Image reconstruction in fluorescence molecular tomography with sparsity-initialized maximum-likelihood expectation maximization

We present a reconstruction method involving maximum-likelihood expectation maximization (MLEM) to model Poisson noise as applied to fluorescence molecular tomography (FMT). MLEM is initialized with the output from a sparse reconstruction-based approach, which performs truncated singular value decomposition-based preconditioning followed by fast iterative shrinkage-thresholding algorithm (FISTA) to enforce sparsity. The motivation for this approach is that sparsity information could be accounted for within the initialization, while MLEM would accurately model Poisson noise in the FMT system. Simulation experiments show the proposed method significantly improves images qualitatively and quantitatively. The method results in over 20 times faster convergence compared to uniformly initialized MLEM and improves robustness to noise compared to pure sparse reconstruction. We also theoretically justify the ability of the proposed approach to reduce noise in the background region compared to pure sparse reconstruction. Overall, these results provide strong evidence to model Poisson noise in FMT reconstruction and for application of the proposed reconstruction framework to FMT imaging

Quantitative performance characterization of three-dimensional noncontact fluorescence molecular tomography

© 2016 The Authors.Fluorescent proteins and dyes are routine tools for biological research to describe the behavior of genes, proteins, and cells, as well as more complex physiological dynamics such as vessel permeability and pharmacokinetics. The use of these probes in whole body in vivo imaging would allow extending the range and scope of current biomedical applications and would be of great interest. In order to comply with a wide variety of application demands, in vivo imaging platform requirements span from wide spectral coverage to precise quantification capabilities. Fluorescence molecular tomography (FMT) detects and reconstructs in three dimensions the distribution of a fluorophore in vivo. Noncontact FMT allows fast scanning of an excitation source and noninvasive measurement of emitted fluorescent light using a virtual array detector operating in free space. Here, a rigorous process is defined that fully characterizes the performance of a custom-built horizontal noncontact FMT setup. Dynamic range, sensitivity, and quantitative accuracy across the visible spectrum were evaluated using fluorophores with emissions between 520 and 660 nm. These results demonstrate that high-performance quantitative three-dimensional visible light FMT allowed the detection of challenging mesenteric lymph nodes in vivo and the comparison of spectrally distinct fluorescent reporters in cell culture

Video-Rate Fluorescence Molecular Tomography for Hand-held and Multimodal Molecular Imaging

In the United States, cancer is the second leading cause of death following heart disease. Although, a variety of treatment regimens are available, cancer management is complicated by the complexity of the disease and the variability, between people, of disease progression and response to therapy. Therefore, advancements in the methods and technologies for cancer diagnosis, prognosis and therapeutic monitoring are critical to improving the treatment of cancer patients. The development of improved imaging methods for early diagnosis of cancer and of near real-time monitoring of tumor response to therapy may improve outcomes as well as the quality of life of cancer patients. In the last decade, imaging methods including ultrasound, computed tomography: CT), magnetic resonance imaging: MRI), single photon emission computed tomography: SPECT), and positron emission tomography: PET), have revolutionized oncology. More recently optical techniques, that have access to unique molecular reporting strategies and functional contrasts, show promise for oncologic imaging This dissertation focuses on the development and optimization of a fiber-based, video-rate fluorescence molecular tomography: FMT) instrument. Concurrent acquisition of fluorescence and reference signals allowed the efficient generation of ratio-metric data for 3D image reconstruction. Accurate depth localization and high sensitivity to fluorescent targets were established to depths of \u3e10 mm. In vivo accumulation of indocyanine green dye was imaged in the region of the sentinel lymph node: SLN) following intradermal injection into the forepaw of rats. These results suggest that video-rate FMT has potential as a clinical tool for noninvasive mapping of SLN. Spatial and temporal co-registration of nuclear and optical images can enable the fusion of the information from these complementary molecular imaging modalities. A critical challenge is in integrating the optical and nuclear imaging hardware. Flexible fiber-based FMT systems provide a viable solution. The various imaging bore sizes of small animal nuclear imaging systems can potentially accommodate the FMT fiber imaging arrays. In addition FMT imaging facilitates co-registering the nuclear and optical contrasts in time. In this dissertation, the feasibility of integrating the fiber-based, video-rate FMT system with a commercial preclinical NanoSPECT/CT platform was established. Feasibility of in vivo imaging is demonstrated by tracking a monomolecular multimodal-imaging agent: MOMIA) during transport from the forepaw to the axillary lymph nodes region of a rat. These co-registered FMT/SPECT/CT imaging results with MOMIAs may facilitate the development of the next generation preclinical and clinical multimodal optical-nuclear platforms for a broad array of imaging applications, and help elucidate the underlying biological processes relevant to cancer diagnosis and therapy monitoring. Finally, I demonstrated that video-rate FMT is sufficiently fast to enable imaging of cardiac, respiratory and pharmacokinetic induced dynamic fluorescent signals. From these measurements, the image-derived input function and the real-time uptake of injected agents can be deduced for pharmacokinetic analysis of fluorescing agents. In a study comparing normal mice against mice liver disease, we developed anatomically guided dynamic FMT in conjunction with tracer kinetic modeling to quantify uptake rates of fluorescing agents. This work establishes fiber-based, video-rate FMT system as a practical and powerful tool that is well suited to a broad array of potential imaging applications, ranging from early disease detection, quantifying physiology and monitoring progression of disease and therapies

Graph- and finite element-based total variation models for the inverse problem in diffuse optical tomography

Total variation (TV) is a powerful regularization method that has been widely applied in different imaging applications, but is difficult to apply to diffuse optical tomography (DOT) image reconstruction (inverse problem) due to complex and unstructured geometries, non-linearity of the data fitting and regularization terms, and non-differentiability of the regularization term. We develop several approaches to overcome these difficulties by: i) defining discrete differential operators for unstructured geometries using both finite element and graph representations; ii) developing an optimization algorithm based on the alternating direction method of multipliers (ADMM) for the non-differentiable and non-linear minimization problem; iii) investigating isotropic and anisotropic variants of TV regularization, and comparing their finite element- and graph-based implementations. These approaches are evaluated on experiments on simulated data and real data acquired from a tissue phantom. Our results show that both FEM and graph-based TV regularization is able to accurately reconstruct both sparse and non-sparse distributions without the over-smoothing effect of Tikhonov regularization and the over-sparsifying effect of L$_1$ regularization. The graph representation was found to out-perform the FEM method for low-resolution meshes, and the FEM method was found to be more accurate for high-resolution meshes.Comment: 24 pages, 11 figures. Reviced version includes revised figures and improved clarit

Review of optical breast imaging and spectroscopy

Diffuse optical imaging and spectroscopy of the female breast is an area of active research. We review the present status of this field and discuss the broad range of methodologies and applications. Starting with a brief overview on breast physiology, the remodeling of vasculature and extracellular matrix caused by solid tumors is highlighted that is relevant for contrast in optical imaging. Then, the various instrumental techniques and the related methods of data analysis and image generation are described and compared including multimodality instrumentation, fluorescence mammography, broadband spectroscopy, and diffuse correlation spectroscopy. We review the clinical results on functional properties of malignant and benign breast lesions compared to host tissue and discuss the various methods to improve contrast between healthy and diseased tissue, such as enhanced spectroscopic information, dynamic variations of functional properties, pharmacokinetics of extrinsic contrast agents, including the enhanced permeability and retention effect. We discuss research on monitoring neoadjuvant chemotherapy and on breast cancer risk assessment as potential clinical applications of optical breast imaging and spectroscopy. Moreover, we consider new experimental approaches, such as photoacoustic imaging and long-wavelength tissue spectroscopy

Video-rate fluorescence diffuse optical tomography for in vivo sentinel lymph node imaging

We have developed a fiber-based, video-rate fluorescence diffuse optical tomography (DOT) system for noninvasive in vivo sentinel lymph node (SLN) mapping. Concurrent acquisition of fluorescence and reference signals allowed the efficient generation of ratio-metric data for 3D image reconstruction. Accurate depth localization and high sensitivity to fluorescent targets were established in to depths of >10 mm. In vivo accumulation of indocyanine green (ICG) dye was imaged in the region of the SLN following intradermal injection into the forepaw of rats. These results suggest that video-rate fluorescence DOT has significant potential as a clinical tool for noninvasive mapping of SLN