Doctor of Philosophy, Case Western Reserve University, 2011, Biomedical Engineering

Ca2+ cycling between the cellular and subcellular compartments plays an important role in regulating cardiac contraction. Disturbance in Ca2+ handling occurs in heart failure and is closely related to abnormal contractile performance. The influx of extracellular Ca2+ through L-type calcium channel is the trigger and a key player in the Ca2+ cycling process. However, there are limited ways to measure it in vivo. Recently, manganese (Mn2+)-enhanced MRI (MEMRI) has been proposed as a promising probe to assess Ca2+ uptake because Mn2+ also enters the cell through the Ca2+ channels. However, quantitative analysis and substantial validation are still lacking, which has limited the application of MEMRI as an in vivo method for quantitative delineation of the Ca2+ influx rate. In the current thesis project, a quantitative MEMRI method was developed and validated using small animal models. The sensitivity to subtle alterations in Ca2+ influx rate was demonstrated in a qualitative MEMRI study using a genetically manipulated mouse model that manifested slightly altered L-type Ca2+ channel activity. To provide quantitative estimation of Mn2+ dynamics, fast T1 mapping techniques were developed based on the direct linear relationship between Mn2+ concentration and proton R1. An ECG-triggered saturation recovery Look-Locker (SRLL) method and a model-based compressed sensing method was developed and validated, respectively. When these two methods were combined, rapid T1 mapping (< 80s) of both myocardium and blood were achieved at high spatial resolution (234x469 μm2). Subsequently, a kinetic model was developed to determine Ca2+ influx rate from the quantitative MEMRI measurements. The robustness and accuracy of estimated Ca2+ influx rate was validated using perfusion MEMRI datasets with L-type Ca2+ channel activity well controlled by buffer ingredients. In conclusion, the accomplishment of this project provides a robust MEMRI method for in vivo quantification of L-type Ca2+ (open full item for complete abstract)

Committee: Xin Yu (Committee Chair); Chris Flask (Committee Member); Mark Griswold (Committee Member); David Rosenbaum (Committee Member); David Wilson (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Medical Imaging; Radiation; Radiology

Doctor of Philosophy, Case Western Reserve University, 2009, Biomedical Engineering

In the recent years molecular imaging has become an important tool in biomedical research. To quantify physiology from image data, compartment modeling has been shown to be useful by analyzing the pharmacokinetics from molecular images. However, some challenges still exist and limit the application of compartment modeling in a routine basis. Methods to resolve some of the existing challenges are proposed and validated in this thesis. First, non-invasive methods are developed to measure the input functions required in compartment modeling and parameter estimation for positron-emission tomography (PET) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies. Methods for image-derived input functions are developed and validated against the reference input functions. Second, a software environment is established to integrate functions that handle image analysis and modeling analysis based on COmpartment Model Kinetic Analysis Tool (COMKAT). Methods to enhance speed and interface for COMKAT have been implemented as described in this thesis. With the methods and software developed in this thesis, researchers can quantify in vivo pharmacokinetics with molecular imaging methods to measure the physiology and metabolism non-invasively in a routine basis.

Committee: Raymond Muzic PhD (Advisor); Xin Yu PhD (Committee Chair); Gerald Saidel PhD (Committee Member); Peter Faulhaber MD (Committee Member) Subjects: Biomedical Research; Engineering

PhD, University of Cincinnati, 2011, Arts and Sciences: Mathematical Sciences

This dissertation includes two parts: developing a new model for individual pharmacokinetics (PK) and applying a Bayesian three-stage hierarchical model to population PK. As to individual PK, the standard methodology is compartment modeling characterized by physiological mechanisms. Parameters in individual PK are estimated based on data from a single individual. In the individual PK part, the relationship between drug concentration and time for an individual was modeled, and the kinetic parameters for an individual were characterized and quantified. Specifically, a piecewise absorption model without physiological compartment mechanisms was developed and applied for Mycophenolic acid (MPA) data that does not obey a one compartment first-order absorption pattern. In the second part of this dissertation, a Bayesian three-stage hierarchical model was applied to population PK using simulated multi-occasion PK data with both inter-individual variability (IIV) and inter-occasion variability (IOV). This Bayesian approach was applied to three PK models. First, a PK model with independent IOV was studied, and different variances at different occasions were estimated. Second, a PK model with multivariate covariates and correlated and constrained IOV was studied, and unequal constrains in the variance matrix was modeled. Third, a PK model with arbitrary IOV was studied, and four inverse Whishart priors for IOV with different scale matrices were investigated. Based on the result and analysis, a recommendation of choosing the prior distribution was made according to whether or not a reliable source of the covariance matrix exists. For all population PK models, Gibbs sampling and Metropolis-Hasting algorithm were implemented using SAS IML to generate samples from posterior distributions.

Committee: Siva Sivaganesan PhD (Committee Chair); James Deddens PhD (Committee Member); Seongho Song PhD (Committee Member); Paul Horn PhD (Committee Member) Subjects: Statistics

MS, University of Cincinnati, 2008, Engineering : Mechanical Engineering

Vehicle noise, vibration and harshness (NVH) problems can be analyzed using numerical methods such as finite element and boundary element analysis approaches, which are generally complex and time consuming. In order to speed the analysis and reduce the calculation burden, an enhanced, simplified numerical acoustic cavity formulation is developed, used and verified for the analysis of several vehicle NVH problems. The simplified model can incorporate multiple acoustic cavities joined by flexible panels to represent adjacent vehicle compartments. Several models are created with different cavity and panel configurations, and transfer functions predicted by these models are compared with corresponding transfer functions from measured vehicle data. The comparison results show that the developed simplified model provides reasonable accuracy for the analysis and simulation of vehicle compartment acoustics. While the initial goal of the simplified model was to develop a tool to observe general trends and effects associated with perturbations in the dimensions and configurations of joined vehicle compartments, results show sufficient accuracy for the model to be used for more detailed analyses as well. Additionally, an active noise control (ANC) system is proposed for tuning vehicle interior response, whereas traditional vehicle ANC is intended to suppress unwanted vehicle response. The proposed concept is adapted from the basic filtered-x least mean squares (FXLMS) algorithm and is studied numerically, utilizing simulated control input speakers inside the passenger compartment. An optimal configuration of these speakers is determined in order to maximize the effectiveness of the ANC system and then the proposed approach is demonstrated using a powertrain noise example in which individual engine firing orders are targeted for shaping either by reducing or enhancing the spectral content.

Committee: Teik Lim PhD (Committee Chair); Randall Allemang PhD (Committee Member); Jay Kim PhD (Committee Member) Subjects: Acoustics; Engineering; Mechanical Engineering