Estimation of Outer-Middle Ear Transmission using DPOAEs and Fractional-Order Modeling of Human Middle Ear

Our ability to hear depends primarily on sound waves traveling through the outer and middle ear toward the inner ear. Hence, the characteristics of the outer and middle ear affect sound transmission to/from the inner ear. The role of the middle and outer ear in sound transmission is particularly important for otoacoustic emissions (OAEs), which are sound signals generated in a healthy cochlea, and recorded by a sensitive microphone placed in the ear canal. OAEs are used to evaluate the health and function of the cochlea; however, they are also affected by outer and middle ear characteristics. To better assess cochlear health using OAEs, it is critical to quantify the impact of the outer and middle ear on sound transmission. The reported research introduces a noninvasive approach to estimate outer-middle ear transmission using distortion product otoacoustic emissions (DPOAEs). In addition, the role of the outer and middle ear on sound transmission was investigated by developing a physical/mathematical model, which employed fractional-order lumped elements to include the viscoelastic characteristics of biological tissues. Impedance estimations from wideband refectance measurements were used for parameter fitting of the model. The model was validated comparing its estimates of the outer-middle ear sound transmission with those given by DPOAEs. The outer-middle ear transmission by the model was defined as the sum of forward and reverse outer-middle ear transmissions. To estimate the reverse transmission by the model, the probe-microphone impedance was calculated through estimating the Thevenin-equivalent circuit of the probe-microphone. The Thevenin-equivalent circuit was calculated using measurements in a number of test cavities. Such modeling enhances our understanding of the roles of different parts of the outer and middle ear and how they work together to determine their function. In addition, the model would be potentially helpful in diagnosing pathologies of cochlear or middle ear origin

Fractional order models of the human respiratory system

The fractional calculus is a generalization of classical integer-order integration and derivation to fractional (non-integer) order operators. Fractional order (FO) models are those models which contain such fractional order operators. A common representation of these models is in frequency domain, due to its simplicity. The dynamical systems whose model can be approximated in a natural way using FO terms, exhibit specific features, such as viscoelasticity, diffusion and a fractal structure; hence the respiratory system is an ideal application for FO models. Although viscoelastic and diffusive properties were intensively investigated in the respiratory system, the fractal structure was ignored. Probably one of the reasons is that the respiratory system does not pose a perfect symmetry, hence failing to satisfy one of the conditions for being a typical fractal structure. In the 70s, the respiratory impedance determined by the ratio of air-pressure and air-flow, has been introduced in a model structure containing a FO term. It has also been shown that the fractional order models outperform integer-order models on input impedance measurements. However, there was a lack of underpinning theory to clarify the appearance of the fractional order in the FO model structure. The thesis describes a physiologically consistent approach to reach twofold objectives: 1. to provide a physiologically-based mathematical explanation for the necessity of fractional order models for the input impedance, and 2. to determine the capability of the best fractional order model to classify between healthy and pathological cases. Rather than dealing with a specific case study, the modelling approach presents a general method which can be used not only in the respiratory system application, but also in other similar systems (e.g. leaves, circulatory system, liver, intestines). Furthermore, we consider also the case when symmetry is not present (e.g. deformations in the thorax - kyphoscoliose) as well as various pathologies. We provide a proof-of-concept for the appearance of the FO model from the intrinsic structure of the respiratory tree. Several clinical studies are then conducted to validate the sensitivity and specificity of the FO model in healthy groups and in various pathological groups

Parameter Estimation of the Arterial System

There are a number of disorders that originate from or involve faulty operation of the cardiovascular system. Diseases such as atherosclerosis, diabetes and hypertension can have a debilitating effect on blood flow. This makes the tools for simulating the effects of such diseases on blood flow important. Measures, such as pulse wave velocity, that are generated by models of the cardiovascular system can be important indicators of cardiac health. Although physically measurable, obtaining some parameters comes with a high cost and discomfort to the patient. Models can provide an assessment of many important parameters. The purpose of this project was to create a robust computer generated model of the arterial system. This model is a one-dimensional/Womersley model that used transmission line hemodynamic theory to calculate the blood pressure waveforms and then the Womersley theory to calculate the flow velocity in various areas of the human body. The accuracy of the model was tested using data from eight subjects. The model provided realistic and individualized cardiovascular parameters without requiring any major adjustment to the internal algorithms

Computational fluid dynamics indicators to improve cardiovascular pathologies

In recent years, the study of computational hemodynamics within anatomically complex vascular regions has generated great interest among clinicians. The progress in computational fluid dynamics, image processing and high-performance computing haveallowed us to identify the candidate vascular regions for the appearance of cardiovascular diseases and to predict how this disease may evolve. Medicine currently uses a paradigm called diagnosis. In this thesis we attempt to introduce into medicine the predictive paradigm that has been used in engineering for many years. The objective of this thesis is therefore to develop predictive models based on diagnostic indicators for cardiovascular pathologies. We try to predict the evolution of aortic abdominal aneurysm, aortic coarctation and coronary artery disease in a personalized way for each patient. To understand how the cardiovascular pathology will evolve and when it will become a health risk, it is necessary to develop new technologies by merging medical imaging and computational science. We propose diagnostic indicators that can improve the diagnosis and predict the evolution of the disease more efficiently than the methods used until now. In particular, a new methodology for computing diagnostic indicators based on computational hemodynamics and medical imaging is proposed. We have worked with data of anonymous patients to create real predictive technology that will allow us to continue advancing in personalized medicine and generate more sustainable health systems. However, our final aim is to achieve an impact at a clinical level. Several groups have tried to create predictive models for cardiovascular pathologies, but they have not yet begun to use them in clinical practice. Our objective is to go further and obtain predictive variables to be used practically in the clinical field. It is to be hoped that in the future extremely precise databases of all of our anatomy and physiology will be available to doctors. These data can be used for predictive models to improve diagnosis or to improve therapies or personalized treatments.En els últims anys, l'estudi de l'hemodinàmica computacional en regions vasculars anatòmicament complexes ha generat un gran interès entre els clínics. El progrés obtingut en la dinàmica de fluids computacional, en el processament d'imatges i en la computació d'alt rendiment ha permès identificar regions vasculars on poden aparèixer malalties cardiovasculars, així com predir-ne l'evolució. Actualment, la medicina utilitza un paradigma anomenat diagnòstic. En aquesta tesi s'intenta introduir en la medicina el paradigma predictiu utilitzat des de fa molts anys en l'enginyeria. Per tant, aquesta tesi té com a objectiu desenvolupar models predictius basats en indicadors de diagnòstic de patologies cardiovasculars. Tractem de predir l'evolució de l'aneurisma d'aorta abdominal, la coartació aòrtica i la malaltia coronària de forma personalitzada per a cada pacient. Per entendre com la patologia cardiovascular evolucionarà i quan suposarà un risc per a la salut, cal desenvolupar noves tecnologies mitjançant la combinació de les imatges mèdiques i la ciència computacional. Proposem uns indicadors que poden millorar el diagnòstic i predir l'evolució de la malaltia de manera més eficient que els mètodes utilitzats fins ara. En particular, es proposa una nova metodologia per al càlcul dels indicadors de diagnòstic basada en l'hemodinàmica computacional i les imatges mèdiques. Hem treballat amb dades de pacients anònims per crear una tecnologia predictiva real que ens permetrà seguir avançant en la medicina personalitzada i generar sistemes de salut més sostenibles. Però el nostre objectiu final és aconseguir un impacte en l¿àmbit clínic. Diversos grups han tractat de crear models predictius per a les patologies cardiovasculars, però encara no han començat a utilitzar-les en la pràctica clínica. El nostre objectiu és anar més enllà i obtenir variables predictives que es puguin utilitzar de forma pràctica en el camp clínic. Es pot preveure que en el futur tots els metges disposaran de bases de dades molt precises de tota la nostra anatomia i fisiologia. Aquestes dades es poden utilitzar en els models predictius per millorar el diagnòstic o per millorar teràpies o tractaments personalitzats.Postprint (published version

Um modelo para a simulação de sinais Doppler ultra-sonicos provenientes de fluxo sanguínio pulsátil

Doutoramento em Engenharia ElectrotécnicaO detector ultra-sónico de fluxo sanguíneo usa o efeito Doppler para estimar de forma não invasiva a velocidade do sangue na circulação. Tem sido bastante usado nas ultimas quatro décadas para detectar a presença de estenoses. O desenvolvimento de novas técnicas de processamento do sinal Doppler necessita de sinais de teste cujas características sejam conhecidas ou possam ser medidas com precisão. Isto é difícil de obter com sinais Doppler medidos in vivo devido à elevada variação do fluxo sanguíneo de pessoa para pessoa e também com o estado fisiológico da pessoa no momento da medida, por exemplo a tensão arterial influencia significativamente o fluxo sanguíneo. Um modelo para gerar sinais Doppler simulados cujas características sejam controláveis e/ou mensuráveis é uma ferramenta bastante útil, pois permite que as novas técnicas de processamento do sinal Doppler sejam testadas em condições controladas. Permite, também, estudar o efeito de viários factores que afectam o espectro do sinal Doppler. Habitualmente o efeito individual dos viários factores não pode ser identificado quando são usados sinais medidos in vivo. Neste trabalho foi desenvolvido um modelo para gerar sinais Doppler ultra-sónicos simulados. O modelo contêm dois sub-modelos, um para o fluxo sanguíneo nos membros inferiores de um ser humano e outro para gerar os sinais simulados a partir do campo de velocidades do sangue e das características do instrumento. O fluxo sanguíneo nos membros inferiores foi simulado com um análogo eléctrico para a rede vascular dos membros inferiores. Cada artéria foi simulada por uma linha de transmissão com perdas e as redes vasculares periféricas por um circuito Windkessel com três elementos. O circuito eléctrico foi implementado com o simulador de circuitos SPICE. Para simular a interacção entre os glóbulos vermelhos e o campo de ultra-sons o vaso sanguíneo foi dividido em pequenos volumes elementares. As contribuições dos volumes elementares foram todas somadas para gerar o sinal Doppler simulado. O modelo fez algumas aproximações como sejam, por exemplo, considerar o fluxo sanguíneo laminar e sem rotação. As características dos sinais gerados pelo modelo são bastante parecidas com as esperadas para o sinal Doppler real. O modelo desenvolvido foi usado para estudar a influencia que a aceleração sanguínea, o tamanho do volume de amostragem e a duração da janela de amostragem têm na largura de banda eficaz do espectro do sinal Doppler. Foi deduzida uma formula que estima a largura de banda eficaz a partir das contribuições individuais do alargamento espectral devido à não estacionaridade, do alargamento espectral intrínseco, do alargamento espectral devido à duração da janela de amostragem e ainda da gama das velocidades que passam pelo volume de amostragem. Foram, ainda, deduzidas expressões em forma fechada para o espectro de potência do sinal Doppler devido unicamente à gama de velocidades que atravessam um volume de amostragem com forma Gaussiana colocado num perfil de velocidades com forma exponencial. Foram, também, obtidas expressões para a largura de banda eficaz no caso especial do volume de amostragem Gaussiano ter simetria esférica e estar colocado no centro do vaso sanguíneo.The Doppler ultrasonic blood ow detector estimates non-invasively the velocity of blood in the circulatory system. It has been extensively used in the last four decades for the detection of stenoses in the circulation. The development of new signal processing techniques for the Doppler signal requires test signals with known or measurable characteristics. This is very di cult to achieve with Doppler signals obtained in vivo because of the variability of blood ow between persons and with physiological state, for example blood pressure. A model for generating simulated Doppler signals whose characteristics are controllable and/or measurable is a useful tool because it permits the test of new processing techniques under controlled conditions. It permits also the study of the e ect of various factors on the Doppler spectrum. Usually these e ects cannot be isolated with in vivo measurements. During this work a model for the generation of simulated Doppler ultrasound signals was developed. It comprised two sub-models one for blood ow in the human lower limb and the other for generating simulated signals from the blood velocity eld and the instrument's characteristics. Blood ow in the lower limb was modelled by an electric analogue for the lower limb vascular tree. Each artery was modelled by a lossy transmission line and the peripheral vascular beds by three{element Windkessel models. The electric analogue circuit was implemented with the SPICE circuit simulator. To simulate the inter-action of the blood cells with the ultrasonic eld the vessel was divided into small elemental volumes whose contributions were added together to generate the simulated Doppler signal. The model assumed irrotational laminar ow and some other simplifying approximations. The characteristics of the signals generated by the model were similar to those expected for the Doppler signal. The model was used to study the in- uence of blood acceleration, sample volume size and data segment duration on the root mean square (rms) width of the Doppler spectrum. A simple formula was derived for estimating the Doppler rms spectral width from the individual contribution of non-stationarity broadening, intrinsic broadening, window broadening and the range of blood velocities passing through the sample volume. In addition closed form expressions were derived for the Doppler power spectrum due solely to the range of blood velocities passing through a Gaussian sample volumes placed in irrotational laminar ow with a velocity pro le obeying a simple power law. Closed form expressions were also obtained for the root mean square spectral width in the special case of a spherically symmetric Gaussian sample volume placed in the centre of the vessel

Investigation of Heat Therapies using Multi-Scale Models and Statistical Methods

Ph.DDOCTOR OF PHILOSOPH

Guidewire-mounted thermal sensors to assess coronary hemodynamics

The vessels of the coronary circulation are prone to arteriosclerotic disease, which can lead to the development of obstructions to blood flow. The conventional way to diagnose the severity of this type of disease is by coronary angiography. This method, however, only provides insight into the morphology of the coronary vessels, whereas for an accurate diagnosis a measure for the actual flow impediment is needed. To perform these measurements, sensor-tipped guidewires have been developed to measure intra-coronary pressure and blood flow velocity. Diagnosis of coronary disease based on the time-average of these measurements have been shown to improve the clinical outcome of treatment significantly. However, since the coronary vessels are embedded in the (contracting) cardiac muscle, the interpretation of these indices is complicated and can be improved by simultaneously assessing the dynamics of coronary pressure and flow. The research described in this thesis therefore focusses on the one hand on developing devices for the simultaneous assessment of coronary pressure and flow dynamics and on the other hand on modeling the heart and coronary vessels to support the interpretation of these dynamic measurements. In the development of a device which can measure both coronary pressure and flow, two different strategies have been chosen. In the first strategy, a method has been developed to operate an already clinically used pressure sensor-tipped guidewire (pressure wire) as a thermal anemometer to also measure flow. In an in-vitro model it has been demonstrated that the power required to electrically heat the sensor is a measure for the shear rate at the sensor surface and that the method can be used to assess coronary flow reserve (CFR). By slightly adapting the method and combining it with a continuous thermodilution method, it has also been shown that the dynamics of both pressure and volumetric flow can be measured simultaneously in physiological representative in-vitro and ex-vivo experiments. The main drawbacks of this thermal method with a pressure wire are the relatively high sensor temperature required and the inability to detect flow reversal. In the second strategy, a new flow sensor, embedded in a flexible polyimide chip, has been specially designed to be mounted on a guidewire. The flow sensing element consists of a heater, operated at constant power, and thermocouples measuring the temperature difference up- and downstream from the heater. To gain insight into the working principle and the importance of the different design parameters, an analytical model has been developed. Experiments where upscaled sensors have been subjected to steady and pulsatile flow, indicate that the model is able to reproduce the experimental results fairly well but that the sensitivity to shear rate is rather limited in the physiological range. This sensitivity to shear rate can possibly be improved by operating the heater at constant temperature, which has been investigated with invitro experiments with upscaled sensors and a finite element analysis of the real, small size sensor. These studies have demonstrated that constant temperature operation of the heater is beneficial over constant power operation and that the dynamics of physiological coronary shear rate, including retrograde flow, can be assessed at an overheat temperature of only 5 K. From these characterization studies a new design of the sensor has been proposed, which is currently being manufactured to be tested in both in-vitro and ex-vivo experiments. To support the interpretation of the dynamic pressure and flow measurements, a numerical model of the heart and coronary circulation has been developed. The model is based on the coupling of four interacting parts: A model for the left ventricle which is based on the mechanics of a single myofiber, a 1D wave propagation model for the large epicardial coronary arteries, a stenosis element, and a Windkessel representation of the coronary micro-vessels. Comparison of the results obtained with the model with experimental observations described in literature has shown that the model is able to simulate the effect of different types of disease on coronary hemodynamics. After further validation, the model can be used as a tool to study the effect of combinations of epicardial and/or microcirculatory disease on pressure- and flow-based indices. To model the relation between the pressure and flow waves in the coronary arteries correctly, as well as to assist in the decision-making regarding the mechanical treatment of coronary stenoses, the mechanical behaviour of the coronary arterial wall is required. Therefore, a mixed numerical-experimental method has been employed to fit a micro-structurally based constitutive model to in-situ extensioninflation experiments on porcine coronary arteries. It has been demonstrated that the model can accurately describe the experimental data and, additionally, it has been found that the most influential parameter, describing the collagen fiber orientation, can be considered constant at physiological loading. In further research, this can be used to tackle over-parameterization issues inherent to fitting similar constitutive models to data obtained in a clinical setting. In this thesis, a computational model of the coronary circulation is presented and methods for simultaneous pressure and flow assessment are introduced. By operating an already clinically used pressure wire as a thermal anemometer, a methodology was developed which is close to clinical application, while a new sensor was designed to be more accurate in different flow conditions