Engineering Commons^™

Logarithmic Intensity Compression In Fluorescence Guided Surgery Applications, Alisha V. Dsouza, Huiyun Lin, Jason Gunn, Brian W. Pogue

Dartmouth Scholarship

The use of fluorescence video imaging to guide surgery is rapidly expanding, and improvements in camera readout dynamic range have not matched display capabilities. Logarithmic intensity compression is a fast, single-step mapping technique that can map the useable dynamic range of high-bit fluorescence images onto the typical 8-bit display and potentially be a variable dynamic contrast enhancement tool. We demonstrate a ∼4.6  times improvement in image quality quantified by image entropy and a dynamic range reduction by a factor of ∼380 by the use of log-compression tools in processing in vivo fluorescence images.

Molecular Dyes Used For Surgical Specimen Margin Orientation Allow For Intraoperative Optical Assessment During Breast Conserving Surgery, David M. Mcclatchy, Venkataramanan Krishnaswamy, Stephen C. Kanick, Jonathan T. Elliott, Wendy A. Wells, Richard J. Barth Jr., Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

A variety of optical techniques utilizing near-infrared (NIR) light are being proposed for intraoperative breast tumor margin assessment. However, immediately following a lumpectomy excision, the margins are inked, which preserves the orientation of the specimen but prevents optical interrogation of the tissue margins. Here, a workflow is proposed that allows for both NIR optical assessment following full specimen marking using molecular dyes which have negligible absorption and scattering in the NIR. The effect of standard surgical inks in contrast to molecular dyes for an NIR signal is shown. Further, the proposed workflow is demonstrated with full specimen intraoperative imaging on …

Macroscopic Optical Imaging Technique For Wide-Field Estimation Of Fluorescence Depth In Optically Turbid Media For Application In Brain Tumor Surgical Guidance, Kolbein K. Kolste, Stephen C. Kanick, Pablo A. Valdés, Michael Jermyn, Brian C. Wilson, David W. Roberts, Keith D. Paulsen, Frederic Leblond

Dartmouth Scholarship

A diffuse imaging method is presented that enables wide-field estimation of the depth of fluorescent molecular markers in turbid media by quantifying the deformation of the detected fluorescence spectra due to the wavelength-dependent light attenuation by overlying tissue. This is achieved by measuring the ratio of the fluorescence at two wavelengths in combination with normalization techniques based on diffuse reflectance measurements to evaluate tissue attenuation variations for different depths. It is demonstrated that fluorescence topography can be achieved up to a 5 mm depth using a near-infrared dye with millimeter depth accuracy in turbid media having optical properties representative of …

Spatial Frequency Analysis Of Anisotropic Drug Transport In Tumor Samples, Stewart Russell, Kimberley S. Samkoe, Jason R. Gunn, P Jack Hoopes, Thienan A. Nguyen, Milo J. Russell, Robert R. Alfano, Brian W. Pogue

Dartmouth Scholarship

Directional Fourier spatial frequency analysis was used on standard histological sections to identify salient directional bias in the spatial frequencies of stromal and epithelial patterns within tumor tissue. This directional bias is shown to be correlated to the pathway of reduced fluorescent tracer transport. Optical images of tumor specimens contain a complex distribution of randomly oriented aperiodic features used for neoplastic grading that varies with tumor type, size, and morphology. The internal organization of these patterns in frequency space is shown to provide a precise fingerprint of the extracellular matrix complexity, which is well known to be related to the …

Continuous Correction Of Differential Path Length Factor In Near-Infrared Spectroscopy, Tanveer Talukdar, Jason H. Moore, Solomon G. Diamond

Dartmouth Scholarship

In continuous-wave near-infrared spectroscopy (CW-NIRS), changes in the concentration of oxyhemoglobin and deoxyhemoglobin can be calculated by solving a set of linear equations from the modified Beer-Lambert Law. Cross-talk error in the calculated hemodynamics can arise from inaccurate knowledge of the wavelength-dependent differential path length factor (DPF). We apply the extended Kalman filter (EKF) with a dynamical systems model to calculate relative concentration changes in oxy- and deoxyhemoglobin while simultaneously estimating relative changes in DPF. Results from simulated and experimental CW-NIRS data are compared with results from a weighted least squares (WLSQ) method. The EKF method was found to effectively …

Dual-Tracer Background Subtraction Approach For Fluorescent Molecular Tomography, Kenneth M. Tichauer, Robert W. Holt, Fadi El-Ghussein, Scott C. Davis, Kimberly S. Samkoe, Jason R. Gunn, Frederic Leblond, Brian W. Pogue

Dartmouth Scholarship

Diffuse fluorescence tomography requires high contrast-to-background ratios to accurately reconstruct inclusions of interest. This is a problem when imaging the uptake of fluorescently labeled molecularly targeted tracers in tissue, which can result in high levels of heterogeneously distributed background uptake. We present a dual-tracer background subtraction approach, wherein signal from the uptake of an untargeted tracer is subtracted from targeted tracer signal prior to image reconstruction, resulting in maps of targeted tracer binding. The approach is demonstrated in simulations, a phantom study, and in a mouse glioma imaging study, demonstrating substantial improvement over conventional and homogenous background subtraction image reconstruction …

A Digital X-Ray Tomosynthesis Coupled Near Infrared Spectral Tomography System For Dual-Modality Breast Imaging, Venkataramanan Krishnaswamy, Kelly E. Michaelsen, Brian W. Pogue, Steven P. Poplack, Ian Shaw, Ken Defrietas, Ken Brooks, Keith D. Paulsen

Dartmouth Scholarship

A Near Infrared Spectral Tomography (NIRST) system has been developed and integrated into a commercial Digital Breast Tomosynthesis (DBT) scanner to allow structural and functional imaging of breast in vivo. The NIRST instrument uses an 8-wavelength continuous wave (CW) laser-based scanning source assembly and a 75-element silicon photodiode solid-state detector panel to produce dense spectral and spatial projection data from which spectrally constrained 3D tomographic images of tissue chromophores are produced. Integration of the optical imaging system into the DBT scanner allows direct co-registration of the optical and DBT images, while also facilitating the synergistic use of x-ray contrast as …

Improved Tumor Contrast Achieved By Single Time Point Dual-Reporter Fluorescence Imaging, Kenneth M. Tichauer, Kimberley S. Samkoe, Kristian J. Sexton, Jason R. Gunn, Tayyaba Hasan, Brian W. Pogue

Dartmouth Scholarship

In this study, we demonstrate a method to quantify biomarker expression that uses an exogenous dual-reporter imaging approach to improve tumor signal detection. The uptake of two fluorophores, one nonspecific and one targeted to the epidermal growth factor receptor (EGFR), were imaged at 1 h in three types of xenograft tumors spanning a range of EGFR expression levels (n  =  6 in each group). Using this dual-reporter imaging methodology, tumor contrast-to-noise ratio was amplified by >6 times at 1 h postinjection and >2 times at 24 h. Furthermore, by as early as 20 min postinjection, the dual-reporter imaging signal …

Combined Fluorescence And Reflectance Spectroscopy For In Vivo Quantification Of Cancer Biomarkers In Low- And High-Grade Glioma Surgery, Pablo A. ValdéS, Anthony Kim, Keith D. Paulsen, Frederic Leblond, Olga M. Conde, Brent T. Harris, David W. Roberts

Dartmouth Scholarship

Biomarkers are indicators of biological processes and hold promise for the diagnosis and treatment of disease. Gliomas represent a heterogeneous group of brain tumors with marked intra- and inter-tumor variability. The extent of surgical resection is a significant factor influencing post-surgical recurrence and prognosis. Here, we used fluorescence and reflectance spectral signatures for in vivo quantification of multiple biomarkers during glioma surgery, with fluorescence contrast provided by exogenously-induced protoporphyrin IX (PpIX) following administration of 5-aminolevulinic acid. We performed light-transport modeling to quantify multiple biomarkers indicative of tumor biological processes, including the local concentration of PpIX and associated photoproducts, total hemoglobin …

Automated Classification Of Breast Pathology Using Local Measures Of Broadband Reflectance, Ashley M. Laughney, Venkataramanan Krishnaswamy, Pilar Beatriz Garcia-Allende, Olga M. Conde, Wendy A. Wells, Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

We demonstrate that morphological features pertinent to a tissue's pathology may be ascertained from localized measures of broadband reflectance, with a mesoscopic resolution (100-μm lateral spot size) that permits scanning of an entire margin for residual disease. The technical aspects and optimization of a k-nearest neighbor classifier for automated diagnosis of pathologies are presented, and its efficacy is validated in 29 breast tissue specimens. When discriminating between benign and malignant pathologies, a sensitivity and specificity of 91 and 77% was achieved. Furthermore, detailed subtissue-type analysis was performed to consider how diverse pathologies influence scattering response and overall classification efficacy. The …

Image Guided Near-Infrared Spectroscopy Of Breast Tissue In Vivo Using Boundary Element Method, Subhadra Srinivasan, Colin M. Carpenter, Hamid R. Ghadyani, Senate J. Taka, Peter A. Kaufman, Roberta M. Diflorio-Alexander, Wendy A. Wells, Brian W. Pogue, Keith D. Paulsen

Dartmouth Scholarship

We demonstrate quantitative functional imaging using image-guided near-infrared spectroscopy (IG-NIRS) implemented with the boundary element method (BEM) for reconstructing 3-D optical property estimates in breast tissue in vivo. A multimodality MRI-NIR system was used to collect measurements of light reflectance from breast tissue. The BEM was used to model light propagation in 3-D based only on surface discretization in order to reconstruct quantitative values of total hemoglobin (HbT), oxygen saturation, water, and scatter. The technique was validated in experimental measurements from heterogeneous breast-shaped phantoms with known values and applied to a total of seven subjects comprising six healthy individuals …

Comparing Implementations Of Magnetic-Resonance-Guided Fluorescence Molecular Tomography For Diagnostic Classification Of Brain Tumors, Scott C. Davis, Kimberley S. Samkoe, Julia A. O’Hara, Summer L. Gibbs-Strauss, Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

Fluorescence molecular tomography (FMT) systems coupled to conventional imaging modalities such as magnetic resonance imaging (MRI) and computed tomography provide unique opportunities to combine data sets and improve image quality and content. Yet, the ideal approach to combine these complementary data is still not obvious. This preclinical study compares several methods for incorporating MRI spatial prior information into FMT imaging algorithms in the context of in vivo tissue diagnosis. Populations of mice inoculated with brain tumors that expressed either high or low levels of epidermal growth factor receptor (EGFR) were imaged using an EGF-bound near-infrared dye and a spectrometer-based MRI-FMT …

Automated Identification Of Tumor Microscopic Morphology Based On Macroscopically Measured Scatter Signatures, Pilar Beatriz Garcia-Allende, Venkataramanan Krishnaswamy, P Jack Hoopes, Kimberley S. Samkoe, Olga M. Conde, Brian W. Pogue

Dartmouth Scholarship

An automated algorithm and methodology is presented to identify tumor-tissue morphologies based on broadband scatter data measured by raster scan imaging of the samples. A quasi-confocal reflectance imaging system was used to directly measure the tissue scatter reflectance in situ, and the spectrum was used to identify the scattering power, amplitude, and total wavelength-integrated intensity. Pancreatic tumor and normal samples were characterized using the instrument, and subtle changes in the scatter signal were encountered within regions of each sample. Discrimination between normal versus tumor tissue was readily performed using a K-nearest neighbor classifier algorithm. A similar approach worked …

Methodology Development For Three-Dimensional Mr-Guided Near Infrared Spectroscopy Of Breast Tumors, Colin M. Carpenter, Subhadra Srinivasan, Brian W. Pogue, Keith D. Paulsen

Dartmouth Scholarship

Combined Magnetic Resonance (MR) and Near Infrared Spectroscopy (NIRS) has been proposed as a unique method to quantify hemodynamics, water content, and cellular size and packing density of breast tumors, as these tissue constituents can be quantified with increased resolution and overlaid on the structural features identified by the MR. However, the choices in how to reconstruct and visualize this information can have a dramatic impact on the feasibility of implementing this modality in the clinic. This is especially true in 3 dimensions, as there is often limited optical sampling of the breast tissue, and methods need to accurately reflect …

Non-Invasive Raman Tomographic Imaging Of Canine Bone Tissue, Matthew V. Schulmerich, Jacqueline H. Cole, Kathryn A. Dooley, Michael D. Morris, Jaclynn M. Kreider, Steven A. Goldstein, Subhadra Srinivasan, Brian W. Pogue

Dartmouth Scholarship

Raman spectroscopic diffuse tomographic imaging has been demonstrated for the first time. It provides a noninvasive, label-free modality to image the chemical composition of human and animal tissue and other turbid media. This technique has been applied to image the composition of bone tissue within an intact section of a canine limb. Spatially distributed 785-nm laser excitation was employed to prevent thermal damage to the tissue. Diffuse emission tomography reconstruction was used, and the location that was recovered has been confirmed by micro-computed tomography (micro-CT) images.

With recent advances, diffuse tomography shows promise for in vivo clinical imaging.^{1, …}

Receiver Operating Characteristic And Location Analysis Of Simulated Near-Infrared Tomography Images, Xiaomei Song, Brian W. Pogue, Hamid Dehghani, Shudong Jiang, Keith D. Paulsen, Tor D. Tosteson

Dartmouth Scholarship

Receiver operating characteristic (ROC) analysis was performed on simulated near-infrared tomography images, using both human observer and contrast-to-noise ratio (CNR) computational assessment, for application in breast cancer imaging. In the analysis, a nonparametric approach was applied for estimating the ROC curves. Human observer detection of objects had superior capability to localize the presence of heterogeneities when the objects were small with high contrast, with a minimum detectable threshold of CNR near 3.0 to 3.3 in the images. Human observers were able to detect heterogeneities in the images below a size limit of 4 mm, yet could not accurately find the …

Imaging Breast Adipose And Fibroglandular Tissue Molecular Signatures By Using Hybrid Mri-Guided Near-Infrared Spectral Tomography, Ben Brooksby, Brian W. Pogue, Shudong Jiang, Hamid Dehghani, Subhadra Srinivasan, Christine Kogel, Tor D. Tosteson, John Weaver, Steven P. Poplack, Keith D. Paulsen

Dartmouth Scholarship

Magnetic resonance (MR)-guided near-infrared spectral tomography was developed and used to image adipose and fibroglandular breast tissue of 11 normal female subjects, recruited under an institutional review board-approved protocol. Images of hemoglobin, oxygen saturation, water fraction, and subcellular scattering were reconstructed and show that fibroglandular fractions of both blood and water are higher than in adipose tissue. Variation in adipose and fibroglandular tissue composition between individuals was not significantly different across the scattered and dense breast categories. Combined MR and near-infrared tomography provides fundamental molecular information about these tissue types with resolution governed by MR T1 images.

Contrast-Detail Analysis Characterizing Diffuse Optical Fluorescence Tomography Image Reconstruction, Scott C. Davis, Brian W. Pogue, Hamid Dehghani, Keith D. Paulsen

Dartmouth Scholarship

Contrast-detail analysis is used to evaluate the imaging performance of diffuse optical fluorescence tomography (DOFT), characterizing spatial resolution limits, signal-to-noise limits, and the trade-off between object contrast and size. Reconstructed images of fluorescence yield from simulated noisy data were used to determine the contrast-to-noise ratio (CNR). A threshold of CNR=3 was used to approximate a lowest acceptable noise level in the image, as a surrogate measure for human detection of objects. For objects 0.5 cm inside the edge of a simulated tissue region, the smallest diameter that met this criteria was approximately 1.7 mm, regardless of contrast level, and test …

Improved Quantification Of Small Objects In Near-Infrared Diffuse Optical Tomography, Subhadra Srinivasan, Brian W. Pogue, Hamid Dehghani, Shudong Jiang, Xiaomei Song, Keith D. Paulsen

Dartmouth Scholarship

Diffuse optical tomography allows quantification of hemoglobin, oxygen saturation, and water in tissue, and the fidelity in this quantification is dependent on the accuracy of optical properties determined during image reconstruction. In this study, a three-step algorithm is proposed and validated that uses the standard Newton minimization with Levenberg-Marquardt regularization as the first step. The second step is a modification to the existing algorithm using a two-parameter regularization to allow lower damping in a region of interest as compared to background. This second stage allows the recovery of the actual size of an inclusion. A region-based reconstruction is the final …