The blood-brain barrier BBB refers to the set of specialized endothelial cells that line the vasculature in the brain and effectively control movement of molecules into and out of the brain. While necessary for proper brain function, the BBB blocks 98% of drugs from entering the brain and is the most significant barrier to developing therapies for neurodegenerative diseases. Active transport allows some specific molecules to cross the BBB, but therapeutic development using this route has had limited success. A number of techniques have been used to bypass the BBB, but are often highly invasive and ineffective. Over the last two decades, a minimally invasive technique to transiently open the BBB has been under development that utilizes transcranial focused ultrasound (FUS) in combination with intravascular microbubble contrast agents. This method is often carried out in conjunction with magnetic resonance imaging (MRI) to guide and assess BBB opening and has been referred to as MRI guided FUS (MRgFUS). Because of the utility of mouse models of neurological disease and the exploratory nature of MRgFUS, systems that allow BBB opening in mice are a useful and necessary tool to develop and evaluate this method for clinical application. In this dissertation project, a custom built, cost-effective FUS system for opening the BBB in mice was developed, with the objective of using this device to deliver therapeutics to the brain. Being a custom device, it was necessary to evaluate the ultrasound output, verify in vivo safety, and anticipate the therapeutic effect. The scope of the work herein consists of the design, construction, and evaluation of system that fulfills these requirements. The final constructed system cost was an order of magnitude less than any commercially available MRgFUS system. At this low price point, the hardware could allow the implementation of the methodology in many more research areas than previously possible. Additionally, to anticipate the therapeutic effect, molecules of pharmacologically-relevant sizes were delivered to brain with a novel, multispectral approach. Results demonstrated that the device was able to safely open the BBB, and macromolecule delivery showed that both molecule size and FUS pressure both influence the amount and distribution of molecules in the brain. Using different ultrasound pressures, the threshold for BBB opening was found to be ≥ 180 kPa (0.13 MI). The threshold for damage was found to be ≥ 420 kPa (0.30 MI), and was minor at this pressure, but extensive for higher pressure (870 kPa, 0.62 MI), in which minor damage was caused by this pressure. Performing a novel implementation of a diffusion model on the fluorescence images of 500, 70, and 3 kDa dextran resulted in calculated diffusion coefficients of 0.032 ± 0.015, 12 ± 6.0, and 0.13 ± 0.094 square microns per second, respectively.

Nous proposons l’innovation «TR-NEWS retardée» comme une extension des méthodes TR-NEWS,issues de la symbiose du retournement temporel (RT) et des méthodes de spectroscopie d’ondes élastiques non linéaires (NEWS), avec pour principales applications le contrôle non destructif (CND) et l’imagerie ultrasonore médicale. Nous confirmons expérimentalement les bonnes performances des méthodes TR-NEWS pour : (i) des échantillons de composite CFRP aux propriétés dispersives ultrasonores autour de 10 MHz, favorisant ainsi la réverbérabilité de la propagation acoustique; (ii) des mesures de propriétés non classiques de la peau porcine par une instrumentation multi-échelles acousto-mécanique élaborée dans le cadre du projet PLET(Propriétés Locales Visco-Élastiques de la peau par TR-NEWS) financé par la Région Centre Val de Loire. via les simulations numériques 1D pseudo spectrales de propagations acoustiques non linéaires dans les CFRP, nous identifions et localisons les sources locales de défauts et de microendommagements. Elles valident l’identification d’un crack unique proche de la zone de focalisation. La non linéarité supposée de type contact acoustique (CAN),mesurée par «TR-NEWS retardée»et comparée aux techniques classiques d’inversion d’impulsion utilisées en imagerie médicale, permet une identification préservant la représentation temporelle de l’information. Ainsi, ce système d’instrumentation acousto-mécanique envisage la mesure de paramètres multi-échelles de non linéarité des tissus biologiques via les paramètres de Preisach-Mayergoyz (espaces PM) permettant de décrire leur vieillissement. Le chargement basse fréquence uniaxial (0.1-10Hz) synchronisé aux caractérisations ultrasonores haute fréquence (20MHz) via «TR-NEWS retardé» suggère une nouvelle classe de dispositifs dotée d’une perspective de multimodalité dédiée à l’imagerie ultrasonore non invasive des propriétés biomécaniques des organismes vivants. / In this thesis the possibility of nonlinear ultrasonic NDT is investigated for complex materials and biological tissues. The delayed TR-NEWS signal processing methodis developed, which is based on the TR-NEWS method. TR-NEWS is a method well-suited for materials with complex structure: it allows spatio-temporal focusing of a long ultrasonic chirp signal to the region near the receiving transducer, forming an impulse pulse. The received signal power and SNR are increased as a result.Delayed TR-NEWS allows the use of this focused wave pulse as a new basis for either the signal optimisation or, alternatively, for the detection of nonlinearity by the breakdown of linear superposition. This method is used in physical experiments and simulations. The physical experiments are made on an undamaged CFRP block and a porcine skin sample. The skin is tested in a synchronised acoustomechanical setup specially designed in the course of this thesis. In 1D pseudospectral simulations for CFRP, it is determined that while classical nonlinearity cannot probably be detected in ultrasonic NDT, it could be possible to detect nonclassical nonlinear effects such as those from cracks and microdamage.Physical experiments and 2D FEM simulations of linear, undamaged CFRP are compared for studying the delayed TR-NEWS method, its applicability in optimising the focused wave, and also for creating an interaction of waves at the focusing region with a linear superposition prediction. This suggests the possibility of detecting nonlinearities by comparing the actual signal from interaction to the linear prediction.Finally, more 2D simulations are conducted for CFRP with a single contact gap nonlinearity near the focusing region. The nonlinearity is measured by PI and delayed TR-NEWS. It is determined that delayed TR-NEWS is able to detect the defect at least as well as the PI method. It is ascertained that the PM hysteresis model could describe the nonclassical nonlinearity of damaged materials and biological tissues. Asynchronised acoustomechanical test setup is created to test such multiscale nonlinearity. The simultaneous mechanical load test and ultrasonic delayed TR-NEWS test can be used to measure the mechanical properties of skin

Les techniques de thérapie par ultrasons sont apparues très récemment avec la découverte des ultrasons de haute intensité focalisée. La thrombolyse ultrasonore extracorporelle en fait partie et se base sur la destruction mécanique du thrombus causée par la cavitation acoustique. Cependant, c'est un phénomène mal contrôlé. Ainsi, un meilleur contrôle de l'activité de cavitation et sa localisation pendant la thérapie est essentiel pour considérer le développement d'un dispositif thérapeutique. Un prototype a déjà été conçu et amélioré avec une boucle de rétroaction en temps réel afin de contrôler l'activité de puissance de cavitation. Cependant, pour surveiller le traitement en temps réel, un système d'imagerie ultrasonore doit être incorporé dans le dispositif thérapeutique. Il doit être capable de localiser le thrombus, de positionner la focale du transducteur thérapeutique, de contrôler la destruction complète du thrombus et d'évaluer en temps réel l'activité de cavitation. Le travail actuel se focalise principalement sur le développement de techniques d'imagerie ultrasonore passive utilisées pour reconstituer les cartographies d'activité de cavitation. Différents algorithmes de formation de voies ont été examinés et validés par des simulations de sources ponctuelles, des expériences in vitro sur fil et des expériences de cavitation dans une cuve d'eau. Il a été démontré que l'algorithme de formation de voie le plus précis pour la localisation du point focale de cavitation est la technique de cartographie passive acoustique pondérée avec le facteur de cohérence de phase (PAM-PCF). En outre, des tests in vivo sur un modèle animal d'ischémie des membres aigus ont été évalués. Enfin, certaines optimisations du système d'imagerie développé précédemment ont été réalisées comme l'imagerie 3D, l'implémentation en temps réel et l'imagerie hybride combinant l'imagerie active anatomique avec les cartographies de cavitation passive / Ultrasound therapy techniques emerged very recently with the discovery of high intensity focused ultrasound (HIFU) technology. Extracorporeal ultrasound thrombolysis is one of these promising innovative low-invasive treatment based on the mechanical destruction of thrombus caused by acoustic cavitation mechanisms. Yet, it is a poorly controlled phenomenon and therefore raises problems of reproducibility that could damage vessel walls. Thus, better control of cavitation activity during the ultrasonic treatment and especially its localization during the therapy is an essential approach to consider the development of a therapeutic device. A prototype has already been designed and improved with a real-time feedback loop in order to control the cavitation power activity. However, to monitor the treatment in real-time, an ultrasound imaging system needs to be incorporated into the therapeutic device. It should be able to first spot the blood clot, to position the focal point of the therapy transducer, control the proper destruction of the thrombus, and evaluate in real-time the cavitation activity. Present work focusses mainly on the development of passive ultrasound techniques used to reconstruct cavitation activity maps. Different beamforming algorithms were investigated and validated through point source simulations, in vitro experiments on a wire, and cavitation experiments in a water tank. It was demonstrated that an accurate beamforming algorithm for focal cavitation point localization is the passive acoustic mapping weighted with the phase coherence factor (PAM-PCF). Additionally, in vivo testing on an animal model of acute limb ischemia was assessed. Finally, some optimizations of the previous developed imaging system were carried out as 3D imaging, real-time implementation, and hybrid imaging combining active anatomical imaging with passive cavitation mapping

Une sonde HIFU transoesophagienne a été proposée comme une alternative aux traitements actuels de fibrillation auriculaire. Le présent travail décrit une étude de faisabilité de l'ablation thermique transoesophagienne sur des coeurs battant in vivo chez des primates non humains et ex vivo sur un cœur isolé / Transesophageal HIFU was proposed as an alternative to the current atrial fibrillation treatments. The present work described a feasibility study of transesophageal thermal ablation in the heart on beating hearts in vivo non-human primates and ex vivo on isolated heart

The Achilles tendon is the largest tendon in the human body, which elastically stores and releases energy to facilitate walking and running. Tendons can suffer from a range of pathologies, most notably that of complete rupture, which affects athletes, physically active workers and the aged. There is a growing demand for in vivo methods of objectively measuring tendon health for aiding diagnosis, monitoring therapy and for assessment of new treatments. Knowledge of the changes in mechanical properties during the healing process is also limited and new methods to accurately and consistently estimate these could provide insights into the healing process and guide future research efforts. This thesis presents the development and use of 2D ultrasound elastography, a quantitative strain estimation imaging technique, as a tool to measure changes in the tensile mechanical properties of the Achilles tendon. This technique performs frame-to-frame block matching of image texture to track motion in an ultrasound signal sequence and create a strain estimation field from the spatial derivative of the motion. Elastography in the image-lateral direction of sagittal plane scans is of particular interest as this is in line with the longitudinal axis of the tendon, but presents extra accuracy issues from out of plane motion and lower image spatial resolution. Tendon rupture also presents unique problems to image acquisition and analysis- patient pain and safety are important considerations and disruption of the ultrasound texture can make 2D motion tracking more difficult. A new 2D elastography block matching algorithm, named `AutoQual', was developed to enable accurate tracking of motion in the image-lateral direction and reduce the impact of artefacts and errors common with damaged Achilles tendons image sequences. It was shown to outperform a multiscale block matching method when tested using ultrasound sequences from in vivo and gelatine phantom experiments. The input parameters of this algorithm were then optimised using the phantom data for benchmarking. The AutoQual algorithm was then used to analyse ultrasound sequences from a 24-week longitudinal study of 21 subjects with ruptured Achilles tendons to assess lateral, axial and principal strains during controlled passive motion of the foot or axial palpation of the ultrasound probe. Lateral and principal strains from controlled dorsiflexion were shown to be more repeatable and more sensitive to change than axial strains with manual palpation. This experience with lateral strain imaging from ruptured Achilles tendons gave an increased knowledge of the strain imaging artefacts and features that can occur. These are described in detail in order that they may be further mitigated in quantitative analysis by optimising acquisition protocols, further amendment of the block tracking algorithm, or exclusion of erroneous areas when selecting regions of interest. Regularisation is a potential solution to some common artefacts such as discontinuities from poor tracking in shadow regions. Regularisation of the lateral displacement fields is investigated using 2D bicubic smoothing splines. The regularisation parameters used are shown to have minimal effect on quantitative analysis and can aid visual clarity or reduce artefacts within certain settings. However, regularisation was also shown to cause large errors when parameters were set more aggressively. Finally, it is identified that cumulative lateral strain measurement of the Achilles and other tendons is feasible but that future work is needed to further improve the quality of force and cross sectional area measurements in order to infer mechanical properties accurately. Repeatable high force motion protocols also need to be developed to measure healthy tendons and to ensure comparable results between different patients and research groups.

Acute appendicitis is a common cause of abdominal surgery in children, and is the result of appendiceal luminal obstruction and subsequent inflammation. The clinical presentation is often variable, allowing imaging to play a central role in disease identification and characterization. Ultrasound is often the modality of choice for diagnosis of appendicitis in children. Ready availability and lack of ionizing radiation are attractive features of sonography, though operator dependence is a potential barrier. Computed tomography (CT) was historically the preferred modality in children, as in adults, but recent awareness of the risks of radiation has reduced its usage. The purpose of this article is to detail the imaging findings of appendicitis in children. The discussion will focus on typical signs of appendicitis seen on ultrasound, CT, and magnetic resonance imaging. Considerations for percutaneous drainage by interventional radiology will also be presented. Finally, the evolution of imaging algorithms for appendicitis will be discussed.

Interspeech posture (ISP) is a term used to define the position of a person’s articulators when they are preparing to speak. Research suggests that ISP may be representative of a speaker’s phonological knowledge in a particular language, as determined empirically with ultrasound measures of the tongue in English-French bilinguals (Wilson & Gick, 2014). It is possible, therefore, that measuring ISP could be a diagnostic tool for determining phonological knowledge in bilingual speakers. However, more information on ISP in typical adult bilingual speakers is needed before diagnostic claims can be made. For example, ISP is believed to be language specific, and the typical ISP for each language must be determined. Therefore, the purpose of this study was to extend the research by Wilson and Gick (2014) to investigate ISP in Spanish-English speaking adults. To this end, 13 bilingual Spanish-English adults were asked to produce 30 sentences while speaking in monolingual and bilingual modes. While they were speaking, ultrasound images of the oral cavity were obtained by placing a probe sub-mentally and analyzing the position of the tongue using Articulate Assistant Advanced 2.0 software (Articulate Instruments, 2012). Tongue and palate contour measurements were made by using a curved tongue spline that was manually drawn and semi-automatically fit to each speaker’s tongue/palate contour. ISP was measured using the participant’s tongue tip height along a reference angle from the probe to the alveolar ridge. Additionally, monolingual English speaking adults were asked to rate the accentedness of each bilingual’s speech in English as a behavioral correlate of language proficiency. Overall results of this study were non-significant; bilingual Spanish-English speakers utilized similar postures in monolingual Spanish and English modes, and in bilingual mode, in contrast with the findings of Wilson and Gick (2014). Accentedness ratings in English v indicated that the bilingual speakers were relatively uniform in their lack of accentedness. Although overall results from this study differ from those of Wilson and Gick (2014) a subset of their participants- speakers that were rated as having non-native accents- had similar results in that they also showed no difference in ISP. Related ISP’s across languages may be due to participants having native sounding English but non-native Spanish. Due to contrasting findings from Wilson and Gick (2014), further investigation with accented speakers is needed to determine if distinct ISPs exist for bilingual Spanish-English speakers.

The widespread use of synthetic drugs and as feed additives has resulted in the release of large amounts of biologically active chemicals into the environment. Exposure to environmentally relevant concentrations of chemicals can have severe effects on human health. Therefore, effective degradation of these synthetic, biologically active compounds is of paramount importance. Diphenhydramine (DPH) has been selected as a target compound for ultrasound remediation. The results demonstrated that ultrasound-induced degradation has potential applications in managing aqueous media contaminated with DPH. Atorvastatin and roxarsone have been selected as representative substrates for chloroperoxidase (CPO) catalyzed transformation of pollutants. These studies demonstrate atorvastatin and roxarsone can be degraded efficiently by CPO. The transformation products of each compound were identified and the mechanisms of CPO catalysis postulated. This study provides a foundation for assessing the feasibility of applying CPO in the remediation of water and soil contaminated with pharmaceuticals and feed additives.

No description available.

This thesis describes the development and applications of an extension of DWS which enables the recovery of ‘localized’ mechanical properties, in a specified region of a complex jelly-like object which is inhomogeneous, marked out by the focal volume of an ultrasound transducer, also called the region-of-interest (ROI). Introduction of the sinusoidal forcing creates a sinusoidal phase variation in the detected light in a DWS experiment which modulates the measured intensity autocorrelation, g2 (τ ). Decay in the modulation depth with τ is used to recover the visco-elastic spectrum of the material in the ROI. En route to this, growth of the mean-squared dis- placement (MSD) with time is extracted from the modulation depth decay, which was verified first by the usual DWS experimental data from an homogeneous object with properties matching those in the ROI of the inhomogeneous object and then those obtained by solving the generalized Langevin equation (GLE) modelling the dynamics of a typical scattering centre in the ROI. A region-specific visco-elastic spectral map was obtained by scanning the inhomogeneous object by the ultrasound focal volume. Further, the resonant modes of the vibrating ROI were measured by locating the peaks of the modulation depth variation in g2(τ ) with respect to the ultrasound frequency. These resonant modes were made use of to recover elasticity of the material of the object in the ROI. Using a similar strategy, it was also shown that flow in pipe can be detected and flow rate computed by ‘tagging’ the photons passing through the pipe with a focussed ultrasound beam. It is demonstrated, both through experiments and simulations that the ultrasound-assisted technique devel- oped is better suited to both detect and quantitatively assess flow in a background of Brownian dynamics than the usual DWS. In particular, the MSD of particles in the flow, which shows forth a super-diffusive dynamics with MSD growing following τ α with α < 2, is captured over larger intervals of τ than was possible using existing methods. On the theoretical front, the main contribution is the derivation of the GLE, with multiplicative noise modulating the interaction ‘spring constant’. The noise is derived as an average effect of the micropolar rotations suffered by the ‘bath’ particles on the ‘system’ particle modelled. It has been shown that the ‘local’ dynamics of the system particle is nontrivially influenced by the dynamics, both translation and rotation, of ‘nonlocal’ bath particles.