Diffusion tensor imaging (DTI) provides a unique approach to probing the microstructure of biological tissues noninvasively and DTI-based tractography is an irreplaceable tool to measure anatomical connectivity in human brain in vivo. However, due to the limitations of DTI techniques and tractography algorithms, tracked pathways might not be completely accurate. Thus, quantifying the agreement between DTI tractography and histological measurements of true fiber pathways is critical for progress in the field. A series of validation studies of DTI tractography is presented in this thesis, including (1) assessment of the relationship between DTI tractography-derived corticocortical connectivity and histological 'ground truth' on a regional and voxelwise basis; (2) localizing the divergence between DTI tractography and histology, followed by qualitative analysis of the reasons for those discrepancies. The work presented here is based on a non-human primate animal model, which has comparable parameters to magnetic resonance imaging (MRI) human data, and thus provides an important guide to interpreting the results of DTI-based tractography measures in the human brain.

Understanding the contribution of individual mechanical stimuli to cardiovascular pathogenesis is critically important for understanding and treating cardiovascular disease, and microfluidic bioreactors are a useful tool for these studies. Cardiovascular bioreactors are uniquely complex because they require the simultaneous application of fluid shear stress and dynamic strain. One of the key shortcomings of current mechanotransduction bioreactors that we wanted to address in this thesis was the effect of dynamic strain on the fluid shear conditions in a bioreactor system. In this thesis, we designed, developed and validated a microfluidic bioreactor system which can accurately recapitulate the major hemodynamic mechanical parameters of shear stress and strain. We characterized the system using computational modeling and validated computational models by developing novel three dimensional particle velocimetry (PIV) techniques. Computational modeling of the microfluidic bioreactor during dynamic strain demonstrated that shear stress experience by cells in a bioreactor is altered by applying dynamic strain. The PIV methods developed allowed us to visualize the three dimensional fluid velocity profile in the bioreactor during dynamic strain and allowed us to measure and validate the computational models of bioreactor dynamics. In addition, we applied this system to investigate the effects of mechanical stimuli on omental mesothelium.

Purpose: This study evaluates a new magnetic resonance imaging method for detecting calcium deposits, using their characteristic susceptibility effects, in practical conditions to provide insight into its clinical value for detecting breast microcalcifications at high field (7T). Methods: Signatures of calcium deposits in phase images were detected via cross-correlation between the images and a library of templates containing simulated phase signatures of deposits. The influences of deposit position, signal-to-noise ratio, spatial resolution, high-pass filtering, and fat suppression on the method were determined and used to optimize the method for detecting simulated microcalcifications inserted in silico into breast MRI of healthy controls. Results: In images acquired with a clinical scanner and acquisition times below 12 minutes, simulated microcalcifications with sizes of 0.8 1.0 mm were detected in images with voxel sizes of (0.4 mm)3 and (0.6 mm)3 with sensitivity and specificity of 75-87% and 54-87%, respectively; smaller microcalcifications with sizes of 0.6 0.7 mm were detected better in images with voxel size of (0.4 mm)3, with sensitivity and specificity of 87% and 54%, respectively, than in images with voxel size of (0.6 mm)3, with sensitivity and specificity of 56-78% and 44-47%, respectively. Conclusions: The new method is promising for detecting large microcalcifications (approximately 0.8 1.0 mm in longest dimension) within the breast at 7T. Detection of smaller deposits may be possible in images with higher spatial resolution; unfortunately, these images take too long to acquire using current MR methods and therefore are clinically impractical. Although mammography can detect smaller microcalcifications with sensitivity between 74-95%, and specificity between 89-99%, this alternative MRI method does not expose breasts to ionizing radiation, is not affected by breast density, and can be combined with other quantitative MRI exams to increase the diagnostic specificity of breast MRI.

The objective of this dissertation is to investigate the accuracy of point and surface based image space to physical space registration performed using a spatially tracked A-mode ultrasound transducer to localize features and to determine the applicability of these techniques for use in interactive, image-guided surgery. The accuracy of subcutaneous marker localization has been demonstrated using a phantom. An spatially tracked A-mode ultrasonic localization system was constructed. The system was used to examine the accuracy of transcutaneous localization of bone implanted fiducial marker analogs. The relationship between the number of signals used to localize the fiducial markers and localization accuracy was determined. Validation was performed by comparison to an optical system. The accuracy of surface registrations based on matching the outer surface of the skull as identified by ultrasound and in CT images has been estimated in a phantom. The ultrasonic localization system was modified for use in localizing the outer surface of the skull. The effect of changes in the image model parameters and image slice thickness on registration error were examined. The effect of variations in the speed of sound was also examined. The surface registration results were validated by comparison to a fiducial marker registration. A preliminary study on the accuracy of surface registrations in twelve human patients has been performed. The ultrasonic localization system was enhanced to synchronize the acquisition of ultrasonic and optical information. Patient motion in the CT images was compensated for using the Nbar system of the CRW stereotactic frame. The surface registration results were evaluated for three different speed of sound values corresponding to the speed of sound in the tissue components of human scalp. The correlation between the number of ultrasonic points used in the surface registration algorithm and the surface registration error was evaluated. Fiducial markers attached to the CRW stereotactic frame were used to validate the surface registration results. These experiments have demonstrated a spatially tracked A-mode ultrasound transducer capable of localizing both point and surface features that can be used in registration processes for interactive, image-guided procedures.

<p> Sudden cardiac death is the primary cause of mortality in the industrialized world. Ventricular tachycardia and lethal arrhythmias such as ventricular fibrillation are believed to be the result of reentrant electrical activity, i.e., self-sustained electrical activity which continues to re-excite regions of cardiac tissue independently of the natural pacemaker rhythm. The mechanisms behind fibrillation initiation, maintenance, and termination by a defibrillatory shock are largely unknown. </p> <p> Cardiac fibrillation is characterized by a complex spatial interaction of non-stationary spiral waves; however, the nature of this interaction is an ongoing topic of investigation. The organizing center of reentry is a topological defect called a phase singularity in two dimensions, a filament in three dimensions; an understanding of fibrillation behavior may be obtained by localizing and tracking these defects. Experimentally, the electrodynamic behavior is typically investigated via optical mapping using voltage-sensitive fluorescent dyes. </p> <p> In this thesis, a technique to detect phase singularities based upon topological charge was applied to nonlinear time-series and phase portrait analysis of optical signals, and later extended to filament detection; this procedure was shown to be both efficient and mathematically robust. An alternate method to reconstruct the phase portrait was also explored and shown to overcome some of the limitations of the time-series method as well as permitting singularity detection closer to initiation than previously allowed. Numerically examining the interaction dynamics of a simple filament configuration paralleling that seen in experimental preparations indicated that a critical bifurcation in filament life-time exists between attractive and repulsive behavior along with annihilation by mutual collision and collapse by shrinkage; which could be represented by a difference of Yukawa potentials by treating the filaments as a pair of point charges. The inclusion of optical depth effects into a numerical model of three-dimensional filament activity was studied, and suggested that these effects have a significant impact on observed epicardial activity. Finally, a three-dimensional geometric reconstruction of an isolated, perfused heart with the fluorescence information as a texture map, previously developed as a proof-of-concept, was shown to be a viable tool for whole-heart singularity visualization.</p>

The objective of this research was to design and develop a system capable of displaying cortical brain function during image-guided neurosurgery. Brain function was determined using a cortical stimulator, classified according to function type, and displayed along with pre-operative tomographic and rendered images of the brain. In addition to displaying brain function acquired from the patient undergoing surgery, a probabilistic map of functional information acquired from a database or previous patients may also be displayed. This information is stored in an atlas coordinate system and can be mapped to the patient's coordinate system for display during surgery. The entire system was tested and evaluated during three human neurosurgery procedures. Functional information corresponding to speech, motor, and sensory regions was identified and displayed during surgery. This data was then mapped to a common reference database using a non-linear registration algorithm to evaluate the feasibility of using this system to create a functional atlas of the human brain.

Raman Spectroscopy has been shown to have the potential for providing differential diagnosis in the cervix with high sensitivity and specificity in previous in vitro and in vivo studies. Two clinical studies further evaluated the potential of near infrared Raman spectroscopy to detect cervical dysplasia in a clinical setting. In the first study, the Raman spectral features of the different pathologies found in the cervix were characterized and mathematical algorithms were developed to classify the spectra according to pathology. The second study examined and quantified the sources of spectral variability within a given pathology. Experiments using organotypic raft cultures examined the biochemical and cellular basis for the spectral differences seen between normal and dysplastic tissue. These studies have laid the foundation for the development of Raman spectroscopy as a non-invasive, real-time diagnostic tool for cervical dysplasia.

The correlation between the stiffness and health of tissue is an accepted form of organ disease assessment. As a result, there has been a significant amount of interest in developing methods to image elasticity parameters (i.e. elastography). This work presents a technique that frames the elastography imaging problem within a non-rigid iterative registration approach. Through the use of finite element modeling and image comparison methods, material properties are varied in order to optimize the registration between a post-compressed image and a model-generated compressed image. The results shown here demonstrate the strong connection between image similarity and appropriate tissue parameters and the algorithm's ability to detect contrast in tissue stiffness. Simulations demonstrate that the method is effective over a wide range of scenarios. Also, we were successfully able to localize regions of stiffness within phantom data taken in both CT and MRI. By casting elasticity image reconstruction within the context of image similarity, the method is generalized to all forms of medical imaging.

The Vanderbilt University Free Electron Laser (FEL) is a tunable source of pulsed infrared radiation with pulse characteristics unlike those of most laser systems. A primary objective of the research presented in this dissertation is to investigate the effects of chromophore and pulse characteristics in the ablation of soft tissues with the (FEL). The working hypothesis of the research project is that results of ablation of soft tissues with the FEL cannot be solely explained by the selective absorption of protein components in the tissue, and that the pulse characteristics of the laser play an important role. Three related studies are presented in this dissertation. First, the ablation depth and ablation threshold of rat dermis irradiated with the FEL at many wavelengths were measured and analyzed to reveal gross effects of the ablation process. Second, acoustic transients generated during the ablation of rat dermis and gelatin samples were measured and analyzed to reveal the effects of protein absorption and mechanical strength in the ablation process. Finally, numerical modeling of the ablation process was employed to investigate the effect of the temporal pulse structure of the laser and the effect of dynamic absorption of water on the ablation process. The results of the studies presented here led to the following conclusions. First, the ablation of soft tissues irradiated with the FEL is largely described by a steady-state ablation model, indicating that the mechanism of ablation is predominantly photothermal in nature. Second, the ablation of soft tissues with infrared FEL radiation is a surface-mediated process, similar to that of traditional ultraviolet laser tissue ablation. Third, the dynamic absorption of water plays a significant role in the process. Finally, protein absorption of the incident radiation results in the targeted destruction of the tissue structural matrix at wavelengths where the absorption of protein represents a significant fraction of the overall absorption cross-section.

The purpose of this research is to study and quantify the effects of system and human factors on objective workload, subjective workload and physiological stress in residents and attending physicians working in an emergency department (ED) at a Level I trauma center. The study design is a time-motion task analysis that incorporates objective, subjective, and physiological measures of stress and workload. Several procedural methods and workload assessment techniques were developed, integrated and used to dissect the dynamic ED work environment. Descriptive statistics characterizing this environment are calculated and compared to previous studies. Methodologies developed for measuring workload continuously are implemented and discussed. The study demonstrates the applicability of human factors engineering to describe a medical work environment and identify potential shortcomings in system and provider-level care.