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For almost a century, the electrical properties of the brain and the nervous system have been investigated to gain a better understanding of their mechanisms and to find cures for pathological conditions. Despite the fact that today's advancements in surgical techniques, research, and medical imaging have improved our ability to treat brain disorders, our knowledge of the brain and its functions is still limited. Culturing dissociated cortical neurons on Micro-Electrode Array dishes is a powerful experimental tool for investigating functional and structural characteristics of in-vitro neuronal networks, such as the cellular basis of brain learning, memory and synaptic developmental plasticity. This dissertation focuses on combining MEAs with novel electrophysiology experimental paradigms and statistical data analysis to investigate the mechanisms that regulate brain development at the level of synaptic formation and growth cones. The goal is to use a mathematical approach and specifically designed experiments to investigate whether dissociated neuronal networks can dependably display long and short-term plasticity, which are thought to be the building blocks of memory formation in the brain. Quantifying the functional evolution of dissociated neuronal networks during in- vitro development, using a statistical analysis tool was the first aim of this work. The results of the False Discovery Rate analysis show an evolution in network activity with changes in both the number of statistically significant stimulus/recording pairs as well as the average length of connections and the number of connections per active node. It is therefore proposed that the FDR analysis combined with two metrics, the average connection length and the number of highly connected "supernodes" is a valuable technique for describing neuronal connectivity in MEA dishes. Furthermore, the statistical analysis indicates that cultures dissociated from the same brain tissue display trends in their temporal evolution that are more similar than those obtained with respect to different batches. The second aim of this dissertation was to investigate long and short-term plasticity responsible for memory formation in dissociated neuronal networks. In order to address this issue, a set of experiments was designed and implemented in which the MEA electrode grid was divided into four quadrants, two of which were chronically stimulated, every two days for one hour with a stimulation paradigm that varied over time. Overall network and quadrant responses were then analyzed to quantify what level of plasticity took place in the network and how this was due to the stimulation interruption. The results demonstrate that here were no spatial differences in the stimulus-evoked activity within quadrants. Furthermore, the implemented stimulation protocol induced depression effects in the neuronal networks as demonstrated by the consistently lower network activity following stimulation sessions. Finally, the analysis demonstrated that the inhibitory effects of the stimulation decreased over time, thus suggesting a habituation phenomenon. These findings are sufficient to conclude that electrical stimulation is an important tool to interact with dissociated neuronal cultures, but localized stimuli are not enough to drive spatial synaptic potentiation or depression. On the contrary, the ability to modulate synaptic temporal plasticity was a feasible task to achieve by chronic network stimulation. / Electrical and Computer Engineering

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal. / This thesis provides evidence to support the hypothesis that synaptic plasticity in the primary somatosensory cortex is a cellular correlate of associative learning, that the process depends upon acetylcholine and that only certain cortical neurons display this plasticity. In a first series of experiments, single-imit recordings were carried out in the barrel cortex of awake, adult rats subjected to whisker pairing, an associative learning paradigm where deflections of the recorded neuron's principle vibrissa were repeatedly paired with those of a non-adjacent one. On average, this form of sensory preconditioning increased the responses of a recorded unit to the stimulation of the non-adjacent vibrissa. In contrast, following explicitly unpaired control experiments, neuronal responsiveness decreased. The effect of pairing was further enhanced by local, microiontophoretic delivery of NMDA and the nitric oxide synthase inhibitor L-NAME and reduced by the NMDA receptor competitive antagonist AP5. These results and the fact that the influence of the pharmacological agents on neuronal excitability were either transient (liinited to the delivery period) or simply absent indicated that the somatosensory cerebral cortex is one site where plasticity emerges following whisker pairing. In subsequent experiments, using a similar conditioning paradigm that relied on evoked potential rather than single-unit recordings, increases in the responses of cortical neurons to the non-adjacent whisker were blocked by atropine sulfate, an antagonist of muscarinic cholinoreceptors. Administration of norn-ial saline or atropine methyl nitrate, a muscarinic antagonist that did not cross the blood-brain barrier, instead of atropine sulfate, did not affect plasticity. Analysis of the behavioral state of the animal showed that the changes observed in the evoked potential could not be attributed to fluctuations m the behavioral state of the animal. By combining the results described in this thesis with data foimd in related literature, the author hypothesizes that whisker pairing induces an acetylcholine-dependent form of plasticity within the somatosensory cortex through Hebbian mechanisms.

A estimulação elétrica periférica (PES), que abrange diversas técnicas com respostas fisiológicas diversas, tem apresentado em alguns casos resultados clínicos promissores para o tratamento da dor e reabilitação clínica. No entanto, as respostas encontradas são heterogêneas, principalmente porque há uma falta de compreensão em relação ao seu mecanismo de ação. Neste estudo, buscamos avaliar os efeitos da PES através da medição da ativação cortical cerebral utilizando a espectroscopia funcional por infravermelho (fNIRS). A fNIRS é um método de imagem óptica funcional que avalia mudanças hemodinâmicas nas concentrações de hemoglobina oxigenada (HbO) e desoxigenada (HbR), relacionadas à atividade cortical. Nós hipotetizamos que a PES do nervo acessório espinal (ASN) pode promover a ativação do córtex motor (MC) e do córtex pré-frontal dorsolateral (DLPFC), relacionados ao processamento da dor. Quinze voluntários saudáveis receberam estimulação elétrica ativa e sham em um ensaio clínico randomizado cruzado. A resposta hemodinâmica à estimulação elétrica unilateral direita do nervo acessório com 10 Hz foi medida pela espectroscopia funcional por um sistema de 40 canais. A variação de HbO nas áreas corticais de interesse mostrou ativação do DLPFC direito (p=0,025) e do MOTOR esquerdo (p=0,042) no grupo ativo comparado com sham. Em relação ao DLPFC esquerdo (p=0,610) e ao MOTOR direito (p=0,154), não houve diferença estatística entre os grupos. Como na modulação top-down, a estimulação bottom-up do nervo acessório parece ativar as mesmas áreas corticais, relacionadas às dimensões sensório-discriminativas e afetivo-motivacionais da dor. Esses resultados fornecem evidência adicional para desenvolver e otimizar o uso clínico da estimulação elétrica periférica. / Peripheral electrical stimulation (PES), which encompasses several techniques with heterogeneous physiological responses, has shown in some cases remarkable outcomes for pain treatment and clinical rehabilitation. However, results are still mixed, mainly because there is a lack of understanding regarding its neural mechanisms of action. In this study, we aimed to assess its effects by measuring cortical activation as indexed by functional near infrared spectroscopy (fNIRS). fNIRS is a functional optical imaging method to evaluate hemodynamic changes in oxygenated (HbO) and de-oxygenated (HbR) blood hemoglobin concentrations in cortical capillary networks that can be related to cortical activity. We hypothesized that PES of accessory spinal nerve (ASN) can promote cortical activation of motor cortex (MC) and dorsolateral prefrontal cortex (DLPFC) pain processing cortical areas. Fifteen healthy volunteers received both active and sham ASN electrical stimulation in a crossover design. The hemodynamic response to unilateral right ASN burst electrical stimulation with 10 Hz was measured by a 40- channel fNIRS system. The effect of ASN electrical stimulation over HbO concentration in cortical areas of interest was observed through the activation of right- DLPFC (p=0.025) and left-MOTOR (p=0.042) in the active group but not in sham group. Regarding left-DLPFC (p=0.610) and right-MOTOR (p=0.174) there was no statistical difference between groups. As in non-invasive brain stimulation (NIBS) topdown modulation, bottom-up electrical stimulation to the accessory spinal nerve seems to activate the same critical cortical areas on pain pathways related to sensorydiscriminative and affective-motivational pain dimensions. These results provide additional mechanistic evidence to develop and optimize the effects of peripheral neural electrical stimulation.

This thesis is divided into three main parts. In the first, we discuss that, although permutation tests can provide exact control of false positives under the reasonable assumption of exchangeability, there are common examples in which global exchangeability does not hold, such as in experiments with repeated measurements or tests in which subjects are related to each other. To allow permutation inference in such cases, we propose an extension of the well known concept of exchangeability blocks, allowing these to be nested in a hierarchical, multi-level definition. This definition allows permutations that retain the original joint distribution unaltered, thus preserving exchangeability. The null hypothesis is tested using only a subset of all otherwise possible permutations. We do not need to explicitly model the degree of dependence between observations; rather the use of such permutation scheme leaves any dependence intact. The strategy is compatible with heteroscedasticity and can be used with permutations, sign flippings, or both combined. In the second part, we exploit properties of test statistics to obtain accelerations irrespective of generic software or hardware improvements. We compare six different approaches using synthetic and real data, assessing the methods in terms of their error rates, power, agreement with a reference result, and the risk of taking a different decision regarding the rejection of the null hypotheses (known as the resampling risk). In the third part, we investigate and compare the different methods for assessment of cortical volume and area from magnetic resonance images using surface-based methods. Using data from young adults born with very low birth weight and coetaneous controls, we show that instead of volume, the permutation-based non-parametric combination (NPC) of thickness and area is a more sensitive option for studying joint effects on these two quantities, giving equal weight to variation in both, and allowing a better characterisation of biological processes that can affect brain morphology.

Made available in DSpace on 2016-06-02T19:44:14Z (GMT). No. of bitstreams: 1 5134.pdf: 3904591 bytes, checksum: 196f7357f34d96d134a0ae6d9483aa8f (MD5) Previous issue date: 2013-03-05 / The literature has pointed to an increase in the incidence of children with visual impairments associated with neurological disorders and other disabilities, but the educational implications of the association of such impediments is considered a minor theme in the training of special education teachers. The present study aimed to develop and evaluate a collaborative consultation program in the field of visual impairment with a team of professionals of a special school for students with intellectual disabilities. The participants were the research/consultant, five teachers, two class assistants, a speech therapist, a physical therapist, a psychologist and an occupational therapist, plus 46 students with ages between 7 and 37 years. The study was carried out in three stages: preliminary step of conducting ethical procedures; Study-1, the diagnosis of institutional conditions; and Study-2, the intervention. The latter involved: a) theoretical training of 35 hours of lessons; b) practice based on case studies based on the development of a visual evaluation process of students, with the purpose of raising subsidies for educational planning and to apply the theoretical knowledge in practice; and c) final evaluation of the consultation/training program. The results of student s characterization showed that 30.4% were diagnosed with cerebral palsy; 30.4% with intellectual disabilities; 19.6% with Down syndrome, and 19.6% with other diagnoses. 83% of the students have already been through ophthalmological inspection with an average age of 4.2 years in first query. Two students were diagnosed with optic nerve atrophy and congenital cataracts, which was not reported by the parents to the school. As for the observation of visual difficulties, the parents have made 11 references, whereas the professionals made only 3. The results of the evaluation process of visual changes, duly complemented by medical information, were: 16 students (34.8%) showed no detected changes; 20 (43.5%) with minor changes (strabismus, refraction errors); 3 (6.5%) with visual impairment of ocular origin; 3 (6.5%) with cortical visual impairment; 1 (2.1%) with ocular and cortical visual impairment; and 3 (6.5%) with suspicion of visual impairment. The visual impairment was predominant among the cases of cerebral palsy. The case studies resulted in referrals to ophthalmological consultations, guidance to parents, propositions of pedagogical strategies, in addition the adjustment of materials and environment. The results concerning the evaluation of the collaborative consultation program showed that it was satisfactory regarding the professional development of the consultant and the consultees and regarding the possibilities of solving the addressed problem. The study highlights the need of ophthalmic and visual development assessment among students with intellectual and multiple disabilities and emphasizes the importance of collaborative practice between specialists, family and school professionals to an understanding of the problem of a student with visual impairment associated with intellectual or multiple disabilities. In addition, it suggests the need of a support network for teachers of special education, of generalist formation, what also includes teachers specialized in the visual impairment area, as well as other professionals with technical knowledge. / A literatura tem apontado um aumento na incidência de crianças com deficiência visual associada a distúrbios neurológicos e a outras deficiências, sendo as implicações educacionais da associação desses impedimentos um tema pouco considerado na formação dos professores de educação especial. O presente estudo teve como objetivo desenvolver e avaliar um programa de consultoria colaborativa na área da deficiência visual junto a uma equipe de profissionais de uma escola especial para alunos com deficiência intelectual. Foram participantes o pesquisador/consultor, cinco professoras, duas auxiliares de classe, uma fonoaudióloga, uma fisioterapeuta, uma psicóloga e uma terapeuta ocupacional, além de 46 alunos, de 7 a 37 anos. O estudo foi desenvolvido em três etapas, a saber: Etapa Preliminar de condução dos procedimentos éticos; Estudo 1, do diagnóstico das condições institucionais; e Estudo 2 da intervenção. Esta última envolveu: a) formação teórica de 35 horas/aula; b) parte prática baseada em estudos de casos através do desenvolvimento de um processo de avaliação visual dos alunos com a finalidade de levantar subsídios para o planejamento pedagógico e de aplicar na prática os conhecimentos teóricos; e c) avaliação final do programa através de análise de conhecimentos pré e pós-programa, entrevista e avaliação quantitativa pelos profissionais. Os resultados de caracterização dos alunos mostraram 30,4% com diagnóstico de paralisia cerebral; 30,4% com deficiência intelectual; 19,6% com síndrome de Down, e, 19,6% com outros diagnósticos. Haviam realizado consulta oftalmológica, 83,0% dos alunos, com uma média de idade da primeira consulta de 4,2 anos. Dois alunos tiveram diagnóstico de atrofia de nervo óptico e um de catarata congênita, que não foi comunicada pelos pais à escola. Quanto à observação de dificuldades visuais os pais fizeram 11 referências, enquanto os profissionais apenas três. Os resultados da avaliação das alterações visuais dos alunos complementada por informações médicas identificaram: 16 alunos (34,8%) sem alterações detectadas; 20 (43,5%) com alterações leves (estrabismo, erros de refração); três (6,5%) de deficiência visual de origem ocular; três (6,5%) de deficiência visual cortical; um (2,1%) com deficiência visual ocular e cortical; e três (6,5%) com suspeita de deficiência visual. A deficiência visual foi predominante entre os casos de paralisia cerebral. Os estudos de casos resultaram em encaminhamentos para consultas oftalmológicas, orientação aos pais, proposição de estratégias pedagógicas além de adaptação de materiais e ambiente. Os resultados quanto à avaliação do programa de consultoria colaborativa mostraram que foram satisfatórios do ponto de vista do desenvolvimento profissional, de ambas as partes, consultor e consultantes, e quanto às possibilidades de resolução da problemática abordada. O estudo destaca a necessidade da avaliação oftalmológica e do desenvolvimento visual entre alunos com deficiência intelectual e múltipla, e enfatiza a relevância da prática colaborativa entre especialistas, profissionais da escola e família para a compreensão da problemática do aluno com deficiência visual associada à deficiência intelectual ou múltipla. Além disso, sugere a necessidade de uma rede de apoio para os professores de educação especial, de formação, generalista, que inclui também professores especializados na área da deficiência visual, assim como outros profissionais com conhecimentos técnicos.

Identification of human or nonhuman skeletal remains is important in assisting the police and law enforcement officers for the investigation of forensic cases. Identification of bone can be difficult, especially in fragmented remains. It has been reported that 25 to 30% of medicolegal cases, which involved nonhuman skeletal remains have been mistaken for human. In such cases, histomorphometric method was used to identify human and nonhuman skeletal remains. However, literature has shown that histomorphometric data for human and nonhuman bone were insufficient. Additionally, age estimation in bone may help in the identification of human individual, which can be done by using a histomorphometric method. Age estimation is based on bone remodeling process, where microstructural parameters have strong correlations with age. Literature showed that age estimation has been done on the American and European populations. However, little work has been done in the Asian population. The aims of this project were thus, to identify human and nonhuman bone, and to estimate age in human bones by using histomorphometric analysis. In this project, 64 human bones and 65 animal bones were collected from the mortuary of the Universiti Kebangsaan Malaysia Medical Centre and the Zoos in Malaysia, respectively. A standard bone preparation was used to prepare human and nonhuman bone thin sections for histomorphometric assessment. Assessments were made on the microstructural parameters such as cortical thickness, medullary cavity diameter, osteon count, osteon diameter, osteon area, osteon perimeter, Haversian canal diameter, Haversian canal area, Haversian canal perimeter, and Haversian lamella count per osteon by using image analysis, and viewed under a transmitted light microscope. The microstructural measurements showed significant differences between human and nonhuman samples. The discriminant functions showed correct classification rates for 81.4% of cases, and the accuracy of identification was 96.9% for human and 66.2% for animal. Human age estimation showed a standard error of estimate of 10.41 years, comparable with those in the literature. This study project offers distinct advantages over currently available histomorphometric methods for human and nonhuman identification and human age estimation. This will have significant implications in the assessment of fragmentary skeletal and forensic population samples for identification purposes.

Temporomandibular disorders (TMD) are a family of prevalent chronic pain disorders affecting masticatory muscles and/or the temporomandibular joint. There is no unequivocally recognized peripheral aetiology for idiopathic TMD. The central nervous system (CNS) may initiate and/or maintain the pain in idiopathic TMD due to sustained or long-term nociceptive input that induces maladaptive brain plasticity, and/or to inherent personality-related factors that may reduce the brain's capacity to modulate nociceptive activity. The main aim of this thesis is to determine whether there are structural neural abnormalities in patients with TMD, and whether these abnormalities are related to TMD pain characteristics, or to neuroticism. The specific aims are to delineate in TMD: (1) gray matter (GM) brain abnormalities and the contribution of pain and neuroticism to abnormalities; (2) the contribution of abnormal brain GM aging in focal cortical regions associated with nociceptive processes; and (3) abnormalities in brain white matter and trigeminal nerve and the contribution of pain. In groups of 17 female patients with TMD and 17 age- and sex- matched controls, magnetic resonance imaging revealed that patients with TMD had: (1) thicker cortex in the somatosensory, ventrolateral prefrontal and frontal polar cortices than controls, (2) cortical thickness in motor and cognitive areas that was negatively related to pain intensity, orbitofrontal cortical thickness that was negatively correlated to pain unpleasantness, and thalamic GM volume correlated to TMD duration, (3) an abnormal relationship between neuroticism and orbitofrontal cortical thickness, (4) abnormal GM aging in nociceptive, modulatory and motor areas, (5) widespread abnormalities in white matter tracts in the brain related to sensory, motor and cognitive functions, (6) reduced trigeminal nerve integrity related to pain duration, and (7) abnormal connectivity in cognitive and modulatory brain regions. In sum, this thesis demonstrates for the first time abnormalities in both peripheral nerve and CNS in patients with TMD.

Temporomandibular disorders (TMD) are a family of prevalent chronic pain disorders affecting masticatory muscles and/or the temporomandibular joint. There is no unequivocally recognized peripheral aetiology for idiopathic TMD. The central nervous system (CNS) may initiate and/or maintain the pain in idiopathic TMD due to sustained or long-term nociceptive input that induces maladaptive brain plasticity, and/or to inherent personality-related factors that may reduce the brain's capacity to modulate nociceptive activity. The main aim of this thesis is to determine whether there are structural neural abnormalities in patients with TMD, and whether these abnormalities are related to TMD pain characteristics, or to neuroticism. The specific aims are to delineate in TMD: (1) gray matter (GM) brain abnormalities and the contribution of pain and neuroticism to abnormalities; (2) the contribution of abnormal brain GM aging in focal cortical regions associated with nociceptive processes; and (3) abnormalities in brain white matter and trigeminal nerve and the contribution of pain. In groups of 17 female patients with TMD and 17 age- and sex- matched controls, magnetic resonance imaging revealed that patients with TMD had: (1) thicker cortex in the somatosensory, ventrolateral prefrontal and frontal polar cortices than controls, (2) cortical thickness in motor and cognitive areas that was negatively related to pain intensity, orbitofrontal cortical thickness that was negatively correlated to pain unpleasantness, and thalamic GM volume correlated to TMD duration, (3) an abnormal relationship between neuroticism and orbitofrontal cortical thickness, (4) abnormal GM aging in nociceptive, modulatory and motor areas, (5) widespread abnormalities in white matter tracts in the brain related to sensory, motor and cognitive functions, (6) reduced trigeminal nerve integrity related to pain duration, and (7) abnormal connectivity in cognitive and modulatory brain regions. In sum, this thesis demonstrates for the first time abnormalities in both peripheral nerve and CNS in patients with TMD.

Résumé : L’interaction entre la douleur et le système moteur est bien connue en clinique et en réadaptation. Il est sans surprise que la douleur est un phénomène considérablement invalidant, affectant la qualité de vie de ceux et celles qui en souffrent. Toutefois, les bases neurophysiologiques qui sous-tendent cette interaction demeurent, encore aujourd’hui, mal comprises. Le but de la présente étude était de mieux comprendre les mécanismes corticaux impliqués dans l’interaction entre la douleur et le système moteur. Pour ce faire, une douleur expérimentale a été induite à l’aide d’une crème à base de capsaïcine au niveau de l’avant-bras gauche des participants. L'effet de la douleur sur la force des projections corticospinales ainsi que sur l’activité cérébrale a été mesuré à l’aide de la stimulation magnétique transcrânienne (TMS) et de l’électroencéphalographie (EEG), respectivement. L’analyse des données EEG a permis de révéler qu'en présence de douleur aiguë, il y a une augmentation de l’activité cérébrale au niveau du cuneus central (fréquence têta), du cortex dorsolatéral préfrontal gauche (fréquence alpha) ainsi que du cuneus gauche et de l'insula droite (toutes deux fréquence bêta), lorsque comparée à la condition initiale (sans douleur). Également, les analyses démontrent une augmentation de l'activité du cortex moteur primaire droit en présence de douleur, mais seulement chez les participants qui présentaient simultanément une diminution de leur force de projections corticales (mesurée avec la TMS t=4,45, p<0,05). Ces participants ont également montré une plus grande connectivité entre M1 et le cuneus que les participants dont la douleur n’a pas affecté la force des projections corticospinales (t=3,58, p<0,05). Ces résultats suggèrent qu’une douleur expérimentale induit, chez certains individus, une altération au niveau des forces de projections corticomotrices. Les connexions entre M1 et le cuneus seraient possiblement impliquées dans la survenue de ces changements corticomoteurs. / Abstract : The interaction between pain and the motor system is well-known in clinic. For instance, it is well documented that pain significantly complicates the rehabilitation of the patients. The aim of the present study was to better understand the cortical mechanisms underlying the interaction between pain and the motor system. Nineteen healthy adults participated in the study. The effect of pain (induced with a capsaicin cream) on brain activity and on the corticomotor system was assessed with electroencephalography (EEG) and transcranial magnetic stimulation (TMS), respectively. For EEG, 15 non-overlapping, 2-seconds artifacts were randomly selected for each participant. Intracranial source current density and functional connectivity was determined using sLORETA software. When participants experienced experimentally-induced inflammatory pain, their resting state brain activity increased significantly in the central cuneus (theta frequency), left dorsolateral prefrontal cortex (alpha frequency), and both left cuneus and right insula (beta frequency; all ts >3.66; all ps<0.01). A pain-evoked increase in the right primary motor cortex (M1) activity was also observed (beta frequency), but only among participants who showed a simultaneous reduction in the strength of the corticospinal projections (quantified using the recruitment curves obtained with TMS; t=4.45, p<0.05). These participants further showed greater beta motor-cuneus connectivity than participants for whom pain did not affect M1 somatotopy (t=3.58, p<0.05). These results suggest that pain-evoked increases in M1 beta power are intimately tied to alterations in corticospinal system. Moreover, we provide evidence that beta motor-cuneus connectivity is related to the corticomotor alterations induced by pain.