Optical dosimetry tools and Monte Carlo based methods for applications in image guided optical therapy in the brain

Purpose: The long-term goal of this research is to determine the feasibility of using near infra-red light to stimulate drug release in metastatic lesions within the brain. In this work, we focused on developing the tools needed to quantify and verify photon fluence distribution in biological tissue. To accomplish this task, an optical dosimetry probe and Monte Carlo based simulation code were fabricated, calibrated and developed to predict light transport in heterogeneous tissue phantoms of the skull and brain. Empirical model (EM) of photon transport using CT images as input were devised to provide real-time calculations capable of being translated to preclinical and clinical applications. Methods and Materials: A GPU based 3D Monte Carlo code was customized to simulate the photon transport within head phantoms consisting of skull bone, white and gray matter with differing laser beam properties, including flat, Gaussian, and super-Gaussian profiles that are converging, parallel, or diverging. From these simulations, the local photon fluence and tissue dosimetric distribution was simulated and validated through the implementation of a novel titanium-based optical dosimetry probe with an isotropic acceptance and 1.5mm diameter. Empirical models (EM) of photon transport were devised and calibrated to MC simulated data to provide 3D fluence and optical dosimetric maps in real-time developed around on a voxel-based convolution technique. Optical transmission studies were performed using human skull bone samples to determine the optical transmission characteristics of heterogeneous bone structures and the effectiveness of the Monte Carlo in simulating this heterogeneity. These tools provide the capability to develop and optimize treatment plans for optimal release of pharmaceuticals to metastatic breast cancer in the brain. Results: At the time of these experiments, the voxel-based CUDA MC code implemented and further developed in this study had not been validated by measurement. A novel optical dosimetry probe was fabricated and calibrated to measure the absolute photon fluence (mW/mm2) in phantoms resembling white matter, gray matter and skull bone and compared to 3D Monte Carlo simulated data. The TiO2-based dosimetry probe was shown to have superior linearity and isotropicity of response to previous Nylon based probes, and was better suited to validate the Monte Carlo using localized 3D measurement (\u3c 25% systematic error for white matter, gray matter and skull bone phantoms along illumination beam axis up to a depth of 2cm in homogeneous tissue and 3.8cm in heterogeneous head phantom). Next, the transport parameters of the empirical algorithm was calibrated using the 3D Monte Carlo and EMs and validated by optical dosimetry probe measurements (with error of 10.1% for White Matter, 45.1% for Gray Matter and 22.1% for Skull Bone phantoms) along illumination beam axis. Conclusions: The design and validation of the Monte Carlo, the optical dosimetry probe and the Empirical algorithm increases the clinical feasibility of optical therapeutic planning to narrow down the complex possibilities of illumination conditions, further compounded by the heterogeneous structure of the brain, such as varying skull thicknesses and densities. Our ultimate goal is to design a fast Monte Carlo based optical therapeutic protocol to treat brain metastasis. The voxelated nature of the MC and EM provides the necessary 3D photon distribution to within 25% error to guide future clinical studies involving optically triggered drug release

Image-Guided Interventions Using Cone-Beam CT: Improving Image Quality with Motion Compensation and Task-Based Modeling

Cone-beam CT (CBCT) is an increasingly important modality for intraoperative 3D imaging in interventional radiology (IR). However, CBCT exhibits several factors that diminish image quality — notably, the major challenges of patient motion and detectability of low-contrast structures — which motivate the work undertaken in this thesis. A 3D–2D registration method is presented to compensate for rigid patient motion. The method is fiducial-free, works naturally within standard clinical workflow, and is applicable to image-guided interventions in locally rigid anatomy, such as the head and pelvis. A second method is presented to address the challenge of deformable motion, presenting a 3D autofocus concept that is purely image-based and does not require additional fiducials, tracking hardware, or prior images. The proposed method is intended to improve interventional CBCT in scenarios where patient motion may not be sufficiently managed by immobilization and breath-hold, such as the prostate, liver, and lungs. Furthermore, the work aims to improve the detectability of low-contrast structures by computing source–detector trajectories that are optimal to a particular imaging task. The approach is applicable to CBCT systems with the capability for general source–detector positioning, as with a robotic C-arm. A “task-driven” analytical framework is introduced, various objective functions and optimization methods are described, and the method is investigated via simulation and phantom experiments and translated to task-driven source–detector trajectories on a clinical robotic C-arm to demonstrate the potential for improved image quality in intraoperative CBCT. Overall, the work demonstrates how novel optimization-based imaging techniques can address major challenges to CBCT image quality

Modeling Aspects and Computational Methods for Some Recent Problems of Tomographic Imaging

In this dissertation, two recent problems from tomographic imaging are studied, and results from numerical simulations with synthetic data are presented. The first part deals with ultrasound modulated optical tomography, a method for imaging interior optical properties of partially translucent media that combines optical contrast with ultrasound resolution. The primary application is the optical imaging of soft tissue, for which scattering and absorption rates contain important functional and structural information about the physiological state of tissue cells. We developed a mathematical model based on the diffusion approximation for photon propagation in highly scattering media. Simple reconstruction schemes for recovering optical absorption rates from boundary measurements with focused ultrasound are presented. We show numerical reconstructions from synthetic data generated for mathematical absorption phantoms. The results indicate that high resolution imaging with quantitatively correct values of absorption is possible. Synthetic focusing techniques are suggested that allow reconstruction from measurements with certain types of non-focused ultrasound signals. A preliminary stability analysis for a linearized model is given that provides an initial explanation for the observed stability of reconstruction. In the second part, backprojection schemes are proposed for the detection of small amounts of highly enriched nuclear material inside 3D volumes. These schemes rely on the geometrically singular structure that small radioactive sources represent, compared to natural background radiation. The details of the detection problem are explained, and two types of measurements, collimated and Compton-type measurements, are discussed. Computationally, we implemented backprojection by counting the number of particle trajectories intersecting each voxel of a regular rectangular grid covering the domain of detection. For collimated measurements, we derived confidence estimates indicating when voxel trajectory counts are deviating significantly from what is expected from background radiation. Monte Carlo simulations of random background radiation confirm the estimated confidence values. Numerical results for backprojection applied to synthetic measurements are shown that indicate that small sources can be detected for signal-to-noise ratios as low as 0.1%

Developments in PET-MRI for Radiotherapy Planning Applications

The hybridization of magnetic resonance imaging (MRI) and positron emission tomography (PET) provides the benefit of soft-tissue contrast and specific molecular information in a simultaneous acquisition. The applications of PET-MRI in radiotherapy are only starting to be realised. However, quantitative accuracy of PET relies on accurate attenuation correction (AC) of, not only the patient anatomy but also MRI hardware and current methods, which are prone to artefacts caused by dense materials. Quantitative accuracy of PET also relies on full characterization of patient motion during the scan. The simultaneity of PET-MRI makes it especially suited for motion correction. However, quality assurance (QA) procedures for such corrections are lacking. Therefore, a dynamic phantom that is PET and MR compatible is required. Additionally, respiratory motion characterization is needed for conformal radiotherapy of lung. 4D-CT can provide 3D motion characterization but suffers from poor soft-tissue contrast. In this thesis, I examine these problems, and present solutions in the form of improved MR-hardware AC techniques, a PET/MRI/CT-compatible tumour respiratory motion phantom for QA measurements, and a retrospective 4D-PET-MRI technique to characterise respiratory motion. Chapter 2 presents two techniques to improve upon current AC methods that use a standard helical CT scan for MRI hardware in PET-MRI. One technique uses a dual-energy computed tomography (DECT) scan to construct virtual monoenergetic image volumes and the other uses a tomotherapy linear accelerator to create CT images at megavoltage energies (1.0 MV) of the RF coil. The DECT-based technique reduced artefacts in the images translating to improved μ-maps. The MVCT-based technique provided further improvements in artefact reduction, resulting in artefact free μ-maps. This led to more AC of the breast coil. In chapter 3, I present a PET-MR-CT motion phantom for QA of motion-correction protocols. This phantom is used to evaluate a clinically available real-time dynamic MR images and a respiratory-triggered PET-MRI protocol. The results show the protocol to perform well under motion conditions. Additionally, the phantom provided a good model for performing QA of respiratory-triggered PET-MRI. Chapter 4 presents a 4D-PET/MRI technique, using MR sequences and PET acquisition methods currently available on hybrid PET/MRI systems. This technique is validated using the motion phantom presented in chapter 3 with three motion profiles. I conclude that our 4D-PET-MRI technique provides information to characterise tumour respiratory motion while using a clinically available pulse sequence and PET acquisition method

Propagation of terahertz radiation in non-homogeneous materials and structures

The work undertaken is concerned with looking at how terahertz frequency radiation (here defined as 300 GHz -10 THz) propagates through media which have a random structure ("non-homogeneous materials"). Materials of this type are important in a wide range of applications, but are of particular interest in security and surveillance. Propagation of terahertz radiation through non-homogeneous materials is not well understood: both interference and scattering effects become important in this spectral range, where the wavelength and size and separation of the scattering centres are often commensurable. A simple model, which uses the phase change of a wave to describe its transmission through media having relatively small changes in refractive index is developed and compared with both exact theories and experimentally obtained measurements. Overall, a satisfactory agreement between the experimental data for transmission through arrays of cylinders, textiles and powders is seen. It is well known that pulses of terahertz radiation from optoelectronic sources have a complex shape. Post detection signal processing routines can be used to clean up the experimentally determined signals. The development of such algorithms is described, before they are applied to experimental results to determine: the minimum size of gaps between slabs to mimic voids in media; and the response of various compounds to a sharply terminated input pulse. The investigation of scattering from random structures requires the construction of a spectrometer having the capability to measure THz pulses scattered at different angles. Such a system ideally requires fibre-fed detection schemes to be used. The construction of a scattering spectrometer is described and its performance outlined. Pulses of terahertz which have been scattered by a sample of interest can be reconstructed, using methods from conventional tomography, to produce images of the phantom under test. Such measurements are outlined here. To our knowledge, this is the first time that tomography has been undertaken using a fixed sample and rotating detector arrangement

High resolution laboratory x-ray tomography for biomedical research : From design to application

Laboratory x-ray micro- and nano-tomography are emerging techniques in biomedical research. Through the use of phase-contrast, sufficient contrast can be achieved in soft tissue to support medical studies. With ongoing developments of x-ray sources and detectors, biomedical studies can increasingly be performed at the laboratory and do not necessary require synchrotron radiation. Particularly nano-focus x-ray sources offer new possibilities for the study of soft tissue. However, with increasing resolution, the complexity and stability requirements on laboratory systems advance as well. This thesis describes the design and implementation of two systems: a micro- CT and a nano-CT, which are used for biomedical imaging.To increase the resolution of the micro-CT, super-resolution imaging is adopted and evaluated for x-ray ima- ging, grating-based imaging and computed tomography utilising electromagnetic stepping of the x-ray source to acquire shifted low-resolution images to estimate a high-resolution image. The experiments have shown that super-resolution can significantly improve the resolution in 2D and 3D imaging, but also that upscaling during the reconstruction can be a viable approach in tomography, which does not require additional images.Element-specific information can be obtained by using photon counting detectors with energy-discriminating thresholds. By performing a material decomposition, a dataset can be split into multiple different materials. Tissue contains a variety of elements with absorption edges in the range of 4 – 11 keV, which can be identified by placing energy thresholds just below and above these edges, as we have demonstrated using human atherosclerotic plaques.An evaluation of radiopaque dyes as alternative contrast agent to identify vessels in lung tissue was performed using phase contrast micro-tomography. We showed that the dye solutions have a sufficiently low density to not cause any artefacts while still being able to separate them from the tissue and distinguish them from each other.Finally, the design and implementation of the nano-CT system is discussed. The system performance is assessed in 2D and 3D, achieving sub-micron resolution and satisfactory tissue contrast through phase contrast. Applica- tion examples are presented using lung tissue, a mouse heart, and freeze dried leaves