Les douleurs neuropathiques, celles qui sont provoquées par des lésions du système nerveux central ou périphérique, sont les plus difficiles à traiter du fait de leur résistance aux traitements antalgiques classiques. Les traitements utilisés aujourd’hui font appel à des classes thérapeutiques non spécifiquement ciblées sur la douleur, en particulier des antidépresseurs et des anticonvulsivants. Leur efficacité limitée ne repose en fait que sur des observations empiriques. Une meilleure connaissance des processus physiopathologiques sous-tendant les douleurs neuropathiques constitue un préalable à toute innovation thérapeutique, et c’est à cette fin que je me suis appliqué à développer deux modèles de douleurs neuropathiques chez le rat pour en étudier les caractéristiques comportementales, fonctionnelles, cellulaires et biochimiques. Le premier modèle visait à l’induction d’une douleur neuropathique centrale provoquée par la section complète de la moelle épinière au niveau thoracique (T8-T9) ; le second a consisté à injecter, directement au niveau spinal, par voie intrathécale (i.t.), le facteur neurotrophique BDNF (Brain Derived Neurotrophic Factor ; dont l’implication dans les voies de signalisation nociceptive est bien établie dans la littérature). Dans les deux cas, les conséquences pro-algiques de ces interventions ont été comparées à celles induites par la ligature unilatérale du nerf sciatique, qui constitue encore aujourd’hui un modèle classique, mais très imparfait, d’une douleur neuropathique périphérique. Dès le 2ème jour après la section spinale, et jusqu’au moins deux mois plus tard, les rats lésés présentent une forte allodynie mécanique (test des filaments de von Frey) dans le territoire cutané juste en avant de la lésion. Cet effet traduit bien une neuropathie centrale car il n’existe pas chez les rats « sham » qui ont subi l’intégralité de l’intervention chirurgicale à l’exception de la section spinale. L’allodynie mécanique est associée à une induction significative de l’expression (RTqPCR) de marqueurs de souffrance neuronale (ATF-3) et d’activation microgliale (OX-42, récepteurs P2X4, P2X7 et TLR4) et astrocytaire (GFAP), ainsi que du BDNF et de cytokines pro-inflammatoires (IL-1ß, IL-6, TNF-α), mais de façon plus transitoire, ceci dans les ganglions de racines dorsales et/ou la moelle épinière dorsale (comme à la suite de la ligature du nerf sciatique, mais avec des cinétiques différentes). Pour sa part, l’injection intrathécale i.t. d’une dose infra-nanomolaire unique de BDNF (0.3 – 3.0 ng) induit aussi une forte allodynie et une hyperalgésie mécaniques, au niveau des pattes postérieures, qui se développent en 3-5 jours, et perdurent pendant deux semaines. Cependant, au contraire de la section spinale (et de la ligature du nerf sciatique), l’injection i.t. de BDNF ne provoque pas d’activation microgliale ni d’induction de cytokines. Elle entraine en revanche une auto-induction du BDNF, qui semble clé pour l’hyperalgésie puisque celle-ci peut être, en grande partie, supprimée par l’administration d’un inhibiteur du récepteur TrkB du BDNF, la cyclotraxine B (20 mg/kg i.p.), comme d’ailleurs l’hyperalgésie induite par la ligature du nerf sciatique. Au plan pharmacologique, un antalgique opiacé comme le tapentadol s’est révélé efficace dans les deux modèles. De même, les anticonvulsivants, comme la prégabaline et la gabapentine, ont réduit la douleur neuropathique chez les rats injectés par le BDNF i.t. et chez les rats CCI-SN. En conclusion, il semble que l’injection intrathécale de BDNF, qui évite la réalisation de lésions par intervention chirurgicale, puisse constituer un nouveau modèle pertinent de douleur neuropathique chez le rat. De plus, nos résultats laissent à penser que le blocage de la voie de signalisation BDNF-TrkB pourrait ouvrir de nouvelles pistes pour la réduction des douleurs neuropathiques périphériques. (...) / Neuropathic pain, caused by lesions of central or peripheral nervous system, is difficult to treat because of its resistance to classical antalgic treatments. Most of pharmacotherapeutic treatments of neuropathic pain (antidepressants, anticonvulsants) currently used are only based on empirical data and are not specifically aimed at relieving pain. Better knowledge of the mechanisms underlying neuropathic pain is an absolute prerequesite to develop new and innovative treatments. With the aim of contributing to elucidate these mechanisms, I developed two models of neuropathic pain in rats, and studied their behavioral, pharmacological, cellular and biochemical characteristics. The first model consisted of the induction of central neuropathic pain by complete transection of the spinal cord at T8-T9 level. The second one consisted of the administration of BDNF (Brain Derived Neurotrophic Factor; which implication in nociceptive signaling pathways is well established in the literature), directly at the spinal level, via intrathecal (i.t.) injection. In both cases, pro-algesic consequences of these interventions have been compared to those induced by unilateral ligation of the sciatic nerve, which is still considered as a classical, although not really satisfactory, model of peripheral neuropathic pain. From the second day after spinal cord transection up to (at least) 2 months later, lesioned rats developed a strong mechanical allodynia (von Frey filaments test) within a limited cutaneous territory just rostral to the surgical scar. This effect really reflected central neuropathic pain because it did not occur in control, « sham operated » animals, that underwent the same surgical intervention except the spinal cord transection. Mechanical allodynia was associated with marked overexpression of markers of neuronal injury (ATF-3), microglial activation (OX-42, P2X4, P2X7 and TLR4 receptors), astrocyte activation (GFAP), as well as upregulation of transcripts encoding BDNF and pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α, but only transiently for the latter cytokine), in dorsal root ganglia and/or spinal cord. Therefore, spinal cord transection triggered a strong neuroinflammatory reaction, like that occurring after peripheral nerve lesion, but with different time course and amplitude. On the other hand, intrathecal injection of an infra-nanomolar dose of BDNF (0.3 – 3.0 ng) also induced a strong mechanical allodynia and hyperalgesia at hindpaw level, which developed within 3-5 days and lasted for at least two weeks. However, in sharp contrast with spinal cord transection (and sciatic nerve ligation), i.t. injection of BDNF did not induce any microglial activation and/or proinflammatory cytokines upregulation. Intrathecal (exogenous) BDNF-induced (endogenous) BDNF auto-induction might play a key role in the maintenance of i.t. BDNF-induced hyperalgesia as the latter can be reversed by pharmacological blockade of the BDNF receptor TrkB (with cyclotraxin B at 20 mg/kg i.p., which also reversed sciatic nerve ligation-induced hyperalgesia). Pharmacological investigations showed that the opioid antalgic drug tapentadol and anticonvulsants such as pregabalin and gabapentin efficiently reduced neuropathic pain in i.t. BDNF i.t. as well as in sciatic nerve-ligated rats. Accordingly, intrathecal injection of BDNF might represent a new non-surgical model of neuropathic pain in rats. Moreover, our results indicate that blockade of BDNF-TrkB signaling could open new therapeutic perspectives for alleviating peripheral neuropathic pain. This innovative pharmacological approach should also be explored in the case of central neuropathic pain caused by spinal cord injury.

The thesis deals with the subjective perception of quality of life of persons that have suffered a spinal cord injury. The Theoretical part is devoted to the quality of life, its definitions, concepts, factors and measuring. Further, it focuses on spinal cord injuries and their consequences with regard to functionality of extremities and organs. It describes types of handicap, process and components of physical therapy. It also deals with psychological stress of a person dealing with the injury and its consequences. Focus is in particular applied to coping strategies and adaptation mechanisms. The third chapter of the Practical part is devoted to the quality of life of a specific target group, i.e. of persons that have suffered spinal cord injury. It introduces the factors and specific aspects contributing to the perception of quality of life. It also addresses some of the frequent mistakes and stereotypes in approaches to people with handicap. In the Empirical part, we have found out that people who suffered spinal cord injury perceive the lower level of quality of life in the area of health and relationships. We did not find statistically significant differences in subjective perception of quality of life depending on the level of handicap, or time that has passed since the injury. As part of...

Injury and neurodegenerative conditions of the spinal cord can lead to paralysis and loss of sensation. Cell therapeutic approaches can restore sensory innervation of the spinal cord following injury and protect spinal cord cells from degeneration. This thesis primarily focuses on the restoration of deaffarented sensory fibres following injury to the dorsal root and spinal cord. These injuries lead to the formation of a non-permissive glial scar that prevents sensory axons from reinnervating spinal cord targets. It takes advantage of a dorsal root injury model that closely mimics spinal root avulsion injuries occurring in humans. In the first part of the thesis, three different neural progenitor types from human or murine sources are tested for their regenerative properties following their transplantation to the site of dorsal root avulsion injury. In the second part, the ability of murine neural progenitors to protect spinal motor neurons from a neurodegenerative process is tested. In the first original research article, I show that human embryonic stem cell derived neural progenitors are able to restore sensorimotor functions, mediated by the formation of a tissue bridge that allows ingrowth of sensory axons into the spinal cord. In the second research article, I present that murine boundary cap neural crest stem cells, a special type of neural progenitor that governs the entry of sensory axons into the spinal cord during development, are unable to form a permissive tissue bridge. This is possibly caused by the contribution of transplant derived ingrowth non-permissive glial cells. In the third research article, I show that human neural progenitors derived from foetal sources are capable of stimulating sensory ingrowth and that they ameliorate the glial scar. When this approach is combined with the delivery of sensory outgrowth stimulating neurotrophic factors, these cells fail to form a permissive tissue bridge and fail to modify the glial scar. In the final research article, murine boundary cap neural crest stem cells are shown to protect motor neurons, which harbor an amyotrophic lateral sclerosis causing mutation, from oxidative stress. Oxidative stress is a pathological component of amyotrophic lateral sclerosis in human patients. Taken together, this thesis provides first evidence that sensory regeneration following a spinal root avulsion injury can be achieved by transplantation of human neural progenitors. In addition, it introduces murine boundary cap neural crest stem cells as interesting candidates for the cell therapeutic treatment of amyotrophic lateral sclerosis.

Spinal cord injury (SCI) is an acute and devastating event that results in significant and permanent life changes for the individuals who are injured, as well as their families and friends. Depression has received more attention from clinicians and researchers than any other psychological issue among persons with SCI. Measurement of depression in this population has a variety of methodological issues, including inconsistent assessments used (self-report versus clinical interviews), varying definitions of depression, inclusion and exclusion of physical symptoms in the assessment process, and use of measures that do not represent DSM-IV criteria for major depressive disorder. The primary goal of this study was to evaluate the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR) and provide descriptive analyses of this measure with persons with SCI. Results showed that somatic symptoms were more frequently endorsed than psychological symptoms in this population. Additionally, scores on the QIDS-SR were significantly associated with a depression diagnosis in the patient's medical chart. However, QIDS-SR scores were not found to be correlated inversely with quality of life scores as predicted. The QIDS-SR was shown to have good internal consistency and convergent validity with patients with SCI. However, it failed to demonstrate construct validity. The QIDS-SR has the potential to be a valid measure with this population and further analysis of the psychometric properties with patients with SCI is warranted.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2018-07-19T18:05:15Z No. of bitstreams: 1 Paulo Roberto da Costa Palácio.pdf: 1422325 bytes, checksum: 51b63e3f97165219831c853176256d9e (MD5) / Made available in DSpace on 2018-07-19T18:05:15Z (GMT). No. of bitstreams: 1 Paulo Roberto da Costa Palácio.pdf: 1422325 bytes, checksum: 51b63e3f97165219831c853176256d9e (MD5) Previous issue date: 2017-12-18 / Introduction: Spinal cord injury (LM) is a tragic event that can profoundly affect a patient's life, with physical, psychological, social and environmental implications. Causing the loss of functional independence and reduced expectation and quality of life. The objective of this study was to evaluate if the photobiomodulation is able to influence the treatment of LM, promoting greater functionality and directly reflecting the quality of life of these individuals. Methods: The sample consisted of 25 patients. They were divided into two groups (Control and Photobiomodulation). The control group received physiotherapeutic treatment plus placebo photobiomodulation and the Photobiomodulation group received physiotherapeutic treatment and 12 sessions of low power laser therapy three times a week. All subjects completed the Life Quality Questionnaire (WHOQOL-bref) and the Functional Independence Measure (MIF) scale before, immediately after and 30 days after photobiomodulation. The data were analyzed statistically accepting a p <0.05 and the Shapiro-Wilk test was used for data normality. For the non-parametric variables, the following tests were used: Friedman and Mann-Whitney and for anova parametric variables for repeated measurements and Pearson correlation. Results: There were no statistically significant differences between the groups Photobiomodulation and control, in any of the domains and periods evaluated in the MIF. In the comparison between the groups, statistically significant results were observed in the psychological (0.001), Social (0.001) and General Quality of Life (0.001) domains. Statistically significant results were observed in the correlation between Physical domain and Perception of Quality of life (0.018 and 0.001, respectively) in the periods before and after 30 days of photobiomodulation. Conclusion: It was concluded that FBM was able to promote a significant influence in the social and psychological domains of individuals with LM, representing a good perception in the general quality of life of this population, but did not promote an influence on the functional independence of individuals with LM. / Introdução: A lesão medular (LM) é um evento trágico que pode afetar profundamente a vida de um paciente, com implicações físicas, psicológicas, sociais e ambientais. Causando a perda da independência funcional e redução da expectativa e qualidade de vida. O objetivo deste estudo foi avaliar se a fotobiomodulação é capaz de influenciar no tratamento de LM, promovendo maior funcionalidade e refletindo diretamente na qualidade de vida desses indivíduos. Métodos: A amostra foi composta de 25 pacientes. Foram divididos em dois grupos (Controle e Fotobiomodulação). O grupo controle recebeu o tratamento fisioterápico mais a fotobiomodulação placebo e o grupo Fotobiomodulação recebeu o tratamento fisioterápico e 12 sessões de laserterapia de baixa potência, três vezes por semana. Todos os indivíduos preencheram o Questionário de qualidade Vida (WHOQOL-bref) e a escala da Medida de Independência Funcional (MIF) antes, imediatamente após e 30 dias após a fotobiomodulação. Os dados foram analisados estatisticamente aceitando um p<0,05 e empregou-se o teste de Shapiro-Wilk para normalidade dos dados. Para as variáveis não paramétricas foi utilizado os testes: Friedman e Mann-Whitney e para as variáveis paramétricas anova para medidas repetidas e correlação de Pearson. Resultados: Não foram encontradas diferenças estatisticamente significantes entre os grupos Fotobiomodulação e controle, em nenhum dos domínios e períodos avaliados na MIF. Na comparação entre os grupos foram observados resultados estatisticamente significantes nos domínios psicológico (0,001), Social (0,001) e Qualidade de Vida Geral (0,001). Observou-se resultados estatisticamente significantes na correlação entre domínio Físico e a Percepção da Qualidade de vida (0,018 e 0,001, respectivamente) nos períodos pré e pós 30 dias da fotobiomodulação. Conclusão: Concluiu-se que a FBM foi capaz de promover uma influência significante nos domínios social e psicológico dos indivíduos com LM, representando uma boa percepção na qualidade de vida geral desta população, porém não promoveu uma influência na independência funcional dos indivíduos com LM.

Title: Evaluation of the spasticity level in wheelchair bound individuals, observing movement in a virtual reality environment Objective: Investigate whether people watching movement in virtual reality, experience changes in the level of spasticity due to intervention of the therapeutic programme. Methods: A pilot study was orchestrated with probands diagnosed with spastic paraplegia due to an incomplete spinal cord lesion. Seven probands have partaken in the study (5 men and 2 women) aged 49 ± 8 years. All probands were clients of Centrum Paraple, where they have been undergoing a regular rehabilitation programme. In addition to their regular programme they have undergone a virtual reality therapeutic programme, where each intervention consisted of 10 minutes spent in a therapeutic virtual environment. 3 probands resigned after the first intervention. Interventions were organized into 5 consecutive days. The levels of spasticity were evaluated by a modified Tardieu scale on plantar flexors of both ankles and knee joints of both lower limbs. Furthermore, a modified, subjective spasticity scale was created in order to observe individual, subjective inputs of each proband. Using this scale, probands evaluated their feelings towards individual spasticity changes on a scale 1-10 (0 = no spasticity, 10...

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Spinal cord injury is a very significant clinical as well as social problem with extensive consequences, affecting the patient and also his/her family. Great efforts have been devoted to searching for an effective treatment, which would improve their situation. This thesis evaluated the effects of the natural compound curcumin on spinal cord injury using an experimental balloon compression model. Male Wistar rats were randomized into two groups following the lesion induction, namely vehicle- or curcumin-treated. The behavioral recovery was evaluated using a set of locomotor and sensory tests and a histological and imunohistochemical analysis was performed. The qPCR method was used to observe the expression of some genes related to regeneration and immune response. It was demonstrated that curcumin improved locomotor recovery after the spinal cord injury, particularly in the early stages. Morphometric analysis of the gray and white matter sparing didn't confirm any differences between the two groups. Nevertheless, the glial scar formation was significantly reduced around the central part of the lesion in the curcumin treated group and also the NF-κB activity was substantially inhibited. The gene expression analysis demontrated downregulation of Gfap and Rantes genes and upregulation of the Irf5 gene...

Title: Evaluation of the spasticity level in wheelchair bound individuals, observing movement in a virtual reality environment Objective: Investigate whether people watching movement in virtual reality, experience changes in the level of spasticity due to intervention of the therapeutic programme. Methods: Two case studies were orchestrated, both of probands diagnosed with spastic paraplegia due to an incomplete spinal cord lesion. Both probands did undergo a therapeutic programme in virtual reality, where each intervention consisted of 30 minutes in said programme. Interventions were organised in 10 consecutive days in the case of the first proband and 5 consecutive days in the case of the second. The levels of spasticity before and after each intervention were taken into account and evaluated by a modified Tardieu scale on plantar flexors of both ankle and knee joints of both lower limbs. Furthermore, a modified, subjective spasticity scale was created in order to observe individual, subjective inputs of each proband. Using this scale, probands evaluated their feelings towards individual spasticity changes on a scale 1-10 (0 = no spasticity, 10 = unbearable spasticity sensations). This evaluation took place before and after each individual intervention. Results: Seven hypotheses were defined in...

Purpose: To assess if a balance retraining program using the NintendoTM Wii Fit: 1) can improve balance, gait, and quality of life in ambulatory individuals with incomplete spinal cord injury (iSCI), 2) can improve standing tolerance in individuals with iSCI, 3) requires individuals to work outside of their limits of stability, 4) can determine if there is a relationship between changes in standing balance measures and the RAND Short Form 36 (RAND SF-36) health measure, 5) can determine if there is a change in postural stability, control, and adaptation to the virtual reality (VR) environment. Problem Statement: There are no studies to date on the effects of an intensive virtual reality balance training program on gait, balance, or quality of life in the iSCI population. Relevance: There is a need for continued research to support effective treatment techniques in individuals with iSCI to maximize each individual's potential. Subjects: Five males with a mean age of 58.6 years who had an iSCI greater than one year post injury. Inclusion: 1) iSCI, 2) ambulate with or without assistive devices, AFOs, and no greater than minimal assistance for a minimum of 10 meters, 3) tolerate static standing for at least 5 minutes at a time with no greater than minimal assistance. Exclusion: 4 Significant orthopedic impairments, pain or a spinal stabilization device that may limit standing or ambulation. Methods: A repeated measures design with three pretests over three weeks, a post-test within one week of the intervention, and a four week follow up. Outcome measures: 10 meter walk test (10MWT), Timed Up and Go (TUG), Forward Functional Reach Test (FFRT) and Lateral Functional Reach Test (LFRT), RAND SF-36. Intervention consisted of one hour sessions with varied games using the Nintendo Wii Fit twice per week for seven weeks. Subjects' subjective reports were collected during the intervention phase. Survey data was also collected at post-test. Results: There were statistically significant changes found in FFRT that were clinically meaningful (Z = -1.84, p = 0.07; average change scores 8.00 centimeters). The changes were also maintained at the four week follow up post-test. Subject reports suggested improvements in balance, endurance, and mobility with daily tasks at home. There was a high correlation between the change scores of the TUG and the RAND SF-36 (r=0.90). Discussion: The training using the NintendoTM Wii Fit improved balance in all five individuals with iSCI. There was an increase in standing during the intervention with decrease in rests. VR training practices task specific training of standing balance. Further research is needed to assess different gaming options to focus on task specific training of gait and mobility.