Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Lesões medulares resultam em uma perda irreversível da função abaixo do sítio da lesão. Esses comprometimentos são permanentes e ocorrem devido à perda de neurônios localmente e também dos tratos axonais ascendentes e descendentes da medula espinal. Na tentativa de criar um ambiente favorável à regeneração dos axônios lesionados, células da glia embainhante olfatória (GEO) vêm sendo transplantadas como estratégia de tratamento em animais submetidos a diferentes modelos experimentais de lesões medulares. Entretanto, um consenso sobre o potencial terapêutico desse tipo de transplante celular ainda precisa ser estabelecido. O objetivo do presente trabalho foi verificar a eficácia do transplante de lâmina própria (LP) olfatória (que possui células da GEO) e de LP respiratória (desprovido de células da GEO), quando implantadas imediatamente, 2 ou 4 semanas após a realização da transecção da medula espinal. Doze semanas após a realização dos implantes, os animais que receberam LP olfatória e respiratória apresentaram uma melhora sutil na função motora dos membros posteriores. Além disso, o transplante de LP olfatória quando realizado imediatamente após a lesão reduziu a hiperatividade do reflexo de retirada, enquanto o implante desse tipo de tecido 4 semanas pós-lesão produziu uma discreta depressão dependente de frequência do reflexo de Hoffman (um análogo elétrico do reflexo monossináptico de estiramento). Nas diferentes janelas terapêuticas utilizadas, o transplante de ambos os tipos de LP produziu resultados comparáveis em relação à preservação do tecido medular, brotamento de neuritos e regeneração de fibras mielínicas no local da lesão, indicando que o tempo decorrido antes da realização dos transplantes não parece limitar os efeitos regenerativos. Todavia, as fibras mielínicas observadas no sítio da transecção nos animais que receberam LP olfatória 2 e 4 semanas pós-lesão possuíam menor área, diâmetro e espessura da bainha de mielina quando comparados aos animais que receberam LP respiratória nesses mesmos períodos. O transplante imediato de LP olfatória e respiratória também favoreceu o restabelecimento das conexões entre as fibras axonais lesionadas com núcleos do tronco encefálico e até mesmo com a região do córtex somatossensorial, como indicado pela presença de neurônios nessas regiões marcados positivamente com um marcador axonal retrógrado. Um número maior de fibras positivas para 5-HT foi observado no coto proximal dos grupos transplantados com ambos os tipos de LP em comparação às regiões da lesão e do coto caudal. Fibras positivas para CGRP estavam presentes em número considerável no local da lesão. A recuperação locomotora e a regeneração axonal no local da lesão foram limitadas e comparáveis entre os grupos transplantados nos diferentes tempos com LP olfatória e respiratória, sugerindo que esses resultados não estão exclusivamente relacionados à presença de células da GEO nos enxertos utilizados. Um melhor entendimento sobre o potencial restaurativo desse tipo de transplante é necessário a fim de justificar a aplicação dessa terapia em humanos. / Spinal cord injury (SCI) results in an irreversible loss of function below the injury site. These permanent disabilities occur due to local neuronal death and loss of ascending and descending axons in the spinal cord. In attempt to create a favorable environment for the re-growth of injured axons, olfactory ensheathing cells (OECs) have been transplanted as a treatment strategy in animals submitted to different experimental models of SCI. However, a consensus on the efficacy of this cellular transplantation has yet to be reached. The main focus of the present study was explore the efficacy of olfactory lamina propria (OLP, graft containing OECs) or respiratory lamina propria (RLP, graft without OECs) when transplanted immediately, 2-week or 4-week after spinal cord transection. After 12 weeks of transplantation, animals with OLP and RLP grafts showed a subtle hindlimb motor improvement. Furthermore, the transplantation of OLP when performed immediately after injury reduced the withdrawal reflex over-responsiveness, while the implantation of this tissue 4 weeks post-injury produced a discrete frequency-dependent habituation of the Hoffman reflex (the electrical analogue of the classic tendon jerk reflex). In all therapeutic windows used, both lamina propria grafts produced comparable results for tissue sparing, fibers sprouting and re-growth of myelinated fibers at the lesion site, indicating that delayed transplantation approach does not seem to limit the regenerative effects. However, the myelinated fibers observed at the transection site of animals that received OLP 2 or 4 weeks after injury had a smaller myelinated fiber area, diameter and myelin sheath thickness when compared to those animals transplanted with RLP grafts in the same periods. The immediate transplantation of OLP and RLP also foster limited supraspinal axonal re-connection as shown by the presence of neurons stained by retrograde tracing in brainstem nuclei and in the somatosensory cortex. A larger number of 5-HT positive axons were found in the cranial stump of both lamina propria groups compared to the lesion and caudal regions. CGRP positive axons were present in considerable numbers at the SCI site. The locomotor recovery and axon reparative effects were limited and similar between groups transplanted at different times with OLP and RLP, suggesting that these results could not be exclusively related to OECs. In conclusion, a greater understanding of the restorative potential of these tissue grafts is necessary to strengthen the rationale for application of this treatment in humans.

L’objectif de ce travail a été de tester l’hypothèse selon laquelle l’effet bénéfique de l’administration de la forme recombinante de l’activateur tissulaire du plasminogène (rt-PA) chez le patient victime d’un accident vasculaire cérébral (AVC) ischémique ne résulte pas uniquement de son action fibrinolytique mais aussi de sa capacité à augmenter le brain-derived neurotrophic factor (BDNF) dans le cerveau. Dans ce but, nous avons conduit une première étude visant à évaluer chez l’animal sain, l’effet du rt-PA sur les taux cérébraux de BDNF. Dans une seconde approche, nous avons étudié l’effet du rt-PA sur les taux sériques de BDNF chez le patient victime d’un AVC ischémique et chez l’animal soumis à une ischémie cérébrale focale. Le sang a été prélevé chez l’Homme à l’admission (J0), J1, J7 et J90 après l’AVC, et chez le Rat avant et après (1h, 4h et 24h) l’ischémie. Le BDNF a été mesuré dans le cerveau par technique de Western blot et dans le sang par technique ELISA. Dans les deux études le rt-PA (Actilyse®) a été administré sous forme d’un bolus suivi d’une perfusion d’une heure. La première étude montre que 1) le rt-PA augmente les taux de BDNF dans l’hippocampe, 2) le traitement par MK801 (un antagoniste des récepteurs NMDA) mais pas par l’acide tranexamique (un inhibiteur de la plasmine) annule l’effet du rt-PA sur les taux de BDNF. La deuxième étude met en évidence que 1) la récupération neurologique est meilleure chez les patients recevant le rt-PA, 2) le traitement par rt-PA augmente les taux sériques de BDNF à J1 et J7 chez l’Homme, mais ne modifie pas les taux sanguins de BDNF chez l’animal, 3) les taux de BDNF ne sont pas corrélés à la récupération neurologique mais sont inversement corrélés au score cardiovasculaire du patient. En conclusion, nos résultats suggèrent que le rt-PA peut exercer un effet protecteur extra-fibrinolytique en augmentant les taux de BDNFm par une potentialisation de l’activité glutamatergique. Même si le rt-PA induit une meilleure récupération neurologique et augmente les taux circulants de BDNF chez les patients victimes d’un AVC, l’absence de corrélation entre ces deux paramètres n’est pas en faveur de l’utilisation du BDNF circulant comme un marqueur prédictif de récupération neurologique, mais pourrait être un reflet de la capacité de l’endothélium à sécréter le BDNF. / Our objective was to test the hypothesis that the beneficial effect of the administration of the recombinant form of tissue plasminogen activator (rt-PA) in ischemic stroke patient not only results from its fibrinolytic activity but also from its ability to increase brain-derived neurotrophic factor (BDNF) in the brain. To this end, we conducted an initial study to evaluate the effect of rt-PA on brain BDNF levels in healthy animals. In a second study, we investigated the effect of rt-PA on serum BDNF levels in ischemic stroke patients and in animals subjected to permanent focal cerebral ischemia. Blood samples were obtained from patient on admission (D0), D1, D7 and D90 after stroke and in rats before and after (1h, 4h and 24h) ischemia. BDNF was measured in the brain by Western blot and in the blood by ELISA. In both studies, the rt-PA (Actilyse®) was administered as a bolus followed by an infusion of one hour. The first study evidences that 1) rt-PA increases the BDNF levels in the hippocampus, 2) treatment with MK801 (a NMDA receptor antagonist) but not with tranexamic acid (a plasmin inhibitor) canceled the effect of rt-PA on BDNF levels. The second study exhibits that 1) neurological recovery was higher in the patients receiving rt-PA, 2) treatment with rt-PA increases serum BDNF at D1 and D7 in patients, but does not change the blood BDNF levels in animals, 3) BDNF levels are not correlated with neurological recovery but are inversely correlated to the patient cardiovascular score. In conclusion, our results suggest that rt-PA may have a protective extra-fibrinolytic effect by increasing in BDNF levels through a potentiation of glutamatergic pathway. Although rt-PA induces a better neurological recovery and increases circulating BDNF levels in stroke patients, the lack of correlation between these two parameters is not in favor of using circulating BDNF as a predictive marker of neurological recovery, but could be a reflect of the endothelium ability to synthesize BDNF.

Lesões medulares resultam em uma perda irreversível da função abaixo do sítio da lesão. Esses comprometimentos são permanentes e ocorrem devido à perda de neurônios localmente e também dos tratos axonais ascendentes e descendentes da medula espinal. Na tentativa de criar um ambiente favorável à regeneração dos axônios lesionados, células da glia embainhante olfatória (GEO) vêm sendo transplantadas como estratégia de tratamento em animais submetidos a diferentes modelos experimentais de lesões medulares. Entretanto, um consenso sobre o potencial terapêutico desse tipo de transplante celular ainda precisa ser estabelecido. O objetivo do presente trabalho foi verificar a eficácia do transplante de lâmina própria (LP) olfatória (que possui células da GEO) e de LP respiratória (desprovido de células da GEO), quando implantadas imediatamente, 2 ou 4 semanas após a realização da transecção da medula espinal. Doze semanas após a realização dos implantes, os animais que receberam LP olfatória e respiratória apresentaram uma melhora sutil na função motora dos membros posteriores. Além disso, o transplante de LP olfatória quando realizado imediatamente após a lesão reduziu a hiperatividade do reflexo de retirada, enquanto o implante desse tipo de tecido 4 semanas pós-lesão produziu uma discreta depressão dependente de frequência do reflexo de Hoffman (um análogo elétrico do reflexo monossináptico de estiramento). Nas diferentes janelas terapêuticas utilizadas, o transplante de ambos os tipos de LP produziu resultados comparáveis em relação à preservação do tecido medular, brotamento de neuritos e regeneração de fibras mielínicas no local da lesão, indicando que o tempo decorrido antes da realização dos transplantes não parece limitar os efeitos regenerativos. Todavia, as fibras mielínicas observadas no sítio da transecção nos animais que receberam LP olfatória 2 e 4 semanas pós-lesão possuíam menor área, diâmetro e espessura da bainha de mielina quando comparados aos animais que receberam LP respiratória nesses mesmos períodos. O transplante imediato de LP olfatória e respiratória também favoreceu o restabelecimento das conexões entre as fibras axonais lesionadas com núcleos do tronco encefálico e até mesmo com a região do córtex somatossensorial, como indicado pela presença de neurônios nessas regiões marcados positivamente com um marcador axonal retrógrado. Um número maior de fibras positivas para 5-HT foi observado no coto proximal dos grupos transplantados com ambos os tipos de LP em comparação às regiões da lesão e do coto caudal. Fibras positivas para CGRP estavam presentes em número considerável no local da lesão. A recuperação locomotora e a regeneração axonal no local da lesão foram limitadas e comparáveis entre os grupos transplantados nos diferentes tempos com LP olfatória e respiratória, sugerindo que esses resultados não estão exclusivamente relacionados à presença de células da GEO nos enxertos utilizados. Um melhor entendimento sobre o potencial restaurativo desse tipo de transplante é necessário a fim de justificar a aplicação dessa terapia em humanos. / Spinal cord injury (SCI) results in an irreversible loss of function below the injury site. These permanent disabilities occur due to local neuronal death and loss of ascending and descending axons in the spinal cord. In attempt to create a favorable environment for the re-growth of injured axons, olfactory ensheathing cells (OECs) have been transplanted as a treatment strategy in animals submitted to different experimental models of SCI. However, a consensus on the efficacy of this cellular transplantation has yet to be reached. The main focus of the present study was explore the efficacy of olfactory lamina propria (OLP, graft containing OECs) or respiratory lamina propria (RLP, graft without OECs) when transplanted immediately, 2-week or 4-week after spinal cord transection. After 12 weeks of transplantation, animals with OLP and RLP grafts showed a subtle hindlimb motor improvement. Furthermore, the transplantation of OLP when performed immediately after injury reduced the withdrawal reflex over-responsiveness, while the implantation of this tissue 4 weeks post-injury produced a discrete frequency-dependent habituation of the Hoffman reflex (the electrical analogue of the classic tendon jerk reflex). In all therapeutic windows used, both lamina propria grafts produced comparable results for tissue sparing, fibers sprouting and re-growth of myelinated fibers at the lesion site, indicating that delayed transplantation approach does not seem to limit the regenerative effects. However, the myelinated fibers observed at the transection site of animals that received OLP 2 or 4 weeks after injury had a smaller myelinated fiber area, diameter and myelin sheath thickness when compared to those animals transplanted with RLP grafts in the same periods. The immediate transplantation of OLP and RLP also foster limited supraspinal axonal re-connection as shown by the presence of neurons stained by retrograde tracing in brainstem nuclei and in the somatosensory cortex. A larger number of 5-HT positive axons were found in the cranial stump of both lamina propria groups compared to the lesion and caudal regions. CGRP positive axons were present in considerable numbers at the SCI site. The locomotor recovery and axon reparative effects were limited and similar between groups transplanted at different times with OLP and RLP, suggesting that these results could not be exclusively related to OECs. In conclusion, a greater understanding of the restorative potential of these tissue grafts is necessary to strengthen the rationale for application of this treatment in humans.

Este estudo teve o propósito de avaliar a recuperação funcional ao longo do tempo em indivíduos submetidos à cirurgia para tratamento de fraturas que acometeram o ângulo mandibular associados ou não à fraturas de parassínfise, ou que acometeram o côndilo mandibular unilateralmente, por meio da força de mordida e mobilidade mandibular associados à análise eletromiográfica (EMG) em diversas condições clínicas. A força de mordida foi registrada por meio de gnatodinamômetro na região dos molares do lado fraturado e contralateral à fratura e entre os incisivos centrais. A captação eletromiográfica foi obtida a partir dos músculos masseteres e temporais. A mensuração da mobilidade mandibular foi realizada com paquímetro digital, na condição clínica de abertura bucal, lateralidade direita e esquerda, e na protrusão mandibular, máximas. Os indivíduos que constituíram a amostra deste estudo foram alocados em três grupos: Grupo 1 - 7 indivíduos que sofreram fratura de ângulo mandibular (FAM); Grupo 2 - 5 indivíduos que sofreram fratura do côndilo mandibular (FCM); Grupo 3 - Grupo controle (sem fratura avaliação única) com 12 indivíduos. As fraturas foram tratadas cirurgicamente em ambiente hospitalar utilizando-se acesso intra-bucal para o Grupo 1 e extra-bucal para o Grupo 2, e por meio de fixação interna em todos os casos, com a utilização de técnicas já discutidas na literatura. O tempo de acompanhamento total foi de 2 meses para os Grupos 1 e 2. Nas avaliações realizadas, os Grupos 1 e 2 apresentaram redução da força de mordida na 1ª semana com aumentos nas avaliações subsequentes até o 2º mês de pós-operatório. Houve uma elevação da atividade eletromiográfica nos períodos pós-operatórios iniciais para ambos os grupos, sendo que o Grupo 1 apresentou uma redução regular na atividade eletromiográfica nas avaliações subsequentes. No entanto, o Grupo 2 apresentou um padrão irregular nos dados eletromiográficos apresentando grande variabilidade ao longo do período avaliado. Quanto à mobilidade mandibular no Grupo 1, ao 2o mês de pós-operatório, a amplitude de todos os movimentos mandibulares avaliados atingiu ao menos 90% dos valores obtidos pelo Grupo 3 - controle. Para o Grupo 2, os valores atingiram patamares próximos a 80%, sendo que, apenas a condição clínica de protrusão mostrou-se reduzida porém em valor atingindo ao menos 74% dos valores obtidos pelo Grupo 3 - controle. / This study had the purpose of evaluating the functional recovery over a time period by assessing mandibular motion range, maximum bite force, combined with electromyographic activity (EMG) in patients surgically treated for mandibular angle fractures associated or not with parassymphysis fractures, and for unilateral condylar process fractures. The bite force was recorded by gnathodynamometer in the region of the molars on ipsilateral and contralateral sides of the fracture and between the central incisors. The electromyographic signals were obtained from masseter and temporal muscles. Mandibular mobility was assessed based on the measurements performed with a digital pachymeter, considering the maximum standards for mouth opening, right and left lateral movement, and protrusion. The subjects that composed the study sample were separated in three groups: Group 1 - composed by 7 subjects who sustained mandibular angle fractures, Group 2 - composed by 5 subjects who sustained unilateral condylar process fractures and the Group 3 - control group composed by 12 subjects. The subjects were surgically treated under general anesthesia using intraoral approach for group 1 and extraoral approach for group 2. The surgical techniques were already discussed in the literature. The follow up was 2 months for Groups 1 and 2. In the assessments, Groups 1 and 2 revealed a reduction of bite force with an increase during the subsequent evaluations, until the 2nd month postoperative. Regarding the EMG activity, in Group 1 the values were higher in the former evaluation declining throughout subsequent evaluations. Conversely, in Group 2 the values followed a different and irregular pattern with great variability during the evaluation period. The mandibular motion range was almost fully recovered by Group 1 and, Group 2 achieved more than 80% in every assessment except for protrusion. In this clinical condition, the values were reduced nevertheless they were acceptable, representing at least 74% of the value obtained by the control group.

Caffeine is one of the most popular psychostimulant drugs worldwide. Its effects are exerted through a variety of complex mechanisms, apparently primarily via interactions with adenosine A1 and A2A receptors. This drug has also been proven to elicit neuroprotective responses in a number of different brain disorders of the Central Nervous System (CNS), as well as provide enhancement of cognitive abilities. Moreover, a biphasic set of functional and structural neurological changes are often found in these receptors among diverse vertebrates. I investigated the effects of chronic caffeine exposure on functional recovery of the dorsal light reflex (DLR) in hemilabyrinthectomized common goldfish, Carassius auratus. In this lesion model the unilateral removal of vestibular organs results in the temporary loss of gravitational regulated postural control, which over time corrects itself by a vestibular compensation (VC) mechanism and can be quantified via the DLR. We compared the functional recovery over 24 post -surgery days in goldfish continuously held in a caffeine solution of 2.5mg/L (n=10), 5.0mg/L (n=10), 10.0mg/L (n=11) or a control 0.0mg/L (n=9). Compared to a sham surgery group (n=11), statistically significant changes in the DLR of all hemilabyrinthectomized goldfish was observed on day 1. The control group recovered over the study period by approaching but not entirely reaching sham surgery DLR. The 2.5mg/L and 5.0mg/L groups initiated postural recovery similar to the controls, but then regressed to a stronger DLR. Beginning on day 10 the caffeine groups deviated from the control and all three experimental caffeine groups were statistically different from the control group on days 15-24. Results suggest early caffeine exposure may be innocuous; however, chronic exposure inhibits the functional recovery process.

No description available.

Une lésion traumatique de la moelle épinière est une affection de la moelle épinière résultant d’un impact direct sur la colonne vertébrale. D’installation brusque par compression, lacération, distraction ou section de la moelle épinière, les lésions médullaires traumatiques entraînent l’interruption partielle ou totale de la transmission de l’influx nerveux et le développement des troubles neurologiques. Ces troubles sont de gravité et de durée variables, limitant significativement la capacité fonctionnelle du patient dans les activités quotidiennes. Il s’agit d’une affection lourde de conséquences à cause de la morbidité et mortalité élevées comparativement à la population générale et d’une qualité de vie amoindrie à la suite de diverses complications à long terme. Ces lésions représentent un fardeau considérable pour le patient, sa famille et le système de santé dans son ensemble. Ceux qui survivent d’une LTME présentent, selon les cas, des évolutions cliniques très variables. Les résultats à long terme vont d’une récupération complète à une incapacité fonctionnelle très sévère. Selon les cas, différents scenarios sont possibles. Certains patients récupèrent considérablement sur le plan neurologique et sur le plan fonctionnel, tandis que d’autres patients ont une récupération très limitée, développant ainsi une invalidité qui les rend totalement dépendants. Au cours des dernières décennies, il y a eu beaucoup d’avancées médicales qui ont permis d’améliorer le diagnostic et la prise en charge rapide dans la phase aiguë. Fort malheureusement, très peu de progrès ont été réalisés sur les thérapies pouvant rétablir la transmission de l’influx nerveux interrompue et entraîner une restitution ad integrum. Tôt après la survenue de la lésion médullaire, la prédiction des résultats neurofonctionnels à long terme reste une préoccupation majeure pour les cliniciens, les patients et leurs familles. Cependant, les résultats à long terme suivant une LTME sont, à l’heure actuelle, difficiles à prédire avec précision à cause de la variabilité observée dans l’évolution clinique et la diversité des facteurs qui influencent ces résultats. Quelques études ont identifié plusieurs prédicteurs de résultats à long terme suivant une lésion médullaire. Cependant, il existe encore des lacunes relatives à la modélisation prédictive dans ce domaine. Ces lacunes sont liées à la sélection des variables indépendantes à utiliser dans la prédiction mais aussi à la pertinence clinique des résultats à prédire. L’objectif général de ce travail a consisté donc à étudier les caractéristiques de la phase d’hospitalisation aigue qui sont susceptibles de prédire les résultats neurofonctionnels à long terme après une LTME, et d’aider les cliniciens dans la prise en charge des patients. Plus précisément, ce travail consistait à (1) identifier les prédicteurs aigus des résultats neurologiques à long terme, (2) déterminer les prédicteurs aigus des résultats fonctionnels tout en établissant leur ordre d’importance et leurs points de coupure, (3) identifier les profils d’amélioration neurologique associés à la récupération fonctionnelle. Dans une première étude, nous avons identifié par une revue systématique de la littérature les variables liées aux caractéristiques du patient, de la lésion et de la prise en charge ayant une valeur prédictive des résultats neurologiques à long terme. Ces prédicteurs ont ensuite été classifiés dans un cadre conceptuel en quatre catégories en fonction de la constance de leur valeur prédictive. Cette étude a permis de mettre en évidence l’existence des prédicteurs émergents comme les biomarqueurs céphalorachidiens, sanguins et radiologiques, qui ont démontré une association significative aux résultats neurologiques bien que non encore suffisamment explorés. Deuxièmement, nous avons déterminé par une étude de cohorte, les prédicteurs aigus des résultats fonctionnels à long terme. Au moyen d’un arbre de régression, nous avons élaboré quatre phénotypes de récupération fonctionnelle en fonction des trois variables issues de l’examen neurologique initial, à savoir la sensibilité à la piqure, le score moteur ASIA des membres inférieurs et le score moteur ASIA des membres supérieurs. Cette étude a permis de déterminer les points de coupure sur ces variables d’intérêt. Enfin, dans une autre étude de cohorte, nous avons déterminé les profils d’amélioration neurologiques associés à la récupération fonctionnelle. La validation externe des résultats de ces deux dernières études dans une large cohorte de blessés médullaires issus d’une population différente est une prochaine étape nécessaire pour la translation clinique de ces algorithmes. En effet, l’identification de profils/phénotypes cliniques pourrait permettre aux cliniciens de mieux orienter et évaluer les stratégies de traitement et de réadaptation pour la clientèle des blessés médullaires. / A traumatic spinal cord injury (SCI) is damage to the spinal cord resulting from a direct impact on the spine. From sudden installation by compression, laceration, distraction, or section of the spinal cord, traumatic SCI causes partial or total interruption of the conduction of nerve impulses and the development of neurological disorders. These disorders vary in severity and duration, significantly limiting the functional capacity of the patient in daily activities. Traumatic SCI is a disease with serious consequences due to high morbidity and mortality compared to the general population, and reduced quality of life because of various long-term complications. These injuries represent a tremendous burden to the patients, their families, and the health care system. Those surviving a SCI present variable clinical evolution, and the long-term outcomes range between a full recovery and a severe functional disability. Depending on the case, different scenarios are possible. Some patients may significantly recover, both neurologically and functionally, while others have very limited recovery, the latter becoming dependent. In recent decades, there have been many medical advances that have improved diagnosis and rapid management in the acute phase. Unfortunately, very little progress has been made on effective therapies to restore the conduction of the interrupted nerve impulses. Early after the onset of a spinal cord injury, predicting long-term neurofunctional outcomes remains a major concern for clinicians, patients, and their families. However, it is currently difficult to accurately predict long-term neurofunctional outcomes, because of the variability in clinical evolution and the diversity of factors influencing these outcomes. A few studies have identified several predictors of long-term outcomes following a SCI. However, there are still gaps in predictive modeling in this area. These gaps are related to the selection of independent variables to be used in prediction but also to the clinical relevance of the results to be predicted. The overall objective of this work was to study the acute predictors of long-term neurofunctional outcomes following a SCI. More specifically, this work consisted of (1) identifying acute predictors of long-term neurological outcomes, (2) determining acute predictors of functional outcomes while determining their relative importance and cut-off, and (3) identifying neurological improvement profiles associated with functional recovery. Firstly, we conducted a systematic review of the literature and identified predictors of long-term neurological outcomes that are related to the patient, SCI, and management characteristics. These predictors were then classified in a new conceptual framework into four categories based on the consistency in the studies and their predictive value. This study highlighted the significant role of the initial neurological variables, as well as the existence of emerging predictors such as cerebrospinal, blood, and radiological biomarkers, which demonstrated a significant association with neurological outcomes although not yet sufficiently studied. Secondly, we conducted a cohort study to determine, the acute predictors of long-term functional outcomes. Using a regression tree, we determined four functional recovery phenotypes based on 3 variables from the initial neurological examination, namely the pinprick sensory score, the lower-extremity ASIA motor score, and the upper-extremity ASIA motor score. This study also defined the cut-off on these variables of interest. Finally, in another cohort study, we identified neurological improvement phenotypes associated with functional recovery. External validation of these results in a large cohort of individuals with SCI from a different population is a necessary next step for the clinical translation of these algorithms. Indeed, the identification of clinical profiles/phenotypes could allow clinicians to better guide and evaluate treatment and rehabilitation strategies for patients with SCI.

Bien que la plasticité ipsilesionnelle suite à un accident vasculo-cérébral (AVC) soit bien établie, la réorganisation du cortex contralésionnel et son effet sur la récupération fonctionnelle restent toujours non élucidés. Les études publiées présentent des points de vue contradictoires sur le rôle du cortex contralésionnel dans la récupération fonctionnelle. La taille de lésion pourrait être le facteur déterminant la réorganisation de ce dernier. Le but principal de cette étude fut donc d’évaluer l’effet des AVC de tailles différentes dans la région caudal forelimb area (CFA) du rat sur la réorganisation physiologique et la récupération comportementale de la main. Suite à une période de récupération spontanée pendant laquelle la performance motrice des deux membres antérieurs fut observée, les cartes motrices bilatérales du CFA et du rostral forelimb area (RFA) furent obtenues. Nous avons trouvé que le volume de lésion était en corrélation avec le niveau de récupération comportementale et l’étendue de la réorganisation des RFA bilatéraux. Aussi, les rats ayant de grandes lésions avaient des plus grandes représentations de la main dans le RFA de l’hémisphère ipsilésionnel et un déficit de fonctionnement plus persistant de la main parétique. Dans l’hémisphère contralésionnel nous avons trouvé que les rats avec des plus grandes représentations de la main dans le RFA avaient des lésions plus grandes et une récupération incomplète de la main parétique. Nos résultats confirment l’effet du volume de lésion sur la réorganisation du cortex contralésionnel et soulignent que le RFA est l’aire motrice la plus influencée dans le cortex contralésionnel. / While our understanding of ipsilesional plasticity and its role in recovery of hand function following ischemic stroke has increased dramatically, the reorganization of the contralesional motor cortex and its effect on recovery remain unclear. Currently published studies offer contradictory views on the role of contralesional motor cortex in recovery. Lesion extent has been suggested as the factor determining the type of reorganization of the contralesional motor cortex. The primary goal of this study was thus to evaluate the effect of unilateral strokes of different sizes in caudal forelimb area (CFA) of the rat on both physiological reorganization and behavioral recovery. At the end of a period of spontaneous recovery during which we monitored motor performance of both limbs, we obtained bilateral maps of the CFA and the putative premotor area of the rat – rostral forelimb area (RFA). We found that lesion volume in the CFA correlates with both the extent of behavioral recovery of the paretic hand and the extent of both ipsi and contralesional cortical reorganization. We found that rats with bigger lesions had larger hand representations in the ipsilesional hemisphere and more persistent deficits of the paretic hand. In the contralesional hemisphere we found that rats with larger hand representation in the RFA had bigger lesions and incomplete recovery of the paretic hand. Our results confirm the effect of lesion volume on the reorganization of the contralesional motor cortex and highlight contralesional RFA as the motor cortical area most influenced by lesion volume for future investigations.

Introduction et objectifs : La survenue d'une lésion médullaire (LM) causant une tétraplégie est un évènement tragique entraînant des conséquences dévastatrices sur la vie des individus et des coûts faramineux pour notre système de santé. Les individus qui subissent une LM traumatique avec tétraplégie nécessitent en général plusieurs semaines d’hospitalisation en centre de soins aigus où ils seront particulièrement à risque de complications médicales. Alors que des facteurs reliés au traumatisme initial ou au patient sont reconnus pour déterminer leur évolution clinique, l’impact de la gestion péri-opératoire suivant une LM parmi ces facteurs est encore imprécis. Ainsi, l’objectif principal de ce travail est d’identifier les facteurs influençant le déroulement de la phase d’hospitalisation aigue, en terme d’évolution clinique et d’utilisation de ressources hospitalières, suivant une tétraplégie aigue. Ensuite, afin de déterminer leur pertinence clinique à long terme, le second objectif de ce projet consiste à déterminer si ceux-ci ont également un impact sur la récupération fonctionnelle six mois post lésion. Méthodologie et résultats : Une étude rétrospective basée sur une banque de données prospective collectée dans un centre de traumatologie tertiaire, ainsi qu’une étude prospective prédictive ont été complétées. En plus de différents facteurs sociodémographiques et reliés au traumatisme initial (non-modifiables), une admission précoce en centre de soins spécialisés et la diminution de la survenue de complications représente des facteurs importants modifiables qui améliorent l’évolution clinique et l’utilisation de ressources en phase d’hospitalisation aigue. Une gestion chirurgicale et péri-opératoire spécialisée dans un centre pour LM influence significativement le cours de l’hospitalisation aigue en améliorant différents paramètres cliniques, de même qu’en diminuant les coûts et la durée de séjour en soins aigus chez les patients tétraplégiques. La survenue de complications médicales et l’augmentation du délai de séjour en soins aigus sont des facteurs prédictifs de récupération fonctionnelle sous-optimale six mois post-lésion. Conclusions: Le déroulement de l’hospitalisation aigue peut influencer l’évolution clinique des patients tétraplégiques et l’utilisation des ressources de notre système de santé. Mais également, le déroulement de l’hospitalisation peut avoir un impact significatif sur la récupération fonctionnelle plus de six mois post lésion. Une gestion péri-opératoire et chirurgicale précoce en centres de soins spécialisés en LM est fortement suggérée suivant une tétraplégie traumatique aigue, afin d’optimiser l’évolution clinique et le transfert des patients en réadaptation fonctionnelle intensive pour ainsi optimiser leur récupération fonctionnelle. Ceci pourrait également significativement diminuer la charge économique sur notre système de santé. Retombées : En soulevant l’importance d’une gestion optimale en soins aigus, cette étude permet d’appuyer les recommandations actuelles, de faible niveau, suggérant le transfert rapide de patients avec LM en centre spécialisés. Une gestion hospitalière aigue centrée vers la prévention des complications médicales et la récupération neuro-fonctionnelle doit être mise en place le plus tôt possible suivant une LM et particulièrement suivant une tétraplégie. Ce travail permettra ainsi de justifier l’élaboration de projets subséquents qui permettront d’élaborer des protocoles de gestion clinique et administratif plus précis, pour mieux encadrer et définir l’importance des centres de soins aigus spécialisés, et pour favoriser le transfert de connaissances en centres non spécialisés. / Introduction and objectives: The occurrence of a spinal cord injury (SCI) causing tetraplegia is a tragic event leading to devastating consequences on the life of individuals and huge costs to our healthcare system. Individuals who experience a traumatic SCI (TSCI) with tetraplegia require several weeks of hospitalisation in an acute care center where they are at risk of various medical complications. While factors related to the initial trauma or to the patient’s baseline characteristics are recognized to determine their clinical outcome, the impact of the perioperative management following a TSCI is still unclear. Thus, the main objective of this study is to identify factors influencing the course of acute care hospitalization in terms of clinical outcome and use of hospital resources following acute tetraplegia. Then, in order to determine clinical relevance of these factors in longer-term outcome of patients, the second objective of this project is to determine if these factors also have an impact on the functional recovery six months post injury. Methods and results: A retrospective cohort study in a single level-1 trauma center specialized in SCI care, and a predictive prospective study were completed. Early admission to a specialized SCI center and a decreased incidence of medical complications during acute care hospitalization were found to significantly improve clinical outcomes and decrease resource utilization during acute care. Higher occurrence of medical complications and longer acute care length of stay were significant predictors of lower functional recovery (as measured by the Spinal Cord Independence Measure six-months post injury). Conclusions: Optimization of acute care hospitalization in a specialized center may improve clinical outcomes and decrease hospital resource utilization following acute tetraplegia and thereby have a positive impact on the 6-month functional recovery. Early admission and complete perioperative management in a specialized SCI center is thus recommended following tetraplegia. This could also reduce the economic burden on our healthcare system. Clinical applications and future directions: By highlighting the importance of high-quality care following acute SCI, this study supports current recommendations suggesting prompt transfer to a specialized acute care center following tetraplegia. Acute care management focussing on the early prevention of medical complications and optimization of recovery should be provided as early as possible following tetraplegia. Future projects working towards development of precise clinical and administrative protocols for acute SCI care will help to better regulate and define the importance of specialized centers, and to promote knowledge transfer.