3-D lung deformation and function from respiratory-gated 4-D x-ray CT images : application to radiation treatment planning.

Many lung diseases or injuries can cause biomechanical or material property changes that can alter lung function. While the mechanical changes associated with the change of the material properties originate at a regional level, they remain largely asymptomatic and are invisible to global measures of lung function until they have advanced significantly and have aggregated. In the realm of external beam radiation therapy of patients suffering from lung cancer, determination of patterns of pre- and post-treatment motion, and measures of regional and global lung elasticity and function are clinically relevant. In this dissertation, we demonstrate that 4-D CT derived ventilation images, including mechanical strain, provide an accurate and physiologically relevant assessment of regional pulmonary function which may be incorporated into the treatment planning process. Our contributions are as follows: (i) A new volumetric deformable image registration technique based on 3-D optical flow (MOFID) has been designed and implemented which permits the possibility of enforcing physical constraints on the numerical solutions for computing motion field from respiratory-gated 4-D CT thoracic images. The proposed optical flow framework is an accurate motion model for the thoracic CT registration problem. (ii) A large displacement landmark-base elastic registration method has been devised for thoracic CT volumetric image sets containing large deformations or changes, as encountered for example in registration of pre-treatment and post-treatment images or multi-modality registration. (iii) Based on deformation maps from MOFIO, a novel framework for regional quantification of mechanical strain as an index of lung functionality has been formulated for measurement of regional pulmonary function. (iv) In a cohort consisting of seven patients with non-small cell lung cancer, validation of physiologic accuracy of the 4-0 CT derived quantitative images including Jacobian metric of ventilation, Vjac, and principal strains, (V?1, V?2, V?3, has been performed through correlation of the derived measures with SPECT ventilation and perfusion scans. The statistical correlations with SPECT have shown that the maximum principal strain pulmonary function map derived from MOFIO, outperforms all previously established ventilation metrics from 40-CT. It is hypothesized that use of CT -derived ventilation images in the treatment planning process will help predict and prevent pulmonary toxicity due to radiation treatment. It is also hypothesized that measures of regional and global lung elasticity and function obtained during the course of treatment may be used to adapt radiation treatment. Having objective methods with which to assess pre-treatment global and regional lung function and biomechanical properties, the radiation treatment dose can potentially be escalated to improve tumor response and local control

Rapid Segmentation Techniques for Cardiac and Neuroimage Analysis

Recent technological advances in medical imaging have allowed for the quick acquisition of highly resolved data to aid in diagnosis and characterization of diseases or to guide interventions. In order to to be integrated into a clinical work flow, accurate and robust methods of analysis must be developed which manage this increase in data. Recent improvements in in- expensive commercially available graphics hardware and General-Purpose Programming on Graphics Processing Units (GPGPU) have allowed for many large scale data analysis problems to be addressed in meaningful time and will continue to as parallel computing technology improves. In this thesis we propose methods to tackle two clinically relevant image segmentation problems: a user-guided segmentation of myocardial scar from Late-Enhancement Magnetic Resonance Images (LE-MRI) and a multi-atlas segmentation pipeline to automatically segment and partition brain tissue from multi-channel MRI. Both methods are based on recent advances in computer vision, in particular max-flow optimization that aims at solving the segmentation problem in continuous space. This allows for (approximately) globally optimal solvers to be employed in multi-region segmentation problems, without the particular drawbacks of their discrete counterparts, graph cuts, which typically present with metrication artefacts. Max-flow solvers are generally able to produce robust results, but are known for being computationally expensive, especially with large datasets, such as volume images. Additionally, we propose two new deformable registration methods based on Gauss-Newton optimization and smooth the resulting deformation fields via total-variation regularization to guarantee the problem is mathematically well-posed. We compare the performance of these two methods against four highly ranked and well-known deformable registration methods on four publicly available databases and are able to demonstrate a highly accurate performance with low run times. The best performing variant is subsequently used in a multi-atlas segmentation pipeline for the segmentation of brain tissue and facilitates fast run times for this computationally expensive approach. All proposed methods are implemented using GPGPU for a substantial increase in computational performance and so facilitate deployment into clinical work flows. We evaluate all proposed algorithms in terms of run times, accuracy, repeatability and errors arising from user interactions and we demonstrate that these methods are able to outperform established methods. The presented approaches demonstrate high performance in comparison with established methods in terms of accuracy and repeatability while largely reducing run times due to the employment of GPU hardware

Modelling and verification of doses delivered to deformable moving targets in radiotherapy

During the last two decades, advanced treatment techniques have been developed in radiotherapy to achieve more conformal beam targeting of cancerous lesions. The advent of these techniques, such as intensity modulated radiotherapy (IMRT), volumetric modulated arc radiothreapy (VMAT), Tomotherapy etc., allows more precise localisation of higher doses to complex-shaped target volumes, thereby sparing more healthy tissue. In this context, motion management is a critical issue in contemporary radiotherapy (RT). That anatomic structures move during respiration is well known and much research is presently being devoted to strategies to contend with organ motion. However, moving structures are typically regarded as rigid bodies. The fact that many structures deform as a result of motion makes their resultant dose distributions difficult to measure and calculate, and has not been fully accounted for. The potential for ineffective treatments that do not take into account motion and anatomic deformation is self-evident. This thesis addresses the pressing need to investigate dose distributions in targets that deform during and/or between treatments, to ensure robust calculations for dose accumulation and delivery, thus providing the most positive outcomes for patients. This involves the direct measurement of complex and re-distributed dose in deforming objects (an experimental model), as well as calculations of the deformed dose distribution (a mathematical model). The comparison thereof aims to validate the dose deformation technique, thereby to apply the method to a clinical example such as liver stereotactic body radiotherapy. To facilitate four-dimensional deformable dosimetry for both external beam radiotherapy and brachytherapy, methodologies for three-dimensional deformed dose measurements were developed and employed using radiosensitive polymer gel combined with a cone beam optical computed tomography (CT) scanner. This includes the development of a novel prototype deformable target volume using a tissue-equivalent, deformable gel dosimetric phantom, dubbed “defgel”. This can reproducibly simulate targets subject to a range of mass- and density-conserving deformations representative of those observable in anatomical targets. This novel tool was characterised in terms of its suitability for the measurement of dose in deforming geometries. It was demonstrated that planned doses could be delivered to the deformable gel dosimeter in the presence of different deformations and complex spatial re-distributions of dose in all three dimensions could be quantified. For estimating the cumulative dose in different deformed states, deformable image registration (DIR) algorithms were implemented to ‘morph’ a dose distribution calculated by a treatment planning system. To investigate the performance of DIR and dose-warping technique, two key studies were undertaken. The first was to systematically assess the accuracy of a range of different DIR algorithms available in the public domain and quantitatively examine, in particular, low-contrast regions, where accuracy had not previously been established. This work investigates DIR algorithms in 3D via a systematic evaluation process using defgel suitable for verification of mass- and density-conserving deformations. The second study was a full three-dimensional experimental validation of the dose-warping technique using the evaluated DIR algorithm and comparing it to directly measured deformed dose distributions from defgel. It was shown that the dose-warping can be accurate, i.e. over 95% passing rate of 3D-gamma analysis with 3%/3mm criteria for given extents of deformation up to 20 mm For the application of evaluating patient treatment planning involving tumour motion/deformation, two key studies were undertaken in the context of liver stereotactic body radiotherapy. The first was a 4D evaluation of conventional 3D treatment planning, combined with 4D computed tomography, in order to investigate the extent of dosimetric differences between conventional 3D-static and path-integrated 4D-cumulative dose calculation. This study showed that the 3D planning approach overestimated doses to targets by ≤ 9% and underestimated dose to normal liver by ≤ 8%, compared to the 4D methodology. The second study was to assess a consequent reduction of healthy tissue sparing, which may increase risk for surrounding healthy tissues. Estimates for normal tissue complications probabilities (NTCP) based on the two dose calculation schemes are provided. While all NTCP were low for the employed fractionation scheme, analysis of common alternative schemes suggests potentially larger uncertainties exist in the estimation of NTCP for healthy liver and that substantial differences in these values may exist across the different fractionation schemes. These bodies of work have shown the potential to quantify such issues of under- and/or over-dosages which are quite patient dependent in RT. Studies presented in this work consolidate gel dosimetry, image guidance, DIR, dose-warping and consequent dose accumulation calculation to investigate the dosimetric impact and make more accurate evaluation of conventional 3D treatment plans. While liver stereotactic body radiotherapy (SBRT) was primarily concerned for immediate clinical application, the findings of this thesis are also applicable to other organs with various RT techniques. Most importantly, however, it is hoped that the outcomes of this thesis will help to improve treatment plan accuracy. By considering both computation and measurement, it is also hoped that this work will open new windows for future work and hence provide building blocks to further enhance the benefit of radiotherapy treatment

Measuring and Modeling Fluid Dynamic Processes using Digital Image Sequence Analysis

In this thesis novel motion models have been developed and incorporated into an extended parameter estimation framework that allows to accurately estimate the parameters and regularize them if needed. The performance of this framework has been increased to real time and implemented on inexpensive graphics hardware. Confidence and situation measures have been designed to discard inaccurate estimates. A phase field approach was developed to estimate piecewise smooth motion while detecting object boundaries at the same time. These algorithmic improvements have been successfully applied to three areas of fluid dynamics: air-sea interaction, microfluidics and plant physiology. At the ocean surface, the fluxes of heat and momentum have been measured with thermographic techniques, both spatially and temporally highly resolved. These measurement techniques present milestones for research in air-sea interaction, where point measurements and particle based laboratory measurements represent the state-of-the art. Calculations were done with two models, both making complement assumptions. Still, results derived from both models agree remarkably well. Measurements were conducted in laboratory settings as well as in the field. Microfluidic flow was measured with a new approach to molecular tagging velocimetry that explicitly models Taylor dispersion. This has lead to an increase in accuracy and applicability. Inaccuracies and problems of previous approaches due to Taylor dispersion were successfully evaded. Ground truth test measurements have been conducted, proving the accuracy of this novel technique. For the first time, flow velocities were measured in the xylem of plant leaves with active thermography. This represents a technique for measuring these flows on extended leaf areas on free standing plants, minimizing the impact caused by the measurement. Ground truth measurements on perfused leafs were performed. Measurements were also conducted on free standing plants in a climatic chamber, to measure xylem flows and relate flow velocities to environmental parameter. With a cuvette, environmental factors were varied locally. These measurements underlined the sensitivity of the new approach. A linear relationship in between flow rates and xylem diameter was found

The Mechanics And Molecular Regulation Of Heart Valve Morphogenesis

Congenital heart defects (CHD) affect over 1% of the American population and are the origin of substantial healthcare costs. A majority of these defects involve malformations of the valvuloseptal apparatus, which is the precursor to the valves of the heart. Due to the necessity of valves for proper heart function, most moderate to severe valve defects require surgical intervention. Corrective surgery is costly and can result in complications and/or restrictions on the patient's lifestyle. Current genetic evidence for CHD is inadequate to explain the variety and prevalence of these defects, suggesting that misguided molecular and mechanical signaling may be responsible. Unfortunately, the role of mechanical and molecular signaling in normal valve development is only beginning to be elucidated, making the detection of defective valves difficult. An understanding of these mechanical and molecular cues and their effect on valve mechanics in normal development is essential for effective treatment of CHDs. In this dissertation, we focus on the capacity of mechanical and molecular signals to direct valve morphology and mechanical properties. We first validate two mechanical testing techniques to characterize the mechanical properties of avian valves through development. This revealed a monotonic increase in valve stiffness which was concomitant with a rapid transition from globular to planar geometry. We then investigated the capacity of transforming growth factor beta 3 (TGF[beta] 3) and serotonin (5-HT) to stimulate biomechanical remodeling in avian valves. TGF[beta] 3 significantly increased valve stiffness through cell contraction, proliferation, and extracellular matrix synthesis. 5-HT modulated TGF[beta] 3 remodeling in both in vitro and in vivo models. This demonstrated a plausible molecular mechanism for the stiffness increase observed during development. To investigate the role of mechanical signaling, we developed a model of growth and remodeling (shape change) that is driven by mechanical stimuli. The consequences of particular assumptions about growth were illustrated with numerical examples. We then built a computational model of valve growth involving both the fluid and solid domains of the atrioventricular (AV) canal and valve. The distribution of the fluid loads on the valve was correlated with the natural morphology of the valve. The computational framework allowed the effects of pressure and shear tractions to be individually interpreted. These results provided a potential mechanical mechanism to explain the valve morphology observed during development. The dissertation concludes with a chapter on teaching and outreach that stemmed from my involvement in the NSF GK-12 program. Conclusions and future directions are discussed

Spatio-Temporal Analysis of Flows Close to Free Water Surfaces

In order to examine the air-water gas exchange, a detailed knowledge is needed about the flow field within and beneath the water-side viscous boundary layer. Therefore a novel measurement technique is developed for the spatio-temporal analysis of flows close to free water surfaces. A fluid volume is illuminated by LEDs. Small spherical particles are added to the fluid, functioning as a tracer. A camera pointing to the water surface from above records the image sequences. The distance of the spheres to the surface is coded by means of a supplemented dye, which absorbs the light of the LEDs. By using LEDs flashing with two different wavelengths, it is possible to use particles variable in size. The velocity vectors are obtained by using an extension of the method of optical flow. The vertical velocity component is computed from the temporal change of brightness. Using 3D parametric motion models the shear stress at surfaces can be estimated directly, without previous calculation of the vector fields. Hardware and algorithmics are tested in several ways: A laminar falling film serves as reference flow. The predicted parabolic profile of this stationary flow can be reproduced very well. Buoyant convective turbulence acts as an example for an instationary inherently 3D flow. The direct estimation of the wall shear rate is applied to sequences recorded in the context of biofluidmechanics, revealing a substantial improvement compared to conventional techniques