Дисертації з теми "FUS imaging"

La douleur neuropathique est une sensation de douleur anormale qui persiste au-delà du cours temporel de la guérison naturelle. Elle interfère avec la qualité de vie du patient et est associée à plusieurs comorbidités telles que l'anxiété et la dépression. Des études antérieures ont suggéré que la douleur chronique pourrait résulter d’une plasticité neuronale anormale et inadaptée dans les structures connues pour être impliquées dans la perception de la douleur (Bliss et al. 2016). Cela signifie qu'une lésion nerveuse déclencherait une potentialisation à long terme de la transmission synaptique dans les aires cérébrales liées à la douleur (Zhuo et al. 2014). Comme ces régions sont également impliquées dans les aspects émotionnels de la douleur, notre hypothèse est que la plasticité inadaptée susmentionnée dans ces zones cérébrales pourrait constituer un mécanisme clé pour le développement de comorbidités, telles que l'anxiété et la dépression.Au cours de ma thèse, nous avons choisi de tester cette hypothèse de travail par l’étude des altérations de la connectivité fonctionnelle (CF) intrinsèque des réseaux cérébraux par imagerie fonctionnelle ultrasonore (fUS) dans un modèle murin de douleur neuropathique. Cette technique de neuro-imagerie relativement récente a permis de nombreuses avancées en neurosciences, grâce à sa haute résolution spatio-temporelle, à sa sensibilité, mais aussi son adaptabilité, permettant des études chez l’animal anesthésié ou éveillé.Dans une première étude, j’ai mis au point un protocole expérimental permettant d’imager le cerveau des souris éveillées de façon reproductible et avec un minimum de stress et d artefacts de mouvements et ai également été impliquée dans le développement d’un nouvel algorithme d’analyse des signaux générées par ces acquisitions. Cette première approche étant réalisée avec une sonde linéaire en mouvement qui ne permet pas de visualiser l’entièreté du cerveau, dans une seconde étude, j’ai participe au développement d’une nouvelle technologie de sonde compilées et motorisée.Fort de ces développements technologiques, j’ai alors utilisé ces nouvelles approches pour tester mon hypothèse neurobiologique. J’ai entrepris deux études en parallèle chez des animaux anesthésiés pour l’une et éveillés pour la seconde, chez lesquelles nous avons étudié le lien temporel entre les altérations de la CF cérébrale et le développement de la douleur neuropathique et/ou des comorbidités associées. Pour cela, nous avons mesuré la CF (en période de repos) chez des souris atteintes de douleur neuropathique, à trois moments différents : I) 2 semaines après l’induction de la douleur neuropathique (manchon autour du nerf sciatique) II) à 8 semaines post-induction, lorsque l'anxiété émerge et III) à 12 semaines post-induction, lorsque la dépression apparait (12W). Ce suivi longitudinal a également été réalisé en parallèle sur un groupe d’animaux contrôles.Nos résultats indiquent des changements significatifs de la CF dans les principales régions cérébrales impliquées dans la transmission ou la modulation de la sensibilité ou de la douleur, suggérant la mise en place d’une plasticité inadaptée du réseau de la douleur, suite à la lésion nerveuse. De plus, nous observons une évolution temporelle de ces altérations, potentiellement corrélée à l'apparition des comorbidités associées. Ainsi, ces mécanismes pourraient participer à la chronicisation de la douleur
Neuropathic pain is an abnormal pain sensation that persists longer than the temporal course of natural healing. It interferes with the patient’s quality of life and leads to several comorbidities, such as anxiety and depression. It has been suggested that chronic pain may result from abnormal and maladaptive neuronal plasticity in the structures known to be involved in pain perception (Bliss et al. 2016). This means that nerve injury would trigger long-term potentiation of synaptic transmission in pain-related areas (Zhuo et al. 2014). Since these regions are also involved in the emotional aspects of pain, our hypothesis is that the aforementioned maladaptive plasticity in these brain areas could constitute a key mechanism for the development of comorbidities such as anxiety and depression.My PhD aimed at testing this working hypothesis, through the study of brain resting state functional connectivity (FC) using functional ultrasound imaging (fUS) in a mouse model of neuropathic pain. FUS is a relatively recent neuroimaging technique that enabled numerous advances in neuroscience, thanks to its high spatio-temporal resolution, its sensitivity, but also its adaptability, allowing studies in anesthetized or awake animals.In a first study, I developed an experimental protocol allowing the brains of awake mice to be imaged in a reproducible manner and with minimal stress and movement artifacts and was also involved in the development of a new algorithm for the analysis of the signals generated by these acquisitions. As this first approach was carried out with a moving linear probe which does not allow the entire brain to be visualized, in a second study, I participated in the development of a new compiled and motorized probe technology.Building on these technological developments, I then used these new approaches to test my neurobiological hypothesis. I undertook two parallel studies in animals anesthetized for one and awake for the second, in which we studied the temporal link between alterations in cerebral FC and the development of neuropathic pain and/or associated comorbidities. To do this, we measured the resting-state functional connectivity (FC) in anesthetized and in awake head-fixed mice, at three time points: I) 2 weeks after induction of neuropathic pain (cuff around the sciatic nerve), II) at 8 weeks post-induction during the emergence of anxiety (8W) and III) at 12 weeks post-induction during the emergence of depression. This longitudinal follow-up has been conducted concurrently on a control group.Our results show significant changes in FC in major pain-related brain regions in accordance with the development of neuropathic pain symptoms. These findings suggest that the pain network undergoes maladaptive plasticity following nerve injury which could contribute to pain chronification. Moreover, the time course of these connectivity alterations between regions of the pain network could be correlated with the subsequent apparition of associated comorbidities

Les épilepsies sont des hyperactivités neuronales pathologiques largement distribuées au sein du système nerveux. Aborder la question de l'organisation spatiotemporelle de ces crises est un premier pas crucial vers la dissection des mécanismes qui les sous-tendent. Alors qu'il existe de nombreux modèles d'hyperactivité épileptiforme, il est plus difficile d'étudier les crises spontanées, qui sont altérées par la sédation. Dans cette thèse, j'ai développé une approche combinant l'électroencéphalogramme (EEG) avec l'imagerie fonctionnelle ultrasonore (fUS), sur le rat mobile. Ainsi, sur un modèle d'épilepsie absence, j'ai pu enregistrer simultanément la survenue des crises et les variations hémodynamiques, marqueurs du métabolisme cellulaire. Le suivi additionnel de l'activité hémodynamique n'avait pas d'effet en soi sur l'occurrence et la durée des crises épileptiques. L'analyse des enregistrements a permis de mettre en évidence des corrélations entre les activités électriques et vasculaires durant les crises. Tandis que le thalamus présentait des zones d'hyperperfusion pendant les crises, le cortex présentait des corrélats variables suivant les aires, avec une hyperémie des aires somato-sensorielles accompagnée parfois d'une baisse de perfusion des tissus adjacents. La sensibilité du fUS a révélé, à partir d'événements uniques, qu'une série de pointe-ondes observée par une électrode EEG ne s'accompagne pas toujours d'une hyperactivité vasculaire au même endroit. Ainsi, cette approche permet de délimiter le contour des aires présentant une activité vasculaire pendant les crises et montre une dichotomie partielle entre les composantes électriques et vasculaires des crises
Epilepsies consist in neuronal hyperactivities distributed across the nervous system that need first to be located in order to later decipher the mechanisms of these pathologies. While there are many models of epileptiform hyperactivity, it is more difficult to study spontaneous seizures, which are altered by sedation. In this thesis, I developed an approach that combines electroencephalography (EEG) and functional ultrasound imaging (fUS), on the mobile rat. Thus, on a model of absence epilepsy, I could record simultaneously the occurrence of seizures and the hemodynamic variations, which reflect cellular metabolism. Seizures were unaltered by the recording protocol, compared to rats with EEG alone. Correlations were observed between electric and vascular activities. The thalamus showed areas of hyperperfusion during seizures. The cortex exhibited different correlates in distinct areas, with hyperaemia in somato-sensory areas, occasionally associated with a decrease in perfusion in adjacent tissue. The sensitivity of fUS, which could resolve blood changes from single occurrences, revealed that series of spike-wave discharges recorded from an EEG electrode were not always associated with vascular hyperactivity in the same region. Thus, this approach can delimit the contour of areas presenting vascular activity during seizures and shows a partial dichotomy between the electric and vascular components of seizures

Mes travaux de thèse portent sur l’application de l’imagerie fUS (functional ultrasound imaging) à l’imagerie cérébrale préclinique chez le petit animal. Le but était de transformer cette technique d’imagerie cérébrale récente en un véritable outil de quantification de l’état cérébral. Les objectifs principaux ont été de démontrer la faisabilité de l’imagerie fUS chez le petit animal non anesthésié ainsi que de passer du modèle rat au modèle souris - modèle de choix en imagerie préclinique en neurosciences - de surcroît de façon non invasive. J’ai tout d’abord mis au point une nouvelle séquence d’imagerie ultrasonore ultrarapide (Multiplane Wave imaging), permettant d’améliorer le rapport signal-à-bruit des images grâce à l’augmentation virtuelle de l’amplitude du signal émis, sans diminuer la cadence ultrarapide d’acquisition. Dans un deuxième temps j’ai démontré la possibilité d’imager le cerveau de la souris et du jeune rat anesthésiés par échographie Doppler ultrarapide, de manière transcrânienne et complètement non invasive, sans chirurgie ni injection d’agents de contraste. J’ai ensuite mis au point un montage expérimental, une séquence ultrasonore et un protocole expérimental permettant de réaliser de l’imagerie fUS de manière minimalement invasive chez des souris éveillées et libres de leurs mouvements. Enfin, j’ai démontré la possibilité d’utiliser le fUS pour étudier la connectivité fonctionnelle du cerveau au repos (sans stimulus) chez des souris éveillées ou sédatées. L’imagerie fUS et la combinaison « modèle souris » + « minimalement invasif » + « animal éveillé » + « connectivité fonctionnelle » constituent un outil précieux pour la communauté des neuroscientifiques travaillant sur des modèles animaux pathologiques ou de nouvelles molécules pharmacologiques
My work focuses on the application of fUS (functional ultrasound) imaging to preclinical brain imaging in small animals. The goal of my thesis was to turn this recent vascular brain imaging technique into a quantifying tool for cerebral state. The main objectives were to demonstrate the feasibility of fUS imaging in the non-anaesthetized small rodents and to move from rat model imaging to mouse model imaging –most used model for preclinical studies in neuroscience-, while developing the least invasive imaging protocols. First, I have developed a new ultrafast ultrasonic imaging sequence (Multiplane Wave imaging), improving the image signal-to-noise ratio by virtually increasing emitted signal amplitude, without reducing the ultrafast framerate. Then, I have demonstrated the possibility to use ultrafast Doppler ultrasound imaging to image both the mouse brain and the young rat brain, non-invasively and through the intact skull, without surgery or contrast agents injection. Next, I have developed an experimental setup, an ultrasound sequence and an experimental protocol to perform minimally invasive fUS imaging in awake and freely-moving mice. Finally, I have demonstrated the possibility to use fUS imaging to study the functional connectivity of the brain in a resting state in awake or sedated mice, still in a transcranial and minimally invasive way. fUS imaging and the combination of "mouse model" + "minimally invasive" + "awake animal" + "functional connectivity" represent a very promising tool for the neuroscientist community working on pathological animal models or new pharmacological molecules

Neurons connect to their remote targets via axons, which usually survive for the lifetime of an organism. Spatiotemporal regulation of the axonal proteome by local protein synthesis (LPS) plays a critical role in neuronal wiring and axon survival, raising the intriguing possibility that some neurological disorders involve LPS dysfunction. To visualise LPS in situ, I optimised multiple imaging techniques to investigate Netrin-1-induced translation in cultured retinal axons. Total axonal protein synthesis measured by metabolic and puromycin labelling indicates axons experience stage-dependent alterations in translation rate upon Netrin-1 stimulation. Remarkably, Netrin-1 triggers a burst of β-actin synthesis starting within 20 seconds of cue application at multiple non-repetitive sites visualised by single molecule translation imaging, an approach that allows direct visualisation of translation dynamics in response to external stimuli. Further studies have shown that local translation can occur on Rab7a-associated late endosomes, where mRNA recruitment and translation are coordinately regulated. Notably, mRNAs encoding mitochondria-related proteins are found translating on late endosomes docking in the vicinity of mitochondria, suggesting late endosomes act as ‘platforms’ for the localised synthesis of mitochondrial proteins necessary for maintaining mitochondrial integrity. Moreover, this process is affected in axons expressing the Charcot-Marie-Tooth disease type 2B (CMT2B)-related Rab7a mutants, leading to abnormal mitochondrial biogenesis and activity and compromised axon survival. Finally, attenuated de novo protein synthesis is observed in axons expressing amyotrophic lateral sclerosis (ALS)-associated fused in sarcoma (FUS) mutants and hypomethylated wild-type FUS. Live imaging reveals mislocalised mutant or hypomethylated FUS granules are transported along axons and accumulate at growth cones, possibly irreversibly trapping RNA molecules, resulting in reduced distance travelled by RNA granules in axons. Furthermore, mutant FUS expression results in defective retinal projections in vivo, highlighting the importance of RNA metabolism and local translation in axonal homeostatic mechanisms. In conclusion, aberrant translational activity in axons leads to prominent axonopathy, which recapitulates features of early stages of neurological diseases, providing the basis for novel therapeutic strategies.

La thérapie par faisceaux ultrasonores focalisés de forte intensité (HIFU / High Intensity Focused Ultrasound) est une nouvelle technique d’ablation tissulaire, fondée sur la focalisation de faisceaux ultrasonores de forte intensité pour réaliser une élévation de température capable de créer une nécrose thermique. Le cerveau a été jusqu’à présent peu accessible aux ultrasons car il est protégé par la boîte crânienne. Mais de nouvelles techniques de focalisation par correction des aberrations des faisceaux ultrasonores laissent espérer des applications prochaines en intracrânien, où l’HIFU pourrait constituer une intéressante alternative à la chirurgie et à la radiothérapie stéréotaxique. Le but général de ce travail a été de tester la thérapie HIFU contrôlée par Imagerie de Résonance Magnétique (IRM) pour le traitement des tumeurs cérébrales dans un modèle petit animal in vivo de tumeur cérébrale. Nous espérons ainsi fournir des apports sur la thérapie HIFU et ses effets biologiques sur le cerveau et les tumeurs cérébrales, connaissances nécessaires avant de passer à des études cliniques chez l’homme. Le plan de ce travail est le suivant : 1) développement d’un protocole de thérapie HIFU contrôlé par IRM sur le cerveau sain et sur un modèle de tumeur RG2 greffée en intracérébral chez le rat ; 2) étude des effets biologiques de l’HIFU par l’IRM et l’examen anatomo-pathologique sur le tissu cérébral sain et la tumeur RG2 en intracérébral, montrant une sensibilité variable des tissus à l’hyperthermie ; 3) étude de sécurité (tolérance et effets indésirables), démonstration d’efficacité sur la tumeur RG2 (ralentissement de l’évolution tumorale et augmentation de la survie des animaux traités). En conclusion, l’HIFU a montré sa précision et son efficacité dans le traitement de la tumeur RG2 greffée en intracérébral chez le rat. Cette technique n’est cependant pas exempte de complications, notamment un œdème périlésionnel et des hémorragies intratumorales
High Intensity Focused Ultrasound (HIFU) therapy is an innovative approach for tissue ablation, based on high intensity focused ultrasound beams. At focus, HIFU induces a temperature elevation and the tissue can be thermally destroyed. For transcranial brain therapy, the skull bone is a major limitation but new adaptive techniques for focusing ultrasound through the skull are underway and in the near future HIFU therapy could be an interesting alternative to brain surgery and radiotherapy.The overall aim of this work is to test HIFU therapy guided by Magnetic Resonance Imaging (MRgHIFU) for the treatment of brain tumors in an in vivo brain tumor model in rodent in order to provide inputs for future regulatory approval for clinical trial with a clinical prototype. In this work: 1) a dedicated system for transcranial MRgHIFU in an in vivo rat brain tumor model was developed, and a full protocol was applied in healthy brain tissue of rats and in transplanted tumors; 2) the biological effects of HIFU therapy was evaluated using MRI and histology in healthy brain tissue and in RG2 brain tumor, showing a different tissue sensibility for hyperthermia; 3) tolerance and side effects were investigated and the treatment was shown to improve the animal survival time by 50%. In conclusion, HIFU therapy has proved its accuracy and efficacy in the treatment of the RG2 brain tumor transplanted intracerebral in rats. However this technique is not free of complications, in particular edema and hemorrhages

The study of low mass star formation in our local Galaxy is particularly suited to HERSCHEL. The SPIRE spectrometer and photometer aboard the spacecraft operate in the ~ 200 - 600�m range and are well suited to probe the cold, dusty environments in molecular clouds where prestellar cores reside. The SPIRE FTS spectrometer is an interferometer, and this instrument design has strengths and weaknesses which are im- portant to understand when using data from the instrument. Herschel is set to continue groundbreaking work in the infrared, building upon earlier work from ISO, IRAS, and SPITZER, probing deep into star forming regions and improving our knowledge of the processes within. In this PhD thesis, we outline the current body of knowledge in low mass star formation. We examine the properties of the SPIRE FTS as a spectrometerusing a small, laboratory designed desktop FTS. We study the intrinsic properties of the instrument, as a way of understanding issues we are likely to see when using the SPIRE FTS in ight. With these issues firmly in mind, we examine the creation and use of SLIDE - an interactive IDL-based tool for processing SPIRE FTS data. SLIDE can extract line and continuum information from SPIRE FTS SEDs. We outline the creation, testing and use of SLIDE and provide examples of the use of SLIDE in astronomy with some examples from the literature. We then use the line information we extract from a variety of sources with the spectrometer, to examine how SED fitting from photometer data could be affected by line contamination. We simulate a wide range of greybodies with noise and line con- tamination and examine how SED fitting is affected. Our simulations conclude that line contamination is not enough to affect the recovery of temperature and spectral index B significantly. Finally we use the information we have deduced to examine SPIRE FTS SEDs of L1689B - a prestellar core located in Ophiuchus. Our SED fitting of the core confirms that this core is starless with no internal heating source, and the spectral index profile over the core morphology is consistent with an increasing density of fractal aggregrate grains towards the centre. The increase in grain density and spectral index profile is also in agreement with previous CO depletion data. Fractal grain growth of this nature is consistent with dust grain models.

The work presented in this thesis deals with the magneto-optical imaging (MOI) technique, which was developed during the PhD course of the candidate, with an equipment at the international state-of-the-art. The quantitative theoretical formalism was critically reproduced and verified, along with a careful calibration procedure. A novel, big improvement was brought for all the MOI experiments, aimed at the quantitative reconstruction of the current density, by an iterative procedure (Supercond. Sci. Technol. 16, 71 (2003)). The new MOI method was then applied to study a wide class of superconducting materials and a thorough study about the electrodynamics of superconducting films was accompanied by a research in the high energy nuclear field for creating suitable nanometric-size defects. In particular: the anisotropic interaction of correlated nanostructures with vortices was verified for the first time (Phys. Rev. B 68, 014507 (2003)); controlled micro-modulations of the superconducting properties through confined high-energy heavy-ion irradiation were achieved and nonlocal electrodynamics plus new vortex matter phases were observed; the measurements of hybrid heterostructures (superconducting/ferromagnetic bi-layers) was joining the studies of macroscopic quantum physics of vortices and of the macroscopic (but localized) spin structures (interacting with vortices indeed), in the ferromagnetic film.

Medical imaging physics has advanced a lot in recent years, providing clinicians and researchers with increasingly detailed images that are well suited to be analyzed with a quantitative approach typical of hard sciences, based on measurements and analysis of clinical interest quantities extracted from images themselves. Such an approach is placed in the context of quantitative imaging. The possibility of sharing data quickly, the development of machine learning and data mining techniques, the increasing availability of computational power and digital data storage which characterize this age constitute a great opportunity for quantitative imaging studies. The interest in large multicentric databases that gather images from single research centers is growing year after year. Big datasets offer very interesting research perspectives, primarily because they allow to increase statistical power of studies. At the same time, they raised a compatibility issue between data themselves. Indeed images acquired with different scanners and protocols could be very different about quality and measures extracted from images with different quality might be not compatible with each other. Harmonization techniques have been developed to circumvent this problem. Harmonization refers to all efforts to combine data from different sources and provide users with a comparable view of data from different studies. Harmonization can be done before acquiring data, by choosing a-priori appropriate acquisition protocols through a preliminary joint effort between research centers, or it can be done a-posteriori i.e. images are grouped into a single dataset and then any effects on measures caused by technical acquisition factors are removed. Although the a-priori harmonization guarantees best results, it is not often used for practical and/or technical reasons. In this thesis I will focus on a-posteriori harmonization. It is important to note that when we consider multicentric studies, in addition to the technical variability related to scanners and acquisition protocols, there may be a demographic variability that makes single centers samples not statistically equivalent to each other. The wide individual variability that characterize human beings, even more pronounced when patients are enrolled from very different geographical areas, can certainly exacerbate this issue. In addition, we must consider that biological processes are complex phenomena: quantitative imaging measures can be affected by numerous confounding demographic variables even apparently unrelated to measures themselves. A good harmonization method should be able to preserve inter-individual variability and remove at the same time all the effects due acquisition technical factors. Heterogene ity in acquisition together with a great inter-individual variability make harmonization very hard to achieve. Harmonization methods currently used in literature are able to preserve only the inter-subjects variability described by a set of known confounding variables, while all the unknown confounding variables are wrongly removed. This might lead to incorrect harmonization, especially if the unknown confounders play an important role. This issue is emphasized in practice, as sometimes happens that demographic variables that are known to play a major role are unknown. The final goal of my thesis is a proposal for an harmonization method developed in the context of amyloid Positron Emission Tomography (PET) which aim to remove the effects of variability induced by technical factors and at the same time are able to keep all the inter-individual differences. Since knowing all the demographic confounders is almost impossible, both practically and a theoretically, my proposal does not require the knowledge of these variables. The main point is to characterize image quality through a set of quality measures evaluated in regions of interest (ROIs) which are required to be as independent as possible from anatomical and clinical variability in order to exclusively highlight the effect of technical factors on images texture. Ideally, this allows to decouple the between-subjects variability from the technical ones: the latter can be directly removed while the former is automatically preserved. Specifically, I defined and validated 3 quality measures based on images texture properties. In addition I used a quality metric already existing, and I considered the reconstruction matrix dimension to take into account image resolution. My work has been performed using a multicentric dataset consisting of 1001 amyloid PET images. Before dealing specifically with harmonization, I handled some important issues: I built a relational database to organize and manage data and then I developed an automated algorithm for images pre-processing to achieve registration and quantification. This work might also be used in other imaging contexts: in particular I believe it could be applied in fluorodeoxyglucose (FDG) PET and tau PET. The consequences of harmonization I developed have been explored at a preliminary level. My proposal should be considered as a starting point as I mainly dealt with the issues of quality measures, while the harmonization of the variables in itself was done with a linear regression model. Although harmonization through linear models is often used, more sophisticated techniques are present in literature. It would be interesting to combine them with my work. Further investigations would be desirable in future.

Ladislav Fuks' works are under-recognized in English-speaking academic discourse. He is a valuable contributor not only to the Holocaust Literature genre, but also to film and literature in general. His two English-translated works, Mr. Theodore Mundstock and The Cremator, as well as the film adaptation of The Cremator, examine the role imagination can play in art that addresses atrocity, allowing for a heightened subjective impact on the audience. I critically and comparatively examine Fuks' work to establish his value to literature and Holocaust art. In the first chapter, I frame my argument with questions of art's abilities to represent atrocity and provide relevant background information relating to Fuks' and his experience in wartime Prague. In Chapter Two, I closely read Mr. Theodore Mundstock, concentrating specifically on Fuks' use of metaphor, presentation of incredulity, and commentary on the imagination's capabilities in confronting terror. Chapter Three compares Mr. Theodore Mundstock to the â Momikâ section of David Grossman's See Under: Love, focusing on similarities between the title characters. Chapter Four examines Fuks' use of the grotesque in The Cremator and its film adaptation. Chapter Five compares Fuks' works to Aharon Appelfeld's novel Badenheim 1939, emphasizing each author's reliance on the audience's retrospective prescience, which provides a significant psychological impact and avoids contributing to the over-saturation of Holocaust information on the public. I conclude that Fuks should be more highly regarded and widely recognized both academically and in popular culture, as he exhibits similar features as other, more celebrated Holocaust writers, and his innovative contributions defend the value of literature in representing atrocity.
Master of Arts

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The present dissertation proposes a sensoring technique of autonomous vehicles based on the fusion of inertial sensors and data collected from a camera. The autonomous vehicle designed in this project was built using "Mecanum" wheels, which gives the vehicle the capability to move in any direction without having to change orientation. The sensoring system proposed is based on the Extended Kalman Filter using quaternions for the fusion of inertial sensors and computer vision, with the objective of finding the global position and orientation of the system. The inertial measurements used in these systems are made by an accelerometer and a gyroscope. The computer vision aspect of the project is done by a digital camera and an image processing software, which is designed to capture colored points in the image. The theory used to design the vehicle?s controller is based on the Lyapunov?s Stability Theory. This project presents a theoretical basis related to the various elements that compose the system, the mathematical basis used in the filter?s implementation and the controller?s design, a general view of the vehicle?s structure used to validate the theory and the results obtained in practical tests. The system?s performance analysis was based on the analysis of graphics that shows the vehicle?s trajectory, the position and orientation of the system over time and the stability of the proposed control law. The obtained results shows that the proposed objectives were met in a satisfactory manner.
A presente disserta??o prop?e uma t?cnica de sensoreamento de ve?culos aut?nomos baseada na fus?o de sensores inerciais e de dados provenientes de uma c?mera. O ve?culo aut?nomo utilizado neste trabalho foi constru?do a partir de rodas "Mecanum", que lhe conferem a caracter?stica de omnidirecionalidade, ou seja, ? capaz de movimenta??o em todas as dire??es, sem a necessidade de mudan?a de orienta??o. O sensoreamento proposto ? fundamentado no Filtro de Kalman Estendido utilizando quat?rnios para a fus?o de sensores inerciais e vis?o computacional, com o objetivo de encontrar a posi??o global e orienta??o do sistema. As medi??es inerciais utilizadas nestes sistemas s?o realizadas por uma Unidade de Medi??es Inerciais (IMU). J? a vis?o computacional fica a cargo de uma c?mera aliada a um processamento de imagens, o qual tem por fun??o captar pontos coloridos na imagem. A teoria utilizada para a constru??o do controlador do ve?culo ? baseada na teoria de estabilidade de Lyapunov. Este controlador tem como prop?sito controlar o deslocamento linear e n?o linear do ve?culo omnidirecional. Sendo assim, este trabalho apresenta uma base te?rica relacionada aos diversos elementos que comp?em o sistema, a fundamenta??o matem?tica utilizada para a implementa??o do filtro e da formula??o do controlador, uma vis?o geral da constru??o do ve?culo utilizado para validar a teoria e os resultado obtidos a partir de testes pr?ticos. A an?lise do desempenho do sistema p?de ser feita a partir da an?lise de gr?ficos que mostram a trajet?ria realizada pelo ve?culo, a posi??o e orienta??o do sistema ao longo do tempo e a estabilidade da lei de controle proposta. Os resultados obtidos evidenciam que os objetivos propostos foram alcan?ados de forma satisfat?ria.

Photo-switchable chromophores are fluorescent inorganic dyes or proteins characterized by the tunability of their emission depending on the properties of the exciting radiation such as wavelength or intensity. The opportunities o ered by this kind of markers in the field of fluorescence microscopy, range from super-resolution imaging to molecular intracellular sensing of pH, calcium or second messengers. In this thesis I have studied the properties of two photo switchable GFP Mut2 mutants (E222Q and Mut2GQ) and their possible applications to biological fluorescence pump and probe imaging. From a strictly biological point of view the choice of a biological marker such as GFPs is very convenient since the uorescent label can be engineered to be naturally expressed by the cell under study. The risk of compromising or altering the cell cycle is reduced and, at the same time, labeling a ect the parent as well the daughter cells. These two mutants o er the possibility to investigate the role of the proton network around the GFP chromophore (in the case of the E222Q mutant) and the external protonation (in the case of the Mut2GQ mutant) of the GFP chromophore on the photo-switching. From the physical point of view, GFP Mut2 mutants, when excited by a less energetic pump wavelength, are characterized by long-lived non-fluorescent states whose depopulation can be triggered by irradiation with a more energetic probe beam. The first effect of the photo-induced depopulation of the long-lived state is the enhancement of the fluorescence signal due to the fact that the molecules are no more prevented to be excited to the high quantum yield singlet excited state. I have been able not only to characterize the fluorescence enhancement ratio of the GFP-Mut2 mutants, but also the characteristics relaxation times of the population and depopulation processes of the dark state. These parameters have a dependence on physical properties of their surroundings such as pH and viscosity, that could be exploited in imaging and sensing applications. Basing on this characterization I reasoned that the fluorescence enhancement (called in the thesis Enhancement Ratio) and the related relaxation time (Photoswitching Time) characteristic of these GFP mutants and other photoswitchable proteins, could be the basis for a new functional imaging technique. With this new protocol for image acquisition (called Beating Mode) it is possible to acquire images in which the contrast agent is not only the fluorescence intensity, but also the Enhancement Ratio or the Photoswitching Times. This imaging protocol can be easily extended to other photo-switchable proteins and by further characterizing their photo-switching properties as a function of pH or viscosity, it will offer the possibility to map biological functions in the samples. Here I outline and test the algorithms to perform what I called Intensity Modulation Beating Mode Imaging. However it must be noted that in order to reach the ultimate application of this technique, namely to perform intra-cellular sensing experiments via the detection of the photoswithcing parameters, the GFP mutants should be further engineered to allow cell transfection or membrane adhesion. This molecular biology step goes beyond the aim of my thesis. In this work, after the first introductory theoretical Chapters, I present a theoretical introduction to photo switchable GFP mutants in terms of physical and conformational properties (Chapter 3). In Chapter 4 we present the characterization of the behavior of the photo switching properties of the two mutants under study as a function of physical characteristics of the surroundings such as pH and viscosity. In the same Chapter we also present a joined theoretical-simulative model in order to analyze, in terms of FCS analysis, the coupling of the uorescence properties with the long lived dark state conformational dynamics. In Chapter 5, we describe the new image acquisition protocol developed in this work and called Beating Mode, both in terms of its potentialities and limitations, with a particular interest in the rationalization of the best operative condition and the applicability to biological sample. In Chapter 6 the applications of the Beating Mode protocol are finally outlined.

High-resolution gamma-ray spectroscopy is one of the most powerful and sensitive tools to investigate Nuclear Structure. Significant progress in this field was achieved through the use of arrays of Compton-suppressed high purity germanium detectors, leading for instance to the discovery of phenomena such as nuclear superdeformation. However, it is apparent that the present generation devices are not suited to the expected experimental conditions at the planned and under construction radioactive ion beam facilities. Devices with higher efficiency and sensitivity should be developed. The solution which has been proposed since the mid-nineties relies on the possibility to determine the position and the energy deposition of the individual interaction points of a photon within a germanium crystal, and on the capability to reconstruct the photon scattering sequence through powerful signal analysis algorithms. The results of Monte Carlo simulations suggest that indeed an array of germanium detectors using such techniques, which are known as Pulse Shape Analysis and gamma-ray tracking, will reach the performance required to operate effectively at the future radioactive ion beam facilities. Presently, two major projects aim at the construction of an array of germanium detectors based on the pulse shape analysis and gamma ’–ray tracking techniques, namely GRETA in the USA and AGATA in Europe. The present work describes the results obtained during the first in-beam test performed with the prototype detector of AGATA. The goal of the experiment was essentially to measure the precision on the position of the individual interaction points extracted with pulse shape analysis algorithms. Such a precision plays an essential role in determining the overall performance of the array. Chapter 1 deals briefly with the most actual topics in Nuclear Structure studies, pointing to the necessity to develop new generation radioactive ion beam facilities, as well as new detection systems such as AGATA. The status of the AGATA project is reviewed in Chapter 2, together with a short introduction to the principles of gamma-ray tracking and of pulse shape analysis. The results from the in-beam test with the AGATA prototype detector are presented in Chapter 3, where the data analysis procedure is described in detail. Finally, in Chapter 4 a possible technique to extract the position resolution of the AGATA detectors through Compton imaging techniques is presented, together with some preliminary results.

La navigation spatiale est une fonction complexe qui nécessite de combiner des informations sur l’environnement et notre mouvement propre pour construire une représentation du monde et trouver le chemin le plus direct vers notre but. Cette intégration multimodale suggère qu’un large réseau de structures corticales et sous-corticales interagit avec l’hippocampe, structure clé de la navigation. Je me suis concentrée chez la souris sur la navigation de type séquence (ou stratégie égocentrique séquentielle) qui repose sur l’organisation temporelle de mouvements associés à des points de choix spatialement distincts. Après avoir montré que l’apprentissage de cette navigation de type séquence nécessitait l’hippocampe et le striatum dorso-médian, nous avons caractérisé le réseau fonctionnel la sous-tendant en combinant de l’imagerie Fos, de l’analyse de connectivité fonctionnelle et une approche computationnelle. Les réseaux fonctionnels changent au cours de l’apprentissage. Lors de la phase précoce, le réseau impliqué comprend un ensemble de régions cortico-striatales fortement corrélées. L’hippocampe était activé ainsi que des structures impliquées dans le traitement d’informations de mouvement propre (cervelet), dans la manipulation de représentations mentales de l’espace (cortex rétrosplénial, pariétal, entorhinal) et dans la planification de trajectoires dirigées vers un but (boucle cortex préfrontal-ganglions de la base). Le réseau de la phase tardive est caractérisé par l’apparition d’activations coordonnées de l’hippocampe et du cervelet avec le reste du réseau. Parallèlement, nous avons testé si l’intégration de chemin, de l’apprentissage par renforcement basé modèle ou non-basé modèle pouvaient reproduire le comportement des souris. Seul un apprentissage par renforcement non-basé modèle auquel une mémoire rétrospective était ajoutée pouvait reproduire les dynamiques d’apprentissage à l’échelle du groupe ainsi que la variabilité individuelle. Ces résultats suggèrent qu’un modèle d’apprentissage par renforcement suffit à l’apprentissage de la navigation de type séquence et que l’ensemble des structures que cet apprentissage requiert adaptent leurs interactions fonctionnelles au cours de l’apprentissage
Spatial navigation is a complex function requiring the combination of external and self-motion cues to build a coherent representation of the external world and drive optimal behaviour directed towards a goal. This multimodal integration suggests that a large network of cortical and subcortical structures interacts with the hippocampus, a key structure in navigation. I have studied navigation in mice through this global approach and have focused on one particular type of navigation, which consists in remembering a sequence of turns, named sequence-based navigation or sequential egocentric strategy. This navigation specifically relies on the temporal organization of movements at spatially distinct choice points. We first showed that sequence-based navigation learning required the hippocampus and the dorsomedial striatum. Our aim was to identify the functional network underlying sequence-based navigation using Fos imaging and computational approaches. The functional networks dynamically changed across early and late learning stages. The early stage network was dominated by a highly inter-connected cortico-striatal cluster. The hippocampus was activated alongside structures known to be involved in self-motion processing (cerebellar cortices), in mental representation of space manipulations (retrosplenial, parietal, entorhinal cortices) and in goal-directed path planning (prefrontal-basal ganglia loop). The late stage was characterized by the emergence of correlated activity between the hippocampus, the cerebellum and the cortico-striatal structures. Conjointly, we explored whether path integration, model-based or model-free reinforcement learning algorithms could explain mice’s learning dynamics. Only the model-free system, as long as a retrospective memory component was added to it, was able to reproduce both the group learning dynamics and the individual variability observed in the mice. These results suggest that a unique model-free reinforcement learning algorithm was sufficient to learn sequence-based navigation and that the multiple structures this learning required adapted their functional interactions across learning

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A fus~ao de imagens tem-se destacado na area de processamento de imagens, atrav es da ideia de combinar duas ou mais imagens que apresentem caracter sticas distintas (provenientes de diferentes sensores) ou alguma degrada c~ao (regi~oes desfocadas, mal iluminadas, com baixo contraste). O foco e uma propriedade intimamente relacionada com a qualidade da imagem. Em algumas situa c~oes, n~ao e poss vel manter simultaneamente todas as regi~oes da paisagem bem focadas. Uma alternativa e utilizar a fus~ao de imagens para combinar os focos diferentes de uma foto em apenas uma imagem com todas as regi~oes melhor focadas. Este trabalho apresenta uma ideia de utilizar diferentes t ecnicas de fus~ao de imagens em conjunto para compor o resultado nal. Para tanto, as imagens de entrada s~ao divididas em blocos, nos quais s~ao aplicados os algoritmos de fus~ao escolhidos. Em seguida, escolhe-se a t ecnica que atuou melhor em cada bloco, atrav es de uma m etrica de qualidade de imagem (como a PSNR (Peak Signal to Noise Ratio)), formando um mosaico com os melhores resultados. Dois algoritmos existentes na literatura envolvendo a fus~ao de imagens no dom nio da frequ^encia baseados em foco s~ao descritos: Contraste no dom nio da DCT (Transformada Discreta de Cosseno) e Frequ^encia Espacial. Modi ca c~oes s~ao feitas em ambas as t ecnicas a m de melhorar os crit erios de sele c~ao para cada bloco, por meio da de ni c~ao da escolha de um bloco inteiro ou dos pixels (ou coe cientes) individualmente. A qualidade da imagem nal e avaliada utilizando m etricas conhecidas, como a PSNR, RMSE (Root Mean Square Error), SSIM (Structural Similarity), entre outras. Tanto para as melhorias quanto para a combina c~ao de algoritmos, os resultados s~ao equivalentes ou superiores quando comparados aos das t ecnicas originais. Em caso de igualdade da qualidade, o algoritmo melhorado possui execu c~ao mais r apida que o original, justi cando assim o seu uso. O tempo de execu c~ao de cada algoritmo e avaliado, mostrando que as t ecnicas de combina c~ao aumentam o tempo de processamento, pois os algoritmos s~ao executados sequencialmente. Nesse caso, a utiliza c~ao de paralelismo pode acelerar a execu c~ao. Uma vez que a combina c~ao adiciona um processamento extra, estudos de viabilidade podem ser realizados para cada caso, a m de considerar a real necessidade do aumento da qualidade da imagem fundida, em detrimento dos recursos a serem utilizados.

Intracellular chloride and pH are fundamental regulators of neuronal excitability and they are often co-modulated during excitation-inhibition activity. The study of their homeostasis requires simultaneous measurements in vivo in multiple neurons. Combining random mutagenesis screening, protein engineering and two-photon-imaging this thesis work led to the discovery of new chloride-sensitive GFP mutants and to the establishment of ratiometric imaging procedures for the quantitative combined imaging of intraneuronal pH and chloride. These achievements have been demonstrated in vivo in the mouse cortex, in real-time monitoring the dynamic changes of ions concentrations during epileptic-like discharges, and in glioblastoma primary cells, measuring osmotic swelling responses to various drugs treatment.

Intracellular chloride and pH are fundamental regulators of neuronal excitability and they are often co-modulated during excitation-inhibition activity. The study of their homeostasis requires simultaneous measurements in vivo in multiple neurons. Combining random mutagenesis screening, protein engineering and two-photon-imaging this thesis work led to the discovery of new chloride-sensitive GFP mutants and to the establishment of ratiometric imaging procedures for the quantitative combined imaging of intraneuronal pH and chloride. These achievements have been demonstrated in vivo in the mouse cortex, in real-time monitoring the dynamic changes of ions concentrations during epileptic-like discharges, and in glioblastoma primary cells, measuring osmotic swelling responses to various drugs treatment.

La scoperta di oggetti antichi solleva una serie di questioni quali la corretta determinazione del contesto storico-culturale, la provenienza ed il metodo di lavorazione, oltre alla scelta dei trattamenti e delle condizioni di restauro e conservazione. Vengono qui presentati risultati riguardo l’applicazione di tecnologie neutroniche nel campo dei beni culturali e promettenti prospettive future nel binomio scienza-tecnologia per lo studio di oggetti archeologici. Vengono discusse attività relative allo sviluppo di strumentazione ad hoc quali un sistema di posizionamento successivamente integrato nello strumento Prompt Gamma Activation Imaging/Neutron Tomography (PGAI/NT) e l’utilizzo del fotomoltiplicatore al silicio (SiPM) accoppiato con un cristallo scintillante YAP come rivelatore di neutroni e gamma al fine di ottenere un sistema di rivelazione di piccole dimensioni, compatto e a basso costo. Vengono poi presentati quattro risultati significativi riguardo l’utilizzo di tecniche neutroniche ‘standard’ su oggetti di reale interesse archeologico. Da ultimo, alcuni risultati preliminari riguardanti l’applicazione della nuova tecnica di Prompt Gamma Activation Imaging (PGAI) combinata con la Neutron Radiography (NR) su due preziosi pezzi, quali due teste in bronzo dorato provenienti dalle porte del Battistero di Firenze del Ghiberti, completeranno lo studio.
The discovery of ancient artefacts often raises a variety of questions such as the correct determination of its historical and cultural time-frame, the place and method of production, the choice of treatments and conditions for restoration and preservation. Research results about the application of neutron technology in the field of cultural heritage are presented together with promising perspectives for the future of science and technology within cultural heritage studies. Activities on neutron instrumentation such as sample positioning system for Prompt Gamma Activation Imaging/Neutron Tomography (PGAI/NT) instrument and the use of silicon-photomultiplier (SiPM) as neutrons and gammas detector coupled by YAP crystal to obtain small and compact, low cost, portable detector system, are discussed. The systematic assessment of neutron diffraction application to the study of archaeological objects is also carried out. Four significant results from the use of ‘standard’ techniques on real archaeological objects are reported. Finally, results about first preliminary measurement by the new Prompt Gamma Activation Imaging (PGAI) combined with Neutron Radiography (NR) on two precious gilded bronze heads from the monumental doors of the Florence Baptistery by Lorenzo Ghiberti will complete the study.

This work concerns the microwave imaging (MWI) for breast cancer. The full process to develop an experimental phantom is detailed. The models used in the simulation stage are presented in an increasing complexity. Starting from a simplified homogeneous breast where only the tumor is placed in a background medium, moving to an intermediate complexity model where a rugged fibroglandular structure other than tumor has been placed and reaching a realistic breast model derived from the nuclear magnetic resonance phantoms. The reconstruction is performed in 2D using the linear TR-MUSIC algorithm tested in the monostatic and multistatic approaches. The description of the developed phantom and the instruments involved are detailed along with the already planned improvements. The simulated and experimental results are compared. Finally a classification stage based on the leading technique known as “deep learning”, an improved branch of the machine learning, is adopted using mammographic images.

Radiographic techniques, usually, don’t give information about the chemical composition of a sample. However, thanks to the K-edge differential technique, it is possible to highlight the presence of target chemical elements with the radiography. This technique takes advantage on the K-edge discontinuity of the X-rays mass absorption coefficient. Considering a target element and acquiring two radiographies with monochromatic beams under and over the K-edge energy, the main difference between the two images is due to the presence of the element itself. To apply this peculiar radiographic technique, using the traditional X-ray tubes, two ways are possible: 1. Monochromatizing the beam coming out through the Bragg diffraction and acquiring the two radiographic images at the energies under and over the K-edge of the target; 2. For a target element with atomic number Z, using a set of three filters of the elements Z, Z+1 and Z-1, acquiring three different radiographies that, after the digital subtraction, would give images similar to the ones obtained with monochromatic beams. Both the two techniques have been employed in Ferrara, giving attention to the development of portable instruments, thus to promote their application in situ. For the first, the work of the thesis has been focused on the implementation of a new goniometric set-up, in respect of the existing one, and on the alignment of all the components (X-ray tube, Bragg diffraction crystal and detectors). For the second, the research has mainly regarded the use of balanced filters on canvas mock-ups painted with cadmium, copper and cobalt based pigments and their superimposition with other ones. The filters has been tested using the radiographic scanning systems developed in Ferrara. The new radiographic scanner for in situ application has been designed, realized and tested in the PhD period. Its reduced dimensions have allowed its use also on a big dimension painting (195 x 154 cm) in the Gallery of Palazzo Bellomo in Siracuse.
Tipicamente le tecniche radiografiche non permettono di ottenere informazioni riguardanti gli elementi chimici presenti in un campione. Tuttavia, grazie alla tecnica differenziale al K-edge, anche tramite la radiografia è possibile evidenziare la presenza di elementi chimici bersaglio. La tecnica sfrutta la discontinuità del K-edge nel coefficiente di assorbimento di massa dei raggi X. Considerando un elemento target e acquisendo due radiografie con fasci monocromatici di energia sotto e sopra il K-edge, la maggiore differenza tra le due immagini sarà dovuta alla presenza dell’elemento stesso. Per effettuare questa particolare tecnica radiografica, sfruttando i classici tubi a raggi X, si possono percorrere due vie: 1. monocromatizzare il fascio uscente tramite diffrazione di Bragg e acquisire le due immagini radiografiche alle energie sopra e sotto il K-edge del target; 2. per un elemento bersaglio di numero atomico Z, usare un set di tre filtri degli elementi Z, Z+1 e Z-1, acquisendo tre radiografie diverse che, dopo sottrazione digitale, daranno immagini simili a quelle ottenute con i fasci monocromatici. Entrambe le tecniche sono state impiegate a Ferrara, ponendo particolare attenzione allo sviluppo di strumenti portatili, così da favorirne la loro applicazione in situ. Per la prima, il lavoro di tesi si è concentrato sull’implementazione di un sistema goniometrico rispetto a quello esistente e sull’allineamento di tutte le sue parti (tubo a raggi X, cristallo per la diffrazione di Bragg e rivelatori). Per la seconda, la ricerca ha riguardato maggiormente l’applicazione dei filtri bilanciati a provini su tela di pigmenti a base di cadmio, rame e cobalto e della loro sovrapposizione con altri pigmenti. I filtri sono stati testati impiegando i sistemi a scansione per le radiografie sviluppati a Ferrara. Il nuovo scanner radiografico per le applicazioni in situ è stato progettato, realizzato e testato durante questo lavoro di tesi. Le sue ridotte dimensioni, ne hanno consentito l’applicazione anche su un dipinto di grandi dimensioni (195 x 154 cm) nella Galleria di Palazzo Bellomo di Siracusa.

Without light, there would be no sight. Light acts as a probe in various measurement techniques ranging from imaging to spectroscopy, from small scale cantilever displace- ment measurement in atomic force microscopy to large scale mirror motion in interfer- ometry, light detection and ranging (LIDAR) and many other fields. As the light probe intensity rises, it not only allows reducing the background noise effect, but it also aids precision to the measurement by reducing the photon noise (shot-noise) contribution. However, increasing intensity beyond certain threshold level is not always advantageous for ultra sensitive measurements. For example in the detection of gravitational waves, the current power circulating in the large scale interferometers can not be increased further without introducing other noise sources like thermal effects on the mirrors, un- wanted scattered photons, and back action due to radiation pressure. In the imaging of delicate photo sensitive sample, high power can causes cell damage or it may lead to disturb the regular process under investigation, viz. favouring certain biochemical reaction, which do not correspond to natural in vitro behaviour. At low intensity, pho- ton noise is an important concern and quantum states of light with correlated photon fluctuation can ideally represent a fruitful way to build specific measurement strategies to surpass the limitation of standard approach based on classical light sources, offering an avenue of solutions for ultra sensitive measurements. This thesis work focuses on two application of quantum enhanced measurement strate- gies. The first part of the thesis work has been dedicated to the realization of the first wide-field microscope with Sub Shot Noise (SSN) sensitivity. This is based on the ex- ploitation of quantum correlations in the Squeezed Vacuum state. In the second part, the investigations have made on the role of the quantum correlated beams in an unusual interferometric scheme, in which two identical optical interferometers are subject to the same phase fluctuation. The scheme, in the classical regime, has been already imple- mented in a large scale experiment devoted to the search of possible quantum gravity (QG) effects at Fermilab.

Il lavoro presentato in questa tesi si concentra sullo sviluppo e sul miglioramento della strumentazione e dei metodi applicati all'imaging a trasmissione di neutroni. Le attività di ricerca sono state svolte presso il laboratorio di "Imaging and Materials Science and Engineering" (IMAT). Questa struttura fa parte della sorgente di neutroni ISIS presso il Rutherford Appleton Laboratory (UK). I neutroni qui sono prodotti dalla spallazione di un bersaglio di tungsteno colpito da protoni con energia di 800 MeV. I neutroni risultanti vengono moderati e convogliati attraverso le guide dei fasci verso l'area sperimentale IMAT. Lo spettro dei neutroni è caratterizzato dalla presenza di neutroni termici e freddi con una lunghezza d'onda compresa tra 0,68 e 6,8 A. IMAT è stato progettato per acquisire impulsi di neutroni in modalità tempo di volo, registrando il tempo di arrivo dei neutroni, relativo alla loro energia, con una risoluzione temporale massima di 10 ns. Questa analisi viene eseguita con un rilevatore di nuova generazione, che è una combinazione di un convertitore di neutroni “MicroChannel Plate” e un readout elettronico “TIMEPIX”. Mediante questo apparato, radiografie e tomografie con un campo visivo di 28 mm^2 possono essere generate con una risoluzione spaziale di 55 um e a particolari energie dei neutroni incidenti. Una fotocamera CMOS di maggiori dimensioni può essere utilizzata in combinazione con gli scintillatori a 6LiF/ZnS per acquisire immagini fino a 200 * 200 mm^2 in modalità white-beam. Ciò apre diverse possibilità. Da una parte, la tecnica di imaging neutronico risolta in energia può essere utilizzata per studiare composizione e texture dei campioni tramite software di analisi dei Bragg Edge, a costo di un campo visivo ridotto. Dall’altra, i campioni più grandi possono essere studiati con fotocamere standard basate su CMOS o CCD, ma perdendo qualsiasi informazione sull'energia dei neutroni in ingresso. In questo lavoro, la prima parte è dedicata alla descrizione della strumentazione IMAT, incluso il progetto della beamline, l'area sperimentale e i rivelatori. La seconda parte è diretta a casi di studio basati su queste nuove tecniche di strumentazione e di imaging. In particolare, nel campo del patrimonio culturale, tali metodi non distruttivi sono utilizzati, in quanto i campioni sono spesso piccoli e delicati. Per esempio, abbiamo analizzato una perla "soufflè". La loro particolarità risiede nel fatto che sono vuote all'interno. L'ispezione della struttura morfologica della parte interna e l'individuazione dei diversi orientamenti dei cristalliti sono stati condotti con tecniche di imaging risolte in energia. Un secondo esperimento, presentato in questa tesi, riguarda lo studio di una serie di griglie metalliche con una dimensione fino a 200 * 10 mm^2. In questo caso, un modo rapido e non distruttivo per verificare lo spessore dello strato di carburo di boro di 1 um depositato sulle lamelle è stato implementato con successo, considerando un'incertezza di 120 nm. La terza parte è rivolta a mostrare due nuovi metodi sviluppati per migliorare la fotocamera del rivelatore MCP in termini di risoluzione spaziale e affidabilità. Per quanto riguarda la risoluzione spaziale, è stata testata una nuova procedura basata su un algoritmo di centroiding. Questo metodo di acquisizione consente di superare il vincolo fisico dato dalla dimensione dei pixel del readout elettronico e di acquisire immagini con risoluzioni fino a quattro volte superiori. Inoltre, è stato sviluppato un sistema per migliorare le immagini generate dal rivelatore MCP in post-elaborazione. Uno dei punti deboli del readout TIMEPIX installato sul rivelatore MCP è il fatto di essere costituito da quattro matrici di pixel assemblate insieme. Ciò porta a notevoli artefatti che possono causare problemi nell'analisi dei dati. Una procedure con software specifico è stata implementata per risolvere il problema.
The work presented in this thesis focuses on the development and improvement of instrumentation and methods applied to neutron transmission imaging. In particular, the research activities have been performed at the "Imaging and Materials Science and Engineering" (IMAT) instrument. This facility is a part of the ISIS neutron source at the Rutherford Appleton Laboratory, in UK. The neutrons here are produced by spallation of a tungsten target hit by protons with energy of 800 MeV. The resulting neutrons are then moderated and convoyed through beam guides towards the IMAT experimental area. The neutrons spectrum in this case is characterized by the presence of thermal and cold neutrons with a wavelength in the range of 0.68 - 6.8 A. IMAT has been designed to acquire neutron pulses in Time-Of-Flight mode, by recording the time of arrival of neutrons, related to their energy, with a maximum of 10 ns timing resolution. This analysis is performed with a new generation detector, that is a combination of a MicroChannel Plate neutron converter with a TIMEPIX electronic readout. By means of this apparatus, radiographies and tomographies with a field of view of 28 mm^2 can be generated with a spatial resolution of 55 \textmu m and with respect to specific neutron energies. Beside this device, a larger CMOS camera can be used in combination with 6LiF/ZnS based neutron screen scintillators to acquire images up to 200 * 200 mm^2 in white-beam imaging. Such configuration opens several possibilities in different case scenarios. In one hand, the energy-resolved neutron imaging technique can be used to investigate the phase fraction composition and texture of the samples via Bragg Edge analysis software tools, at the cost of a reduced field of view. On the other hand, bigger samples can be studied with standard CMOS or CCD based white-beam imaging cameras, but loosing any information about the energy of the incoming neutrons. In this work, the first part is devoted to the description of the IMAT instrumentation, including the beamline design, the experimental area and the detectors. The second part is directed to case studies that made use of these novel instrumentation and imaging techniques. In particular, the cultural heritage takes advantage of such non-destructive methods where small and delicate specimens must be analysed. In this class of examples, a "soufflè" pearl was considered. The peculiarity of these cultured pearls resides in the fact that they are empty inside. The inspection of the morphological structure of the inner part, as well as the individuation of the different orientations of the nacres crystallites was conducted with energy-resolved imaging. A second experiment, presented in this thesis, regards the diagnosis of a series of metallic grids with a size up to 200 * 10 mm^2. For this case, a fast and non destructive way to verify the thickness of 1 um boron carbide layer deposited over the lamellae was successfully implemented, within an uncertainty of 120 nm. The third part is directed to show two new methods developed to improve the MCP detector camera in terms of spatial resolution and reliability. For what concerns the spatial resolution, a new procedure based on a centroiding algorithm has been tested. This acquisition method enables the possibility to go over the physical constraint given by the dimension of the pixels of the electronic readout and to acquire images with a resolutions up to four times higher. Furthermore, an improvement to the resulting images generated by the MCP detector has been developed, based on a post-processing approach. Actually, one of the weak spots of the TIMEPIX readout installed on the MCP detector is that it is constituted by four matrices of pixels assembled together. This brings to noticeable artifacts which, in some cases, may produce issues in the data analysis. A procedure, including a customized software, was implemented to fix such problem.

2016 - 2017
Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI) are techniques that have seen a remarkable success and a fast growth over the past decades. Thanks to its non-invasivity and non-descrutivity, the MRI enhances its potential to perform inspections and studies of the internal structure of intact samples such as fruits and vegetables. without modifications caused by the measurements Due to the presence of a high water content in these products, MRI can be useful to obtain information about tissue properties and, thanks to the high sensitivity, can trace water distribution and migration. The characteristic NMR relaxation times are used as parameters for the quantification of water content or for the extraction of information related to changes in microstructure. The idea behind this thesis is the investigation of new methodologies intended to carry out fast and accurate evaluation of moisture content in a food matrix through MRI. At the same time the development of appropriate protocols and analysis tools allowing a simple extraction of those information in a reproducible and reliable way. Two different approaches have been used, both based on data extracted by MR Imaging and a comparison of the two methods is presented. The goal is to exploit MRI as a real measurement instrument with a simple and fast measurement protocol: to achieve this goal we need to identify quantitative MR parameters that provide the most relevant information with respect to the physical quantities we want to measure. To use and validate the MRI as quantitative tool is our major challenge and the results obtained in this thesis keep us confident about the achievement of this goal. This could hopefully open a way for new methods to perform MRI analysis. [edited by Author]
XVI n.s. (XXX ciclo)

Positron emission tomography is an imaging technique that appeared to be a valid instrument for cancers detection and neuro-imaging studies. Since first models built during 1960s, an incredible effort has been done by researchers to develop scanners more and more advanced with higher specificity and efficiency. Monte Carlo simulations have shown to be a very important tool during design phase of PET prototypes thanks to their ability to simulate systems with many coupled degrees of freedom, as it happens when particles interact with matter. This Thesis work has started in the frame the Crystal Clear Collaboration when the EndoTOFPET scanner was already under development. This prototype is an high spatial resolution scanner for the study of pancreatic carcinoma and prostatic cancer, composed by a PET head mounted on an ultrasound endoscope and a PET plate to be placed outside the body. The Collaboration has chosen to use Monte Carlo simulations to support the design of this project and two simulations toolkits were available: Geant4 and SLitrani. In this work both the toolkits are studied and ray tracing in scintillator crystals are tested. In particular photon extraction efficiency is simulated under different surface treatments as coating and wrapping. Also the influence of the crystals geometry on light output is tested simulating different scintillators sections and lengths. Both Geant4 and SLitrani have shown to give similar results under these conditions. A main issue was observed regarding secondary particles since Geant4 is able to simulate their production while it is not possible with SLitrani. On other hand crystals anisotropy for optical photons can be activated in SLitrani. Light yield measurements were performed in laboratory on LYSO and PbWO 4 crystals to have a comparison with the results obtained by mean of simulations. Good agreements are obtained for what regards surfaces treatments while more tuning was required to simulate the effect of surface imperfections and diffusion inside crystals. For the Collaboration purposes, Geant4 results more reliable and it allows to use GATE, an open source software specifically developed for the simulation of medical imaging scanners. Due to the peculiar structure of the PET prototype it was necessary to develop a code to simulate the electronic chain, responsible for transforming the gammas detected in usable data for image reconstruction. Different coincidences sorting algorithms were studied and methods to introduce instrumental uncertainties in data were developed and reported in this work. Simulations of EndoTOFPET scanner with different scintillator dimensions, modules geometries and plate configurations were performed. Sensibility and spatial resolution were used as elements of comparison and results collected by simulations are reported and analysed in this work. Time of flight was tested applying different time resolutions while system response to DOI analysis was studied too. Thanks to these first simulations, valuable information for the developing of this prototype were collected.

High-frequency seismograms contain features that reflect the random inhomogeneities of the earth. In this work I use an imaging method to locate the high contrast small- scale heterogeneity respect to the background earth medium. This method was first introduced by Nishigami (1991) and than applied to different volcanic and tectonically active areas (Nishigami, 1997, Nishigami, 2000, Nishigami, 2006). The scattering imaging method is applied to two volcanic areas: Campi Flegrei and Mt. Vesuvius. Volcanic and seismological active areas are often characterized by complex velocity structures, due to the presence of rocks with different elastic properties. I introduce some modifications to the original method in order to make it suitable for small and highly complex media. In particular, for very complex media the single scattering approximation assumed by Nishigami (1991) is not applicable as the mean free path becomes short. The multiple scattering or diffusive approximation become closer to the reality. In this thesis, differently from the ordinary Nishigami’s method (Nishigami, 1991), I use the mean of the recorded coda envelope as reference curve and calculate the variations from this average envelope. In this way I implicitly do not assume any particular scattering regime for the "average" scattered radiation, whereas I consider the variations as due to waves that are singularly scattered from the strongest heterogeneities. The imaging method is applied to a relatively small area (20 x 20 km), this choice being justified by the small length of the analyzed codas of the low magnitude earthquakes. I apply the unmodified Nishigami’s method to the volcanic area of Campi Flegrei and compare the results with the other tomographies done in the same area. The scattering images, obtained with frequency waves around 18 Hz, show the presence of high scatterers in correspondence with the submerged caldera rim in the southern part of the Pozzuoli bay. Strong scattering is also found below the Solfatara crater, characterized by the presence of densely fractured, fluid-filled rocks and by a strong thermal anomaly. The modified Nishigami’s technique is applied to the Mt. Vesuvius area. Results show a low scattering area just below the central cone and a high scattering area around it. The high scattering zone seems to be due to the contrast between the high rigidity body located beneath the crater and the low rigidity materials located around it. The central low scattering area overlaps the hydrothermal reservoirs located below the central cone. An interpretation of the results in terms of geological properties of the medium is also supplied, aiming to find a correspondence of the scattering properties and the geological nature of the material. A complementary result reported in this thesis is that the strong heterogeneity of the volcanic medium create a phenomenon called "coda localization". It has been verified that the shape of the seismograms recorded from the stations located at the top of the volcanic edifice of Mt. Vesuvius is different from the shape of the seismograms recorded at the bottom. This behavior is justified by the consideration that the coda energy is not uniformly distributed within a region surrounding the source for great lapse time.

High-frequency seismograms contain features that reflect the random inhomogeneities of the earth. In this work I use an imaging method to locate the high contrast small- scale heterogeneity respect to the background earth medium. This method was first introduced by Nishigami (1991) and than applied to different volcanic and tectonically active areas (Nishigami, 1997, Nishigami, 2000, Nishigami, 2006). The scattering imaging method is applied to two volcanic areas: Campi Flegrei and Mt. Vesuvius. Volcanic and seismological active areas are often characterized by complex velocity structures, due to the presence of rocks with different elastic properties. I introduce some modifications to the original method in order to make it suitable for small and highly complex media. In particular, for very complex media the single scattering approximation assumed by Nishigami (1991) is not applicable as the mean free path becomes short. The multiple scattering or diffusive approximation become closer to the reality. In this thesis, differently from the ordinary Nishigami’s method (Nishigami, 1991), I use the mean of the recorded coda envelope as reference curve and calculate the variations from this average envelope. In this way I implicitly do not assume any particular scattering regime for the "average" scattered radiation, whereas I consider the variations as due to waves that are singularly scattered from the strongest heterogeneities. The imaging method is applied to a relatively small area (20 x 20 km), this choice being justified by the small length of the analyzed codas of the low magnitude earthquakes. I apply the unmodified Nishigami’s method to the volcanic area of Campi Flegrei and compare the results with the other tomographies done in the same area. The scattering images, obtained with frequency waves around 18 Hz, show the presence of high scatterers in correspondence with the submerged caldera rim in the southern part of the Pozzuoli bay. Strong scattering is also found below the Solfatara crater, characterized by the presence of densely fractured, fluid-filled rocks and by a strong thermal anomaly. The modified Nishigami’s technique is applied to the Mt. Vesuvius area. Results show a low scattering area just below the central cone and a high scattering area around it. The high scattering zone seems to be due to the contrast between the high rigidity body located beneath the crater and the low rigidity materials located around it. The central low scattering area overlaps the hydrothermal reservoirs located below the central cone. An interpretation of the results in terms of geological properties of the medium is also supplied, aiming to find a correspondence of the scattering properties and the geological nature of the material. A complementary result reported in this thesis is that the strong heterogeneity of the volcanic medium create a phenomenon called "coda localization". It has been verified that the shape of the seismograms recorded from the stations located at the top of the volcanic edifice of Mt. Vesuvius is different from the shape of the seismograms recorded at the bottom. This behavior is justified by the consideration that the coda energy is not uniformly distributed within a region surrounding the source for great lapse time.

Il mio lavoro di tesi è stato mirato allo sviluppo di materiali per manipolazione della luce. Il principale obiettivo è stato quello di fabbricare e caratterizzare cristalli fotonici basati su materiali innovativi ad alto indice di rifrazione. Terminato questo progetto, l’obiettivo del mio lavoro si è spostato verso lo sviluppo di materiali per applicazioni biologiche: imaging anti-Stokes e sensing del pH intracellulare. In dettaglio, ho lavorato sulla nanofabbricazione e la caratterizzazione di cristalli fotonici a base di dicalcogenuri di metalli di transizione (TMD). In questo progetto ho dimostrato la potenzialità dei TMD per l’applicazione in fotonica che deriva da un indice di rifrazione sorprendentemente elevato nel loro intervallo di trasparenza. I TMD hanno limiti di fabbricazione che ne impediscono l’applicazione efficiente in fotonica. Nel mio lavoro ho dimostrato che questi limiti possono essere superati convertendo l’ossido di metallo di transizione corrispondente ad alta temperatura in presenza di un agente calcogenizzante. La sintesi dell’ossido di metallo di transizione è stata fatta con atomic layer deposition, tecnica di deposizione di film sottili estremamente potente che permette di controllare con estrema precisione la composizione e lo spessore del film depositato, oltre che di avere perfetta conformalità su qualunque substrato. In questo lavoro, ho prodotto, caratterizzato e modellizzato per la prima volta cristalli fotonici a base di TMD, dimostrando la possibilità di superare forti limiti di fabbricazione con tecniche semplici. Concluso questo progetto, il mio lavoro sulla manipolazione della luce è continuato, cambiando però l’interesse principale verso materiali per biotecnologie. In dettaglio, ho portato avanti un progetto di cui mi sono occupato durante la tesi di laurea che aveva come obiettivo lo sviluppo di materiali ad alta efficienza per up-conversion sensibilizzato basato su annichilazione tripletto-tripletto (TTA-UC). Il TTA-UC è una tecnica che permette di generare fotoni ad alta energia partendo da un’eccitazione ad energia minore, che è molto interessante per l’energia solare ma recentemente ha trovato applicazione anche in ambito biotecnologico come colorante ad alto contrasto e ad emissione anti-Stokes. L’applicabilità del TTA-UC a sistemi biologici è ancora sotto indagine perché le tipiche molecole che vengono utilizzate hanno una pessima solubilità in acqua. Nel mio lavoro, questo problema è stato affrontato e risolto sviluppando nano-micelle autoassemblate caricate con i cromofori per TTA-UC. Questa tecnica ha permesso di solubilizzare in acqua e in ambiente biologico i componenti per TTA-UC mantenendo un’alta efficienza. In parallelo, ho portato avanti il lavoro sulle applicazioni biotecnologiche con un obiettivo diverso, il sensing raziometrico del pH intracellulare utilizzando una particolare classe di nanocristalli core/shell chiamati dot-in-bulk (DiB). Questi nanocristalli hanno un’emissione a due colori che consiste in bande di fotoluminescenza molto separate che originano dal core e dalla shell, rispettivamente. La differente esposizione degli eccitoni di core e di shell all’ambiente circostante determina una diversa sensibilità a specie ossidanti e riducenti come ioni H+ e OH-, rispettivamente. In dettaglio, il core è poco influenzato dall’ambiente, mentre per la shell vale l’opposto. Questa doppia sensibilità rende i DiB estremamente interessanti per il sensing raziometrico. Nel mio lavoro, ho dimostrato per prima cosa la sensibilità al pH in soluzione. Verificata la non tossicità dei DiB per le cellule, questi ultimi sono stati inclusi in cellule HEK sia fissate che vive, dimostrando in entrambi i casi la possibilità di misurare una variazione di pH indotta esternamente. Questa è la prima dimostrazione di sensori di pH raziometrici a singola particella basati su nanocristalli inorganici a doppia emissione.
My PhD was mainly focused on efficient materials for photon managing in several applications. The major topic I dealt with during my thesis was the development and the characterization of photonic crystals based on novel, extremely high refractive index materials. As a parallel project, my focus was the development of materials for biological applications such as high contrast, anti-Stokes imaging and ratiometric intracellular pH sensing. In detail, I worked on the nanofabrication and characterization of photonic crystals based on transition metal dichalcogenides (TMDs). In this period, I demonstrated the potential of TMDs for their applications to photonics, due to a surprisingly high refractive index in their transparency range. TMDs have some fabrication issues that limit their use in electronics and photonics. However, I demonstrated that these limitations can be lifted by converting the corresponding pre-processed transition metal oxide by annealing it at high temperatures in presence of a chalcogenizing agent. The synthesis of the transition metal oxide was performed with atomic layer deposition, a powerful thin film growth technique that allows for extreme control on thickness and perfect conformality over any substrate. In this work I demonstrated the possibility to overcome strong fabrication constraints for TMDs by producing, characterizing and modeling TMD-based photonic crystals. To my knowledge, this is the first example of nanofabricated structures for photonics made with TMDs. My work on photon managing techiniques continued shifting focus towards biotechnological applications. Specifically, I carried on a project I dealt with during my master thesis that was targeted at the development of high efficiency materials for sensitized triplet-triplet annihilation based up-conversion (TTA-UC) in multicomponent organic systems. Briefly, TTA-UC is a technique that allows for the generation of a high energy light starting from a lower energy excitation. It has great interest in solar energy, but recently it is under the spotlight for its potential as anti-Stokes, high contrast fluorophore for biological imaging. However, TTA-UC biocompatibility is still under investigation because of poor water-solubility of the most efficient materials. In my work, this issue was tackled and solved by developing self-assembled nano-micelles loaded with a model TTA-UC chromophore pair. This approach preserves TTA-UC performances in water and biological media. In parallel, I carried on the work on biological applications of photon managing techniques for a different target, the sensing of intracellular pH with a particular class of core/shell engineered heterostructured nanocrystals called Dot-in-Bulk (DiB). These nanocrystals feature a dual color emission consisting in well separated red and green bands originating from core and shell, respectively. The different exposure to the environment of core and shell determines a different sensitivity to oxidative and reductive species as H+ and OH- ions, respectively. Specifically, the core is weakly affected by the environment, while the opposite is true for the shell. This double sensitivity makes DiB extremely promising for ratiometric pH sensing. In this work, pH sensitivity was first demonstrated in solution. Then, DiB were internalized in human embrionic kidney (HEK) cells. Importantly, viability tests showed no cytotoxicity, demonstrating good biocompatibility for DiB nanocrystals. After the internalization into HEK cells, I was able to track an externally induced modification to cellular pH, demonstrating for the first time a single particle, fully inorganic ratiometric pH sensor based on a dual color emitting structure.

Proper functioning of brain critically depends on cerebral blood inflow and outflow. Moreover, the venous contribution in auto-regulation function and maintaining pressure and blood flow balance in body organs such as brain has been highlighted. Auto-regulating mechanism and cerebral circulation are influenced by many biophysical factors such as aging, posture and gravitational pressure change, and vessel stenosis. Therefore, it is important to gain a satisfactory understanding of physiological and biomechanical properties of the venous system and the interaction between intra- and extracranial compartments under different physiological conditions. For what concerns congenital vascular disease is one of the known leading causes of death in paediatric age. Despite the importance of paediatric haemodynamics, large investigations have been devoted to the evaluation of circulation in adults. The novelties of this study consist in the development of a well calibrated mathematical model of cardiovascular circulation in paediatric subjects as well as adults, simulating the full range posture change effects on hemodynamic physiology from head down tilt to supine and upright, predicting the flow rate change in main neck arteries and veins in microgravity environment, and the IJV asymmetric stenosis (followed by head rotation) effects on the head and neck hemodynamic alteration. The model consists of two parts that simulates the arterial (1D) and brain and venous (0D) vascular tree. The cardiovascular system is built as a network of hydraulic resistances and capacitances to properly model physiological parameters like total peripheral resistance, and to calculate vascular pressure and the related flow rate at any branch of the tree. This dissertation presents the results of the scientific work developed in collaboration with the paediatric hospital of Sant Joan de Déu ,Spain. A data set was provided including information about human vessels network anatomy, blood rheology (blood velocity and flow), vessel status, venous biomechanics factors (inner pressure and wall shear stress) and also volunteers characteristics (age, respiratory rate, bloop pressure and clinical reason of their MRI scan). The model presented here was tuned by using two different MRI datasets. We benefited from the use of 2D and 4D PC-MRI techniques. Results show that the model is able to reproduce the physiological behavior of IJVs and other collateral veins, with average values in good agreement with experimental data of supine paediatric and adult subjects. Physiological age-related parameters were used to adjust left ventricle pressure pulse and cerebral blood flow for paediatrics. Every simulated data fell inside the standard error from the corresponding average experimental value. The model outcomes indicated about 88% correlation with MRI data. Concerning the head rotation effects simulation, the conductance of left IJV was decreased to model the imposed stenosis influenced by torsion-compression force. MR image acquisition and numerical simulation were performed in two situations: the neutral and 80 degree left head rotation. Flow rate and wall shear stress analysis within IJVs demonstrated a strong interindividual dependency. Concerning the posture change and microgravity study, the model in line with literature confirmed the role of peripheral veins in regional blood redistribution during posture change from supine to upright and microgravity environment as hypothesized in literature. Therefore, model outcomes are in excellent agreement with experimental average flows and literature. The methods presented can be used to predict the response of the hemodynamic system in many other physiological and pathological conditions in both paediatric and adult cases. It also provides a virtual laboratory to examine the consequence of a wide range of orthostatic stresses on haemodynamics.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior
In this work, spoke about the importance of image compression for the industry, it is known that processing and image storage is always a challenge in petrobr?s to optimize the storage time and store a maximum number of images and data. We present an interactive system for processing and storing images in the wavelet domain and an interface for digital image processing. The proposal is based on the Peano function and wavelet transform in 1D. The storage system aims to optimize the computational space, both for storage and for transmission of images. Being necessary to the application of the Peano function to linearize the images and the 1D wavelet transform to decompose it. These applications allow you to extract relevant information for the storage of an image with a lower computational cost and with a very small margin of error when comparing the images, original and processed, ie, there is little loss of quality when applying the processing system presented . The results obtained from the information extracted from the images are displayed in a graphical interface. It is through the graphical user interface that the user uses the files to view and analyze the results of the programs directly on the computer screen without the worry of dealing with the source code. The graphical user interface, programs for image processing via Peano Function and Wavelet Transform 1D, were developed in Java language, allowing a direct exchange of information between them and the user
Neste trabalho, apresenta-se a import?ncia da compress?o de imagens para a ind?stria de petr?leo, sabe-se que o processamento e armazenamento de imagens ? sempre um desafio nas grandes empresas de petr?leo, para otimizar o tempo de armazenamento e armazenar um n?mero m?ximo de imagens e dados. ? exposto algumas ferramentas para o processamento e armazenamento de imagens no dom?nio wavelet. A proposta apresentada baseia-se na Fun??o de Peano e na transformada wavelet 1D. O sistema de armazenamento tem como objetivo a otimiza??o do espa?o computacional, tanto para o armazenamento como para transmiss?o de imagens. Sendo necess?rio para isso, a aplica??o da Fun??o de Peano para linearizar as imagens com m?xima concentra??o de pontos vizinhos e a transformada wavelet 1D para decomp?-la. Estas aplica??es permitem extrair informa??es relevantes para o armazenamento de uma imagem com um menor custo computacional e com uma margem de erro muito pequena quando se compara as imagens, original e processada, ou seja, h? pouca perda de qualidade ao aplicar o sistema de processamento apresentado. Os resultados obtidos a partir das informa??es extra?das das imagens s?o apresentados numa interface gr?fica. ? atrav?s da interface gr?fica que o usu?rio visualiza as imagens e analisa os resultados do programa diretamente na tela do computador sem a preocupa??o de lidar com os c?digos fontes. A interface gr?fica, os programas de processamento de imagens via Fun??o de Peano e a TransformadaWavelet 1D foram desenvolvidos em linguagem java, possibilitando uma troca direta de informa??es entre eles e o usu?rio

The overall aim of this thesis was to develop improvements for 3D dosimetry system, based on Fricke solution, in order to achieve accurate 3D absorbed dose distributions by means of visible light transmittance analysis. Such a system would represent a useful tool for 3D treatment planning verification. In particular, the main objectives were: To make a Fricke gel dosimeter selecting proper gelling substance and optimizing gel quantity according to the dosimeter response. To develop a Fricke gel dosimeter preparation protocol in order to establish an optimal elaboration process. To evaluate the characteristics of the Fricke gel dosimeter for dose distribution measurements. To reduce the uncertainties in dose distribution determination using Fricke gel dosimeters. To study the diffusion properties of the Fricke gel dosimeter, allowing a comparison with alternative non-diffusive polymer gel.

Nel migliorare la diagnosi precoce del tumore al seno, a partire dal 2006, è attivo a Trieste uno studio clinico che utilizza la luce di sincrotrone come sorgente di raggi x per eseguire l’esame mammografico (Castelli and et al., 2011). Il sincrotrone Elettra (situato sull’altopiano carsico di Basovizza, Trieste) ospita infatti una facility per l’esecuzione dell’esame mammografico lungo la linea di luce SYRMEP (SYnchrotron Radiation for MEdical Physics). A partire dal 2013 è attivo il progetto SYRMA-CT (finanziato dall’Istituto Nazionale di Fisica Nucleare) che ha come principale obbiettivo quello di attuare il primo studio clinico di Breast Computed Tomography con luce di sincrotone. Il progetto SYRMA-CT (SYnchrotron Radiation for MAmmograpy - Computed Tomography) si inserisce nel trend globale di passaggio dalle immagini 2D a quelle 3D e ingloba al suo interno l’esperienza maturata durante la sperimentazione clinica del programma di Mammografia con la Radiazione di Sincrotrone (MSR). Scopo del presente lavoro di dottorato è quello di estendere la grandezza utilizzata per il calcolo della dose in breast-CT (i.e. Mean Glandular Dose, MGD) alla particolare situazione dell’esame con luce di Sincrotrone. L’esame prevede infatti una situazione di irraggiamento parziale dell’organo (da 3 cm fino ad un massimo di 5 cm) e l’utilizzo di una sorgente monocromatica. Nel corso del lavoro di tesi è stato sviluppato un codice di simulazione Monte Carlo basato sul toolkit GEANT4 che permettesse di calcolare i coefficienti necessari per la stima della dose (DgNct ). Il codice è stato validato confrontandolo sia con la letteratura che con specifiche misure sperimentali alla linea di luce SYRMEP. Due grandezze (che estendono il concetto di MGD) per la stima della dose sono state proposte (Mettivier et al., 2016): MGDt (che tiene conto della dose dovuta alla radiaizone diffusa all’esterno della zona irragiata) e MGDv (che considera solo la dose nella regione irraggiata dell’organo). Il codice sviluppato è inoltre utilizzato per l’ottimizzazione dei parametri energetici che saranno alla base del protocollo d’esame da sottoporre al comitato etico. Sono in fase di studio le distribuzioni di dose che tengono conto delle diverse modalità di ir- raggiamento (quali spiral-CT, irraggiamento di tipi step and go, etc.) nonchè la possibilità di stimare le dosi post-exam attraverso l’ implementazione all’interno del codice delle immagini delle pazienti stesse ottenute durante l’esame.

In this thesis we present the R&D of a Compton Camera (CC) for small object imaging. The CC concept requires two detectors to obtain the incoming direction of the gamma ray. This approach, sometimes named ``Electronic Collimation,'' differs from the usual technique that employs collimators for physically selecting gamma-rays of a given direction. This solution offers the advantage of much greater sensitivity and hence smaller doses. We propose a novel design, which uses two similar Position Sensitive Photomultipliers (Hamamatsu 8500) coupled to different scintillators (one plastic and one inorganic). Assets of just one kind of detector are the simplicity of design and operation. Along the experimental apparatus we present our original algorithm for image reconstruction, that was tested with a Geant4 Monte Carlo code. Employed on experimental data, we obtained a resolution of 6 mm, which is suitable for small animal imaging (such as rats or rabbits) and for small human organs imaging (thyroid and prostate). The prototype was designed to be a compact modular element that can be extended placing more similar detectors side by side
In questa tesi presentiamo il lavoro di ricerca e sviluppo di una Camera Compton (CC) per imaging di piccoli oggetti. Le CC richiedono l'utilizzo di due rivelatori per ottenere la direzione d'incidenza di raggi gamma. Questo approccio, talvolta chiamato ``Collimazione Elettronica,'' si differenzia dalle tecniche usuali che utilizzano collimatori per selezionare fisicamente i raggi gamma di una certa direzione. Questa soluzione offre il vantaggio di una sensibilità maggiore e quindi di dosi inferiori. Proponiamo qui un nuovo sistema, che usa due similari Fotomoltiplicatori sensibili alla posizione (Hamamatsu 8500) accoppiati a differenti scintillatori (uno in plastica ed uno inorganico). Avere un solo tipo di rivelatore comporta una maggiore semplicità di progettazione ed utilizzo. Assieme all'apparato sperimentale, presentiamo il nostro algoritmo originale per la ricostruzione d'immagini, che è stato testato con un codice Monte Carlo scritto con Geant4. Applicando l'algoritmo ai dati sperimentali, abbiamo ottenuto una risoluzione di 6 mm, che è adatta all'imaging di piccoli animali (quali ratti e conigli) e per piccoli organi umani (tiroide e prostata). Il prototipo è stato sviluppato per per essere un elemento modulare compatto, che può essere esteso affiancando altri rivelatori simili

Thesis (Honors paper)--Florida State University, 2009.
Advisor: Dr. Samuel Grant, Florida State University, College of Engineering, Dept. of Biomedical Engineering. Includes bibliographical references.

Myelin is a biological structure present in all the gnathostomata. It is a highly- ordered structure, in which many lipid-enriched and densely compacted phospho- lipid bilayers are rolled up in a cylindrical symmetry around a subgroup of axons. The myelin sheath increases the electrical transverse resistance and reduces the ca- pacitance making the saltatory conduction of action potentials possible and therefore leading to a critically improved performance in terms of nervous impulse conduc- tion speeds and travel lengths. Myelin pathologies are a large group of neurological diseases that often result in death or disability. In order to investigate the main causes of myelin damage and its temporal progression many microscopy techniques are currently employed, such as electron microscopy and histochemistry or fluorescence imaging. However, electron microscopy and histochemistry imaging require complex sample prepara- tion and are therefore unsuitable for live imaging. Fluorescence imaging, as well as its derivatives, confocal and two-photon imaging, relies on the use of fluorescent probes to generate the image contrast but fluorophores and the associated sample processing, when applicable to living specimens, might nonetheless modify the bi- ological properties of the target molecule and perturb the whole biological process under investigation; moreover, fluorescent immunostaining still requires the fixation of the cells. Coherent anti-Stokes Raman Scattering (CARS) microscopy, on the other hand, is a powerful and innovative imaging modality that permits the study of liv- ing specimens with excellent chemical contrast and spatial resolution and without the confounding and often tedious use of chemical or biological probes. This is par- ticularly important in clinical settings, where the patient biopsy must be explanted in order to stain the tissue. In these cases it may be useful to resort to a set of label-free microscopy techniques. Among these, CARS microscopy is an ideal tool to investigate myelin morphology and structure, thanks to its abundance of CH2 bonds. The chemical selectivity of CARS microscopy is based on the properties of the contrast-generating CARS process. This is a nonlinear process in which the energy difference of a pair of incoming photons (“pump” and “Stokes”) matches the energy of one of the vibrational modes of a molecular bond of interest. This vibrational excited state is coherently probed by a third photon (“probe”) and anti-Stokes radi- ation is emitted. In this thesis I shall discuss the development of a multimodal nonlinear opti- cal setup implementing CARS microscopy together with general Four-Wave Mix- ing, Second Harmonic Generation and Sum Frequency Generation microscopies. Moreover, I shall present a novel polarisation-resolved imaging scheme based on the CARS process, which I named Rotating-Polarisation (RP) CARS microscopy and implemented in the same setup. This technique, using a freely-rotating pump-and- probe-beam-polarisation plane, exploits the CARS polarisation-dependent rules in order to probe the degree of anisotropy of the chemical-bond spatial orientations inside the excitation point-spread function and their average orientation, allowing at the same time the acquisition of large-field-of-view images with minimal polarisa- tion distortions. I shall show that RP-CARS is an ideal tool to investigate the highly- ordered structure of myelinated nervous fibres thanks to the strong anisotropy and symmetry properties of the myelin molecular architecture. I shall also demonstrate that this technique allows the fully label-free assessment of the myelin health status both in a chemical model of myelin damage (lysophos- phatidylcholine-exposed mouse nerve) and in a genetic model (twitcher mouse) of a human leukodystrophy (Krabbe disease) while giving useful insights into the pathogenic mechanisms underlying the demyelination process. I shall also discuss the promises of this technique for applications in optical tractography of the nerve fibres in the central nervous system and for the investigation of the effects of ageing on the peripheral nervous system. Moreover, I shall demonstrate by means of numer- ical simulations that RP-CARS microscopy is extremely robust against the presence of scatterers (such as lipid vesicles, commonly found in the peripheral nervous sys- tem). Finally, I shall discuss the results of the exploitation of my multimodal setup in a different area at the boundary of biophysics and nanomedicine: the observation of the internalization of different kinds of nanoparticles (boron-nitride nanotubes, barium-titanate nanoparticles and barium-titanate-core/gold-shell nanoparticles) by cultured cells and the demonstration of the nanopatterned nature of a structure built with two-photon lithography.

Proton therapy is a recent type of radiotherapy that uses high-energy proton beams, and more recently carbon ion beams, to benefit of their physical selectivity. The energy deposited by these particle beams is inversely proportional to their velocity. Therefore they release most of the energy at the end of their path into the tissue. The energy is deposited in a few millimeters, in a zone called the Bragg peak. Before and after the Bragg peak the energy deposition is minimal. The depth and the width of the Bragg peak depends on the beam energy and on the density of tissues located along the beam path. By setting the beam energy, the Bragg peak can be positioned in the tumor site, avoiding the healthy tissues. Because of the sharpness of the Bragg peak zone, proton therapy is advantageous for tumors located near to important body part, such as the brain, spine, and neck. The drawback is that small uncertainties on particle range can have a serious impact on treatment and limit the efficiency of the proton therapy. To obtain more effective treatments in proton therapy real-time range verifications are necessary to perform on-line corrections of the delivered treatment. Among different techniques presented in the literature, positron emission tomography (PET) and prompt gamma imaging (PGI) are the most promising methods for in vivo range verification. PET and PGI are indirect approaches to measure protons penetration depth inside patients because they aim to detect secondary particles resulting from the interaction between proton beams and tissue nuclei. PET imaging detects coincidence gamma rays due to the production of positron emitters and requires some minutes to achieve enough statistics to have a sufficient signal to noise ratio. PGI instead uses prompt gamma rays generated by de-excitation of target nuclei; the quantity of these rays and their temporal emission (few nanoseconds) allow to perform a range verification during treatment with the PGI. Several research groups are evaluating different approaches to realize a prompt gamma imaging system suitable for the use in clinical condition and the optimization of a gamma-ray detector for PGI is still ongoing. The Gammarad project works in this direction and aims to develop an high-performance and solid-state gamma ray detection module (GDM) with a slit camera design. The project is based on a collaboration among Fondazione Bruno Kessler (FBK, Trento, Italy), Politecnico di Milano (Milano, Italy), the Trento Institute for Fundamental Physics and Applications (TIFPA, Trento, Italy ), and the Proton Therapy Center of Trento (Italy). The project is divided into two parts. The first part focuses on the technological development of a gamma-ray imaging module. This module is composed by a gamma-ray detector, based on a solid-state silicon sensor, and an integrated circuit. They are assembled into a compact module with data and control systems. The second part of the project will be dedicated to the experimental validation of the system both in laboratory with radioactive sources and in a real environment, that of proton therapy. The most innovative part of the gamma-ray detector developed for the project is the photo-sensor used for the scintillation light readout. In traditional applications it is a photomultiplier tube (PMT). However, in recent years, Silicon Photomultiplier (SiPM) has become increasingly popular in a variety of applications for its promising characteristics. Among them, current-generation SiPMs offer high gain, high Photon Detection Efficiency (PDE), excellent timing performance, high count-rate capability and good radiation hardness. Due to these characteristics they are used as PMTs replacement in several applications, such as in nuclear medicine (PET), in high-energy physics (calorimeters), astrophysics (Cherenkov telescopes) and in others single-photon or few-photon applications. For its characteristics, the SiPM is also very promising for the scintillator readout in prompt gamma imaging and in high energy gamma-ray spectroscopy. Detectors for these applications must be compact, robust, and insensitive to the magnetic field. They have to provide high performance in terms of spatial, temporal, and energy resolution. SiPMs can satisfy all these requirements but typically they have been used with relatively low energy gamma rays and low photon flux, so manufacturers have optimized them for these conditions. Because of the limited number of micro-cells in a standard SiPM, 625 cells/mm^2 with 40 µm cells, the detector response is non-linear in high energies condition. Increasing the cell density is extremely important to improve the linearity of the SiPM and to avoid the compression of the energy spectrum at high energies, which worsens the energy resolution and makes difficult the calibration of the detector. On the other hand, small cells provide a lower Photon Detection Efficiency (PDE) because of the lower Fill Factor (FF) and as a consequence a lower energy resolution. Summarizing, the energy resolution at high energies is a trade-off between the excess noise factor (ENF) caused by the non-linearity of the SiPM and the PDE of the detector. Moreover, the small cell size provides an ultra-fast recovery time, in the order of a few of nanosecond for the smallest cells. A short recovery time together with a fast scintillator such a LYSO, reduces pile-up in high-rate applications, such as PGI. Based on the above considerations, the aim of this thesis is to develop an optimized gamma-ray detector composed of SiPMs for high-dynamic-range application, such as the scintillation light readout in prompt gamma imaging and in high-energy gamma-ray spectroscopy. SiPMs evaluated for the detector are High-Density (HD) and Ultra-High-Density (UHD) SiPM technologies recently produced at Fondazione Bruno Kessler (FBK). Instead of standard SiPMs, HD and UHD SiPMs have a very small micro-cell pitch, from 30 µm down to 5 µm with a cell density from 1600 cells/mm^2 to 46190 cells/mm^2, respectively. HD SiPMs are produced using a lithography technology with smaller critical dimensions and designed with trenches among SPADs. Small cells have a lower gain which helps to reduce correlated noise, such as After-Pulse and Cross-Talk. Trenches provide an optical and electrical cell isolation, and a smaller dead border around cells which increase the FF limiting PDE losses. UHD SiPMs push the limits of the HD technology even further, by reducing all the feature sizes, such as contacts, resistors and border region around cells. UHD SiPMs have hexagonal cells in a honeycomb configuration which generate a circular active area and a dead border around cells lower than 1 µm. The reduction of this dead boarder can improve the FF in smaller cells although it usually decrease with cell sizes. It is necessary understand how these significant layout changes affect the optical properties of SiPMs to evaluate which SiPM technology provides best performance in high-energy gamma-ray applications. In the first part of the thesis, I presents the characterization of HD and UHD SiPM technologies in terms of PDE, gain, Dark Count Rate, and correlated noise for the cell sizes between 30 and 7.5 µm. The most important markers of SiPMs performance in gamma-ray spectroscopy are however the energy resolution and the linearity when coupled to the scintillator for the detection of high-energy gamma-rays. A typical characterization of the energy resolution of SiPMs, coupled to scintillator crystals, is performed with radioactive source up to 1.5 MeV. However, PGI features gamma ray-energies up to 15 MeV which are not easily provided by the usual laboratory calibration sources. Extrapolating the behaviour of the detector from the "low" energy data is not correct and leads to unreliable data for calibration and performance estimation. Therefore, I developed a novel setup that simulates the LYSO light emission in response to gamma photons up to 30 MeV. A LED (emitting at 420 nm) is driven by a pulse generator, emulating the light emitted by a LYSO scintillator when excited by gamma rays. The pulse generator parameters (amplitude, duration, rise and fall time constants) are adjusted so that the LED emitted photons match the intensity and time distribution of the LYSO emission. The photon number in each light pulse is calibrated from the measurements at 511 keV obtained with a ^(22)Na source and a LYSO crystal coupled to the SiPMs. Using this LED setup I characterized the energy resolution and non-linearity of HD and UHD SiPMs in high-energy gamma-ray conditions. The second part of the thesis provides a detailed description of the scintillator setup and of the setup for the simulation of high-energy gamma-ray response, followed by the results of the characterization performing with these setups. Summarizing the results, the lowest non-linearity is provided by the technology with highest cell density, the RGB-UHD. For the 10 and 12.5 µm-cells we obtained values of 4.5% and 5% respectively at 5 MeV and 6 V over-voltage. On the other hand, we measured the best energy resolution of 2.6% and 2.3% at 5 MeV for the largest SiPM cells of 20 and 25 µm respectively, without the intrinsic term of the scintillator crystal and at 6 V over-voltage. This is due to the dependence of the energy resolution on the photon detection efficiency, which increases with the size of the SiPM cell. The optimal performance of the detector in high-dynamic-range applications, which depends on the several SiPM parameters, such as excess noise factor, photon detection efficiency, and cell sizes of the SiPM, is a trade off between non-linearity and energy resolution. At 5 MeV, the best trade-off for prompt gamma imaging application is reached by the 15 µm-cell. At 10 MeV the 12.5 µm-cell provides the best trade-off, because of the higher number of photons emitted by the scintillator. Furthermore, I distinguish the different components of the energy resolution (intrinsic, statistical, detector and electronic noise) as a function of cell sizes, over-voltage and energy, thanks to the combination of the scintillator and LED setups. The estimation of the intrinsic contribution of the scintillator crystal, coupled to the HD SiPMs, getting consistent results among the several cell sizes. On the basis of previous characterization, HD SiPMs with dimensions of 4x4 mm^2 and 15 µm-cell were chosen to produce the photo-detector module of the gamma camera, optimized for an energy range between 2 and 8 MeV. This module is a 8x8 array of SiPMs which is called tile. The production of the tile requires research on packaging techniques to solve two main challenges: the maximization of the photo-sensitive area and the application of a protective resin, transparent in the near UV to maximize light collection from the LYSO. After some R&D on packaging, I obtained a fully functional tile with 64 SiPMs with a fill factor, ratio between the photo-sensitive area and the total area, of about 86%. This fill factor is comparable to the values obtained when a Through Silicon Vias (TSVs) technique is used to connect SiPMs but without the high production cost and the additional fabrication process complexity of the TSV. It should be highlighted that packaging operations is very critical because it is necessary to produce a tile with all working SiPMs, since defective items can not be replaced in the tile. The last part of the thesis presents the packaging procedure that I have defined to produce photo-detector modules and the characterization of the photo-detector array in terms of energy resolution, position sensitive and non-linearity. The measurements on the tile were carried out jointly with the Gammarad partner of Politecnico di Milano, which provided the ASIC and DAQ for the readout. In conclusion, the R&D activity carried out during this thesis has provided to Gammarad project the final photo-detection module with state of the art performance for high-energy gamma-ray spectroscopy. The characterization of the module shows also a position sensitivity that matches with the SiPM dimensions, and a proper acquisition of high-energy gamma-ray events from 800 keV to 13 MeV. This module will be tested on beam in an experimental treatment room at the Proton therapy facility in Trento by the Gammarad project partners.

L'imaging termico foto-attivato è una tecnica largamente impiegata per la caratterizzazione non invasiva di campioni sintetici e tessuti biologici. Tuttavia, la termografia nel lontano infrarosso risulta limitata da (i) risoluzione spaziale nell'intervallo ~0.1-1 mm, a causa della diffrazione della radiazione termica e agli effetti di diffusione del calore nel campione, e (ii) la difficoltà nel convertire il segnale di temperatura in mappe quantitative delle proprietà termiche (ad esempio, la conducibilità termica) dei campioni in esame. Il mio lavoro di dottorato è stato rivolto ad affrontare e risolvere entrambe queste limitazioni. In primo luogo, è stato sviluppato un nuovo metodo di imaging foto-termico in super risoluzione. La strategia proposta sfrutta la localizzazione automatizzata di incrementi di temperatura indotti sequenzialmente sul campione e rivelati da una convenzionale termocamera. Le variazioni di temperatura, indotte dall’assorbimento di luce laser modulata da parte del campione, vengono localizzate a posteriori mediante un fit gaussiano bidimensionale delle immagine termiche acquisite. L'immagine in super-risoluzione viene infine ricostruita a posteriori sfruttando le coordinate del centro e le ampiezze di tutti i picchi di temperatura rivelati. Poiché la precisione di localizzazione degli incrementi di temperatura risulta limitata solo dal rapporto segnale-rumore delle immagini termografiche, la risoluzione spaziale dell'immagine finale può essere ridotta fino a ~1 μm, corrispondente al limite diffrattivo per la dimensione dello spot laser di eccitazione con lunghezza d'onda visibile. A seguito della validazione sperimentale della tecnica su campioni di riferimento, l’imaging foto-termico in super-risoluzione è stato applicato alla ricostruzione, in modalità label-free, della distribuzione spaziale dei pigmenti di melanina in biopsie di melanoma murino. Le immagini termiche di intere sezioni di tessuto sono state convertite in mappe quantitative della concentrazione molare assoluta dei pigmenti di melanina sfruttando i risultati di simulazioni agli elementi finiti e la soluzione analitica/numerica dell’equazione del calore in tre dimensioni in presenza di illuminazione laser modulata. Parallelamente, lo sviluppo della termografia in super risoluzione è stato ulteriormente esteso alla quantificazione della conducibilità termica del campione. Partendo dalla legge di Fourier, ho dimostrato che la risposta termica di un campione sottoposto ad illuminazione laser modulata dipende esclusivamente dallo spessore e dalla conducibilità termica, indipendentemente dalla diffusività. Tale dipendenza è stata dimostrata su tre ordini di grandezza di conducibilità (0.1-100 W/mK) mediante simulazioni agli elementi finiti, ed è stata sfruttata per la misura della conducibilità termica di campioni di riferimento di spessore variabile. La possibilità di risalire a mappe spaziali della conducibilità è stata dimostrata poi su frammenti di canne d'organo in stagno del XVIII secolo, dove il prodotto della conducibilità termica e dello spessore del campione, quantificato con risoluzione sub-diffrattiva di 40 μm, è stato identificato come un parametro rilevante per la caratterizzazione non invasiva dello stato di conservazione del campione. Combinando le immagini in temperatura con l'estrazione di proprietà termiche ad alta risoluzione spaziale, i risultati di questo lavoro di tesi espandono significativamente le potenzialità delle attuali tecniche di termografia attivata nel caratterizzare quantitativamente l'eterogeneità strutturale e la composizione dei campioni in esame.
Active photo-thermal imaging is a valuable tool for the nondestructive characterization of biological tissues and inorganic materials. Still, far-infrared thermography suffers from (i) typically limited spatial resolution in the ~0.1-1 mm range, due to both light diffraction and heat diffusion effects, and (ii) a difficult conversion of temperature images into quantitative maps of any thermal property (e.g., the thermal conductivity) of the imaged samples. Both these limitations have been tackled during my doctoral work. First, I have focused on the development of a novel super-resolution photo-thermal imaging method. The strategy exploits the automated sub-diffraction centroid localization of sparse temperature increments primed by modulated raster-scanned laser light. The super-resolution image of the light-absorbing centers in the sample is reconstructed by the localized centers and amplitudes of all the temperature peaks imaged by a thermal camera. Provided the fit localization precision is only limited by the shot-noise of thermal emission, the spatial resolution of the rendered image can in principle be tuned down to the ~1 μm diffraction-limited laser spot size at the excitation visible wavelength. Upon experimental validation on reference samples, the application of such an approach has been directed towards the label-free reconstruction of the spatial distribution of melanin pigments in murine melanoma biopsies. Temperature-based images of whole tissue sections have been converted into quantitative maps of the absolute molar concentration of melanin pigments based on the necessary theoretical framework that I have derived by the combination of finite-element simulations with the analytical/numerical solution of the 3D heat equation in the presence of modulated laser illumination. In parallel, the development of super-resolution thermography has been extended to the space-resolved quantification of absolute thermal conductivity values. Starting from Fourier’s law, I have surmised a universal dependence of the thermal response of a laser-irradiated sample on its thickness and thermal conductivity, irrespective of the thermal diffusivity. Such a dependence has been demonstrated over the conductivity decades 0.1-100 W/mK by finite-element simulations, and it has been exploited for proof-of-principle thermal conductivity measurements on thermally thick and thin solid samples. The feasibility of space-resolved measurements has been validated on eighteenth-century tin organ pipe fragments, where the product of the thermal conductivity times the sample thickness, imaged at 40-μm sub-diffraction resolution, has been pointed out as a relevant parameter for the non-destructive characterization of the sample conservation state. By coupling temperature maps with the extraction of thermal properties at high spatial resolution, the results significantly expand the capability of state-of-the-art infrared imaging technology in capturing the structural heterogeneity of the imaged materials.

Depuis le milieu du XXème siècle, les techniques d’imagerie fonctionnelles ont un rôle grandissant dans notre compréhension sur les fonctions du cerveau en conditions physiologique et pathologique. Bien que l’IRMf fasse partie des techniques les plus communément utilisées pour l’imagerie du cerveau complet lors d’études préclinique et clinique, cette modalité souffre de sa résolution spatiotemporelle et sa sensibilité pour enregistrer finement les fonctions et activités cérébrales. Récemment l’imagerie fonctionnelle par ultrason (ifUS) a subi des développements permettant d’être complémentaires à l’IRMf ainsi qu’aux autres techniques d’imagerie cérébrales classiquement employées. Contrairement aux ultrasons focalisés conventionnels, l’imagerie hémodynamique proposé par l’ifUS repose sur une illumination ultrasonore plane permettant la détection des globules rouges en mouvement et la mesure de leur vitesse dans les micro-vaisseaux cérébraux. De ce fait, l’ifUS est indirectement lié à l’activité cérébrale d’où l’importance d’une meilleure compréhension des mécanismes du couplage neuro-vasculaire liant l’activité neuronale et les variations cérébrales d’apport en sang. De plus, cette technique a le potentiel pour fournir des informations précises sur les processus de certaines pathologies à la fois sur des modèles précliniques et chez l’homme. Dans un premier temps, j’exposerais mes travaux sur les récents développements techniques permettant l’ifUS in vivo (i) en condition chronique, (ii) sur l’animal éveillé, libre de mouvement et effectuant une tache comportementale et (iii) des vaisseaux capillaires chez le rongeur et l’homme. Dans un second temps, je démontrerais que l’ifUS in vivo peut fournir des informations nouvelles sur des pathologies telles que l’accident vasculaire cérébrale
Since the middle of the 20th century, functional imaging technologies are making an increasing impact on our understanding on brain functions in both physiological and pathological conditions. Even if fMRI is nowadays one of the most used tool for whole brain imaging in pre-clinical and clinical studies, it lacks sufficient spatiotemporal resolution and sensitivity to assess fine brain function and activity. Functional ultrasound imaging (fUSi) has been recently developed and presents a potential to complement fMRI and other existing brain imaging modalities. Contrary to conventional ultrasound using focus beams, fUSi relies on hemodynamic imaging based on ultrasound plane-wave illumination to detect red blood cells movement and velocity in brain micro-vessels. Consequently, the fUSi signal is indirectly related to brain activity and it is therefore important to better understand the mechanisms of the neurovascular coupling linking neural activity and cerebral blood changes. Here again, fUSi may provide relevant information about disease processes in preclinical models but also in humans. First, I will present recent technical developments allowing in vivo fUSi (i) in chronic condition, (ii) in freely moving and behaving rats and (iii) in rodents and human brain capillaries. Second, I will demonstrate how fUSi could provide new insights in brain pathologies such as stroke

In this thesis the use of widefield imaging techniques and VLBI observations with a limited number of antennas are explored. I present techniques to efficiently and accurately image extremely large UV datasets. Very large VLBI datasets must be reduced into multiple, smaller datasets if today’s imaging algorithms are to be used to image them. I present a procedure for accurately shifting the phase centre of a visibility dataset. This procedure has been thoroughly tested and found to be almost two orders of magnitude more accurate than existing techniques. Errors have been found at the level of one part in 1.1 million. These are unlikely to be measurable except in the very largest UV datasets. Results of a four-station VLBI observation of a field containing multiple sources are presented. A 13 gigapixel image was constructed to search for sources across the entire primary beam of the array by generating over 700 smaller UV datasets. The source 1320+299A was detected and its astrometric position with respect to the calibrator J1329+3154 is presented. Various techniques for phase calibration and imaging across this field are explored including using the detected source as an in-beam calibrator and peeling of distant confusing sources from VLBI visibility datasets. A range of issues pertaining to wide-field VLBI have been explored including; parameterising the wide-field performance of VLBI arrays; estimating the sensitivity across the primary beam both for homogeneous and heterogeneous arrays; applying techniques such as mosaicing and primary beam correction to VLBI observations; quantifying the effects of time-average and bandwidth smearing; and calibration and imaging of wide-field VLBI datasets. The performance of a computer cluster at the Istituto di Radioastronomia in Bologna has been characterised with regard to its ability to correlate using the DiFX software correlator. Using existing software it was possible to characterise the network speed particularly for MPI applications. The capabilities of the DiFX software correlator, running on this cluster, were measured for a range of observation parameters and were shown to be commensurate with the generic performance parameters measured. The feasibility of an Italian VLBI array has been explored, with discussion of the infrastructure required, the performance of such an array, possible collaborations, and science which could be achieved. Results from a 22 GHz calibrator survey are also presented. 21 out of 33 sources were detected on a single baseline between two Italian antennas (Medicina to Noto). The results and discussions presented in this thesis suggest that wide-field VLBI is a technique whose time has finally come. Prospects for exciting new science are discussed in the final chapter.

In this thesis the use of widefield imaging techniques and VLBI observations with a limited number of antennas are explored. I present techniques to efficiently and accurately image extremely large UV datasets. Very large VLBI datasets must be reduced into multiple, smaller datasets if today’s imaging algorithms are to be used to image them. I present a procedure for accurately shifting the phase centre of a visibility dataset. This procedure has been thoroughly tested and found to be almost two orders of magnitude more accurate than existing techniques. Errors have been found at the level of one part in 1.1 million. These are unlikely to be measurable except in the very largest UV datasets. Results of a four-station VLBI observation of a field containing multiple sources are presented. A 13 gigapixel image was constructed to search for sources across the entire primary beam of the array by generating over 700 smaller UV datasets. The source 1320+299A was detected and its astrometric position with respect to the calibrator J1329+3154 is presented. Various techniques for phase calibration and imaging across this field are explored including using the detected source as an in-beam calibrator and peeling of distant confusing sources from VLBI visibility datasets. A range of issues pertaining to wide-field VLBI have been explored including; parameterising the wide-field performance of VLBI arrays; estimating the sensitivity across the primary beam both for homogeneous and heterogeneous arrays; applying techniques such as mosaicing and primary beam correction to VLBI observations; quantifying the effects of time-average and bandwidth smearing; and calibration and imaging of wide-field VLBI datasets. The performance of a computer cluster at the Istituto di Radioastronomia in Bologna has been characterised with regard to its ability to correlate using the DiFX software correlator. Using existing software it was possible to characterise the network speed particularly for MPI applications. The capabilities of the DiFX software correlator, running on this cluster, were measured for a range of observation parameters and were shown to be commensurate with the generic performance parameters measured. The feasibility of an Italian VLBI array has been explored, with discussion of the infrastructure required, the performance of such an array, possible collaborations, and science which could be achieved. Results from a 22 GHz calibrator survey are also presented. 21 out of 33 sources were detected on a single baseline between two Italian antennas (Medicina to Noto). The results and discussions presented in this thesis suggest that wide-field VLBI is a technique whose time has finally come. Prospects for exciting new science are discussed in the final chapter.

Coherent Diffraction Imaging (CDI) is a lens-less technique that allows imaging of matter at a spatial resolution not limited by lens aberrations. This technique exploits the measured diffraction pattern of a coherent beam scattered by periodic and non–periodic objects to retrieve spatial information. The diffracted intensity, for weak–scattering objects, is proportional to the modulus of the Fourier Transform of the object density distribution. Any phase information, needed to retrieve the sample density, has to be retrieved by means of suitable algorithms. This work presents a new approach based on Computational Intelligence, in particular on Genetic Algorithms, to face the phase retrieval problem. This new approach, called Memetic Phase Retrieval, is described, along with its implementation specifically designed and optimized for High Performance Computing hardware. Tests on both simulated and experimental data are performed, showing a remarkable performance improvement with respect to standard algorithms. Memetic Phase Retrieval proves to be a new powerful tool for the study of matter via CDI. Moreover, it represents a novelty, laying the foundations for a more extensive use of Computational Intelligence in the field of CDI and opening new perspectives in those applications in which reliable phase retrieval is necessary.

X-ray phase-contrast tomography is a powerful tool to dramatically increase the visibility of features exhibiting a faint attenuation contrast within bulk samples, as is generally the case of light (low-Z) materials. For this reason, the application to clinical tasks aiming at imaging soft tissues, as e.g., breast imaging, has always been a driving force in the development of this field. In this context, the SYRMA-3D project, which constitutes the framework of the present work, aims to develop and implement the first breast computed tomography system relying on the propagation-based phase-contrast technique at the Elettra synchrotron facility (Trieste, Italy). This thesis finds itself in the ‘last mile’ towards the in-vivo implementation, and the obtained results add some of the missing pieces in the realization of the project. The first part of the work introduces a homogeneous mathematical framework describing propagation-based phase contrast from the sample-induced X-ray refraction, to detection, processing and tomographic reconstruction. The original results reported in the following chapters include the implementation of a pre-processing procedure dedicated for a novel photon-counting CdTe detector; a study, supported by a rigorous theoretical model, on signal and noise dependence on physical parameters such as propagation distance and detector pixel size; hardware and software developments for improving signal-to-noise ratio and reducing the scan time; and, finally, a clinically-oriented study based on comparisons with clinical mammographic and histological images. The last part of the thesis attempts to widen the experimental horizon: first, a quantitative image comparison of the synchrotron-based setup and a clinically available breast-CT scanner is presented and then a practical laboratory implementation is detailed, introducing a monochromatic propagation-based micro-tomography setup making use on a high-power rotating anode source.

This PhD thesis is addressed to the technical and scientific studies carried out in the research field of very high energy (VHE, E > 100GeV) gamma-ray astronomy, a promising discipline which is extending the frontier of our knowledge of the emission by extraterrestrial sources to the highest observable energies of the electromagnetic spectrum. Radio--loud active galactic nuclei (AGNs) are astronomical objects whose emission along relativistic jets is powered by the accretion of matter onto the disk of a supermassive black hole. Depending on the orientation of their relativistic jets, radio--loud AGNs are divided into two categories, among them the so--called blazars. Such objects present one jet oriented at small angles with respect to the line of sight of an observer. To now, the majority of detected extragalactic VHE gamma-ray emitters belongs to the class of blazars. Most of such VHE gamma-ray emitters have been discovered win the last decade thanks to the operation of the current generation of IACTs represented by the MAGIC (Major Atmospheric Imaging Cherenkov) telescopes, H.E.S.S. (High Energy Stereoscopic System) and VERITAS (Very Energetic Radiation Imaging Telescope Array System). The numerous discoveries have been possible thanks to fundamental improvements in sensitivity and the extension of the energy range of these instruments with respect to their predecessors. In addition, the cooperation with instruments observing at other energies, for example in the optical regime and in the gamma-ray range below 100GeV, has emerged to be very important. Along the travel to Earth, the VHE gamma-ray emission of distant sources is attenuated due to the interaction with the extragalactic background light (EBL). This optical to infrared radiation is composed by the star light emission which is partially reprocessed by dust and continuously redshifted by the expansion of the Universe. Due to EBL absorption of VHE gamma-ray radiation, the intrinsic spectrum emitted by blazars is deformed. Such deformation scales with increasing energy of the VHE gamma-ray and with the source distance. For this reason, the AGNs detected in VHE gamma-rays are located at relative short distances. The most distant VHE gamma-ray emitter detected so far is the blazar 3C 279 located at redshift z = 0.536. This PhD thesis is focused on two research activities: a technical and a scientific part carried out within the MAGIC and CTA collaborations. The technical research is dedicated to the development of new IACT mirrors of improved optical performance and optimized price/performance ratio for future IACTs, while the scientific research concerns the detailed analysis of the VHE gamma-ray emission of two distant blazars, 1ES 0806+524 and 1ES 1011+496, observed with the MAGIC telescopes. The status of the development of new IACT mirrors for CTA is presented together with the optical qualifications of the first prototypes. In addition, a study of the reliability of such optical qualifications is reported. The observations of the VHE gamma-ray emission of 1ES 0806+524 and 1ES 1011+496 yield a detailed measure of the differential spectra which offer the possibility to probe the EBL. Finally, the MWL coverage allows a first precise SED determination.
Questa tesi di dottorato riguarda agli studi tecnici e scientifici svolti nell'ambito dell'astrofisica delle altissime energie (VHE; Very High Energy), promettente disciplina che sta estendendo la frontiera delle nostre conoscenze dell'emissione di sorgenti extraterrestri alle energie più alte osservabile dello spettro elettromagnetico spettro elettromagnetico. I nuclei galattici attivi (AGN) detti radio loud, ovvero molto brillanti nelle frequenze radio, sono degli oggetti astronomici la cui radiazione, generata tramite l'accrescimento di materia sul disco di un buco nero supermassivo, viene emessa lungo dei getti relativistiche. Sulla base dell'orientazione dei getti relativistici, AGN radio loud sono divisi in varie categorie tra le quali quella dei blazar. Tali oggetti presentano un getto orientato con degli angoli piccoli rispetto alla linea di vista dell'osservatore. Finora, blazar rappresentano la maggioranza delle sorgenti extragalattiche di emissione raggi gamma ad altissime energie osservate nell'intervallo energetico tra 100 GeV e qualche decina di TeV con i telescopi Cherenkov del tipo IACT (Imaging Atmospheric Cherenkov Telescope). La piè parte elli sorgenti di radiazione gamma VHE è stata scoperta solo negli ultimi anni grazie ai telescopi Cherenkov di nuova generazione, MAGIC (Major Atmospheric Gamma Imaging Cherenkov), H.E.S.S. (High Energy Stereoscopic System) e VERITAS (Very Energetic Radiation Imaging Telescope Array System). Ciò che ha reso possibile queste nuove scoperte sono l'alta sensitività e l'esteso intervallo energetico di questi strumenti. Inoltre, si è rivelato molto importante la cooperazione con altri strumenti che osservano a diversi intervalli di energia, tra cui l'ottico e i raggi gamma sotto i 100 GeV (HE; High Energy). Lungo il percorso verso la terra la radiazione gamma VHE emessa da una sorgente distante viene attenuata a cause dell'interazione con la cosiddetta luce di fondo extragalattica (EBL; Extragalactic Background Light). Questa radiazione ottica ed infrarossa è composta da fotoni emessi dalle stelle e riprocessati dalle polveri, la cui energia si è diluita nel tempo a causa dell'espansione dell'Universo. A cause di questo assorbimento, lo spettro intrinsico emesso dai blazar viene deformato. Tale deformazione spettrale è una funzione crescente dell'energia del fotone gamma e della distanza della sorgente. Per questo motivo, gli AGN osservati ad altissime energie hanno una distanza relativamente corta. La sorgente più lontana nota fino ad ora è il blazar 3C 279, con un redshift a z=0.536. Questa tesi di dottorato è incentrata su due attività di ricerca, una tecnica ed una scientifica, svolte in collaborazione con l'esperimento MAGIC. Mentre la ricerca tecnica è destinata allo sviluppo di nuovi specchi con elevate proprietà ottiche ed un prezzo ottimizzato per futuri telescopi Cherenkov, la ricerca scientifica riguarda le analisi dettagliate della radiazione gamma emessa da due blazar distanti 1ES 0806+524 e 1ES 1011+486 osservati da MAGIC. In conclusione, lo stato dello sviluppo di nuovi specchi per CTA è presentato insieme con le misure ottiche effettuate per i primi prototipi. Inoltre, viene riportato lo studio sull'affidabilità ti tale misure. Le osservazioni ad altissime energie delle sorgenti 1ES 0806+524 e 1ES 1011+496 hanno portato alle misure dettagliate degli spettri differenziali il che da la possibilità di studiare l'EBL. Infine, la copertura MWL permette per la prima volta la precisa determinazione delle SED.

The study of planet formation has become progressively more important in the last few years given the great number of diverse exoplanets recently discovered. It is, indeed, only by studying extrasolar planetary systems embedded in their natal (protoplanetary) discs that we can make statistical studies of the range of outcomes of the planet formation process. In particular, the discs that present a cavity (transitional discs) or a gap in the dust radial profile are related to disc clearing mechanisms by young giant planets. In this Thesis, we analyze observations taken with the most advanced telescopes (ALMA and VLT/SPHERE) combining multi-wavelength observations to discriminate between different formation processes in systems with disc sub-structures. We provide a general overview on protoplanetary discs and planets/binaries, followed by the description of dust and gas dynamics and thermal disc structure. Moreover, we describe the two most accredited scenarios of planet formation: core accretion and gravitational instability. In the second part of the Thesis, we present a work on the dust and gas cavity of the disc around CQ Tau observed with ALMA together with thermochemical models and hydro-dynamical simulations, which provide insight on a massive planet responsible for the clearing of such disc structure. Secondly, we describe an analysis done on a survey of 22 Herbig and F/G type stars imaged by SPHERE that confirms that the large near-infrared excess observed in the SEDs of Group I Herbig stars can be explained by the presence of a large gap in their discs. We spatially resolve spirals in HD 100453, HD 100546, CQ Tau; ring-like disc in HD 169142 and HD 141569; and single inclined thin disc in AK Sco and T Cha. We compare the results with ALMA and PDI observations and with simulations. Moreover, we detect and confirm the presence of a novel gravitationally bound companion to the young MWC 297 star. Finally, we describe a novel routine that exploits the known radial variation of stellar artifacts with wavelength together with the spectral slope of the star.

A novel technology for the detection of single photons has been developed and implemented in 2016 in the Ring Imaging Cherenkov (RICH) detector of the COMPASS Experiment at CERN SPS. Some basic knowledge in the field of particle identification and RICH counters, Micro Pattern Gaseous Detectors (MPGDs) in general and their development for photon detection applications are provided. The characteristics of the COMPASS setup are summarized and the COMPAS RICH-1 detector is described and shown to provide hadron identification in the momentum range between 3 and 55 GeV/c. The THGEM technology is discussed illustrating their characterization as gas multipliers and as reflective photocathodes: large gains and efficient photodetection collections are achieved when using optimized parameters and conditions (hole diameter = THGEM thickness = 0.4 mm; hole pitch = 0.8 mm and no rim; CH4-rich gas mixtures and electric field values > 1 kV/cm at the CsI surface). The intense R&D program leading to the choice of a hybrid THGEM + Micromegas architecture for the novel detectors is summarized: prototypes construction and test results are presented. The beam test performed at CERN with two 300 mm X 300 mm active area hybrid prototypes validated this new technology and allowed to demonstrate efficient detection of Cherenkov photons. The optimal design of the detector, consisting in two layers of THGEMs, the first of which is coated with 300 mm thick layer of CsI, coupled with a Micromegas on a pad segmented anode with an original design of capacitive – resistive readout is presented. All aspects of the construction, test and assembling from the raw material selection to the procedures applied for the quality assessment are described in detail. The challenges encountered during the detectors assembly, the test in the laboratory and the transportation of the chambers to CERN for the assembly and mounting are then illustrated. The production of the photocathode and the final assembly of the four hybrid detectors, covering an active area of 1.4 m^2 are presented. The adventurous installation of the combined Hybrid PDs and Multi Anode Photo Multiplier Tubes with fused silica lenses onto COMPASS RICH-1 and the work for equipping the new detectors with all needed services are presented. The description of the HV control system and of the other services is illustrated and the APV25-based frontend electronics is described together with the studies performed to understand the electronic and physical noises of the new chambers. A preliminary on-line analysis of the detector response and of the performance are presented: an indication that the average number of photons is larger than the neighboring traditional MWPC-based PDs is obtained. The success of the first MPGD-based large area photon detector operating in a physics experiment opens new perspectives in the field of single photon detection.