0,05 para todas as comparações). Após dor evocada pelo QST, a incapacidade relacionada à dor crônica foi positivamente correlacionada com a FIC (β = 0,02) (P <0,05). Os escores de dor durante o CPM foram positivamente correlacionados com a ansiedadetraço, quando a incapacidade relacionada à dor crônica foi igualmente alta (β = 0,39, P = 0,02). A excitabilidade cortical das controles saudáveis permaneceu inalterada após o QST. Conclusões: Estes resultados sugerem que, na SDM, o desequilíbrio entre os sistemas excitatórios e inibitórios descendentes do trato corticoespinhal está associado concomitantemente a maiores níveis de ansiedade-traço e maiores níveis de incapacidade funcional ocasionados pela dor crônica. / Background: High levels of anxiety have been associated with the intensity and pain behavior in patients with acute and chronic pain. It was observed that in subjects with myofascial pain (SDM), stress and anxiety syndrome increase the predisposition for the development of myofascial trigger points. In addition to this, there is a tendency of individuals to experience negative emotions in stressful situations (neuroticism), personality characteristic associated with trait personality that may negatively influence in the experience of pain. Individuals with higher trait anxiety are usually hypersensitive to stimuli and more psychologically reactive. It is conceivable to assume the co-existence of change in cortical excitability, chronic pain and anxiety, in these patients. To improve the understanding of the central mechanisms related to anxiety and chronic pain, we assessed cortical excitability parameters by single and paired pulse transcranial magnetic stimulation (TMS). We hypothesize that corticospinal excitability is modulated by anxiety favoring loss of descendent inhibitory influx. Objectives: This study aimed to answer three questions related to chronic myofascial pain syndrome (MPS): 1) Is the motor cortex excitability, as assessed by transcranial magnetic stimulation parameters (TMS), related to state-trait anxiety? 2) Does anxiety modulate corticospinal excitability changes after evoked pain by Quantitative Sensory Testing (QST)? 3) Does the state-trait anxiety predict the response to pain evoked by QST if simultaneously receiving a heterotopic stimulus [Conditional Pain Modulation (CPM)]? Patient and methods: We included females with chronic MPS (n=47) and healthy controls (n=11), aged from 19 to 65 years. Motor cortex excitability was assessed by TMS, and anxiety was assessed based on the State-Trait Anxiety Inventory. The disability related to pain (DRP) was assessed by the Profile of Chronic Pain scale for the Brazilian population (B:PCP:S), and the psychophysical pain measurements were measured by the QST and CPM. Results: In patients, trait-anxiety was positively correlated to intracortical facilitation (ICF) at baseline and after QST evoked pain (β= 0.05 and β= 0.04, respectively) and negatively correlated to the cortical silent period (CSP) (β= -1.17 and β= -1.23, respectively) (P <0.05 for all comparisons). After QST evoked pain, the DRP was positively correlated to ICF (β= 0.02) (P<0.05). Pain scores during CPM were positively correlated with trait-anxiety when it was concurrently with high DRP (β= 0.39; P= 0.02). Controls’cortical excitability remained unchanged after QST. Conclusions: These findings suggest that, in chronic MPS, the imbalance between excitatory and inhibitory descending systems of the corticospinal tract is associated with higher trait-anxiety concurrent with higher DRP.

L’entrainement mental (EM) par imagerie motrice (IM), qui consiste à simuler mentalement une action sans production motrice, constitue un stimulus efficace pour l’amélioration de la force maximale volontaire. Si aucun retour afférent sensitif n’est présent au cours d’une tâche d’IM, il n’en reste pas moins qu’une activation du cortex somatosensoriel est reportée. En effet, l’efficacité de l’IM repose en partie sur une interaction entre les voies motrices et les voies sensitives. Ainsi, il apparait raisonnable de penser que l’ajout de retours afférents sensitifs pendant l’IM pourrait potentialiser les effets de cette dernière et donc améliorer la performance motrice. L’objectif de cette thèse était d’analyser les mécanismes nerveux impliqués dans l’imagerie motrice combinée à la stimulation somatosensorielle. Dans notre première étude, nous avons montré que l’ajout d’une stimulation somatosensorielle des afférences Ia pendant une tâche d’imagerie pouvait potentialiser l’excitabilité corticospinale. Notre deuxième étude n’a cependant pas permis de mettre en évidence une meilleure efficacité d’un entrainement en imagerie motrice combinée à la stimulation somatosensorielle comparativement à un entrainement par imagerie motrice ou par stimulation somatosensorielle seules sur la force maximale volontaire. Enfin, notre troisième étude suggère que cette apparente inefficacité de la stimulation somatosensorielle à potentialiser les effets de l’imagerie, pourrait être en partie liée à un conflit entre l’activation du réseau neuronal en imagerie et l’activation de mécanismes corticaux suite aux retours afférents induits par la SS. / Mental training, which involves mentally simulating an action without motor output, is an effective stimulus to improve the maximal voluntary contraction. If only the motor pathway is activated, an activation of the somatosensory cortex is observed despite the lack of afferent feedback. Indeed, the motor imagery task efficiency is based in part on an interaction between motor and sensory pathway. Thus, it’s seems reasonable to think that the addition of sensory afferent feedback during motor imagery could potentiate the motor imagery effects and thus improve motor performance. In our first study, we showed that the addition of somatosensory stimulation of Ia-afferents during a motor imagery task could potentiate corticospinal excitability. Our second study, however, did not show a better efficacy of a mental training combined with somatosensory stimulation compared to a mental training or a somatosensory stimulation training alone on the maximal voluntary contraction. Finally, our third study suggests that this apparent inefficiency of somatosensory stimulation to potentiate the effects of motor imagery may be partly related to a conflict between the activation of the neuronal network in imaging and the activation of cortical mechanisms following the afferents feedbacks induced by the somatosensory stimulation.

La recherche de méthodes permettant de lutter contre le déconditionnement neuromusculaire à la suite par exemple d’une opération chirurgicale ou d’une immobilisation prolongée intéresse la communauté scientifique depuis de nombreuses années. Ce projet visait à proposer la technique de vibration locale (LV) comme une méthode alternative aux méthodes classiquement utilisées (e.g. vibration corps entier, stimulation électrique neuromusculaire) pour lutter contre ce déconditionnement neuromusculaire. Le premier objectif de ce travail de thèse était de déterminer les effets d’une application aigüe de LV sur la fonction neuromusculaire des muscles fléchisseurs dorsaux et extenseurs du genou de sujets sains. Nos résultats montrent une modulation de l’excitabilité du système nerveux central en réponse à l’application aigüe de LV, ce qui nous a permis d’envisager de potentielles adaptations si cette technique était utilisée de façon répétée sur plusieurs semaines. Ainsi, la seconde orientation de ce travail était d’évaluer les effets d’une application chronique (entraînement) de LV sur les propriétés fonctionnelles (force, hauteur de saut) et nerveuses (mesurées par stimulation magnétique transcrânienne) de sujets sains, jeunes et âgés. Nos résultats ont montré qu’un entraînement par LV était efficace pour améliorer les capacités fonctionnelles de ces deux populations, ces gains s’accompagnant d’adaptations nerveuses. Ces travaux nous ont alors conduits à la mise en place d’une dernière étude (en cours) à visée clinique, qui évaluait l’efficacité de LV en rééducation post-ligamentoplastie du ligament croisé antérieur du genou. / There is a need to find new methods to limit neuromuscular deconditioning that occurs after a surgery or prolonged immobilization. This thesis aimed to assess local vibration (LV) training as an alternative to methods classically used (e.g. whole body vibration, neuromuscular electrical stimulation) to fight against neuromuscular deconditioning. The first aim of this project was to determine the effects of a 30-min acute exposure to LV on the neuromuscular function of dorsiflexor and knee extensor muscles in a healthy population. Our results showed that acute LV intervention changed central nervous system excitability, allowing us to consider long-term adaptations to prolonged LV. Thus, the second aim of this thesis was to assess the effects of a chronic application (training) of LV on functional (maximal strength, squat jump performance) and neural (assessed with transcranial magnetic stimulation) properties of healthy young and old subjects. Our results showed that 4 to 8 weeks of LV increase functional capacities that were due to neural adaptations. Based on these results, an on-going study assessing the effectiveness of LV during a rehabilitation program for subjects who suffered from anterior cruciate ligament lesion has been proposed.

The observations made in brain-lesioned patients and the result of functional brain imaging studies converge to the hypothesis that the posterior parietal cortex (PPC) is involved in calculation and number processing. However, if numerical disorders generally result from a left parietal lesion, the results of some brain imaging studies suggest that the right PPC could also play a role in number magnitude processing. In order to clarify this question, we used transcranial magnetic stimulation to induce a virtual lesion of the left or right PPC in healthy subjects while they performed number comparison. Our results show that the integrity of the left PPC is a necessary condition for the precise discrimination required during close number comparison; whereas the comparison of far numbers can be performed by either hemisphere as suggested by the fact that this task is affected only by the simultaneous virtual lesion of both hemispheres. In order to better identify which processes underlie the numerical competence of the PPC, we then studied the possible interactions between number processing and visuo-motor functions. Indeed, a meta-analysis performed on functional imaging data revealed that number processing depends on parietal regions, but also on certain premotor areas, which are very close to those involved in the control of finger movements. In a first series of experiments, we thus observed an excitability increase in motor circuits during the enumeration of dots presented on a computer screen. Given that the counting task was performed with both hands at rest, this increase was interpreted as reflecting the mental simulation of pointing movements or sequential finger rising as counting goes on. In a second series of experiments, we showed that information related to number magnitude could interfere with the aperture of the finger grip required to grasp an object. These results suggest that the conformation of the hand to object size shares, with the representation of numbers, common processes for magnitude estimate. In conclusion, our thesis supports the hypothesis that our numerical capacities rely, at least partially, on visuo-motor functions involving the PPC; this could explain why the numerical capacities of the left hemisphere, which is dominant for motor activities, are more precise. / Les observations réalisées chez les patients cérébrolésés ainsi que le résultat des études d'imagerie cérébrale fonctionnelle convergent vers l'hypothèse selon laquelle le cortex pariétal postérieur (CPP) est impliqué dans le traitement des nombres et le calcul. Cependant, si les troubles du calcul résultent le plus souvent d'une lésion pariétale gauche, les résultats de certaines études d'imagerie fonctionnelle suggèrent que le CPP droit pourrait également jouer un rôle dans le traitement de la magnitude des nombres. Afin de clarifier cette question, nous avons utilisé la stimulation magnétique transcrânienne pour induire une lésion virtuelle du CPP gauche ou droit chez des sujets sains réalisant une tâche de comparaison de nombres. Nos résultats montrent que l'intégrité du CPP gauche est une condition nécessaire à la discrimination précise requise lors de la comparaison de nombres proches; la comparaison de nombres éloignés peut, quant à elle, être réalisée par l'un ou l'autre hémisphère comme le suggère le fait que cette tâche n'est affectée que par lésion virtuelle simultanée des deux hémisphères. Afin de mieux appréhender les processus sur lesquels s'appuient les compétences numériques du CPP, nous avons ensuite étudié les interactions possibles entre le traitement des nombres et les fonctions visuo-motrices. En effet, une méta-analyse réalisée sur des données d'imagerie fonctionelle a révélé que le traitement des nombres dépend de régions pariétales, mais également de certaines aires prémotrices, proches de celles impliquées dans le contrôle des mouvements des doigts. Dans une première série d'expériences, nous avons ainsi observé une augmentation de l'excitabilité des circuits moteurs lors du comptage de points présentés sur l'écran d'un ordinateur. Etant donné que la tâche de comptage était réalisée avec les mains au repos, cette augmentation a été interprétée comme le reflet d'une simulation mentale de mouvements de pointage ou d'extension séquentielle des doigts pendant le comptage. Dans une deuxième série d'expériences, nous avons montré que l'information relative à la magnitude des nombres pouvait interférer avec l'ouverture de la pince bidigitale requise pour saisir un objet. Ces résultats suggèrent que la conformation de la main adaptée à la taille des objets partage, avec la représentation des nombres, des processus communs d'estimation de la magnitude. En conclusion, notre travail supporte l'hypothèse selon laquelle nos capacités numériques pourraient, en partie du moins, reposer sur des fonctions visuo-motrices impliquant le CPP ; ceci pourrait expliquer pourquoi les capacités numériques de l'hémisphère gauche, dominant pour les activités motrices, sont plus précises.

Cortical representations are plastic and are allocated based on the proportional use or disuse of a pathway. A steady stream of sensory input maintains the integrity of cortical networks; while in contrast, alterations in afferent activation promote sensorimotor reorganization. After an incomplete spinal cord injury (SCI), damage to the ascending and/or descending pathways induces widespread modifications to the sensorimotor system. Strengthening these spared sensorimotor pathways may be therapeutic by promoting functional recovery after injury. Using a technique called transcranial magnetic stimulation (TMS), we show that the leg motor cortex is facilitated by peripheral sensory inputs via disinhibition and potentiation of excitatory intracortical circuits. Hence, in addition to its crucial role in sensory perception, excitation from peripheral sensory afferents can reinforce muscle activity by engaging, and possibly shaping, the activity of the human motor cortex. After SCI, the amount of excitation produced by afferent stimulation reaching the motor cortex is expectantly reduced and delayed. This reduction of sensory inflow to the motor cortex may contribute to our findings that cortical inhibition is down-regulated after SCI, and this compensation may aid in the recruitment of excitatory networks in the motor cortex as a result of the damage to its output neurons. By repeatedly pairing sensory inputs from a peripheral nerve in the leg with direct cortical activation by TMS, in an intervention called paired associative stimulation, we show that the motor system can be potentiated in both uninjured individuals and after SCI. In the uninjured subjects, we show that in order to produce associative facilitation, the time window required for coincident activation of the motor cortex by TMS and peripheral sensory inputs is not as narrow as previously thought (~100 vs. ~20 ms), likely due to the persistent activation of cortical neurons following activation by TMS. The potential to condition the nervous system with convergent afferent and cortical inputs suggests that paired associative stimulation may serve as a priming tool for motor plasticity and rehabilitation following SCI.

The observations made in brain-lesioned patients and the result of functional brain imaging studies converge to the hypothesis that the posterior parietal cortex (PPC) is involved in calculation and number processing. However, if numerical disorders generally result from a left parietal lesion, the results of some brain imaging studies suggest that the right PPC could also play a role in number magnitude processing. In order to clarify this question, we used transcranial magnetic stimulation to induce a virtual lesion of the left or right PPC in healthy subjects while they performed number comparison. Our results show that the integrity of the left PPC is a necessary condition for the precise discrimination required during close number comparison; whereas the comparison of far numbers can be performed by either hemisphere as suggested by the fact that this task is affected only by the simultaneous virtual lesion of both hemispheres. In order to better identify which processes underlie the numerical competence of the PPC, we then studied the possible interactions between number processing and visuo-motor functions. Indeed, a meta-analysis performed on functional imaging data revealed that number processing depends on parietal regions, but also on certain premotor areas, which are very close to those involved in the control of finger movements. In a first series of experiments, we thus observed an excitability increase in motor circuits during the enumeration of dots presented on a computer screen. Given that the counting task was performed with both hands at rest, this increase was interpreted as reflecting the mental simulation of pointing movements or sequential finger rising as counting goes on. In a second series of experiments, we showed that information related to number magnitude could interfere with the aperture of the finger grip required to grasp an object. These results suggest that the conformation of the hand to object size shares, with the representation of numbers, common processes for magnitude estimate. In conclusion, our thesis supports the hypothesis that our numerical capacities rely, at least partially, on visuo-motor functions involving the PPC; this could explain why the numerical capacities of the left hemisphere, which is dominant for motor activities, are more precise. / Les observations réalisées chez les patients cérébrolésés ainsi que le résultat des études d'imagerie cérébrale fonctionnelle convergent vers l'hypothèse selon laquelle le cortex pariétal postérieur (CPP) est impliqué dans le traitement des nombres et le calcul. Cependant, si les troubles du calcul résultent le plus souvent d'une lésion pariétale gauche, les résultats de certaines études d'imagerie fonctionnelle suggèrent que le CPP droit pourrait également jouer un rôle dans le traitement de la magnitude des nombres. Afin de clarifier cette question, nous avons utilisé la stimulation magnétique transcrânienne pour induire une lésion virtuelle du CPP gauche ou droit chez des sujets sains réalisant une tâche de comparaison de nombres. Nos résultats montrent que l'intégrité du CPP gauche est une condition nécessaire à la discrimination précise requise lors de la comparaison de nombres proches; la comparaison de nombres éloignés peut, quant à elle, être réalisée par l'un ou l'autre hémisphère comme le suggère le fait que cette tâche n'est affectée que par lésion virtuelle simultanée des deux hémisphères. Afin de mieux appréhender les processus sur lesquels s'appuient les compétences numériques du CPP, nous avons ensuite étudié les interactions possibles entre le traitement des nombres et les fonctions visuo-motrices. En effet, une méta-analyse réalisée sur des données d'imagerie fonctionelle a révélé que le traitement des nombres dépend de régions pariétales, mais également de certaines aires prémotrices, proches de celles impliquées dans le contrôle des mouvements des doigts. Dans une première série d'expériences, nous avons ainsi observé une augmentation de l'excitabilité des circuits moteurs lors du comptage de points présentés sur l'écran d'un ordinateur. Etant donné que la tâche de comptage était réalisée avec les mains au repos, cette augmentation a été interprétée comme le reflet d'une simulation mentale de mouvements de pointage ou d'extension séquentielle des doigts pendant le comptage. Dans une deuxième série d'expériences, nous avons montré que l'information relative à la magnitude des nombres pouvait interférer avec l'ouverture de la pince bidigitale requise pour saisir un objet. Ces résultats suggèrent que la conformation de la main adaptée à la taille des objets partage, avec la représentation des nombres, des processus communs d'estimation de la magnitude. En conclusion, notre travail supporte l'hypothèse selon laquelle nos capacités numériques pourraient, en partie du moins, reposer sur des fonctions visuo-motrices impliquant le CPP ; ceci pourrait expliquer pourquoi les capacités numériques de l'hémisphère gauche, dominant pour les activités motrices, sont plus précises.

Les connaissances actuelles de la physiopathologie de la migraine ne permettent pas encore de déterminer avec exactitude le processus pathologique à lorigine de lactivation du système trigémino-vasculaire conduisant à la céphalée migraineuse. Certains arguments sont en faveur danomalies fonctionnelles du cortex cérébral à même denclencher le processus de la crise de migraine. Parmi ces anomalies, une hypersensibilité sensorielle a été décrite de longue date et a conduit à un important travail en neurophysiologie clinique. Ainsi lutilisation des techniques de potentiels évoqués a abouti à divers résultats dont le plus reproductible consiste en un déficit dhabituation des réponses évoquées corticales lors de stimulations sensorielles répétées chez les migraineux en période intercritique. Comprendre lorigine du déficit dhabituation retrouvé chez les migraineux devrait permettre de préciser le rôle du cortex cérébral dans la cascade dactivation menant à la crise de migraine. Nous avons utilisé la stimulation magnétique transcrânienne répétitive (SMTr) chez les migraineux afin de moduler lexcitabilité des cortex visuel et moteur, en enregistrant ses effets respectivement sur les potentiels évoqués visuels et moteurs. La SMTr a ainsi permis détudier lorigine du déficit dhabituation des potentiels évoqués corticaux retrouvé en période intercritique chez les migraineux. Ce déficit dhabituation des réponses corticales semble provenir dun niveau réduit de préactivation corticale mais également dune activité réduite des interneurones inhibiteurs corticaux. Par ailleurs, ce déficit dhabituation ne semble pas être un élément pathogénique prépondérant dans la mesure où sa seule présence chez les sujets sains ne permet pas den faire des migraineux. Il pourrait correspondre soit à un épiphénomène, soit à un des éléments étiopathogéniques de la migraine, au même titre que la prédisposition génétique, les troubles du métabolisme mitochondrial, Il est vraisemblable que le poids relatif de chacun de ces éléments étiopathogéniques participe à lhétérogénéité des migraines.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons and their supporting cells in the brain, brainstem and spinal cord, resulting in muscle paresis and paralysis including the bulbar (speech, chewing, swallowing) and respiratory muscles. The average age at onset is 55 years, and death due to respiratory failure occurs 2-5 years after symptom onset in ~ 85% of cases. Five to 10% of ALS is familial, and about 20% of familial cases are associated with mutations in the superoxide dismutase 1 (SOD1) gene. To date, 118 SOD1 mutations have been reported worldwide (www alsod.org). All are dominantly inherited, except for the D90A mutation, which is typically recessively inherited. D90A homozygous ALS is associated with long (~14 years) survival, and some atypical symptoms and signs. The reason for this is not known. In contrast, most other SOD1 mutations are associated with average survival, while some are associated with aggressive disease having lower motor neuron predominance and survival less than 12 months. The A4V mutation, which is the most frequently occurring SOD1 mutation in the United States, is an example of the latter. Understanding the pathogenic mechanisms of SOD1 mutants causing widely different disease forms like D90A and A4V is of paramount importance. Overwhelming scientific evidence indicates that mutations in the SOD1 gene are cytotoxic by a “gain of noxious” function, which although not fully understood results in protein aggregation and loss of cell function. This thesis explores different ALS-SOD1 gene mutations in British Columbia (BC), Canada. Two hundred and fifty-three ALS patients were screened for SOD1 mutations, and 12 (4.7%) unrelated patients were found to carry one of 5 different SOD1 mutations: A4V (n=2); G72C (n=1); D76Y (n=1); D90A (n=2); and 113T (n=6). Incomplete penetrance was observed in 3/12 families. Bulbar onset disease was not observed in the SOD1 mutation carriers in this study, but gender distribution was similar to previously reported studies. Age at symptom onset for all patients enrolled, with or without SOD1 mutations, was older than reported in previous studies. On average, patients with SOD1 mutations experience a longer diagnostic delay (22.6 months) compared to patients without mutations (12 months). Two SOD1 patients were originally misdiagnosed including the G72C patient who’s presenting features resembled a proximal myopathy. Neuropathological examination of this patient failed to reveal upper motor neuron disease. The I113T mutation was associated with variable age of onset and survival time, and was found in 2 apparently sporadic cases. The D76Y mutation was also found in an apparently sporadic case. I113T and D76Y are likely influenced by other genetic or environmental factors in some individuals. Two patients were homozygous for the D90A mutation, with clinical features comparable to patients originally described in Scandinavia. Clinical and electrophysiological motor neuron abnormalities were observed in heterozygous relatives of one D90A homozygous patient. The A4V patients were similar to those described in previous studies, although one had significant upper motor neuron disease both clinically and neuropathologically. Clinical neurophysiology is essential in the diagnosis of ALS, and helpful in monitoring disease progression. A number of transcranial magnetic stimulation (TMS) studies may detect early dysfunction of upper motor neurons when imaging techniques lack sensitivity. Peristimulus time histograms (PSTHs), which assess corticospinal function via recording of voluntarily activated single motor units during low intensity TMS of the motor cortex, were used to study 19 ALS patients having 5 different SOD1 mutations (including 8 of the 12 patients identified with SOD1 mutations from BC). Results were compared with idiopathic ALS cases, patients with multiple sclerosis (MS), and healthy controls. Significant differences were found in corticospinal pathophysiology between ALS patients with SOD1 mutations, idiopathic ALS, and MS patients. In addition, different SOD1 mutants were associated with significantly different neurophysiologic abnormalities. D90A homozygous patients show preserved if not exaggerated cortical inhibition and slow central conduction, which may reflect the more benign disease course associated with this mutant. In contrast, A4V patients show cortical hyper-excitability and only slightly delayed central conduction. I113T patients display a spectrum of abnormalities. This suggests mutant specific SOD1 pathology(s) of the corticospinal pathways in ALS.

In daily activities, the brain regularly assigns different roles to the hands dependingon task and context. Yet, little is known about the underlying neural processes. Thiscertainly applies to how the brain, where each hemisphere primarily controls onehand, manages the between-hand coordination required in bimanual objectmanipulation. By using behavioral, neurophysiological and functional magneticresonance imaging techniques, the present thesis examines neural mechanisms thatsupport hand coordination during tasks where the two hands apply spatiotemporallycoupled but opposing forces for goal attainment, e.g., as when removing the cap froma bottle. Although the two hands seem to operate symmetrically in such tasks, Study Ishowed that one hand primarily acts while the other assists. Moreover, this roledifferentiation was found to be flexible with the brain appointing either hand asprime actor depending on the spatial congruency between hand forces and desiredmovement consequences. Accordingly, when we remove a cap from a bottle, the handthat grasps the cap, be it left or right depending on overall task constraints, isappointed as prime actor because the twist forces it generates are aligned with thegoal to remove the cap, while the other hand, holding the bottle, applies stabilizingforces in the opposite direction. Changes in hand assignments are caused by amidline shift of lateralized activity throughout the motor system, from distal handmuscles to corticospinal pathways and primary sensorimotor and cerebellar corticalareas (Study I). Although the bimanual actions examined involved both within- andbetween-hand coordination, Study II failed to reveal additional brain activity duringbimanual as compared to matching unimanual actions, except for the primarysensorimotor areas where subpopulations of neurons were preferentially engagedduring either bimanual or unimanual actions. Thus, dedicated neurons in the motorcortices might support critical bimanual coordinative operations. While imagingresults indicated that a mainly left-lateralized parietal-premotor network managedthe task irrespective of prime actor, premotor areas presumably established handassignment by allocating the lead either to the left or the right primary sensorimotorareas (Study I and II). Regarding the process of prime actor selection and hence thecontrol of these premotor networks, imaging results indicate a transitory involvementof prefrontal cortical areas (Study III). The detected areas belong to a networkconsidered critical for cognitive operations such as judgment and decision-making,and for evaluation of utility of actions, including conflict detection. The implicitselection of prime actor during bimanual tasks thus seems to be supported by corticalareas traditionally associated primarily with complex cognitive challenges.