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La myopie est désormais considérée un problème de santé publique par l’Organisation Mondiale de la Santé et de multiples méthodes ont été mises en place afin de contrôler sa progression chez les jeunes en croissance. Parmi celles-ci, les lentilles cornéennes multifocales sont utilisées, permettant une focalisation au niveau de la rétine centrale et un défocus myopique en périphérie. Ce défocus rétinien aurait comme effet de diminuer la progression de la myopie et l’élongation du globe oculaire. Comme plusieurs études ont montré que la rétine est apte à percevoir le défocus et à différencier son sens, l’utilisation d’outils tels que l’électrorétinographie permet d’étudier ce phénomène plus en profondeur. Cette étude vise donc à mesurer la réponse rétinienne, à 5 différentes excentricités, avec l’électrorétinographie lorsqu’on soumet la rétine à un défocus myopique en utilisant des lentilles cornéennes multifocales à addition élevée et à comparer cet effet lorsque le diamètre de leurs zones optiques varie. Le flash global mfERG a été effectué sur 27 participants à trois reprises, soit avec une lentille cornéenne ne causant pas de défocus et avec deux lentilles multifocales ayant des zones optiques de différents diamètres (4mm et 7mm), permettant ainsi de varier l’aire du défocus. Les résultats montrent que l’amplitude de l’onde directe, causée principalement par les photorécepteurs et les cellules bipolaires, n’est pas influencée par le design des lentilles. L’amplitude de l’onde induite est toutefois diminuée de façon significative avec la LC ayant une zone optique plus petite et causant un défocus sur une plus grande surface rétinienne. Cette différence est présente au niveau de l’anneau 5, qui correspond à une excentricité rétinienne de 15,7o à 24,0o. Ceci précise l’endroit qui semblerait le plus sensible au défocus myopique. Ces données peuvent influencer le design des lentilles souples multifocales utilisées pour le contrôle de la myopie. / Myopia is now considered a public health issue by the World Health Organization and multiple methods have been developed to control its progression. Among these methods, soft multifocal contact lenses are used, which allow a focused image on the central retina and a myopic defocus peripherally. This retinal defocus impacts the progression of myopia and axial length. Since several studies have shown that the retina is sensitive to the type of defocus, the use of tools such as electroretinography allow the study of the retinal response in greater depth. The purpose of this study was to evaluate the retinal response, at 5 different eccentricities, with electroretinography when the retina is subjected to myopic defocus using different high addition soft multifocal contact lenses and to compare this effect when the diameter of their optical zones varies. 27 participants performed a global flash mfERG three times, either with a single vision contact lens or with two multifocal lenses carrying different optical zone diameters (4mm and 7mm), allowing for the variation in defocus area. The results show that the amplitude of the direct wave, caused mainly by photoreceptors and bipolar cells, is not influenced by the design of the lenses. The amplitude of the induced wave, however, is significantly decreased when the optical zone is smaller and the lenses cause a defocus over a larger retinal area. This difference is present at ring 5, which corresponds to a retinal eccentricity of 15.7o to 24.0o. This specifies the location that would appear to be most sensitive to myopic defocus. This data may influence the design of multifocal soft lenses used for myopia control.

Au cours des dernières années, un intérêt grandissant concernant les rôles physiologiques des endocannabinoïdes (eCBs) a été observé. Le système eCB est une cible attrayante pour la modulation du système immunitaire et de la douleur périphérique. Bien que le récepteur CB1 soit distribué dans le système nerveux, le récepteur CB2 est traditionnellement associé au système immunitaire. Ce dogme fait maintenant l’objet d’un débat depuis la découverte de l’expression du récepteur CB2 dans certains neurones. La rétine est un modèle important pour l’étude de processus neuronaux. La présence du récepteur CB1 y a été démontrée. Des études fonctionnelles rapportent que l’activation des récepteurs cannabinoïdes affecte le fonctionnement de plusieurs cellules rétiniennes. À ce jour, aucune étude ne s’est intéressée au rôle global des récepteurs CB1 et CB2 dans la rétine. Nous avons investigué les conséquences de l’élimination du récepteur CB1 (cnr1-/-) ou du récepteur CB2 (cnr2-/-) sur la fonction rétinienne mesurée par électrorétinographie. Nous avons également caractérisé la distribution du récepteur CB2 dans la rétine. Pour ce faire, nous avons comparé la spécificité de plusieurs anticorps dirigés contre le récepteur CB2. Seulement l’un des anticorps testés a montré une spécificité satisfaisante. Il a permis de détecter la présence du récepteur CB2 dans les cônes, les bâtonnets, les cellules horizontales, amacrines, bipolaires et ganglionnaires. Nos résultats d’électrorétinographie indiquent que seules les souris cnr2-/- présentent une amplitude accrue de l’onde a des ERG, en conditions scotopiques. En conditions photopiques, l’amplitude de l’onde b des souris cnr2-/- montre un schéma d’adaptation à la lumière différent des autres groupes. Aucun effet significatif n’a été observé chez les animaux cnr1-/-. Ces résultats permettent de conclure que les récepteurs CB1 et CB2 jouent des rôles différents dans le traitement visuel et que le récepteur CB2 semble être impliqué dans l’établissement des réponses rétiniennes. / Cannabinoid receptors (CB1R and CB2R) are among the most abundant G-protein coupled receptors in the central nervous system. The endocannabinoid system is an attractive target for immune system modulation and peripheral pain management. While CB1R is distributed in the nervous system, CB2R has traditionally been associated to the immune system. This dogma is currently a subject of debate since the discovery of CB2R expression in neurons. The retina is an interesting model for neuronal processes’ study. The activation of cannabinoid receptors modulates neurotransmitter release from photoreceptors and could also affect bipolar cell synaptic release. However, the impact of CB1r and CB2R on the retinal function as a whole is currently unknown. In the present study, we investigated the function of cannabinoid receptors in the retina by recording electroretinographic responses (ERG) from mice lacking either CB1 or CB2 receptors (cnr1-/- and cnr2-/-, respectively). We also documented the precise distribution of CB2R by comparing the specificity of library of CB2R antibodies. One of the antibodies tested exhibited a valuable specificity and localized CB2R expression in cones and rods photoreceptors, horizontal cells, some amacrine cells, and bipolar and ganglion cells. In scotopic conditions, the amplitudes of the awave of the ERG were increased in cnr2-/- mice, while they remained unchanged in cnr1-/- mice. Under photopic conditions, b-wave amplitudes of cnr2-/- mice required more light adaptation time to reach stable values. No effect was observed in cnr1-/- mice. These data indicate that CB2R is likely to be involved in shaping retinal responses to light and suggest that CB1 and CB2 receptors could have different roles in visual processing.

Au cours des dernières années, un intérêt grandissant concernant les rôles physiologiques des endocannabinoïdes (eCBs) a été observé. Le système eCB est une cible attrayante pour la modulation du système immunitaire et de la douleur périphérique. Bien que le récepteur CB1 soit distribué dans le système nerveux, le récepteur CB2 est traditionnellement associé au système immunitaire. Ce dogme fait maintenant l’objet d’un débat depuis la découverte de l’expression du récepteur CB2 dans certains neurones. La rétine est un modèle important pour l’étude de processus neuronaux. La présence du récepteur CB1 y a été démontrée. Des études fonctionnelles rapportent que l’activation des récepteurs cannabinoïdes affecte le fonctionnement de plusieurs cellules rétiniennes. À ce jour, aucune étude ne s’est intéressée au rôle global des récepteurs CB1 et CB2 dans la rétine. Nous avons investigué les conséquences de l’élimination du récepteur CB1 (cnr1-/-) ou du récepteur CB2 (cnr2-/-) sur la fonction rétinienne mesurée par électrorétinographie. Nous avons également caractérisé la distribution du récepteur CB2 dans la rétine. Pour ce faire, nous avons comparé la spécificité de plusieurs anticorps dirigés contre le récepteur CB2. Seulement l’un des anticorps testés a montré une spécificité satisfaisante. Il a permis de détecter la présence du récepteur CB2 dans les cônes, les bâtonnets, les cellules horizontales, amacrines, bipolaires et ganglionnaires. Nos résultats d’électrorétinographie indiquent que seules les souris cnr2-/- présentent une amplitude accrue de l’onde a des ERG, en conditions scotopiques. En conditions photopiques, l’amplitude de l’onde b des souris cnr2-/- montre un schéma d’adaptation à la lumière différent des autres groupes. Aucun effet significatif n’a été observé chez les animaux cnr1-/-. Ces résultats permettent de conclure que les récepteurs CB1 et CB2 jouent des rôles différents dans le traitement visuel et que le récepteur CB2 semble être impliqué dans l’établissement des réponses rétiniennes. / Cannabinoid receptors (CB1R and CB2R) are among the most abundant G-protein coupled receptors in the central nervous system. The endocannabinoid system is an attractive target for immune system modulation and peripheral pain management. While CB1R is distributed in the nervous system, CB2R has traditionally been associated to the immune system. This dogma is currently a subject of debate since the discovery of CB2R expression in neurons. The retina is an interesting model for neuronal processes’ study. The activation of cannabinoid receptors modulates neurotransmitter release from photoreceptors and could also affect bipolar cell synaptic release. However, the impact of CB1r and CB2R on the retinal function as a whole is currently unknown. In the present study, we investigated the function of cannabinoid receptors in the retina by recording electroretinographic responses (ERG) from mice lacking either CB1 or CB2 receptors (cnr1-/- and cnr2-/-, respectively). We also documented the precise distribution of CB2R by comparing the specificity of library of CB2R antibodies. One of the antibodies tested exhibited a valuable specificity and localized CB2R expression in cones and rods photoreceptors, horizontal cells, some amacrine cells, and bipolar and ganglion cells. In scotopic conditions, the amplitudes of the awave of the ERG were increased in cnr2-/- mice, while they remained unchanged in cnr1-/- mice. Under photopic conditions, b-wave amplitudes of cnr2-/- mice required more light adaptation time to reach stable values. No effect was observed in cnr1-/- mice. These data indicate that CB2R is likely to be involved in shaping retinal responses to light and suggest that CB1 and CB2 receptors could have different roles in visual processing.

Objetivos: avaliar as alterações morfofuncionais da retina de pacientes com esclerose múltipla (EM) e espectro da neuromielite óptica (ENMO), com ou sem histórico de neurite óptica (NO), por meio de eletrorretinografia de campo total e multifocal (ERGct / ERGmf) e a tomomografia de coerência óptica (TCO). Avaliar as correlações de tais achados entre si e com o potencial evocado visual (PEV), o campo visual (CV) e a sensibilidade ao contraste (SC). Métodos: Pacientes com EM (n = 30), ENMO (n = 30) e controles (n = 29) foram submetidos a avaliação oftalmológica completa incluindo CV, TCO, ERGct, ERGmf, PEV e medida da SC. Os olhos foram distribuídos em 5 grupos: EM com ou sem história de NO (EM + NO e EM - NO), ENMO com ou sem NO (ENMO + NO e ENMO - NO) e controles. Com a TCO foram medidas as espessuras das camadas de fibras nervosas da retina na região macular (CFNRm), camada de células ganglionares (CCG), camada plexiforme interna (CPI), camada nuclear interna (CNI), camada plexiforme externa (CPE), camada nuclear externa (CNE), complexo camada de fotorreceptores + epitélio pigmentário da retina(CFR+EPR) e da camada de fibras nervosas peripapilar (CFNRp). Dados das ondas a, b e potenciais oscilatórios (POs) do ERGct, medidas de amplitude e latência de N1 e P1 do ERGmf, ondas do PEV e medidas do desvio da normalidade do CV foram analisados. Os grupos foram comparados usando equações estimadas generalizadas. Correlações entre as medidas foram avaliadas. Resultados: Redução da sensibilidade do desvioda normalidade do CV, da SC e aumento da latência das ondas do PEV foram identificadas para ambos os grupos. Nos pacientes ENMO+NO apresentaram redução de amplitude ao PEV em relação aos controles, diferentemente aos demais grupos. As medidas de espessura da CCG e da CPI foram significativamente menores nos grupos de olhos dos pacientes em relação aos controles. A RNFLm foi menor em todos os grupos de olhos de pacientes, exceto o grupo ENMO-NO. Não foi observada diferença significativa entre os grupos de olhos estudados nas comparações referenetes às demais camadas da retina. Comparado aos controles, as amplitudes do POs foram maiores nos olhos de pacientes com ENMO, enquanto as latências de N1 e P1 do ERGmf foram menor nos olhos de pacientes com EM. Essas anormalidades foram fortemente correlacionadas com a espessura da camada retiniana intermediária e externa. Os achados do PEV, assim como do CV e SC, se correlacionaram fortemente com as camadas retinianas. Conclusões: as camadas retinianas internas se mostraram reduzidas à TCO tanto nos olhos de pacientes com EM quanto no naqueles com ENMO, mas os achados POs e ERGmf sugerem também envolvimento das outras camadas retinianas nessas afecções. O PEV apresentou alterações distintas para cada doença. O uso combinado da TCO, do ERG e PEV podem ajudar a entender como as duas condições diferem em relação aos danos retinianos / Objectives: To evaluate the morphofunctional alterations of the retina of patients with multiple sclerosis (MS) and spectrum of neuromyelitis optica spectrum disorder (NMOSD), with or without a history of optic neuritis (ON), using full field electroretinogram (ERG) and multifocal electroretinography (mf- ERG) and optical coherence tomography (OCT). To evaluate the correlations of such findings among themselves and with visual evoked potential (VEP), visual field (VF) and contrast sensitivity (CS). Methods: Patients with MS (n = 30), NMOSD (n = 30) and healthy controls (n = 29) were submitted to a complete ophthalmologic evaluation including VF, OCT, ERG, mf-ERG, VEP and SC measurement. The eyes were distributed in 5 groups: MS with or without history of ON (MS + ON and MS - ON), NMOSD with or without ON (NMOSD + ON and NMOSD - ON) and controls. With the OCT were measured the thickness of the retinal nerve fiber layers in the macular region (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), photoreceptor layer (PHOT) and peripapillary retinal nerve fiber layer (pRNFL). The data of the a- and b-waves and oscillatory potentials (OPs) of the ERG, amplitude and peak time of N1 and P1 of mf-ERG, waves of the VEP and VF deviation were analyzed. The groups were compared using generalized estimating equations. Correlations between measurements were evaluated. Results: Reduction of the oVF deviation, CS and increased VEP wave\'s peak times were identified for both groups. In the NMOSD + ON patients, an amplitude redeuction was found in the VEP in relation to the controls, unlike the other groups. The thickness of GCL and IPL was significantly lower in patients\' eyes than controls. mRNFL was lower in all patients, but NMOSD-ON. No significant difference was observed for the remaining layers. Compared to controls, the amplitudes of the POs were higher in the NMOSD group, whereas the mf-ERG\'s N1 and P1 peak time was lower in the MS patients. These abnormalities were strongly correlated with the thickness of the intermediate and outer retinal layers. The findings of the VEP, as well as the VF and SC, correlated strongly with the retinal layers. Conclusions: the inner retinal layers were reduced in both the MS and the NMOSD, but the findings OPs and mf-ERG suggest involvement of the other retinal layers. The VEP presented different alterations for each disease. The combination of OCT, ERG and VEP may help to understand how the two conditions differ in relation to retinal damage

In Canada alone, there were an estimated 800,000 visually impaired people in 2007, costing the federal government an annual amount of $15.8 billion in services, treatments and lost revenue. These costs are estimated to double by the year 2032, as the population ages. The leading causes of visual impairment and blindness is retinal degeneration, characterized by the progressive death of retinal cells. The research presented in this PhD thesis aimed to prevent retinal degeneration by over-expressing the X-linked Inhibitor of Apoptosis (XIAP) in retinal cells using plasmid and adeno-associated viral vectors. The work is divided into four sequential chapters targeted at developing an anti-apoptotic gene therapy strategy to prevent retinal cell death. The first chapter examines XIAP gene therapy in the treatment of Leber’s Hereditary Optic Neuropathy (LHON). In vitro studies using the 661W cone-photoreceptor cell line showed that XIAP over-expression significantly lowers cell death when 661W cells are exposed to a number of apoptotic stimuli. In a mouse model of Leber’s Hereditary Optic Neuropathy (LHON), XIAP expression in retinal ganglion cells (RGCs) protected the ultrastructure of the RGC axons within the optic nerve, in addition to providing evidence of functional protection. The second and third chapters further examine the potential for XIAP gene therapy in the treatment of retinal disease by developing an in vivo model of retinal detachment in cats, followed by evaluating the efficacy of XIAP gene therapy intervention. When XIAP was over-expressed in the photoreceptor cells, there was significant structural protection and trends in preservation of function in this model of degeneration. Finally, the fourth chapter explores an alternate method to viral gene therapy by evaluating the efficacy and toxicity of chitosan microparticles as a protein delivery system to the retina. Results show that chitosan microparticles are mucosal-adhesive and are non-toxic at low concentrations in vitro in 661W cells and in vivo in rats. This thesis work provides strong evidence that XIAP gene therapy is an effective method for preventing retinal degeneration, and works as a broad spectrum gene therapy strategy that can be applied to different forms of retinal degeneration.

Le système endocannabinoïde (eCB) est une cible thérapeutique intéressante pour traiter diverses conditions variées, allant de la modulation du système immunitaire à la prise en charge de la douleur neuropathique. De plus, le système eCB est impliqué dans les processus développementaux comme l’indique une exposition aux cannabinoïdes au cours du développement qui provoque des troubles neurofonctionnels. En raison de leur nature lipophile, les eCBs ne sont pas emmagasinés, mais sont plutôt synthétisés et dégradés sur demande par des enzymes. Ainsi, l’étude du patron d’expression de ces enzymes permettrait de mieux comprendre l’expression et ainsi le rôle joué par les eCBs pendant la formation du système nerveux central. Le récepteur CB1 est grandement distribué dans le système nerveux, alors que le récepteur CB2 est traditionnellement associé au système immunitaire. La découverte récente de l’expression et de l’impact fonctionnel du récepteur CB2 dans certains neurones, notamment au niveau rétinien, modifie la vision traditionnelle des rôles des eCBs. Notamment, une étude de notre laboratoire a montré que la délétion du récepteur CB2 chez des souris transgéniques (cnr2-/-) provoque une augmentation de l’amplitude de l’onde a en électrorétinographie, celle-ci reflétant l’activité des photorécepteurs rétiniens. Cette étude a mis en évidence l’importance du récepteur CB2 dans la vision, du moins au niveau rétinien. Jusqu’à ce jour, aucune étude ne s’est intéressée à l’impact des cannabinoïdes sur l’acuité visuelle. Nous avons caractérisé la distribution rétinienne des enzymes diacylglycérol lipase alpha (DAGLα) et monoacylglycérol lipase (MAGL), responsables respectivement de la synthèse et de la dégradation du ligand eCB 2-arachidonoyl glycérol (2-AG), pendant le développement postnatal. L’enzyme DAGLα est présente dès la naissance et est grandement distribuée dans la rétine, notamment dans les photorécepteurs, les cellules horizontales, amacrines et ganglionnaires. L’enzyme MAGL apparait plus tardivement et est limitée aux cellules amacrines et de Müller. Nos résultats fonctionnels indiquent que l’acuité visuelle des animaux cnr2-/- est plus élevée autant chez les adultes que pendant le développement postnatal. L’administration répétée d’un agoniste inverse du récepteur CB2 produit une augmentation de l’acuité visuelle similaire à la délétion du récepteur CB2 par génie génétique et inversement, l’administration d’un agoniste du récepteur CB2 diminue l’acuité visuelle. Enfin, l’administration d’un inhibiteur de l’enzyme MAGL, responsable de la dégradation du 2-AG, induit une diminution de l’acuité visuelle similaire à celle obtenue par un agoniste du récepteur CB2 tandis que l’administration d’un inhibiteur de l’enzyme DAGL, responsable de la synthèse du 2-AG, provoque une augmentation de l’acuité visuelle. Ces résultats suggèrent que le 2-AG est fortement présent tôt lors du développement rétinien et qu’il pourrait être impliqué dans la maturation structurelle et fonctionnelle de la rétine. De plus, les expériences fonctionnelles ont démontré que les cannabinoïdes affectent non seulement la réponse rétinienne, mais aussi l’acuité visuelle de manière significative. En outre, ces résultats confirment que les cannabinoïdes induisent leurs effets sur la vision exclusivement par le récepteur CB2. Enfin, les résultats de cette thèse accroissent les connaissances actuelles dans un contexte de légalisation grandissante du cannabis à des fins récréatives, puisqu’ils mettent en évidence l’importance des impacts sur l’acuité visuelle. / The endocannabinoid (eCB) system is a great therapeutic target for the treatment of many diseases, ranging from immune system modulation to pain management. This system is implicated in developmental processes as indicated by neurofunctional afflictions following developmental exposition to cannabinoids. Since eCBs are lipophilic, they are not stored in vesicles but rather synthesized and degraded on demand by specific enzymes. Thus, the expression pattern of these enzymes could help to better understand the expression of eCBs, and their role during central nervous system maturation. The CB1 receptor is strongly distributed in the nervous system, while the CB2 receptor is traditionally associated with the immune system. The recent finding of the CB2 receptor expression and function in some neurons, especially in the retina, changes the dogma associated with cannabinoids. A study from our laboratory found that deletion of the CB2 receptor in transgenic mice (cnr2-/-) enhances the a-wave amplitude in electroretinography, this wave reflecting photoreceptor activity. This report highlighted the importance of the CB2 receptor in vision, at least in the retina. Until now, no study aimed at the impact of cannabinoids on visual acuity. We characterized the retinal distribution of diacylglycerol lipase alpha (DAGLα) and monoacylglycerol lipase (MAGL) enzymes, responsible for the synthesis and degradation of the eCB ligand 2-arachidonoyl glycerol (2-AG) during postnatal development. The enzyme DAGLα is expressed since birth and is greatly distributed across the retina such as in photoreceptors, horizontal, amacrine and ganglion cells. The enzyme MAGL is expressed later during development and is present only in amacrine and Müller cells. Our functional results show that the visual acuity of cnr2-/- mice is enhanced in adults and during postnatal development. The repeated administration of a CB2 receptor antagonist yielded a better visual acuity, and inversely a CB2 receptor agonist decreased the visual acuity. Furthermore, the administration of a MAGL inhibitor, the enzyme in charge of 2-AG degradation, induced a strong decrease in visual acuity, similar to that obtained with a CB2 receptor agonist. Inversely, a DAGL inhibitor, the enzyme responsible for 2-AG synthesis, caused an increase in visual acuity. These results suggest that 2-AG is strongly expressed early during retinal development and could be implicated in structural and functional maturation of the retina. Furthermore, we demonstrated that cannabinoids do not only affect retinal function, but also visual acuity. These results confirm that cannabinoids modulate their visual effects exclusively via the CB2 receptor. Finally, in recent years, many countries legalized cannabis for recreational and therapeutic use. The findings from this thesis increase the understanding of cannabinoids since they highlight the great impact of cannabinoids on the visual acuity.

Las enfermedades neurodegenerativas cursan con la degeneración y muerte de las neuronas las cuales son incapaces de suplir su propia muerte. Debido a esta característica enfermedades como el Alzheimer, el Parkinson o el Glaucoma no tienen cura en la actualidad. La retina es una proyección del sistema nervioso central (SNC) encapsulada en el globo ocular y aislada del resto del SNC, lo que la hace fácilmente accesible a la manipulación experimental. En este trabajo estudiamos las alteraciones funcionales de la retina con el electrorretinograma de campo completo (ERG), técnica basada en el registro de la respuesta eléctrica retiniana tras la presentación de un estímulo de luz homogéneo. Así hemos estudiado los efectos de la sección del nervio, del aumento de presión intraocular y de la fototoxicidad, dichas lesiones afectan selectivamente a determinadas poblaciones neuronales retinianas e imitan enfermedades neurodegenerativas como el Glaucoma o la Degeneración Macular Asociada a la Edad. / Neurodegenerative diseases are characterized by degeneration and death of neurons which are unable to recover after a given insult, thus impairing functional recuperation. Because of this, there is no cure for diseases such as Alzheimer, Parkinson or Glaucoma. The retina is a projection of the central nervous system (CNS) located in the eye and therefore, isolated from the rest of the CNS. This makes the retina a very good model for experimental manipulation. In this work we have studied the functional changes in the retina by full field electroretinograme (ERG). This technique records the electric response of the retina after presentation of homogeneous light stimuli. We have studied the effects that optic nerve sections, increase of the intraocular pressure and phototoxicity have on ERG recordings. These lesions impair selectively certain retinal neuronal populations and imitate neurodegenerative diseases as Glaucoma or Age-related Macular Degeneration.

В последние годы распространенность сердечно-сосудистых заболеваний, а также уровень смертности растет, что серьезно угрожает здоровью человека, что требует от врачей ранней диагностики сердечно-сосудистых заболеваний, чтобы выиграть время для последующего лечения пациентов, а результаты сегментации ультразвуковых изображений левого желудочка могут помочь врачам в диагностике сердечно-сосудистых заболеваний, но ультразвуковые изображения левого желудочка имеют характеристики сильного шума, слабых границ и сложной структуры ткани, что делает сегментацию изображения сложной, низкой эффективностью и плохой точностью. Одним из важнейших этапов оценки здоровья сердца является отслеживание и сегментация эндокардиальной границы левого желудочка (ЛЖ) с помощью ЭхоКГ, которая используется для измерения фракции выброса и оценки движения региональной стенки. Недостатком этих методов является необходимость применения обработки изображений вручную или в полуавтоматическом режиме, что требует специальных знаний и навыков. В результате вопрос автоматического отслеживания и сегментации ЛЖ на ЭхоКГ-изображениях является актуальной и практической проблемой. В моем проекте изучается способность полностью обученных моделей глубокого обучения U-Net, U-Net++, MANet, LinkNet, FPN, PSPNet, PAN, DeepLabv3 и DeepLabv3+ автоматически определять область левого желудочка. В то же время в архитектурах U-Net, U-Net++, MANet, LinkNet, PSPNet, PAN, FPN, DeepLabv3 и DeepLabv3+ модули кодировщика затем последовательно заменялись на ResNet18, ResNet34, ResNet5, ResNet101, EfficientNet-b0, EfficientNet-b1, EfficientNet-b3, EfficientNet-b5, EfficientNet-b7 и MobileNetv2, а ImageNet использовался в качестве весов предварительной подготовки; Добавление магистральных сетей в архитектуру модели приводит к более высокой точности сегментации по сравнению с исходной моделью. В рамках той же архитектуры модели EfficientNet в качестве кодировщика достигает лучших результатов сегментации, а EfficientNet-b3 работает лучше. Аналогично, в рамках серии ResNet ResNet34 работает лучше. В модели сегментации этого эксперимента Deeplabv3+ показывает превосходную производительность. Это указывает на то, что в архитектуре модели этого эксперимента интеграция модулей ResNet34 и EfficientNet-b3 в качестве кодировщиков может эффективно и осуществимо автоматизировать распознавание эндокардиальной границы левого желудочка на ультразвуковых изображениях. Кроме того, аугментация данных также в определенной степени повысит точность сегментации модели. / In recent years, the prevalence of cardiovascular diseases. as well as the mortality rate is increasing, which has seriously threatened human health, which requires doctors to diagnose cardiovascular diseases early to gain time for patients' later treatment, and the segmentation results of left ventricular ultrasound images can assist doctors in the diagnosis of cardiovascular diseases, but the left ventricular ultrasound images have the characteristics of strong noise, weak edges and complex tissue structure, which makes the image segmentation difficult, low efficiency and poor precision. One of the most important steps in estimating the health of the heart is the tracking and segmentation of the left ventricular (LV) endocardial border from EchoCG, which is used for measuring the ejection fraction and assessing the regional wall motion. The disadvantage of these methods is the necessity to apply image processing manually or in a semi-automatic mode, which requires special knowledge and skills. As a result, the issue of an automatic tracking and segmentation of the LV on EchoCG-images is an actual and practical problem. In my project, the ability of fully trained Deep Learning Models U-Net, U-Net++, MANet, LinkNet, FPN, PSPNet, PAN, DeepLabv3and DeepLabv3+ to automatically identify the left ventricular region is explored. At the same time, in the U-Net, U-Net++, MANet, LinkNet, PSPNet, PAN, FPN, DeepLabv3 and DeepLabv3+ architectures, the encoder modules were then sequentially replaced with ResNet18, ResNet34, ResNet5, ResNet101, EfficientNet-b0, EfficientNet-b1, EfficientNet-b3, EfficientNet-b5, EfficientNet-b7and MobileNetv2, and ImageNet was used as the pre-training weights; The addition of backbones to the model architecture leads to higher segmentation accuracy compared to the original model. Within the same model architecture, EfficientNet as the encoder achieves better segmentation results, with EfficientNet-b3 performing the best. Similarly, within the ResNet series, ResNet34 performs better. In the segmentation model of this experiment, Deeplabv3+ shows superior performance. This indicates that in the model architecture of this experiment, integrating ResNet34 and EfficientNet-b3 modules as encoders can effectively and feasibly automate the recognition of the endocardial boundary of the left ventricle in ultrasound images. Furthermore, data augmentation will also enhance the model’s segmentation accuracy to a certain extent.

Электроретинография (ЭРГ) — это неинвазивный способ измерения электрической активности сетчатки с помощью световой стимуляции. Сигналы ЭРГ содержат несколько различных компонентов, которые можно использовать для диагностики различных заболеваний сетчатки. Некоторые из этих заболеваний включают дистрофии, связанные с колбочками и палочками, возрастную дегенерацию желтого пятна, диабетическую ретинопатию, глаукому и пигментный ретинит. В этой диссертации использовались различные методы для анализа сигналов ЭРГ, включая методы временной области, частотной области и частотно-временной области. Процесс начался с очистки базы данных сигналов и предварительной обработки извлеченных сигналов. Затем были вычислены стандартные компоненты сигнала, включая a- и b-волны и неявное время, и был проведен анализ сигналов во временной области. Анализ во временной области включал изучение амплитуд и задержек различных компонентов волны, что может дать представление о функционировании различных типов клеток сетчатки. Корреляционный анализ также проводился для изучения взаимосвязи между возрастом пациентов и компонентами сигнала, результаты которого показывают очень слабую корреляцию между возрастом и компонентами, с некоторой значительной корреляцией между отдельными компонентами. В частотной области преобразование Фурье использовалось для извлечения частот сигналов для анализа. Частотное содержимое сигналов ЭРГ может раскрыть информацию о базовых физиологических процессах и потенциальных отклонениях. Однако из-за инвариантной во времени природы частотной области делать выводы, основанные исключительно на этом анализе, может быть сложно. Для анализа частотно-временной области использовалось кратковременное преобразование Фурье (STFT) вместе с анализом спектрограмм. STFT позволяло изучить, как частотное содержимое сигналов менялось с течением времени, обеспечивая более полное представление динамики сигнала. Кроме того, признаки извлекались с использованием различных окон и размеров окон для обучения классификатора машинного обучения с целью классификации сигналов. Вычисленные спектрограммы также использовались для обучения моделей глубокого обучения с различными архитектурами, и результаты сравнивались на основе используемых окон. Результаты показывают, что нет заметной корреляции между возрастом и другими компонентами сигнала во временной области. Это говорит о том, что возраст сам по себе не может быть надежным предиктором характеристик сигнала ERG. В частотной области делать выводы, основанные исключительно на частотном содержании, оказалось сложно из-за инвариантной во времени природы анализа. Более того, очевидно, что размеры окон оказывают более существенное влияние на результирующие признаки по сравнению с функциями окна. Большие размеры окон обеспечивают улучшенное разрешение по частоте, в то время как меньшие окна обеспечивают более высокое разрешение по времени. Это означает, что разрешение по времени и частоте играет более существенную роль в формировании результирующих признаков, чем обработка сигнала, выполняемая самой функцией окна. Анализ сигналов ERG с использованием различных методов, включая методы временной области, частотной области и частотно-временной области, дает ценную информацию о функции сетчатки и потенциальных расстройствах. Сочетание этих подходов, наряду с методами извлечения признаков и машинного обучения, предлагает комплексную структуру для понимания и интерпретации сигналов ERG. Однако тщательное рассмотрение таких факторов, как размеры окон и компромиссы разрешения, имеет решающее значение для получения значимых и точных результатов. / Electroretinography (ERG) is a non-invasive way of measuring the electrical activity of the retina with the help of light stimulation. ERG signals contain several different components which can be used to diagnose various retinal disorders. Some of these disorders include cone and rod related dystrophies, age-related macular degeneration, diabetic retinopathies, glaucoma and retinitis pigmentosa. In this thesis, various methods were utilized to analyze ERG signals, including time-domain, frequency-domain, and time-frequency domain techniques. The process began with cleaning the signals database and preprocessing the extracted signals. Next, standard signal components including the a- and b-waves and implicit times were computed, and time-domain analysis was conducted on the signals. The time-domain analysis involved examining the amplitudes and latencies of the different wave components, which can provide insights into the functioning of different retinal cell types. Correlation analysis was also conducted to examine there’s relationship between the patients’ age and the signal components which the results show very little correlation between the age and the components, with some significant correlation between the individual components. In the frequency domain, Fourier Transform was used to extract signal frequencies for analysis. The frequency content of the ERG signals can reveal information about the underlying physiological processes and potential abnormalities. However, due to the time-invariant nature of the frequency domain, drawing conclusions based solely on this analysis can be challenging. For time-frequency domain analysis, short-time Fourier transform (STFT) was employed along with spectrogram analysis. The STFT allowed for the examination of how the frequency content of the signals evolved over time, providing a more comprehensive representation of the signal dynamics. Additionally, features were extracted using different windows and window sizes for machine learning classifier training to classify the signals. The spectrograms computed were also used to train deep learning models with different architectures, and the results were compared based on the windows used. The findings indicate that there is no discernible correlation between age and other signal components in the time domain. This suggests that age alone may not be a reliable predictor of ERG signal characteristics. In the frequency domain, drawing conclusions based solely on the frequency content proved challenging due to the time-invariant nature of the analysis. Moreover, it is evident that window sizes have a more significant impact on the resulting features compared to window functions. Larger window sizes yield improved frequency resolution, while smaller windows offer higher time resolution. This implies that the time and frequency resolution play a more substantial role in shaping the resulting features than the signal processing performed by the window function itself. The analysis of ERG signals using various techniques, including time-domain, frequency-domain, and time-frequency domain methods, provides valuable insights into retinal function and potential disorders. The combination of these approaches, along with feature extraction and machine learning techniques, offers a comprehensive framework for understanding and interpreting ERG signals. However, careful consideration of factors such as window sizes and resolution trade-offs is crucial for obtaining meaningful and accurate results.