Momentum vectors of fragment ions produced by the Coulomb explosion of CO2z+ (z = 3 - 6) and CS2z+ (z = 3 - 13) in an intense laser field (~50 fs, 1 x 1015 W/cm2) are determined by the triple coincidence imaging technique. The molecular structure from symmetric and asymmetric explosion channels is reconstructed from the measured momentum vectors using a novel simplex algorithm that can be extended to study larger molecules. Physical parameters such as bend angle and bond lengths are extracted from the data and are qualitatively described using an enhanced ionization model that predicts the laser intensity required for ionization as a function of bond length using classical, over the barrier arguments. As a way of going beyond the classical model, molecular ionization is examined using a quantum-mechanical, wave function modified ADK method. The ADK model is used to calculate the ionization rates of H2, N2, and CO2 as a function of initial vibrational level of the molecules. A strong increase in the ionization rate, with vibrational level, is found for H2, while N2 and CO2 show a lesser increase. The prospects for using ionization rates as a diagnostic for vibrational level population are assessed.

Momentum vectors of fragment ions produced by the Coulomb explosion of CO2z+ (z = 3 - 6) and CS2z+ (z = 3 - 13) in an intense laser field (~50 fs, 1 x 1015 W/cm2) are determined by the triple coincidence imaging technique. The molecular structure from symmetric and asymmetric explosion channels is reconstructed from the measured momentum vectors using a novel simplex algorithm that can be extended to study larger molecules. Physical parameters such as bend angle and bond lengths are extracted from the data and are qualitatively described using an enhanced ionization model that predicts the laser intensity required for ionization as a function of bond length using classical, over the barrier arguments. As a way of going beyond the classical model, molecular ionization is examined using a quantum-mechanical, wave function modified ADK method. The ADK model is used to calculate the ionization rates of H2, N2, and CO2 as a function of initial vibrational level of the molecules. A strong increase in the ionization rate, with vibrational level, is found for H2, while N2 and CO2 show a lesser increase. The prospects for using ionization rates as a diagnostic for vibrational level population are assessed.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23073号 / 医博第4700号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 溝脇 尚志, 教授 黒田 知宏, 教授 増永 慎一郎 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

New methods to measure and quantify tissue molecular composition and metabolism are a major driver of discovery in basic and clinical research. Optical methods are well suited for this task based on the non-invasive nature of many imaging and spectroscopy techniques, the variety of exogenous fluorescent probes available, and the ability to utilize label-free endogenous absorption signatures of tissue chromophores including oxy- and deoxy-hemoglobin, water, lipid, collagen, and glucose. Despite significant advances in biomedical imaging, there remain challenges in probing tissue information in a fast, wide-field, and non-invasive manner. Moreover, quantitative in vivo mapping of endogenous biomarkers such as water and lipids remain relatively less explored by the biomedical optics community due to their characteristic extinction spectra, which have distinct spectral features in the shortwave infrared, a wavelength band that has been traditionally more challenging to measure. The work presented in this dissertation was focused on developing instrumentation and algorithms for non-invasive quantification of tissue optical properties, fluorophore concentrations, and chromophore concentrations in a wide-field imaging format. All of the imaging methods and algorithms developed in this thesis extend the capability of the emerging technique called Spatial Frequency Domain Imaging (SFDI). First, a new imaging technique based on SFDI is presented that can quantify the quantum yield of exogenous fluorophores in tissue. This technique can potentially provide a new non-invasive means for in vivo mapping of local tissue environment such as temperature and pH. Next, an angle correction algorithm was developed for SFDI for more accurate estimation of tissue optical properties as well as chromophore concentrations in highly curved tissue, including small animal tumor models. Next, a wide-field label-free optical imaging system was developed to simultaneously measure water and lipids using the shortwave infrared (SWIR) wavelength region. Last, to break the bottleneck of processing speed in optical property inversion, new deep learning based models were developed to provide over 300× processing speed improvement. Together, these projects substantially extend the available contrasts and throughput of SFDI, providing opportunities for new preclinical and clinical applications. / 2020-10-22T00:00:00Z

For many years, microbubbles have been used as ultrasound contrast agents to improve the quality of diagnostics, seeing that they produce more backscattering ultrasound than blood does. Novel types of microbubbles and increased knowledge about their different behaviors have led to other suggested areas of use. One notable example is the poly-vinyl alcohol (PVA) microbubble, which has been discovered to have a unique fracturing mechanism referred to as the pumping-out behavior. The PVA microbubble has the potential to be used, for instance, in local drug delivery of therapeutic gases, but further studies are needed. In this study, the aim was to develop a tool for imaging the pumping-out behavior of the PVA microbubbles. A linear transducer connected to the programmable Verasonics Research System operated by MatLab software was used to achieve it. The designed ultrasound sequences were tested on a tissue-mimicking phantom containing one vessel filled with PVA microbubbles and one with degassed water. The design was divided into two steps. First, an ultrafast imaging sequence, based on plane waves, was developed to achieve adequate acquisition rate for detecting escaping air from the microbubbles. Furthermore, coherent compounding was implemented to compensate for some of the loss in image quality due to the use of plane waves instead of focused waves. The second step of the design was to combine the imaging sequence with destruction pulses so that the pumping-out behavior could be imaged. The designed ultrasound sequence was evaluated by calculating the mean pixel intensities, contrast-to-tissue ratio (CTR), and contrast-to-noise ratio (CNR) of different regions of interest (ROI) in the acquired images. The results of this project agree with the result previously reported in a study of PVA microbubbles made by Kothapalli et al.. Thus, the developed tool can image the pumping-out behavior. However, further improvements to the imaging tool, such as use of a contrast specific method, is recommended for it to become more reliable and useful. In conclusion, the developed imaging tool works for imaging the pumping-out behavior, but improvements should be made. With a useful imaging tool, further studies can be performed to understand the parameters affecting the pumping-out behavior. In the end, the PVA microbubbles can possibly be used as, for example, local drug deliverers in the clinic.

Doctor of Philosophy / Department of Physics / Chii-Dong Lin / Imaging of molecules has always occupied an essential role in physical, chemical and biological sciences. X-ray and electron diffraction methods routinely achieve sub-angstrom spatial resolutions but are limited to probing dynamical timescales longer than a picosecond. With the advent of femtosecond intense lasers, a new imaging paradigm emerges in last decade based on laser-induced electron diffraction (LIED). It has been placed on a firm foundation by the quantitative rescattering theory, which established that large-angle e-ion elastic differential cross sections (DCS) can be retrieved from the LIED spectrum. We further demonstrate that atomic potentials can be accurately retrieved from those extracted DCSs at energies from a few to several tens of electron volts. Extending to molecules, we show mid-infrared (mid-IR) lasers are crucial to generate high-energy electron wavepackets (> 100 eV) to resolve the atomic positions in a molecule. These laser-driven 100 eV electrons can incur core-penetrating collisions where the momentum transfer is comparable to those attained in conventional keV electron diffraction. Thus a simple independent atom model (IAM), which has been widely used in conventional electron diffractions, may apply for LIED. We theoretically examine and validate the applicability of IAM for electron energies above 100 eV using e-molecule large-angle collision data obtained in conventional experiments, demonstrating its resolving powers for bond lengths about 0.05 angstrom. The Validity of IAM is also checked by an experimental LIED investigation of rare gas atoms in the mid-IR regime. We show that the electron’s high energy promotes core-penetrating collisions at large scattering angles, where the e-atom interaction is dominated by the strong short range atomic-like potential. Finally, we analyze the measured LIED spectrum of N[subscript]2 and O[subscript]2 at three mid-IR wavelengths (1.7, 2.0, and 2.3 μm). As expected, the retrieved bond lengths of N[subscript]2 at three wavelengths are about same as the equilibrium N[subscript]2 bond length. For O[subscript]2, the data is also consistent with a bond length contraction of 0.1 angstrom within 4-6 fs after tunnel ionization. This investigation establishes a foundation for this novel imaging method for spatiotemporal imaging of gas-phase molecules at the atomic scale.

Ce travail de thèse s’inscrit dans le cadre de la caractérisation optique à haute cadence en temps réel. Des outils de métrologie ultrarapides ont ainsi été utilisés pour l’étude d’une source laser impulsionnelle ainsi que pour l’imagerie de phénomènes physiques. La mise en place et la caractérisation temporelle d’une source laser impulsionnelle a permis l’observation d’événements anormalement intenses pour certains régimes de fonctionnement, et ces dynamiques ont pu être confirmées numériquement. La compréhension de ces phénomènes présente un intérêt fondamentalmais également pratique, notamment en vue de limiter les dommages optiques dans les sources laser. L’utilisation d’une technique d’imagerie appelée « imagerie par étirage temporel » a permis l’observation de jets liquides à une cadence de 80MHz. Reposant sur le principe de Transformée de Fourier Dispersive, cette technique permet de rendre compte de phénomènes non-répétitifs à des cadences élevées, et ainsi d’outrepasser les limitations imposées par les systèmes d’enregistrement conventionnels. La technique a également permis l’étude d’ondes de choc générées par ablation laser, et la détermination du profil de vitesse de l’onde de choc à travers la zone de mesure. Le phénomène de réflexion d’une onde de choc sur une paroi a également pu être observé. / This PhD work is dedicated to optical characterization in real time. Ultrafast metrology tools have thus been used to study a pulsed laser source and also for physical phenomena imaging. The implementation of a temporally well characterized pulsed laser source allowed the observation of events involving abnormally high intensity, the dynamics of which have also been numerically studied and confirmed. Understanding of these phenomena addresses a fundamental and interesting need to prevent optical damage in laser sources. The use of the imaging technique called “time-stretch imaging” allowed the imaging of liquid sprays at an 80MHz repetition rate. Based on Dispersive Fourier Transform, this technique enables the study of non-repetitive events at high sampling frequency, and thus goes beyond the performance of traditional imaging devices. This technique also allowed the tracking of shockwaves, and thus profiling the shockwave’s velocity variation through its propagation along a certain measuring distance. Shockwave reflection has also been observed.

Les caméras à balayage de fente sont les instruments de détection directe de la lumière les plus précis en termes de résolution temporelle. Ces instruments sont capables de capturer des évènements de l’ordre de la picoseconde à un taux de répétition d’une centaine de mégahertz. Cependant, les performances de la caméra sont limitées par de nombreux phénomènes propres au fonctionnement de cette dernière mais aussi au système l’implémentant. Plusieurs effets dégradant la résolution temporelle sont étudiés. Le premier axe exploré concerne la synchronisation de la caméra avec l’évènement lumineux capturé. Cette investigation débouche sur le développement d’un discriminateur à fraction constante permettant de déclencher la caméra avec un jitter inférieur à 200 fs RMS. Une autre étude présente l’impact qu’ont le bruit d’amplitude et le bruit de phase des lasers usuellement utilisés avec la caméra sur sa synchronisation. Enfin une analyse des phénomènes intrinsèques à la photocathode de la caméra permet d’évaluer la variation du temps de transit des électrons dans celle-ci. / Streak cameras are the direct light detection instruments that are the best in terms of temporal resolution. Those instruments can capture picosecond light events at a hundred megahertz repetition rate. However their characteristics are limited by various phenomena specific to the camera and the implementing system. Several effects that affect the temporal resolution are studied. The first examined line deals with the synchronization of the camera with the studied light event. This inquiry led to the design of a constant fraction discriminator allowing a sub 200 fs RMS jitter triggering. Another study shows the impact of the usually used laser amplitude noise and phase noise on the system’s synchronization. Finally, an analysis of the camera’s photocathode intrinsic phenomena allows estimating the transit time variation of the electrons within the vacuum tube.

À cause de difficultés d’observations, les recherches passées en biomécanique de l’abdomen soumis aux chocs se sont essentiellement limitées à la description de comportements externes. Cette étude s’intéresse au comportement interne d’organes abdominaux à l’aide de techniques récentes : l’échographie ultrarapide et l’élastographie par ondes de cisaillement. Tout d’abord, l’effet de conditions de perfusion sur la géométrie et le module de cisaillement interne de reins de porc ex vivo a été évalué. L’effet considérable de la pression appliquée a été observé, avec 80mmHg en artère conduisant à l’état le proche de l’in vivo. Ensuite, à l’aide de l’échographie ultrarapide, les comportements internes de reins porcins et humains dans cet état de référence ont été observés lors de compressions à des vitesses entre 0.08 et 8 s-1. Si pour le porc, la partie centrale (bassinet) se déforme plus, le rein humain a semblé avoir une déformation plus homogène. Enfin, à partir des résultats, un nouveau protocole a permis d’observer les comportements du côlon et du foie in situ lors d’impacts sur trois sujets d’anatomie. Dans l’ensemble, cette étude montre ainsi la possibilité de quantifier la relation entre chargement externe et interne grâce à l’échographie ultrarapide lors d’impacts / Due to limitations of observation techniques, past researches in impact biomechanics on the abdomen have been mostly limited to the description of the externals responses. This study focuses on the internal response of abdominal organs using recent observation techniques: ultrafast ultrasound imaging and shearwave elastography. First, the effects of perfusion conditions on the geometrical and internal shear moduli of ex vivo porcine kidneys were evaluated. The considerable effect of the applied pressure was observed, with 80mmHg in artery being closest to the in vivo state. Then, the internal responses of porcine and human kidneys were observed during compressions (rates: 0.08 to 8s-1). If in the porcine specimen the central part (pelvis) deformed the most, the human kidney seemed to have a more homogenous response. Finally, a protocol was developed to observe the responses of the colon and the liver in situ during impacts performed on three post mortem human subjects. Overall, this study demonstrates the possibility to establish a link between external and internal responses during impact using ultrafast ultrasound imaging

L'échographie est un outil de diagnostic largement utilisé grâce à des vertus telles que l'acquisition / traitement de données en temps réel, la facilité d'utilisation et la sécurité pour le patient / praticien pendant l'examen. Cependant, comparée à d'autres méthodes d'imagerie telles que la tomographie à rayons X et l'imagerie par résonance magnétique, l'échographie présente l'inconvénient de fournir une qualité d'image relativement basse. Dans cette thèse, nous étudions une méthode capable d'augmenter la qualité d'image, permettant ainsi de meilleurs diagnostics échographiques. Afin d'augmenter le rapport signal / bruit des signaux reçus, nous proposons d'utiliser des signaux modulés en fréquence (chirps). Pour éviter l'effet négatif de la bande passante limitée de la sonde, nous modulons en amplitude les signaux d'excitations afin d'augmenter l'énergie du signal dans les bandes de fréquences où la sonde est moins efficace. Pour compresser l'énergie des échos, nous utilisons des filtres de Wiener afin d'obtenir un bon compromis résolution spatiale / stabilité du bruit. Nous combinons cette méthode appelée REC (Resolution Enhancement Technique) avec l’imagerie ultrarapide. Nous montrons des résultats simulés et expérimentaux (in-vitro, ex-vivo et in-vivo) prometteurs. De plus, nous adaptons REC afin de compenser l'effet d'atténuation tissulaire. Cette amélioration est validée expérimentalement sur des phantoms. Nous adaptons également REC à la propagation non linéaire des ondes ultrasonores, en proposant une technique d'inversion d'impulsions qui utilise REC pour fournir une meilleure résolution et un meilleur rapport contraste / bruit. Ensuite, nous appliquons REC à différents schémas d’acquisition tels que les ondes divergentes et la transmission multi-lignes (MLT). Nous montrons également que la qualité d’image peut être augmentée davantage en tenant compte de la réponse impulsionnelle spatiale de la sonde lorsque REC et MLT sont combinés / Ultrasound imaging is a diagnostic tool widely used thanks to such virtues as real-time data acquisition / processing, ease of use and safety for the patient / practitioner during examination. However, when compared to other imaging methods such as X-ray tomography and Magnetic Resonance Imaging, the echography has the disadvantage to provide relatively low image quality. In this thesis, we study a method that is able to increase the ultrasound image quality, thus paving the way towards improved diagnostics based on echography and novel ultrasound applications. In order to increase the echo signal to noise ratio of the received signals, we propose to use linear frequency modulated signals, also called chirps. To avoid the negative effect of the bandlimited acquisition probe, we apply a pre-enhancement step on the probe excitation signals in order to boost the signal energy in the frequency bands where the probe is less efficient. To compress the echo energy in reception, we use Wiener filters that allow obtaining a good trade-off between the spatial resolution and noise stability. We apply the previously detailed pipeline, also called REC (Resolution Enhancement Technique) on ultrafast imaging schemes. We show promising results in simulation and in-vitro, ex-vivo, in-vivo acquisitions. Furthermore, we adapt REC in such way that the frequency dependent tissue attenuation effect is compensated for. This improvement is validated in simulation and phantom experiments. We also adapt REC to the nonlinear propagation of ultrasound waves, by proposing a pulse inversion technique that uses REC to provide a better image resolution and contrast to noise ratio. Then, we demonstrate the generality of the REC method by applying it to different acquisition schemes such as diverging wave compounding and Multi Line Transmit (MLT). We also show that the image quality can be increased more by taking into account the spatial impulse response of the ultrasound probe when REC and MLT are combined