Multimodal photoacoustic remote sensing (PARS) microscopy combined with swept-source optical coherence tomography (SS-OCT) for in-vivo, non-contact, functional and structural ophthalmic imaging applications

Ophthalmic imaging has long played an important role in the understanding, diagnosis, and treatment of a wide variety of ocular disorders. Currently, available clinical ophthalmic imaging instruments are primarily optical-based, including slit-lamp microscopy, fundus photography, confocal microscopy, scanning laser ophthalmoscopy, and optical coherence tomography (OCT). The development of these imaging instruments has greatly extended our ability to evaluate the ocular environment. Studies have shown that at least 40% of blinding disorders in the United States are either preventable or treatable with timely diagnosis and intervention. OCT is a state-of-the-art imaging technique extensively used in preclinical and clinical applications for imaging both anterior and posterior parts of the eye. OCT has become a standard of care for the assessment and treatment of most ocular conditions. The technology enables non-contact, high-speed, cross-sectional imaging over a large field of view with submicron resolutions. In eye imaging applications, functional extensions of OCT such as spectroscopic OCT and Doppler OCT have been applied to provide a better understanding of tissue activity. Spectroscopic OCT is usually achieved through OCT systems in the visible spectral range, and it enables the amount of light absorption inside the ocular environment to be measured. This indirect optical absorption measurement is used to estimate the amount of ocular oxygen saturation (SO2) which is a well-known biomarker in prevalent eye diseases including diabetic retinopathy, glaucoma, and retinal vein occlusions. Despite all the advancements in functional spectroscopic OCT methods, they still rely primarily on measuring the backscattered photons to quantify the absorption of chromophores inside the tissue. Therefore, they are sensitive to local geometrical parameters, such as retinal thickness, vessel diameters, and retinal pigmentation, and may result in biased estimations. Of the various optical imaging modalities, photoacoustic imaging (PAI) offers unique imaging contrast of optical absorption because PAI can image any target that absorbs light energy. This unique imaging ability makes PAI a favorable candidate for various functional and molecular imaging applications as well as for measuring chromophore concentration. Over the past decade, photoacoustic ophthalmoscopy has been applied for visualizing hemoglobin and melanin content in ocular tissue, quantifying ocular SO2, and measuring the metabolic rate of oxygen consumption (MRO2). Despite all these advantages offered by PAI devices, a major limitation arises from their need to be in contact with the ocular tissues. This physical contact may increase the risk of infection and cause patient discomfort. Furthermore, this contact-based imaging approach applies pressure to the eye and introduces barriers to oxygen diffusion. Thus, it has a crucial influence on the physiological and pathophysiological balance of ocular vasculature function, and it is not capable of studying dynamic processes under normal conditions. To overcome these limitations and to benefit from the numerous advantages offered by photoacoustic ophthalmoscopy, non-contact detection of photoacoustic signals has been a long-lasting goal in the field of ocular imaging. In 2017 Haji Reza et al. developed photoacoustic remote sensing (PARS) for non-contact, non-interferometric detection of photoacoustic signals. PARS is the non-contact, all-optical version of optical-resolution photoacoustic microscopy (OR-PAM), where the acoustically coupled ultrasound transducer is replaced with a co-focused probe beam. This all-optical detection scheme allows the system to measure the photoacoustic pressure waves at the subsurface origin where the pressure is at a maximum. In a very short time, PARS technology has proven its potential for various biomedical applications, including label-free histological imaging, SO2 mapping, and angiogenesis imaging. PARS is an ideal companion for OCT in ophthalmic applications, where the depth-resolved, detailed scattering information of OCT is well complemented by rich absorption information of PARS. This combined multimodal imaging technology has the potential to provide chromophore selective absorption contrast in concert with depth-resolved scattering contrast in the ocular environment. The main goals of this PhD project are to: • Develop a photoacoustic remote sensing microscopy system for in-vivo, non-contact ophthalmic imaging. This is the first time a non-contact photoacoustic imaging has been used for in-vivo imaging of the eye. • Develop a robust and temporally stable multiwavelength light source for functional photoacoustic imaging applications. • Develop a multimodal PARS-OCT imaging system that can image in-vivo and record, simultaneously, functional, and structural information in the anterior segment of a rodent eye. This is the first time a multiwavelength non-contact photoacoustic system is used for in-vivo measurement of oxygen saturation in the ocular environment. • Develop and modify the multimodal PARS-OCT imaging system for non-contact, in-vivo, functional, and structural imaging of the posterior part of the rodent eye

Anatomical Modeling of Cerebral Microvascular Structures: Application to Identify Biomarkers of Microstrokes

Les réseaux microvasculaires corticaux sont responsables du transport de l’oxygène et des substrats énergétiques vers les neurones. Ces réseaux réagissent dynamiquement aux demandes énergétiques lors d’une activation neuronale par le biais du couplage neurovasculaire. Afin d’élucider le rôle de la composante microvasculaire dans ce processus de couplage, l’utilisation de la modélisation in-formatique pourrait se révéler un élément clé. Cependant, la manque de méthodologies de calcul appropriées et entièrement automatisées pour modéliser et caractériser les réseaux microvasculaires reste l’un des principaux obstacles. Le développement d’une solution entièrement automatisée est donc important pour des explorations plus avancées, notamment pour quantifier l’impact des mal-formations vasculaires associées à de nombreuses maladies cérébrovasculaires. Une observation courante dans l’ensemble des troubles neurovasculaires est la formation de micro-blocages vascu-laires cérébraux (mAVC) dans les artérioles pénétrantes de la surface piale. De récents travaux ont démontré l’impact de ces événements microscopiques sur la fonction cérébrale. Par conséquent, il est d’une importance vitale de développer une approche non invasive et comparative pour identifier leur présence dans un cadre clinique. Dans cette thèse,un pipeline de traitement entièrement automatisé est proposé pour aborder le prob-lème de la modélisation anatomique microvasculaire. La méthode de modélisation consiste en un réseau de neurones entièrement convolutif pour segmenter les capillaires sanguins, un générateur de modèle de surface 3D et un algorithme de contraction de la géométrie pour produire des mod-èles graphiques vasculaires ne comportant pas de connections multiples. Une amélioration de ce pipeline est développée plus tard pour alléger l’exigence de maillage lors de la phase de représen-tation graphique. Un nouveau schéma permettant de générer un modèle de graphe est développé avec des exigences d’entrée assouplies et permettant de retenir les informations sur les rayons des vaisseaux. Il est inspiré de graphes géométriques déformants construits en respectant les morpholo-gies vasculaires au lieu de maillages de surface. Un mécanisme pour supprimer la structure initiale du graphe à chaque exécution est implémenté avec un critère de convergence pour arrêter le pro-cessus. Une phase de raffinement est introduite pour obtenir des modèles vasculaires finaux. La modélisation informatique développée est ensuite appliquée pour simuler les signatures IRM po-tentielles de mAVC, combinant le marquage de spin artériel (ASL) et l’imagerie multidirectionnelle pondérée en diffusion (DWI). L’hypothèse est basée sur des observations récentes démontrant une réorientation radiale de la microvascularisation dans la périphérie du mAVC lors de la récupéra-tion chez la souris. Des lits capillaires synthétiques, orientés aléatoirement et radialement, et des angiogrammes de tomographie par cohérence optique (OCT), acquis dans le cortex de souris (n = 5) avant et après l’induction d’une photothrombose ciblée, sont analysés. Les graphes vasculaires informatiques sont exploités dans un simulateur 3D Monte-Carlo pour caractériser la réponse par résonance magnétique (MR), tout en considérant les effets des perturbations du champ magnétique causées par la désoxyhémoglobine, et l’advection et la diffusion des spins nucléaires. Le pipeline graphique proposé est validé sur des angiographies synthétiques et réelles acquises avec différentes modalités d’imagerie. Comparé à d’autres méthodes effectuées dans le milieu de la recherche, les expériences indiquent que le schéma proposé produit des taux d’erreur géométriques et topologiques amoindris sur divers angiogrammes. L’évaluation confirme également l’efficacité de la méthode proposée en fournissant des modèles représentatifs qui capturent tous les aspects anatomiques des structures vasculaires. Ensuite, afin de trouver des signatures de mAVC basées sur le signal IRM, la modélisation vasculaire proposée est exploitée pour quantifier le rapport de perte de signal intravoxel minimal lors de l’application de plusieurs directions de gradient, à des paramètres de séquence variables avec et sans ASL. Avec l’ASL, les résultats démontrent une dif-férence significative (p <0,05) entre le signal calculé avant et 3 semaines après la photothrombose. La puissance statistique a encore augmenté (p <0,005) en utilisant des angiogrammes capturés à la semaine suivante. Sans ASL, aucun changement de signal significatif n’est trouvé. Des rapports plus élevés sont obtenus à des intensités de champ magnétique plus faibles (par exemple, B0 = 3) et une lecture TE plus courte (<16 ms). Cette étude suggère que les mAVC pourraient être carac-térisés par des séquences ASL-DWI, et fournirait les informations nécessaires pour les validations expérimentales postérieures et les futurs essais comparatifs.----------ABSTRACT Cortical microvascular networks are responsible for carrying the necessary oxygen and energy substrates to our neurons. These networks react to the dynamic energy demands during neuronal activation through the process of neurovascular coupling. A key element in elucidating the role of the microvascular component in the brain is through computational modeling. However, the lack of fully-automated computational frameworks to model and characterize these microvascular net-works remains one of the main obstacles. Developing a fully-automated solution is thus substantial for further explorations, especially to quantify the impact of cerebrovascular malformations associ-ated with many cerebrovascular diseases. A common pathogenic outcome in a set of neurovascular disorders is the formation of microstrokes, i.e., micro occlusions in penetrating arterioles descend-ing from the pial surface. Recent experiments have demonstrated the impact of these microscopic events on brain function. Hence, it is of vital importance to develop a non-invasive and translatable approach to identify their presence in a clinical setting. In this thesis, a fully automatic processing pipeline to address the problem of microvascular anatom-ical modeling is proposed. The modeling scheme consists of a fully-convolutional neural network to segment microvessels, a 3D surface model generator and a geometry contraction algorithm to produce vascular graphical models with a single connected component. An improvement on this pipeline is developed later to alleviate the requirement of water-tight surface meshes as inputs to the graphing phase. The novel graphing scheme works with relaxed input requirements and intrin-sically captures vessel radii information, based on deforming geometric graphs constructed within vascular boundaries instead of surface meshes. A mechanism to decimate the initial graph struc-ture at each run is formulated with a convergence criterion to stop the process. A refinement phase is introduced to obtain final vascular models. The developed computational modeling is then ap-plied to simulate potential MRI signatures of microstrokes, combining arterial spin labeling (ASL) and multi-directional diffusion-weighted imaging (DWI). The hypothesis is driven based on recent observations demonstrating a radial reorientation of microvasculature around the micro-infarction locus during recovery in mice. Synthetic capillary beds, randomly- and radially oriented, and op-tical coherence tomography (OCT) angiograms, acquired in the barrel cortex of mice (n=5) before and after inducing targeted photothrombosis, are analyzed. The computational vascular graphs are exploited within a 3D Monte-Carlo simulator to characterize the magnetic resonance (MR) re-sponse, encompassing the effects of magnetic field perturbations caused by deoxyhemoglobin, and the advection and diffusion of the nuclear spins. The proposed graphing pipeline is validated on both synthetic and real angiograms acquired with different imaging modalities. Compared to other efficient and state-of-the-art graphing schemes, the experiments indicate that the proposed scheme produces the lowest geometric and topological error rates on various angiograms. The evaluation also confirms the efficiency of the proposed scheme in providing representative models that capture all anatomical aspects of vascular struc-tures. Next, searching for MRI-based signatures of microstokes, the proposed vascular modeling is exploited to quantify the minimal intravoxel signal loss ratio when applying multiple gradient di-rections, at varying sequence parameters with and without ASL. With ASL, the results demonstrate a significant difference (p<0.05) between the signal-ratios computed at baseline and 3 weeks after photothrombosis. The statistical power further increased (p<0.005) using angiograms captured at week 4. Without ASL, no reliable signal change is found. Higher ratios with improved significance are achieved at low magnetic field strengths (e.g., at 3 Tesla) and shorter readout TE (<16 ms). This study suggests that microstrokes might be characterized through ASL-DWI sequences, and provides necessary insights for posterior experimental validations, and ultimately, future transla-tional trials

Прикладна фізика : українсько-російсько-англійський тлумачний словник. У 4 т. Т. 2. З – Н

Словник охоплює близько 30 тис. термінів з прикладної фізики і дотичних до неї галузей знань та їх тлумачення трьома мовами (українською, російською та англійською). Багато термінів і визначень, наведених у словнику, якими послуговуються у відповідній галузі знань, досі не входили до жодного зі спеціалізованих словників. Словник призначений для викладачів, науковців, інженерів, аспірантів, студентів вищих навчальних закладів, перекладачів з природничих і технічних дисциплін