The development of a novel MRI based method for measuring blood perfusion in neurovascular damage

Diffusion-weighted magnetic resonance imaging (DWI) is a key neuroimaging technique. Multi b-value DWI is composed of an unknown number of exponential components which represent water movement in various compartments, notably tissue and blood vessels. The bi-exponential model, Intravoxel Incoherent Motion (IVIM), is commonly used to fit the perfusion component but does not take account of the multi-component nature of the data. In this work, a new fitting method, the Auto-Regressive Discrete Acquisition Points Transformation (ADAPT) was developed and evaluated on simulated, phantom, volunteer and clinical DWI data. ADAPT is based on the auto-regressive moving average model, making no prior assumptions about the data. ADAPT demonstrated that it could correctly identify the number of components within the diffusion signal. The ADAPT coefficients demonstrated a significant correlation with IVIM parameters and a significantly stronger correlation with cerebral blood volume derived from dynamic susceptibility contrast MRI. A reformulation of the ADAPT method allowed the IVIM parameters to be mathematically derived from the diffusion signal and demonstrated lower bias and more accuracy than currently implemented fitting methods, which are inherently biased. ADAPT provides a novel method for non-invasive determination of diffusion and perfusion biomarkers from complex tissues

Quantification of cardiac magnetic resonance imaging perfusion in the clinical setting at 3T

Dynamic contrast enhanced (DCE) cardiac magnetic resonance imaging (MRI) is well-established as a non-invasive method for qualitatively detecting obstructive coronary artery disease (CAD) which can impair myocardial blood flow and may result in myocardial infarction. Mathematical modelling of cardiac DCE-MRI data can provide quantitative assessment of myocardial blood flow. Quantitative assessment of myocardial blood flow may have merit in further stratification of patients with obstructive CAD and to improve the diagnosis and prognostication of the disease in the clinical setting. This thesis investigates the development of a quantitative analysis protocol for cardiac DCE-MRI data. In the first study presented in this thesis, Fermi and distributed parameter (DP) modelling are compared in single bolus versus dual bolus analysis. For model-based myocardial blood flow quantification, the convolution of a model with the arterial input function (i.e. contrast agent concentration-time curve extracted from the left ventricular cavity) is fitted to the tissue contrast agent concentration-time curve. In contrast to dual bolus DCE-MRI protocols, single bolus protocols reduce patient discomfort and acquisition protocol duration/complexity but, are prone to arterial input function saturation caused in the left ventricular cavity by the high concentration of contrast agent during bolus passage. Saturation effects can degrade the accuracy of quantification using Fermi modelling. The analysis presented in this study showed that DP modelling is less dependent on arterial input function saturation than Fermi modelling in eight healthy volunteers. In a pilot cohort of five patients, DP modelling detected for the first time reduced myocardial blood flow in all stenotic vessels versus standard clinical assessments. In the second study, it was investigated whether first-pass DP modelling can give accurate myocardial blood flow, against ideal values generated by numerical simulations. Unlike Fermi modelling which is convolved with only the first-pass range of the arterial input function, DP modelling is convolved with the entire contrast agent concentration-time course. In noisy and/or dual bolus data, it can be particularly challenging to identify the end point of the first-pass in the arterial input function. This study demonstrated that contrary to Fermi modelling, myocardial blood flow analysis using DP modelling does not depend on the number of time points used for fitting. Furthermore, this data suggests that DP modelling can reduce the quantitative variability caused by subjectivity in selection of the first-pass range in cardiac MR data. This in turn may help to facilitate the development of more automated software algorithms for myocardial blood flow quantification. In the third study, Fermi and DP modelling were compared against invasive clinical assessments and visual MR estimates, to assess their diagnostic ability in detecting obstructive CAD. A single bolus DCE-MRI protocol was implemented in twentyfour patients. In per vessel analysis, DP modelling reached superior sensitivity and negative predictive value in detecting obstructive CAD compared to Fermi modelling and visual estimates. In per patient analysis, DP modelling reached the highest sensitivity and negative predictive value in detecting obstructive CAD. These studies show that DP modelling analysis of cardiac single bolus DCE-MRI data can provide important functional information and can establish haemodynamic biomarkers to non-invasively improve the diagnosis and prognostication of obstructive CAD

Neuroinformatics in Functional Neuroimaging

This Ph.D. thesis proposes methods for information retrieval in functional neuroimaging through automatic computerized authority identification, and searching and cleaning in a neuroscience database. Authorities are found through cocitation analysis of the citation pattern among scientific articles. Based on data from a single scientific journal it is shown that multivariate analyses are able to determine group structure that is interpretable as particular “known ” subgroups in functional neuroimaging. Methods for text analysis are suggested that use a combination of content and links, in the form of the terms in scientific documents and scientific citations, respectively. These included context sensitive author ranking and automatic labeling of axes and groups in connection with multivariate analyses of link data. Talairach foci from the BrainMap ™ database are modeled with conditional probability density models useful for exploratory functional volumes modeling. A further application is shown with conditional outlier detection where abnormal entries in the BrainMap ™ database are spotted using kernel density modeling and the redundancy between anatomical labels and spatial Talairach coordinates. This represents a combination of simple term and spatial modeling. The specific outliers that were found in the BrainMap ™ database constituted among others: Entry errors, errors in the article and unusual terminology

Fundamental and Harmonic Ultrasound Image Joint Restoration

L'imagerie ultrasonore conserve sa place parmi les principales modalités d'imagerie en raison de ses capacités à révéler l'anatomie et à inspecter le mouvement des organes et le flux sanguin en temps réel, d'un manière non invasive et non ionisante, avec un faible coût, une facilité d'utilisation et une grande vitesse de reconstruction des images. Néanmoins, l'imagerie ultrasonore présente des limites intrinsèques en termes de résolution spatiale. L'amélioration de la résolution spatiale des images ultrasonores est un défi actuel et de nombreux travaux ont longtemps porté sur l'optimisation du dispositif d'acquisition. L'imagerie ultrasonore à haute résolution atteint cet objectif grâce à l'utilisation de sondes spécialisées, mais se confronte aujourd'hui à des limites physiques et technologiques. L'imagerie harmonique est la solution intuitive des spécialistes pour augmenter la résolution lors de l'acquisition. Cependant, elle souffre d'une atténuation en profondeur. Une solution alternative pour améliorer la résolution est de développer des techniques de post-traitement comme la restauration d'images ultrasonores. L'objectif de cette thèse est d'étudier la non-linéarité des échos ultrasonores dans le processus de restauration et de présenter l'intérêt d'incorporer des images US harmoniques dans ce processus. Par conséquent, nous présentons une nouvelle méthode de restauration d'images US qui utilise les composantes fondamentales et harmoniques de l'image observée. La plupart des méthodes existantes sont basées sur un modèle linéaire de formation d'image. Sous l'approximation de Born du premier ordre, l'image RF est supposée être une convolution 2D entre la fonction de réflectivité et la réponse impulsionelle du système. Par conséquent, un problème inverse résultant est formé et résolu en utilisant un algorithme de type ADMM. Plus précisément, nous proposons de récupérer la fonction de reflectivité inconnue en minimisant une fonction composée de deux termes de fidélité des données correspondant aux composantes linéaires (fondamentale) et non linéaires (première harmonique) de l'image observée, et d'un terme de régularisation basé sur la parcimonie afin de stabiliser la solution. Pour tenir compte de l'atténuation en profondeur des images harmoniques, un terme d'atténuation dans le modèle direct de l'image harmonique est proposé sur la base d'une analyse spectrale effectuée sur les signaux RF observés. La méthode proposée a d'abord été appliquée en deux étapes, en estimant d'abord la réponse impulsionelle, suivi par la fonction de réflectivité. Dans un deuxième temps, une solution pour estimer simultanément le réponse impulsionelle et la fonction de réflectivité est proposée, et une autre solution pour prendre en compte la variabilité spatiale du la réponse impulsionelle est présentée. L'intérêt de la méthode proposée est démontré par des résultats synthétiques et in vivo et comparé aux méthodes de restauration conventionnelles

True Spatio-Temporal Detection and Estimation for Functional Magnetic Resonance Imaging.

The development of fast imaging in magnetic resonance imaging (MRI) makes it possible for researchers in various fields to investigate functional activities of the human brain with a unique combination of high spatial and temporal resolution. A significant task in functional MRI data analysis is to develop a detection statistic for activation, showing subject’s localized brain responses to pre-specified stimuli. With rare exceptions in FMRI, these detection statistics have been derived from a measurement model under two main assumptions: spatial independence and space-time separability of background noise. One of the main goals of this thesis is to remove these assumptions which have been widely used in existing approaches. This thesis makes three main contributions:(1) a development of a detection statistic based on a spatiotemporally correlated noise model without space-time separability, (2) signal and noise modeling to implement the proposed detection statistic, (3) a development of a detection statistic that is robust to signal-to-noise ratio (SNR), Rician activation detection. For the first time in FMRI, we develop a properly formulated spatiotemporal detection statistic for activation, based on a spatiotemporally correlated noise model without space-time separability. The implementation of the developed detection statistic requires joint signal and noise modeling in three or four dimensions, which is non-trivial statistical model estimation. We complete the implementation with the parametric cepstrum, allowing dramatic reduction of computations in model fitting. These two are totally new contributions to FMRI data analysis. As byproducts, a novel test procedure for space-time separability is proposed and its asymptotic power is analyzed. The developed detection statistic and conventional statistics involving spatial smoothing by Gaussian kernel are compared through a model comparison technique and asymptotic relative efficiency. Most methods in FMRI data analysis are based on magnitude voxel time courses and their approximation by a Gaussian distribution. Since the magnitude images, in fact, obey Rician distribution and the Gaussian approximation is valid under a high SNR assumption, Gaussian modeling may perform poorly when SNR is low. In this thesis, we develop a detection statistic from a Rician distributed model, allowing a robust activation detection regardless of SNR.Ph.D.Electrical Engineering: SystemsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/57634/2/nohjoonk_1.pd

Cuffless Blood Pressure Monitoring: Estimation of the Waveform and its Prediction Interval

Cuffless blood pressure (BP) estimation devices are receiving considerable attention as tools for improving the management of hypertension, a condition that affects 1.13 billion people worldwide. It is an approach that can provide continuous BP monitoring, which is not possible with existing non-invasive tools. Therefore, it yields a more comprehensive picture of the patient’s state. Cuffless BP monitoring relies on surrogate models of BP and the information encoded in alternative physiological measures, such as photoplethysmography (PPG) or electrocardiography (ECG), to continuously estimate BP. Existing models have typically relied upon pulse-wave delay between two arterial segments or other pulse waveform features in the estimation process. However, the models available in the literature (1) provide an estimation of the systolic BP (SBP), diastolic BP (DBP), and mean BP (MAP) only, (2) are validated solely in controlled environments, and (3) do not assign a confidence metric to the estimates. At this point, cuffless methods are not used by clinicians due to their inaccuracy, the validation inadequacy, and/or the unevaluated uncertainty of the existing methods. The first objective of this thesis is to develop a cuffless modeling approach to estimate the BP waveform from ECG and PPG, and extract important BP features, such as the SBP, DBP, and MAP. Access to the full waveform has significant advantages over previous cuffless BP estimation tools in terms of accuracy and access to additional cardiovascular health markers (e.g., cardiac output), as well as potentially providing arterial stiffness. The second objective of this thesis is to validate cuffless BP estimation during activities of daily living, an uncontrolled environment, but also in more challenging physiological conditions such as during exercise. Such validation is important to increase confidence in cuffless BP monitoring, it also helps understand the limitation of the method and how they would affect clinical outcomes. Finally, in an effort to improve confidence in the cuffless BP estimation framework (third objective), a prediction interval (PI) estimation method is introduced. For potential clinical uses, it is imperative to assess the uncertainty of the BP estimate for acute outcome evaluation and it is even more so if cuffless BP is to be employed outside of the clinic. In this thesis, user-specific nonlinear autoregressive models with exogenous inputs (NARX) are implemented using an artificial neural network (ANN) to predict the BP waveforms using ECG and/or PPG signals as inputs. To validate the NARX-based BP estimation framework during activities of daily living, data were collected during six-hours testing phase wherein the participants go about their normal daily living activities. Data are further collected at four-month and six-month time points to validate long-term performance. To broaden the range of BP in the training data, subjects followed a short procedure consisting of sitting, standing, walking, Valsalva maneuvers, and static handgrip exercises. To evaluate the uncertainty of the BP estimates, one-class support vector machines (OCSVM) models are trained to cluster data in terms of the percentage of outliers. New BP estimates are then assigned to a cluster using the OCSVMs hyperplanes, and the PIs are estimated using the BP error standard deviation associated with different training data clusters. The OCSVM is used to estimate the PI for three BP model architectures: NARX models, feedforward ANN models, and pulse arrival time (PAT models). The three BP estimations from the models are fused using the covariance intersection fusion algorithm, which improves BP and PI estimates in comparison with individual model performance. The proposed method models the BP as a dynamical system leading to better accuracy in the estimation of SBP, DBP and MAP when compared to the PAT model. Moreover, the NARX model, with its ability to provide the BP waveform, yields more insight into patient health. The NARX model demonstrates superior accuracy and correlation with “ground truth” SBP and DBP measures compared to the PAT models and a clear advantage in estimating the large range of BP. Preliminary results show that the NARX models can accurately estimate BP even months apart from the training. Preliminary testing suggests that it is robust against variabilities due to sensor placement. The employed model fusion architecture establishes a method for cuffless BP estimation and its PI during activities of daily living that can be used for continuous monitoring and acute hypotension and hypertension detection. The NARX model, with its capacity to estimate a large range of BP, is next tested during moderate and heavy intensity exercise. Participants performed three cycling exercises: a ramp-incremental exercise test to exhaustion, a moderate and a heavy pseudorandom binary sequence exercise tests on an electronically braked cycle ergometer. Subject-specific and population-based NARX models are compared with feedforward ANN models and PAT (and heart rate) models. Population-based NARX models, when trained on 11 participants’ three cycling tests (tested on the participant left out of training), perform better than the other models and show good capability at estimating large changes in MAP. A limitation of the approach is the incapability of the models to track consistent decreases in BP during the exercise caused by a decrease in peripheral resistance since this information is apparently not encoded in either the forehead PPG or ECG signals. Nevertheless, the NARX model shows good precision during the whole 21 minutes testing window, a precision that is increased when using a shorter evaluation time window, and that can potentially be even further increased if trained on more data. The validation protocols and the use of a confidence metric developed in this thesis is of great value for such health monitoring application. Through such methodology, it is hoped that cuffless BP estimation becomes, one day, a well-established BP measurement method

Ultrasound Imaging Innovations for Visualization and Quantification of Vascular Biomarkers

The existence of plaque in the carotid arteries, which provide circulation to the brain, is a known risk for stroke and dementia. Alas, this risk factor is present in 25% of the adult population. Proper assessment of carotid plaque may play a significant role in preventing and managing stroke and dementia. However, current plaque assessment routines have known limitations in assessing individual risk for future cardiovascular events. There is a practical need to derive new vascular biomarkers that are indicative of cardiovascular risk based on hemodynamic information. Nonetheless, the derivation of these biomarkers is not a trivial technical task because none of the existing clinical imaging modalities have adequate time resolution to track the spatiotemporal dynamics of arterial blood flow that is pulsatile in nature. The goal of this dissertation is to devise a new ultrasound imaging framework to measure vascular biomarkers related to turbulent flow, intra-plaque microvasculature, and blood flow rate. Central to the proposed framework is the use of high frame rate ultrasound (HiFRUS) imaging principles to track hemodynamic events at fine temporal resolution (through using frame rates of greater than 1000 frames per second). The existence of turbulent flow and intra-plaque microvessels, as well as anomalous blood flow rate, are all closely related to the formation and progression of carotid plaque. Therefore, quantifying these biomarkers can improve the identification of individuals with carotid plaque who are at risk for future cardiovascular events. To facilitate the testing and the implementation of the proposed imaging algorithms, this dissertation has included the development of new experimental models (in the form of flow phantoms) and a new HiFRUS imaging platform with live scanning and on-demand playback functionalities. Pilot studies were also carried out on rats and human volunteers. Results generally demonstrated the real-time performance and the practical efficacy of the proposed algorithms. The proposed ultrasound imaging framework is expected to improve carotid plaque risk classification and, in turn, facilitate timely identification of at-risk individuals. It may also be used to derive new insights on carotid plaque formation and progression to aid disease management and the development of personalized treatment strategies

Proceedings of the 35th International Workshop on Statistical Modelling : July 20- 24, 2020 Bilbao, Basque Country, Spain

466 p.The InternationalWorkshop on Statistical Modelling (IWSM) is a reference workshop in promoting statistical modelling, applications of Statistics for researchers, academics and industrialist in a broad sense. Unfortunately, the global COVID-19 pandemic has not allowed holding the 35th edition of the IWSM in Bilbao in July 2020. Despite the situation and following the spirit of the Workshop and the Statistical Modelling Society, we are delighted to bring you the proceedings book of extended abstracts