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.

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.

No description available.

Transcranial magnetic stimulation (TMS) is a widely-used investigative technique in motor cortical evaluation. TMS is now being used in the investigation of fatigue to help partition the effects of central fatigue. Few studies have utilized this technique to evaluate the effects of locomotor exercise and none in conditions of extreme exercise. Therefore, the purpose of this thesis was twofold; first, to answer methodological questions pertaining to the use of TMS in fatigue evaluation, particularly of the quadriceps, and second, to investigate the effects of extreme exercise conditions on the development of central and supraspinal fatigue and corticospinal excitability and inhibition. In Studies 1 and 2, the effect of approaching a target force in different ways before the delivery a TMS pulse and the difference between commonly-employed methods of determining TMS intensity on the selection of optimal TMS intensity were investigated. In Study 3, the effect of one night sleep deprivation on cognitive and exercise performance and central parameters was investigated. The effect of a 110-km ultra-trail on the supraspinal component of central fatigue was evaluated in Study 4. The principal findings from this thesis are that during TMS evaluation during brief voluntary contractions, it is essential to deliver the TMS pulse once the force has stabilized at the target and that a stimulus-response curve at 20% MVC is appropriate for determining optimal TMS intensity in exercise and fatigue studies. Furthermore, while sleep deprivation negatively-impacted cognitive and exercise performance, it did not influence neuromuscular parameters nor result in greater central fatigue. Supraspinal fatigue develops and corticospinal excitability increases during endurance/ultra-endurance running and cycling, while the effects on inhibitory corticospinal mechanisms are equivocal and probably depend on exercise characteristics and TMS intensity

L'imagerie par tenseur de diffusion (DTI) est une technique qui permet d'étudier l'organisation et l'état structurel des faisceaux de substance blanche. L'étude de l'intégrité des faisceaux peut aider à comprendre et à déterminer la sévérité du pronostic des patients après un accident ischémique cérébral (AIC). Dans cette thèse, je présente deux études ; dans la première nous avons comparé les résultats obtenus à partir d'un template du faisceau Corticospinal (FCS) à ceux obtenus par la tractographie chez des sujets sains et des patients post-AIC. Dans les deux groupes, les valeurs de la fraction d'anisotropie (FA) obtenues avec la tractographie étaient plus élevées que celles du template. Cependant, chez les patients, les deux méthodes ont détecté une diminution des valeurs de FA du FCS ipsilésionnel, qui était corrélée aux scores moteurs, mais les valeurs de FA obtenues avec le template étaient mieux corrélées avec le signal BOLD généré par la main parétique. La deuxième étude cherchait à savoir si la sévérité de l'aphasie post-AIC pouvait être corrélée à l'atteinte de certaines régions de la substance blanche. L'analyse voxel à voxel a permis d'identifier une zone située à l'intersection des voies dorsale et ventrale du langage, au-dessous de la jonction temporo-pariétale (JTP) gauche. La gravité des dommages dans cette région, évaluée par les valeurs de la FA, était mieux corrélée aux déficits phasiques que le volume de l'infarctus. Dans cette thèse, nous avons trouvé que, après un AIC, l'atteinte du FCS est un bon prédicteur de la sévérité du déficit moteur et celle d'une région localisée au-dessous de la JTP gauche, est un bon prédicteur de la sévérité de l'aphasie.

Le syndrome des mouvements en miroir congénitaux (MMC) est une maladie génétique caractérisée par l’existence de mouvements involontaires symétriques d’une main qui reproduisent à l’identique les mouvements volontaires de l’autre main. Deux structures sont impliquées dans la physiopathologie de cette maladie : le corps calleux (CC) et le faisceau corticospinal (FCS). Deux gènes ont été liés aux MMC à ce jour : DCC et RAD51. Tandis que DCC joue un rôle crucial dans le guidage des axones commissuraux, RAD51 intervient dans la réparation de l’ADN, et son rôle dans le développement du système moteur était inattendu.Chez la souris, nous avons étudié le rôle de RAD51 et DCC dans le développement du FCS et du CC, ainsi que l’implication de ces deux structures dans la latéralisation du contrôle moteur. Nous avons prouvé que DCC contrôle le guidage du FCS à la ligne médiane de façon indirecte. RAD51 intervient dans le développement du neocortex, mais son rôle précis dans le développement du système moteur demeure inconnu. Nous avons par ailleurs comparé un groupe de patients MMC à des volontaires sains afin d’étudier la latéralisation de l’activité corticale lors de la préparation motrice. L’activation et les interactions inter-hémisphériques des aires motrices sont anormales dès la préparation du mouvement chez les patients MMC. L’inhibition de l’aire motrice supplémentaire (AMS) chez les volontaires sains reproduit les défauts d’interactions inter-hémisphériques observés chez les patients. Ces résultats suggèrent que l’AMS est impliquée dans la préparation des mouvements latéralisés, potentiellement en modulant les interactions entre les deux hémisphères via le CC. / Mirror movements are involuntary symmetrical movements of one side of the body that mirror voluntary movements of the other side. Congenital mirror movements (CMM) is a rare genetic disorder transmitted in autosomal dominant manner, in which mirror movements are the only clinical abnormality. Two structures are involved in the physiopathology of CMM: the corpus callosum (CC) and the corticospinal tract (CST). The two main culprit genes identified so far are DCC and RAD51. While the role of DCC in commissural axons guidance during development is well known, RAD51 is involved in DNA repair, and its link with CMM was totally unexpected. In mice, we investigated the role of RAD51 and DCC in the development of the CC and CST, as well as the role of these two structures in motor lateralization. We showed that DCC controls CST midline crossing in an indirect manner. Our work clarified the role of RAD51 in neocortex development, but how RAD51 influences motor system development remains unknown. We compared a group of CMM patients with healthy volunteers to investigate the lateralization of cortical activity during movement preparation. We showed that activation of motor/premotor areas and interhemispheric interactions during movement preparation differed between the CMM patients and healthy volunteers. Transient inhibition of the supplementary motor area (SMA) in the healthy volunteers resulted in abnormal interhemispheric interactions during movement preparation, reminiscent of the situation observed in the patients. These results suggest the SMA is involved in lateralized movements preparation, potentially by modulating interhemispheric interactions via the CC.

La stimulation magnétique transcrânienne (TMS) est une technique d'investigation classiquement utilisée dans l'évaluation du cortex moteur. La TMS est utilisée dans l'étude de la fatigue afin de distinguer sa composante centrale. Peu d'études ont utilisé cette technique pour évaluer les effets de l'exercice locomoteur et aucune dans des conditions extrêmes. Ainsi, l'objectif de cette thèse était double: d'abord, répondre à certaines questions méthodologiques concernant l'utilisation de la TMS dans l'évaluation de la fatigue, en particulier du muscle quadriceps, et deuxièmement, étudier les effets de l'exercice en conditions extrêmes sur le développement de la fatigue centrale et supraspinal ainsi que sur l’excitabilité et l'inhibition corticospinales. Dans les Etudes 1 et 2, l'effet de différentes approches d'une force cible avant l’application d'une impulsion TMS ainsi que les différences entre les principales méthodes utilisées pour déterminer l'intensité optimale de TMS ont été étudiés. Dans l'Etude 3, l'effet d'une nuit de privation de sommeil sur les performances cognitives et physiques et les paramètres centraux a été étudié. L'effet d'un ultra-trail de 110 km sur la composante supraspinale de la fatigue centrale a été évalué dans l'Etude 4. Les conclusions principales de cette thèse sont, sur le plan méthodologique, i) que lors de l'évaluation par TMS pendant de brèves contractions volontaires, il est essentiel d’appliquer l'impulsion de TMS après que la force produite par le sujet se soit stabilisée à la valeur cible et ii) qu'une courbe stimulus-réponse à 20% de la force maximale volontaire est appropriée pour déterminer l'intensité de TMS optimale dans les études portant sur l'exercice et la fatigue. De plus, bien que la privation de sommeil ait des impacts négatifs sur les performances cognitives et à l'exercice, elle n'a pas d'influence sur des paramètres neuromusculaires ni ne provoque une plus grande fatigue centrale. Une fatigue supraspinale se développe et l’excitabilité corticospinale augmente au cours d’exercices d'endurance/ultra-endurance en course à pied et ne vélo, tandis que les effets sur les mécanismes inhibiteurs corticospinaux sont équivoques et probablement dépendent des caractéristiques de l'exercice et de l'intensité de la TMS / Transcranial magnetic stimulation (TMS) is a widely-used investigative technique in motor cortical evaluation. TMS is now being used in the investigation of fatigue to help partition the effects of central fatigue. Few studies have utilized this technique to evaluate the effects of locomotor exercise and none in conditions of extreme exercise. Therefore, the purpose of this thesis was twofold; first, to answer methodological questions pertaining to the use of TMS in fatigue evaluation, particularly of the quadriceps, and second, to investigate the effects of extreme exercise conditions on the development of central and supraspinal fatigue and corticospinal excitability and inhibition. In Studies 1 and 2, the effect of approaching a target force in different ways before the delivery a TMS pulse and the difference between commonly-employed methods of determining TMS intensity on the selection of optimal TMS intensity were investigated. In Study 3, the effect of one night sleep deprivation on cognitive and exercise performance and central parameters was investigated. The effect of a 110-km ultra-trail on the supraspinal component of central fatigue was evaluated in Study 4. The principal findings from this thesis are that during TMS evaluation during brief voluntary contractions, it is essential to deliver the TMS pulse once the force has stabilized at the target and that a stimulus-response curve at 20% MVC is appropriate for determining optimal TMS intensity in exercise and fatigue studies. Furthermore, while sleep deprivation negatively-impacted cognitive and exercise performance, it did not influence neuromuscular parameters nor result in greater central fatigue. Supraspinal fatigue develops and corticospinal excitability increases during endurance/ultra-endurance running and cycling, while the effects on inhibitory corticospinal mechanisms are equivocal and probably depend on exercise characteristics and TMS intensity

No description available.

No description available.

La faiblesse des muscles périphériques, définie par une diminution de la force maximale volontaire en dehors de tout état de fatigue neuromusculaire, est une complication fréquente de la broncho-pneumopathie chronique obstructive (BPCO). La force maximale volontaire dépend à la fois des propriétés musculaires périphériques (i.e. volume et architecture musculaire, qualités contractiles) et de la capacité du système nerveux à activer le muscle maximalement. Dans la BPCO, plusieurs travaux ont souligné l'existence paradoxale d'une perte de force maximale volontaire sans altérations musculaires périphériques et sans qu'un déficit d'activation volontaire n'ait clairement été identifié. Pourtant, les patients atteints de BPCO présentent de nombreuses altérations du système nerveux, compatibles avec une capacité d'activation volontaire altérée.L'objectif de ce travail de thèse était donc de tester l'implication du système nerveux dans la faiblesse musculaire de la BPCO et d'en déterminer les mécanismes sous-jacents. Au cours de nos travaux, nous avons mis en évidence une activité corticale diminuée dans la BPCO lors de contractions maximales et sous-maximales volontaires. Nous avons par ailleurs rapporté une perte d'excitabilité du cortex moteur et un déficit d'activation volontaire spécifique aux patients atteints de faiblesse musculaire. Ces résultats sont en accord avec une implication des altérations cérébrales dans la faiblesse musculaire périphérique de la BPCO. Nous sommes ensuite parvenus à identifier une origine potentielle des altérations cérébrales : les désaturations en O2 au cours du sommeil avec mouvements non-rapides des yeux (NREM). Cette hypothèse a été corroborée par l'observation d'un niveau d'activation volontaire réduit chez les patients désatureurs en sommeil NREM. En revanche, aucune répercussion significative n'a pu être observée sur la force maximale volontaire de ces patients, suggérant l'existence d'un mécanisme compensatoire. In fine, nos résultats constituent une avancée importante dans la compréhension du phénomène de faiblesse musculaire, classiquement attribué à la seule perte de masse musculaire. L'implication du système nerveux central dans la faiblesse musculaire ouvre notamment la voie à de nouvelles modalités de prise en charge par des approches spécifiques, dans l'optique de lutter contre la faiblesse musculaire et ses multiples répercussions négatives dans la vie du patient atteint de BPCO. / Peripheral muscle weakness, as defined by a reduced voluntary strength outside any state of neuromuscular fatigue, is a common complication of chronic obstructive pulmonary disease (COPD). Maximal voluntary strength is determined by both peripheral muscle properties (i.e. muscle volume and architecture, contractile quality) and the nervous system's ability to activate the muscle maximally. In COPD, many studies highlighted the paradoxical existence of maximal voluntary strength loss without any peripheral muscle impairment, and without a clearly identified voluntary activation deficit. However, patients with COPD exhibited several nervous system alterations compatible with a reduced maximal voluntary activation capacity. The aim of this thesis was to test the nervous system implication in COPD muscle weakness and to determine the involved mechanisms. As major results, we found a reduced cortical activity in COPD during maximal and sub-maximal voluntary contractions. Furthermore, we reported reduced motor cortex excitability and voluntary activation deficit, specifically in patients with muscle weakness. These results are in accordance with an involvement of cortical alterations in COPD muscle weakness. Then, we indentified a potential origin for cortical alterations: O2 desaturation during non-rapid eye movement (NREM) sleep. This hypothesis has been corroborated by the observation of a reduced voluntary activation in patients with NREM sleep desaturation. However, no significant repercussion could have been observed on maximal voluntary strength in these patients, suggesting a compensatory mechanism.Our results are an important step forward in understanding the COPD muscle weakness that was classically attributed to loss of muscle mass only. The involvement of the central nervous system in COPD muscle weakness also brings about new patient care opportunities via tailored approaches, in order to fight against muscle weakness and its deleterious consequences on a patient's life.