Abhijit J. Chaudhari

Hyperspectral and multispectral bioluminescence optical tomography for small animal imaging

For bioluminescence imaging studies in small animals, it is important to be able to accurately localize the three-dimensional (3D) distribution of the underlying bioluminescent source. The spectrum of light produced by the source that escapes the subject varies with the depth of the emission source because of the wavelength-dependence of the optical properties of tissue. Consequently, multispectral or hyperspectral data acquisition should help in the 3D localization of deep sources. In this paper, we describe a framework for fully 3D bioluminescence tomographic image acquisition and reconstruction that exploits spectral information. We describe regularized tomographic reconstruction techniques that use semi-infinite slab or FEM-based diffusion approximations of photon transport through turbid media. Singular value decomposition analysis was used for data dimensionality reduction and to illustrate the advantage of using hyperspectral rather than achromatic data. Simulation studies in an atlas-mouse geometry indicated that sub-millimeter resolution may be attainable given accurate knowledge of the optical properties of the animal. A fixed arrangement of mirrors and a single CCD camera were used for simultaneous acquisition of multispectral imaging data over most of the surface of the animal. Phantom studies conducted using this system demonstrated our ability to accurately localize deep point-like sources and show that a resolution of 1.5 to 2.2 mm for depths up to 6 mm can be achieved. We also include an in vivo study of a mouse with a brain tumour expressing firefly luciferase. Co-registration of the reconstructed 3D bioluminescent image with magnetic resonance images indicated good anatomical localization of the tumour.

Initial Characterization of a Dedicated Breast PET/CT Scanner During Human Imaging

We have constructed a dedicated breast PET/CT scanner capable of high-resolution functional and anatomic imaging. Here, we present an initial characterization of scanner performance during patient imaging. Methods: The system consisted of a lutetium oxyorthosilicate–based dual–planar head PET camera (crystal size, 3 × 3 × 20 mm) and 768-slice cone-beam CT. The position of the PET heads (separation and height) could be adjusted for varying breast dimensions. For scanning, the patient lay prone on a specialized bed and inserted a single pendent breast through an aperture in the table top. Compression of the breast as used in mammography is not required. PET and CT systems rotate in the coronal plane underneath the patient sequentially to collect fully tomographic datasets. PET images were reconstructed with the fully 3-dimensional maximum a posteriori method, and CT images were reconstructed with the Feldkamp algorithm, then spatially registered and fused for display. Phantom scans were obtained to assess the registration accuracy between PET and CT images and the influence of PET electronics and activity on CT image quality. We imaged 4 women with mammographic findings highly suggestive of breast cancer (breast imaging reporting and data system, category 5) in an ongoing clinical trial. Patients were injected with 18F-FDG and imaged for 12.5 min per breast. From patient data, noise-equivalent counting rates and the singles-to-trues ratio (a surrogate for the randoms fraction) were calculated. Results: The average registration error between PET and CT images was 0.18 mm. PET electronics and activity did not significantly affect CT image quality. For the patient trial, biopsy-confirmed cancers were visualized on dedicated breast PET/CT on all patient scans, including the detection of ductal carcinoma in situ in 1 case. The singles-to-trues ratio was found to be inversely correlated with breast volume in the field of view, suggesting that larger breasts trend toward increased noise-equivalent counting rates for all other things equal. Conclusion: Scanning of the uncompressed breast with dedicated breast PET/CT can accurately visualize suspected lesions in 3 dimensions.

Fast iterative image reconstruction methods for fully 3D multispectral bioluminescence tomography

We investigate fast iterative image reconstruction methods for fully 3D multispectral bioluminescence tomography for applications in small animal imaging. Our forward model uses a diffusion approximation for optically inhomogeneous tissue, which we solve using a finite element method (FEM). We examine two approaches to incorporating the forward model into the solution of the inverse problem. In a conventional direct calculation approach one computes the full forward model by repeated solution of the FEM problem, once for each potential source location. We describe an alternative on-the-fly approach where one does not explicitly solve for the full forward model. Instead, the solution to the forward problem is included implicitly in the formulation of the inverse problem, and the FEM problem is solved at each iteration for the current image estimate. We evaluate the convergence speeds of several representative iterative algorithms. We compare the computation cost of those two approaches, concluding that the on-the-fly approach can lead to substantial reductions in total cost when combined with a rapidly converging iterative algorithm.

Multimodal characterization of compositional, structural and functional features of human atherosclerotic plaques

Detection of atherosclerotic plaque vulnerability has critical clinical implications for avoiding sudden death in patients with high risk of plaque rupture. We report on multimodality imaging of ex-vivo human carotid plaque samples using a system that integrates fluorescence lifetime imaging (FLIM), ultrasonic backscatter microscopy (UBM), and photoacoustic imaging (PAI). Biochemical composition is differentiated with a high temporal resolution and sensitivity at the surface of the plaque by the FLIM subsystem. 3D microanatomy of the whole plaque is reconstructed by the UBM. Functional imaging associated with optical absorption contrast is evaluated from the PAI component. Simultaneous recordings of the optical, ultrasonic, and photoacoustic data present a wealth of complementary information concerning the plaque composition, structure, and function that are related to plaque vulnerability. This approach is expected to improve our ability to study atherosclerotic plaques. The multimodal system presented here can be translated into a catheter based intraluminal system for future clinical studies.

High-resolution 18F-FDG PET with MRI for monitoring response to treatment in rheumatoid arthritis

Eur J Nucl Med Mol Imaging (2010) 37:1047 DOI 10.1007/s00259-009-1364-x IMAGE OF THE MONTH High-resolution 18 F-FDG PET with MRI for monitoring response to treatment in rheumatoid arthritis Abhijit J. Chaudhari & Spencer L. Bowen & George W. Burkett & Nathan J. Packard & Felipe Godinez & Anand A. Joshi & Stanley M. Naguwa & David K. Shelton & John C. Hunter & John M. Boone & Michael H. Buonocore & Ramsey D. Badawi Received: 20 November 2009 / Accepted: 10 December 2009 / Published online: 30 January 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Molecular imaging can potentially provide means for mon- itoring response to therapy in rheumatoid arthritis (RA) early in the course of disease [1].Quantitative measurements of RA disease activity made in the wrist by whole-body PET scanners, however, have inadequate accuracy because of limited spatial resolution [2]. A high-resolution PET/CT scanner for imaging extremities has been built at our insti- tution [3]. In conjunction with a clinical MRI scanner, high- resolution PET/MR images can be obtained for the wrist. The CT image is used for PET/MR image coregistration. A 57-year-old female with established RA was stable until a recent clinical flare-up in the right wrist. Clinical exami- nation revealed synovitis, swelling, and diminished range of motion. The patient also had a history of osteoarthritis (OA). An extremity 18 F-FDG PET/CT scan immediately following MRI at baseline was performed on this patient. Tumor necrosis factor alpha (TNF-α) inhibitor (etanercept) therapy was then initiated as a part of the patient’s standard of care. The patient was re-scanned 5 weeks after starting treatment. The figure shows high-resolution 18 F-FDG PET images (pseudocolor) overlaid on pre-contrast MRI images (gray This work was funded by the NIH grants UL1-RR024146, R01CA129561, R01EB002138 and the UC Davis Imaging Research Center. A. J. Chaudhari (*) : S. L. Bowen : G. W. Burkett : N. J. Packard : F. Godinez : D. K. Shelton : J. C. Hunter : J. M. Boone : M. H. Buonocore : R. D. Badawi Department of Radiology, UC Davis Medical Center, Sacramento, CA, USA e-mail: ajchaudhari@ucdavis.edu A. A. Joshi Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA S. M. Naguwa Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA scale) at baseline (left column) and 5 weeks (right column). Significant reduction in PET signal (suggesting reduced inflammation) in the synovium and at sites of erosions (white arrows) is visible. The green arrow shows inflammation due to OA. Physician examination at 3 months confirmed that this patient responded positively to etanercept. This case illustrates the potential of high-resolution PET with MRI for quantitative visualization of early response to therapy in RA. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per- mits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. References 1. Brenner W. 18F-FDG PET in rheumatoid arthritis: there still is a long way to go. J Nucl Med. 2004;45(6):927–9. 2. Beckers C, Ribbens C, Andre B, Marcelis S, Kaye O, Mathy L, et al. Assessment of disease activity in rheumatoid arthritis with (18)F-FDG PET. J Nucl Med. 2004;45(6):956–64. 3. Bowen SL, Wu Y, Chaudhari AJ, Fu L, Packard NJ, Burkett GW, et al. Initial characterization of a dedicated breast PET/CT scanner during human imaging. J Nucl Med. 2009;50(9):1401–8.

Excitation spectroscopy in multispectral optical fluorescence tomography: methodology, feasibility and computer simulation studies

Molecular probes used for in vivo optical fluorescence tomography (OFT) studies in small animals are typically chosen such that their emission spectra lie in the 680-850 nm wavelength range. This is because tissue attenuation in this spectral band is relatively low, allowing optical photons even from deep sites in tissue to reach the animal surface and consequently be detected by a CCD camera. The wavelength dependence of tissue optical properties within the 680-850 nm band can be exploited for emitted light by measuring fluorescent data via multispectral approaches and incorporating the spectral dependence of these optical properties into the OFT inverse problem-that of reconstructing underlying 3D fluorescent probe distributions from optical data collected on the animal surface. However, in the aforementioned spectral band, due to only small variations in the tissue optical properties, multispectral emission data, though superior for image reconstruction compared to achromatic data, tend to be somewhat redundant. A different spectral approach for OFT is to capitalize on the larger variations in the optical properties of tissue for excitation photons than for the emission photons by using excitation at multiple wavelengths as a means of decoding source depth in tissue. The full potential of spectral approaches in OFT can be realized by a synergistic combination of these two approaches, that is, exciting the underlying fluorescent probe at multiple wavelengths and measuring emission data multispectrally. In this paper, we describe a method that incorporates both excitation and emission spectral information into the OFT inverse problem. We describe a linear algebraic formulation of the multiple wavelength illumination-multispectral detection forward model for OFT and compare it to models that use only excitation at multiple wavelengths or those that use only multispectral detection techniques. This study is carried out in a realistic inhomogeneous mouse atlas using singular value decomposition and analysis of reconstructed spatial resolution versus noise. For simplicity, quantitative results have been shown for one representative fluorescent probe (Alexa 700) and effects due to tissue autofluorescence have not been taken into account. We also demonstrate the performance of our method for 3D reconstruction of tumors in a simulated mouse model of metastatic human hepatocellular carcinoma.

High-resolution voxelation mapping of human and rodent brain gene expression

Voxelation allows high-throughput acquisition of multiple volumetric images of brain gene expression, similar to those obtained from biomedical imaging systems. To obtain these images, the method employs analysis of spatially registered voxels (cubes). For creation of high-resolution maps using voxelation, relatively small voxel sizes are necessary and instruments will be required for semiautomated harvesting of such voxels. Here, we describe two devices that allow spatially registered harvesting of voxels from the human and rodent brain, giving linear resolutions of 3.3 and 1 mm, respectively. Gene expression patterns obtained using these devices showed good agreement with known expression patterns. The voxelation instruments and their future iterations represent a valuable approach to the genome scale acquisition of gene expression patterns in the human and rodent brain.

Crystal identification in positron emission tomography using nonrigid registration to a Fourier-based template

Modern positron emission tomography (PET) detectors are typically made from 2D modular arrays of scintillation crystals. Their characteristic flood field response (or flood histogram) must be segmented in order to correctly determine the crystal of annihilation photon interaction in the system. Crystal identification information thus generated is also needed for accurate system modeling as well as for detailed detector characterization and performance studies. In this paper, we present a semi-automatic general purpose template-guided scheme for the segmentation of flood histograms. We first generate a template image that exploits the spatial frequency information in the given flood histogram using Fourier-space analysis. This template image is a lower order approximation of the flood histogram, and can be segmented with horizontal and vertical lines drawn midway between adjacent peaks in the histogram. The template is then registered to the given flood histogram by a diffeomorphic polynomial-based warping scheme that is capable of iteratively minimizing intensity differences. The displacement field thus calculated is applied to the segmentation of the template resulting in a segmentation of the given flood histogram. We evaluate our segmentation scheme for a photomultiplier tube based PET detector, a detector with readout by a position-sensitive avalanche photodiode (PSAPD) and a detector consisting of a stack of photomultiplier tubes and scintillator arrays. Further, we quantitatively compare the performance of the proposed method to that of a manual segmentation scheme using reconstructed images of a line-source phantom. We also present an adaptive method for distortion reduction in flood histograms obtained for PET detectors that use PSAPDs.

DigiWarp: a method for deformable mouse atlas warping to surface topographic data

For pre-clinical bioluminescence or fluorescence optical tomography, the animals surface topography and internal anatomy need to be estimated for improving the quantitative accuracy of reconstructed images. The animals surface profile can be measured by all-optical systems, but estimation of the internal anatomy using optical techniques is non-trivial. A 3D anatomical mouse atlas may be warped to the estimated surface. However, fitting an atlas to surface topography data is challenging because of variations in the posture and morphology of imaged mice. In addition, acquisition of partial data (for example, from limited views or with limited sampling) can make the warping problem ill-conditioned. Here, we present a method for fitting a deformable mouse atlas to surface topographic range data acquired by an optical system. As an initialization procedure, we match the posture of the atlas to the posture of the mouse being imaged using landmark constraints. The asymmetric L(2) pseudo-distance between the atlas surface and the mouse surface is then minimized in order to register two data sets. A Laplacian prior is used to ensure smoothness of the surface warping field. Once the atlas surface is normalized to match the range data, the internal anatomy is transformed using elastic energy minimization. We present results from performance evaluation studies of our method where we have measured the volumetric overlap between the internal organs delineated directly from MRI or CT and those estimated by our proposed warping scheme. Computed Dice coefficients indicate excellent overlap in the brain and the heart, with fair agreement in the kidneys and the bladder.

Spatial Distortion Correction and Crystal Identification for MRI-Compatible Position-Sensitive Avalanche Photodiode-Based PET Scanners

Position-sensitive avalanche photodiodes (PSAPDs) are gaining widespread acceptance in modern PET scanner designs, and owing to their relative insensitivity to magnetic fields, especially in those that are MRI-compatible. Flood histograms in PET scanners are used to determine the crystal of annihilation photon interaction and hence, for detector characterization and routine quality control. For PET detectors that use PSAPDs, flood histograms show a characteristic pincushion distortion when Anger logic is used for event positioning. A small rotation in the flood histogram is also observed when the detectors are placed in a magnetic field. We first present a general purpose automatic method for spatial distortion correction for flood histograms of PSAPD-based PET detectors when placed both inside and outside a MRI scanner. Analytical formulas derived for this scheme are based on a hybrid approach that combines desirable properties from two existing event positioning schemes. The rotation of the flood histogram due to the magnetic field is determined iteratively and is accounted for in the scheme. We then provide implementation details of a method for crystal identification we have previously proposed and evaluate it for cases when the PET detectors are both outside and in a magnetic field. In this scheme, Fourier analysis is used to generate a lower-order spatial approximation of the distortion-corrected PSAPD flood histogram, which we call the ldquotemplaterdquo. The template is then registered to the flood histogram using a diffeomorphic iterative intensity-based warping scheme. The calculated deformation field is then applied to the segmentation of the template to obtain a segmentation of the flood histogram. A manual correction tool is also developed for exceptional cases. We present a quantitative assessment of the proposed distortion correction scheme and crystal identification method against conventional methods. Our results indicate that our proposed methods lead to a large reduction in manual labor and indeed can routinely be used for calibration and characterization studies in MRI-compatible PET scanners based on PSAPDs.