Lars R Furenlid

Interests

Research

special expertise in the techniques required to develop and apply advanced x-ray and gamma-ray detectors, and commissioned SPECT, PET, and CT imaging systems. This includes the physics of scintillation and solid-state detectors, methods of optics, pulse-processing electronics, digital data acquisition, and data inversion/assessment/reconstruction with a variety of computational methods. I work closely with and advise Masters and PhD students who carry out fundamental research and develop hardware technologies as part of their thesis/disseration projects.

Teaching

broad physics, chemistry, and structural biology background, mathematics of imaging and spectroscopy, radiochemistry and molecular imaging methods in drug discovery.

Courses

Scholarly Contributions

Journals/Publications

• , X. L., , L. T., , C. S., & , L. R. (2022). Virtual Point Source Synthesis method for 3D Scintillation Detector Characterization.
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  A novel data-processing method was developed to facilitate scintillationdetector characterization. Combined with fan-beam calibration, this method canbe used to quickly and conveniently calibrate gamma-ray detectors for SPECT,PET, homeland security or astronomy. Compared with traditional calibrationmethods, this new technique can accurately calibrate a photon-countingdetector, including DOI information, with greatly reduced time. The enablingpart of this technique is fan-beam scanning combined with a data-processingstrategy called the common-data subset (CDS) method, which was used tosynthesize the detector's mean detector response functions (MDRFs). Using thisapproach, $2N$ scans ($N$ in x and $N$ in y direction) are necessary to finishcalibration of a 2D detector as opposed to $N^2$ scans with a pencil beam. Fora 3D detector calibration, only $3N$ scans are necessary to achieve the 3Ddetector MDRFs that include DOI information. Moreover, this calibrationtechnique can be used for detectors with complicated or irregular MDRFs. Wepresent both Monte-Carlo simulations and experimental results that support thefeasibility of this method.[Journal_ref: ]
• Auer, B., Zeraatkar, N., Goding, J. C., Konik, A., Fromme, T. J., Kalluri, K., Furenlid, L. R., Kuo, P. H., & King, M. A. (2021). Inclusion of quasi-vertex views in a brain-dedicated multi-pinhole SPECT system for improved imaging performance. Physics in medicine and biology.
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  With brain-dedicated multi-detector systems employing pinhole apertures the usage of detectors facing the top of the patient's head (i.e., quasi-vertex views) can provide the advantage of additional viewing from close to the brain for improved detector coverage. In this paper, we report the results of simulation and reconstruction studies to investigate the impact of the quasi-vertex views on the imaging performance of AdaptiSPECT-C, a brain-dedicated stationary SPECT system under development. In this design, both primary and scatter photons from regions located inferior to the brain can contribute to SPECT projections acquired by the quasi-vertex views, and thus degrade AdaptiSPECT-C imaging performance. In this work, we determined the proportion, origin, and nature (i.e., primary, scatter, and multiple-scatter) of counts emitted from structures within the head and throughout the body contributing to projections from the different AdaptiSPECT-C detector rings, as well as from a true vertex view detector. We simulated phantoms used to assess different aspects of image quality (i.e., uniform sphere and Derenzo), as well as anthropomorphic phantoms with multiple count levels emulating clinicalI activity distributions (i.e., DaTscan and perfusion). We determined that attenuation and scatter in the patient's body greatly diminish the probability of the photons emitted outside the volume of interest reaching to detectors and being recorded within the 15% photopeak energy window. In addition, we demonstrated that the inclusion of the residual of such counts in the system acquisition does not degrade visual interpretation or quantitative analysis. The addition of the quasi-vertex detectors increases volumetric sensitivity, angular sampling, and spatial resolution leading to significant enhancement in image quality, especially in the striato-thalamic and superior regions of the brain. Besides, the use of quasi-vertex detectors improves the recovery of clinically relevant metrics such as the striatal binding ratio and mean activity in selected cerebral structures.
• Könik, A., Zeraatkar, N., Kalluri, K. S., Auer, B., Fromme, T. J., He, Y., May, M., Furenlid, L. R., Kuo, P. H., & King, M. A. (2021). Improved Performance of a Multipinhole SPECT for DAT Imaging by Increasing Number of Pinholes at the Expense of Increased Multiplexing. IEEE transactions on radiation and plasma medical sciences, 5(6), 817-825.
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  SPECT imaging of dopamine transporters (DAT) in the brain is a widely utilized study to improve the diagnosis of Parkinsonian syndromes, where conventional (parallel-hole and fan-beam) collimators on dual-head scanners are commonly employed. We have designed a multi-pinhole (MPH) collimator to improve the performance of DAT imaging. The MPH collimator focuses on the striatum and hence offers a better trade-off for sensitivity and spatial resolution than the conventional collimators within this clinically most relevant region for DAT imaging. Our original MPH design consisted of 9 pinholes with a background-to-striatal (Bkg/Str) projection multiplexing of 1% only. In this simulation study, we investigated whether further improvements in the performance of MPH imaging could be obtained by increasing the number of pinholes, hence by enhancing the sensitivity and sampling, despite the ambiguity in reconstructing images due to increased multiplexing. We performed analytic simulations of the MPH configurations with 9, 13, and 16 pinholes (aperture diameters: 4-6mm) using a digital phantom modeling DAT imaging. Our quantitative analyses indicated that using 13 (Bkg/Str: 12%) and 16 (Bkg/Str: 22%) pinholes provided better performance than the original 9-pinhole configuration for the acquisition with 2 or 4 angular views, but a similar performance with 8 and 16 views.
• Liu, Z., Gray, B. D., Barber, C., Wan, L., Furenlid, L. R., Liang, R., Li, Z., Woolfenden, J. M., Pak, K. Y., & Martin, D. R. (2021). PEGylated and Non-PEGylated TCP-1 Probes for Imaging of Colorectal Cancer. Molecular imaging and biology.
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  Previous studies indicate that Tc- and fluorescent-labeled c[Cys-Thr-Pro-Ser-Pro-Phe-Ser-His-Cys]OH (TCP-1) peptides were able to detect colorectal cancer (CRC) and tumor-associated vasculature. This study was designed to characterize the targeting properties of PEGylated and non-PEGylated TCP-1 peptides for CRC imaging.
• Zeraatkar, N., Auer, B., Kalluri, K. S., May, M., Momsen, N. C., Richards, R. G., Furenlid, L. R., Kuo, P. H., & King, M. A. (2021). Improvement in sampling and modulation of multiplexing with temporal shuttering of adaptable apertures in a brain-dedicated multi-pinhole SPECT system. Physics in Medicine & Biology, 66(6), 065004.
• Zeraatkar, N., Kalluri, K. S., Auer, B., May, M., Richards, R. G., Furenlid, L. R., Kuo, P. H., & King, M. A. (2021). Cerebral SPECT imaging with different acquisition schemes using varying levels of multiplexing versus sensitivity in an adaptive multi-pinhole brain-dedicated scanner. Biomedical physics & engineering express, 7(6).
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  Application of multi-pinhole collimator in pinhole-based SPECT increases detection sensitivity. The presence of multiplexing in projection images due to the usage of multiple pinholes can further improve the sensitivity at the cost of adding data ambiguity. We are developing a next-generation adaptive brain-dedicated SPECT system -AdaptiSPECT-C. The AdaptiSPECT-C can adapt the multiplexing level and system sensitivity using adaptable pinhole modules. In this study, we investigated the performance of 4 data acquisition schemes with different multiplexing levels and sensitivities on cerebral SPECT imaging. Schemes #1, #2, and #3 have
• Tao, L., Li, X., Furenlid, L. R., & Levin, C. S. (2020). Deep learning based methods for gamma ray interaction location estimation in monolithic scintillation crystal detectors. Physics in medicine and biology, 65(11), 115007.
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  In this work, we explore deep learning based techniques using the information from mean detector response functions (MDRFs) as a new method to estimate gamma ray interaction location in monolithic scintillation crystal detectors. Compared with searching based methods, deep learning techniques do not require recording all the MDRF information once the prediction networks are trained, which means the memory cost could be significantly reduced. In addition, the event positioning process using deep learning techniques only requires running through the network once, without the need to do searching in the reference dataset. This could greatly speed up the positioning process for each event. We have designed and trained four different neural networks to estimate the gamma ray interaction location given the MDRF data. We have studied network structures consisting only of fully connected (FC) layers, as well as Conv neural networks (CNNs). In addition, we tried to use both regression and classification to generate the final prediction of the gamma ray interaction position. We evaluated the estimation accuracy, testing speed and memory cost (numbers of parameters) of different network architectures, and also compared them with the exhaustive search method. Our results indicate that deep learning based estimation methods with a well designed network structure can achieve a relative positioning error with respect to the ground truth determined by the exhaustive search method of below 1 mm in both x and y directions (depth information is not considered in this work), which would imply a very high performance positioning algorithm for practical monolithic scintillation crystal detectors. The deep learning network also achieves a testing speed that is more than 400 times faster than the exhaustive search method. With proper design of the network structure, the deep learning based positioning methods have the potential to save memory cost by a factor of up to 100.
• Zeraatkar, N., Kalluri, K. S., Auer, B., Konik, A., Fromme, T. J., Furenlid, L. R., Kuo, P. H., & King, M. A. (2020). Investigation of Axial and Angular Sampling in Multi-Detector Pinhole-SPECT Brain Imaging. IEEE transactions on medical imaging, 39(12), 4209-4224.
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  We designed a dedicated multi-detector multi-pinhole brain SPECT scanner to generate images of higher quality compared to general-purpose systems. The system, AdaptiSPECT-C, is intended to adapt its sensitivity-resolution trade-off by varying its aperture configurations allowing both high-sensitivity dynamic and high-spatial-resolution static imaging. The current system design consists of 23 detector heads arranged in a truncated spherical geometry. In this work, we investigated the axial and angular sampling capability of the current stationary system design. Two data acquisition schemes using limited rotation of the gantry and two others using axial translation of the imaging bed were also evaluated concerning their impact on image quality through improved sampling. Increasing both angular and axial sampling in the current prototype system resulted in quantitative improvements in image quality metrics and qualitative appearance of the images as determined in studies with specifically selected phantoms. Visual improvements for the brain phantoms with clinical distributions were less pronounced but presented quantitative improvements in the fidelity (normalized root-mean-square error (NRMSE)) and striatal specific binding ratio (SBR) for a dopamine transporter (DAT) distribution, and in NRMSE and activity recovery for a brain perfusion distribution. More pronounced improvements with increased sampling were seen in contrast recovery coefficient, bias, and coefficient of variation for a lesion in the brain perfusion distribution. The negligible impact of the most cranial ring of detectors on axial sampling, but its significant impact on sensitivity and angular sampling in the cranial portion of the imaging volume-of-interest were also determined.
• Caucci, L., Liu, Z., Jha, A. K., Han, H., Furenlid, L. R., & Barrett, H. H. (2019). Towards Continuous-to-Continuous 3D Imaging in the Real World. Physics in Medicine and Biology.
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  Imaging systems are often modeled as continuous-to-discrete mappings that map the object (i.e., a function of continuous variables such as space, time, energy, wavelength, etc.) to a finite set of measurements. When it comes to reconstruction, some discretized version of the object is almost always assumed, leading to a discrete-to-discrete representation of the imaging system. In this paper, we discuss a method for single photon emission computed tomography~(SPECT) imaging that avoids discrete representations of the object or the imaging system, thus allowing reconstruction on arbitrarily fine set of points.
• Caucci, L., Liu, Z., Jha, A. K., Han, H., Furenlid, L. R., & Barrett, H. H. (2019). Towards continuous-to-continuous 3D imaging in the real world. Physics in medicine and biology, 64(18), 185007.
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  Imaging systems are often modeled as continuous-to-discrete mappings that map the object (i.e. a function of continuous variables such as space, time, energy, wavelength, etc) to a finite set of measurements. When it comes to reconstruction, some discretized version of the object is almost always assumed, leading to a discrete-to-discrete representation of the imaging system. In this paper, we discuss a method for single-photon emission computed tomography (SPECT) imaging that avoids discrete representations of the object or the imaging system, thus allowing reconstruction on an arbitrarily fine set of points.
• Hutton, B. F., Yamaya, T., & Furenlid, L. R. (2019). Dedicated Molecular Imaging Systems for Human Neurological Studies. IEEE Transactions on Radiation and Plasma Medical Sciences.
• Könik, A., Auer, B., De Beenhouwer, J., Kalluri, K., Zeraatkar, N., Furenlid, L. R., & King, M. A. (2019). Primary, scatter, and penetration characterizations of parallel-hole and pinhole collimators for I-123 SPECT. Physics in medicine and biology, 64(24), 245001.
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  Multi-pinhole (MPH) collimators are known to provide better trade-off between sensitivity and resolution for preclinical, as well as for smaller regions in clinical SPECT imaging compared to conventional collimators. In addition to this geometric advantage, MPH plates typically offer better stopping power for penetration than the conventional collimators, which is especially relevant for I-123 imaging. The I-123 emits a series of high-energy (>300 keV, ~2.5% abundance) gamma photons in addition to the primary emission (159 keV, 83% abundance). Despite their low abundance, high-energy photons penetrate through a low-energy parallel-hole (LEHR) collimator much more readily than the 159 keV photons, resulting in large downscatter in the photopeak window. In this work, we investigate the primary, scatter, and penetration characteristics of a single pinhole collimator that is commonly used for I-123 thyroid imaging and our two MPH collimators designed for I-123 DaTscan imaging for Parkinson's Disease, in comparison to three different parallel-hole collimators through a series of experiments and Monte Carlo simulations. The simulations of a point source and a digital human phantom with DaTscan activity distribution showed that our MPH collimators provide superior count performance in terms of high primary counts, low penetration, and low scatter counts compared to the parallel-hole and single pinhole collimators. For example, total scatter, multiple scatter, and collimator penetration events for the LEHR were 2.5, 7.6 and 14 times more than that of MPH within the 15% photopeak window. The total scatter fraction for LEHR was 56% where the largest contribution came from the high-energy scatter from the back compartments (31%). For the same energy window, the total scatter for MPH was 21% with only 1% scatter from the back compartments. We therefore anticipate that using MPH collimators, higher quality reconstructions can be obtained in a substantially shorter acquisition time for I-123 DaTscan and thyroid imaging.
• Li, X., Tao, L., Levin, C. S., & Furenlid, L. R. (2019). Fast gamma-ray interaction-position estimation using k-d tree search. Physics in medicine and biology, 64(15), 155018.
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  We have developed a fast gamma-ray interaction-position estimation method using k-d tree search, which can be combined with various kinds of closeness metrics such as Euclidean distance, maximum-likelihood estimation, etc. Compared with traditional search strategies, this method can achieve both speed and accuracy at the same time using the k-d tree data structure. The k-d tree search method has a time complexity of [Formula: see text], where N is the number of entries in the reference data set, which means large reference datasets can be used to efficiently estimate each event's interaction position. This method's accuracy was found to be equal to that of the exhaustive search method, yielding the highest achievable accuracy. Most importantly, this method has no restriction on the data structure of the reference dataset and can still work with complicated mean-detector-response functions (MDRFs), meaning that it is more robust than other popular methods such as contracting-grid-search (CG) or vector-search (VS) methods that could yield locally optimal instead of globally optimal results.
• Liu, Z., Barber, C., Gupta, A., Wan, L., Won, Y. W., Furenlid, L. R., Chen, Q., Desai, A. A., Zhao, M., Bull, D. A., Unger, E. C., & Martin, D. R. (2019). Imaging assessment of cardioprotection mediated by a dodecafluoropentane oxygen-carrier administered during myocardial infarction. Nuclear medicine and biology, 70, 67-77.
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  The objective of this study was to investigate the cardioprotective effects of a dodecafluoropentane (DDFP)-based perfluorocarbon emulsion (DDFPe) as an artificial carrier for oxygen delivery to ischemic myocardium, using Tc-duramycin SPECT imaging.
• Li, X., Ruiz-Gonzalez, M., & Furenlid, L. R. (2018). An edge-readout, multilayer detector for positron emission tomography. Medical physics, 45(6), 2425-2438.
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  We present a novel gamma-ray-detector design based on total internal reflection (TIR) of scintillation photons within a crystal that addresses many limitations of traditional PET detectors. Our approach has appealing features, including submillimeter lateral resolution, DOI positioning from layer thickness, and excellent energy resolution. The design places light sensors on the edges of a stack of scintillator slabs separated by small air gaps and exploits the phenomenon that more than 80% of scintillation light emitted during a gamma-ray event reaches the edges of a thin crystal with polished faces due to TIR. Gamma-ray stopping power is achieved by stacking multiple layers, and DOI is determined by which layer the gamma ray interacts in.
• Papachristou, M., Kastis, G. A., Stavrou, P. Z., Xanthopoulos, S., Furenlid, L. R., Datseris, I. E., & Bouziotis, P. (2018). Radiolabeled methotrexate as a diagnostic agent of inflammatory target sites: A proof-of-concept study. Molecular medicine reports, 17(2), 2442-2448.
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  Methotrexate (MTX), as a pharmaceutical, is frequently used in tumor chemotherapy and is also a part of the established treatment of a number of autoimmune inflammatory disorders. Radiolabeled MTX has been studied as a tumor‑diagnostic agent in a number of published studies. In the present study, the potential use of technetium‑99m‑labelled MTX (99mTc‑MTX) as a radiotracer was investigated for the identification of inflammatory target sites. The labelling of MTX was carried out via a 99mTc‑gluconate precursor. Evaluation studies included in vitro stability, plasma protein binding assessment, partition‑coefficient estimation, in vivo scintigraphic imaging and ex vivo animal experiments in an animal inflammation model. MTX was successfully labelled with 99mTc, with a radiochemical purity of >95%. Stability was assessed in plasma, where it remained intact up to 85% at 4 h post‑incubation, while protein binding of the radiotracer was observed to be ~50% at 4 h. These preclinical ex vivo and in vivo studies indicated that 99mTc‑MTX accumulates in inflamed tissue, as well as in the spinal cord, joints and bones; all areas with relatively high remodeling activity. The results are promising, and set the stage for further work on the development and application of 99mTc‑MTX as a radiotracer for inflammation associated with rheumatoid arthritis.
• Ruiz-Gonzalez, M., Bora, V., & Furenlid, L. R. (2018). Maximum-Likelihood Estimation of Scintillation Pulse Timing. IEEE transactions on radiation and plasma medical sciences, 2(1), 1-6.
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  Including time-of-flight information in positron emission tomography (PET) reconstruction increases the signal-to-noise ratio if the timing information is sufficiently accurate. We estimate timing information by analyzing sampled waveforms, where the sampling frequency and number of samples acquired affect the accuracy of timing estimation. An efficient data-acquisition system acquires the minimum number of samples that contains the most timing information for a desired resolution. We describe a maximum-likelihood (ML) estimation algorithm to assign a time stamp to digital pulses. The method is based on a contracting-grid search algorithm that can be implemented in a field-programmable gate array and in graphics processing units. The Fisher-information (FI) matrix quantifies the amount of timing information that can be extracted from the waveforms. FI analyses on different segments of the waveform allow us to determine the smallest amount of data that we need to acquire in order to obtain a desired timing resolution. We describe the model and the procedure used to simulate waveforms for ML estimation and FI analysis, the ML-estimation algorithm and the timing resolution obtained from experimental data using a LaBr:Ce crystal and two photomultiplier tubes. The results show that for lengthening segments of the pulse, timing resolution approaches a limit. We explored the method as a function of sampling frequency and compared the results to other digital time pickoff methods. This information will be used to build an efficient data-acquisition system with reduced complexity and cost that nonetheless preserves full timing performance.
• Tsoukalas, C., Psimadas, D., Kastis, G. A., Koutoulidis, V., Harris, A. L., Paravatou-Petsotas, M., Karageorgou, M., Furenlid, L. R., Moulopoulos, L. A., Stamopoulos, D., & Bouziotis, P. (2018). A Novel Metal-Based Imaging Probe for Targeted Dual-Modality SPECT/MR Imaging of Angiogenesis. Frontiers in chemistry, 6, 224.
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  Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof-of-concept study was to develop a dual-modality nanoplatform for targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with Tc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. FeO-DMSA-SMCC-BCZM-Tc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. cell binding studies showed the ability of the FeO-DMSA-SMCC-BCZM-Tc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The FeO-DMSA-SMCC-BCZM-Tc demonstrated quick tumor accumulation starting at 8.9 ± 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 ± 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 ± 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (~7), which is also the case for the tumor-to-muscle ratio (~18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of FeO-DMSA-SMCC-BCZM-Tc for targeted dual-modality imaging. Our findings indicate that FeO-DMSA-SMCC-BCZM-Tc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer.
• Takeda, S., Katsuragawa, M., Orita, T., Moriyama, F., Arai, Y., Sugawara, H., Oshita, S., Yabu, G., Watanabe, S., Takahashi, T., & Furenlid, L. R. (2017). A high-resolution CdTe imaging detector with multi-pinhole optics for in-vivo molecular imaging. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment.
• Bora, V., Barrett, H. H., Fastje, D., Clarkson, E., Furenlid, L., Bousselham, A., Shah, K. S., & Glodo, J. (2016). Estimation of Fano factor in inorganic scintillators. Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment, 805, 72-86.
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  The Fano factor of an integer-valued random variable is defined as the ratio of its variance to its mean. Correlation between the outputs of two photomultiplier tubes on opposite faces of a scintillation crystal was used to estimate the Fano factor of photoelectrons and scintillation photons. Correlations between the integrals of the detector outputs were used to estimate the photoelectron and photon Fano factor for YAP:Ce, SrI2:Eu and CsI:Na scintillator crystals. At 662 keV, SrI2:Eu was found to be sub-Poisson, while CsI:Na and YAP:Ce were found to be super-Poisson. An experiment setup inspired from the Hanbury Brown and Twiss experiment was used to measure the correlations as a function of time between the outputs of two photomultiplier tubes looking at the same scintillation event. A model of the scintillation and the detection processes was used to generate simulated detector outputs as a function of time for different values of Fano factor. The simulated outputs from the model for different Fano factors was compared to the experimentally measured detector outputs to estimate the Fano factor of the scintillation photons for YAP:Ce, LaBr3:Ce scintillator crystals. At 662 keV, LaBr3:Ce was found to be sub-Poisson, while YAP:Ce was found to be close to Poisson.
• Brand, J. F., Furenlid, L. R., Altbach, M. I., Galons, J. P., Bhattacharyya, A., Sharma, P., Bhattacharyya, T., Bilgin, A., & Martin, D. R. (2016). Task-based optimization of flip angle for fibrosis detection in T1-weighted MRI of liver. Journal of medical imaging (Bellingham, Wash.), 3(3), 035502.
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  Chronic liver disease is a worldwide health problem, and hepatic fibrosis (HF) is one of the hallmarks of the disease. The current reference standard for diagnosing HF is biopsy followed by pathologist examination; however, this is limited by sampling error and carries a risk of complications. Pathology diagnosis of HF is based on textural change in the liver as a lobular collagen network that develops within portal triads. The scale of collagen lobules is characteristically in the order of 1 to 5 mm, which approximates the resolution limit of in vivo gadolinium-enhanced magnetic resonance imaging in the delayed phase. We use MRI of formalin-fixed human ex vivo liver samples as phantoms that mimic the textural contrast of in vivo Gd-MRI. We have developed a local texture analysis that is applied to phantom images, and the results are used to train model observers to detect HF. The performance of the observer is assessed with the area-under-the-receiver-operator-characteristic curve (AUROC) as the figure-of-merit. To optimize the MRI pulse sequence, phantoms were scanned with multiple times at a range of flip angles. The flip angle that was associated with the highest AUROC was chosen as optimal for the task of detecting HF.
• Li, X., & Furenlid, L. (2016). An analysis of side readouts of monolithic scintillation crystals. Journal of Nuclear Medicine, 57(supplement 2), 1950--1950.
• Liu, Z., Gray, B. D., Barber, C., Bernas, M., Cai, M., Furenlid, L. R., Rouse, A., Patel, C., Banerjee, B., Liang, R., Gmitro, A. F., Witte, M. H., Pak, K. Y., & Woolfenden, J. M. (2016). Characterization of TCP-1 probes for molecular imaging of colon cancer. Journal of controlled release : official journal of the Controlled Release Society, 239, 223-30.
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  Molecular probes capable of detecting colorectal cancer (CRC) are needed for early CRC diagnosis. The objective of this study was to characterize c[CTPSPFSHC]OH (TCP-1), a small peptide derived from phage display selection, for targeting human CRC xenografts using technetium-99m ((99m)Tc)-labeled TCP-1 and fluorescent cyanine-7 (Cy7)-labeled form of the peptide (Cy7-TCP-1). (99m)Tc-TCP-1 was generated by modifying TCP-1 with succinimidyl-6-hydrazino-nicotinamide (S-HYNIC) followed by radiolabeling. In vitro saturation binding experiments were performed for (99m)Tc-TCP-1 in human HCT116 colon cancer cells. SCID mice with human HCT116 cancer xenografts were imaged with (99m)Tc-TCP-1 or control peptide using a small-animal SPECT imager: Group I (n=5) received no blockade; Group II (n=5) received a blocking dose of non-radiolabeled TCP-1. Group III (n=5) were imaged with (99m)Tc-labeled control peptide (inactive peptide). SCID mice with human PC3 prostate cancer xenografts (Group IV, n=5) were also imaged with (99m)Tc-TCP-1. Eight additional SCID mice bearing HCT116 xenografts in dorsal skinfold window chambers (DSWC) were imaged by direct positron imaging of (18)F-fluorodeoxyglucose ((18)F-FDG) and fluorescence microscopy of Cy7-TCP-1. In vitro(99m)Tc-HYNIC-TCP-1 binding assays on HCT 116 cells indicated a mean Kd of 3.04±0.52nM. In cancer xenografts, (99m)Tc-TCP-1 radioactivity (%ID/g) was 1.01±0.15 in the absence of blockade and was reduced to 0.26±0.04 (P
• Liu, Z., Larsen, B. T., Lerman, L. O., Gray, B. D., Barber, C., Hedayat, A. F., Zhao, M., Furenlid, L. R., Pak, K. Y., & Woolfenden, J. M. (2016). Detection of atherosclerotic plaques in ApoE-deficient mice using (99m)Tc-duramycin. Nuclear medicine and biology, 43(8), 496-505.
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  Apoptosis of macrophages and smooth muscle cells is linked to atherosclerotic plaque destabilization. The apoptotic cascade leads to exposure of phosphatidylethanolamine (PE) on the outer leaflet of the cell membrane, thereby making apoptosis detectable using probes targeting PE. The objective of this study was to exploit capabilities of a PE-specific imaging probe, (99m)Tc-duramycin, in localizing atherosclerotic plaque and assessing plaque evolution in apolipoprotein-E knockout (ApoE(-/-)) mice.
• Woolfenden, J. M., Pak, K. Y., Witte, M. H., Gmitro, A. F., Liang, R., Banerjee, B., Patel, C., Rouse, A. R., Furenlid, L. R., Bernas, M., Cai, M., Barber, C., Gray, B. D., & Liu, Z. (2016). Characterization of TCP-1 molecular imaging probes in mouse models with xenografted human colon cancer.. J Control Release, 239, 223-230.
• Caucci, L., Jha, A. K., Furenlid, L. R., Clarkson, E. W., Kupinski, M. A., & Barrett, H. H. (2015). Image Science with Photon-Processing Detectors. IEEE Nuclear Science Symposium conference record. Nuclear Science Symposium, 2013.
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  We introduce and discuss photon-processing detectors and we compare them with photon-counting detectors. By estimating a relatively small number of attributes for each collected photon, photon-processing detectors may help understand and solve a fundamental theoretical problem of any imaging system based on photon-counting detectors, namely null functions. We argue that photon-processing detectors can improve task performance by estimating position, energy, and time of arrival for each collected photon. We consider a continuous-to-continuous linear operator to relate the object being imaged to the collected data, and discuss how this operator can be analyzed to derive properties of the imaging system. Finally, we derive an expression for the characteristic functional of an imaging system that produces list-mode data.
• Liu, Z., Lerman, L. O., Tang, H., Barber, C., Wan, L., Hui, M. M., Furenlid, L. R., & Woolfenden, J. M. (2015). Inflammation imaging of atherosclerosis in Apo-E-deficient mice using a (99m)Tc-labeled dual-domain cytokine ligand. Nuclear medicine and biology, 41(10), 785-92.
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  Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) play a critical role in initiating and accelerating atherosclerosis. This study evaluated the imaging properties of (99m)Tc-TNFR2-Fc-IL-1RA ((99m)Tc-TFI), a dual-domain cytokine radioligand that targets TNF-α and IL-1β pathways, in assessing atherosclerosis development in apolipoprotein-E-deficient (ApoE(-)(/)(-)) mice.
• Park, R., Miller, B. W., Jha, A. K., Furenlid, L. R., Hunter, W. C., & Barrett, H. H. (2015). A Prototype Detector for a Novel High-Resolution PET System: BazookaPET. IEEE Nuclear Science Symposium conference record. Nuclear Science Symposium, 2012, 2123-2127.
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  We have designed and are developing a novel proof-of-concept PET system called BazookaPET. In order to complete the PET configuration, at least two detector elements are required to detect positron-electron annihilation events. Each detector element of the BazookaPET has two independent data acquisition channels. One side of the scintillation crystal is optically coupled to a 4×4 silicon photomultiplier (SiPM) array and the other side is a CCD-based gamma camera. Using these two separate channels, we can obtain data with high energy, temporal and spatial resolution data by associating the data outputs via several maximum-likelihood estimation (MLE) steps. In this work, we present the concept of the system and the prototype detector element. We focus on characterizing individual detector channels, and initial experimental calibration results are shown along with preliminary performance-evaluation results. We measured energy resolution and the integrated traces of the slit-beam images from both detector channel outputs. A photo-peak energy resolution of ~5.3% FWHM was obtained from the SiPM and ~48% FWHM from the CCD at 662 keV. We assumed SiPM signals follow Gaussian statistics and estimated the 2D interaction position using MLE. Based on our the calibration experiments, we computed the Cramér-Rao bound (CRB) for the SiPM detector channel and found that the CRB resolution is better than 1 mm in the center of the crystal.
• Salçın, E., & Furenlid, L. R. (2015). Event Processing for Modular Gamma Cameras with Tiled Multi-Anode Photomultiplier Tubes. IEEE Nuclear Science Symposium conference record. Nuclear Science Symposium, 2012, 3269-3272.
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  Multi-anode photomultiplier tubes (MAPMTs) are good candidates as light sensors for a new generation of modular scintillation cameras for Single-photon emission computed tomography (SPECT) and Positron emission tomography (PET) applications. MAPMTs can provide improved intrinsic spatial resolution (
• Barber, H. B., Fastje, D., Lemieux, D., Grim, G. P., Furenlid, L. R., Miller, B. W., Parkhurst, P., & Nagarkar, V. V. (2014). Imaging properties of pixellated scintillators with deep pixels. Proceedings of SPIE--the International Society for Optical Engineering, 9215.
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  We have investigated the light-transport properties of scintillator arrays with long, thin pixels (deep pixels) for use in high-energy gamma-ray imaging. We compared 10×10 pixel arrays of YSO:Ce, LYSO:Ce and BGO (1mm × 1mm × 20 mm pixels) made by Proteus, Inc. with similar 10×10 arrays of LSO:Ce and BGO (1mm × 1mm × 15mm pixels) loaned to us by Saint-Gobain. The imaging and spectroscopic behaviors of these scintillator arrays are strongly affected by the choice of a reflector used as an inter-pixel spacer (3M ESR in the case of the Proteus arrays and white, diffuse-reflector for the Saint-Gobain arrays). We have constructed a 3700-pixel LYSO:Ce Prototype NIF Gamma-Ray Imager for use in diagnosing target compression in inertial confinement fusion. This system was tested at the OMEGA Laser and exhibited significant optical, inter-pixel cross-talk that was traced to the use of a single-layer of ESR film as an inter-pixel spacer. We show how the optical cross-talk can be mapped, and discuss correction procedures. We demonstrate a 10×10 YSO:Ce array as part of an iQID (formerly BazookaSPECT) imager and discuss issues related to the internal activity of (176)Lu in LSO:Ce and LYSO:Ce detectors.
• Chaix, C., Kovalsky, S., Kupinski, M. A., Barrett, H. H., & Furenlid, L. R. (2014). Fabrication of the pinhole aperture for AdaptiSPECT. Proceedings of SPIE--the International Society for Optical Engineering, 9214, 921408.
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  AdaptiSPECT is a pre-clinical pinhole SPECT imaging system under final construction at the Center for Gamma-Ray Imaging. The system is designed to be able to autonomously change its imaging configuration. The system comprises 16 detectors mounted on translational stages to move radially away and towards the center of the field-of-view. The system also possesses an adaptive pinhole aperture with multiple collimator diameters and pinhole sizes, as well as the possibility to switch between multiplexed and non-multiplexed imaging configurations. In this paper, we describe the fabrication of the AdaptiSPECT pinhole aperture and its controllers.
• Durko, H. L., & Furenlid, L. R. (2014). Adaptive SPECT imaging with crossed-slit apertures. Proceedings of SPIE--the International Society for Optical Engineering, 9214.
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  Preclinical single-photon emission computed tomography (SPECT) is an essential tool for studying the progression, response to treatment, and physiological changes in small animal models of human disease. The wide range of imaging applications is often limited by the static design of many preclinical SPECT systems. We have developed a prototype imaging system that replaces the standard static pinhole aperture with two sets of movable, keel-edged copper-tungsten blades configured as crossed (skewed) slits. These apertures can be positioned independently between the object and detector, producing a continuum of imaging configurations in which the axial and transaxial magnifications are not constrained to be equal. We incorporated a megapixel silicon double-sided strip detector to permit ultrahigh-resolution imaging. We describe the configuration of the adjustable slit aperture imaging system and discuss its application toward adaptive imaging, and reconstruction techniques using an accurate imaging forward model, a novel geometric calibration technique, and a GPU-based ultra-high-resolution reconstruction code.
• Durko, H. L., Barrett, H. H., & Furenlid, L. R. (2014). High-Resolution Anamorphic SPECT Imaging. IEEE transactions on nuclear science, 61(3), 1126-1135.
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  We have developed a gamma-ray imaging system that combines a high-resolution silicon detector with two sets of movable, half-keel-edged copper-tungsten blades configured as crossed slits. These apertures can be positioned independently between the object and detector, producing an anamorphic image in which the axial and transaxial magnifications are not constrained to be equal. The detector is a 60 mm × 60 mm, one-millimeter-thick, one-megapixel silicon double-sided strip detector with a strip pitch of 59 μm. The flexible nature of this system allows the application of adaptive imaging techniques. We present system details; calibration, acquisition, and reconstruction methods; and imaging results.
• Furenlid, L. R., Barrett, H. H., Barber, H. B., Clarkson, E. W., Kupinski, M. A., Liu, Z., Stevenson, G. D., & Woolfenden, J. M. (2014). Molecular Imaging in the College of Optical Sciences - An Overview of Two Decades of Instrumentation Development. Proceedings of SPIE--the International Society for Optical Engineering, 9186.
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  During the past two decades, researchers at the University of Arizona's Center for Gamma-Ray Imaging (CGRI) have explored a variety of approaches to gamma-ray detection, including scintillation cameras, solid-state detectors, and hybrids such as the intensified Quantum Imaging Device (iQID) configuration where a scintillator is followed by optical gain and a fast CCD or CMOS camera. We have combined these detectors with a variety of collimation schemes, including single and multiple pinholes, parallel-hole collimators, synthetic apertures, and anamorphic crossed slits, to build a large number of preclinical molecular-imaging systems that perform Single-Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), and X-Ray Computed Tomography (CT). In this paper, we discuss the themes and methods we have developed over the years to record and fully use the information content carried by every detected gamma-ray photon.
• Han, L., Miller, B. W., Barber, H. B., Nagarkar, V. V., & Furenlid, L. R. (2014). A New Columnar CsI(Tl) Scintillator for iQID detectors. Proceedings of SPIE--the International Society for Optical Engineering, 9214, 92140D.
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  A 1650 μm thick columnar CsI(Tl) scintillator for upgrading iQID detectors, which is a high-resolution photon-counting gamma-ray and x-ray detector recently developed at the Center for Gamma-Ray Imaging (CGRI), has been studied in terms of sensitivity, spatial resolution and depth-of-interaction effects. To facilitate these studies, a new frame-parsing algorithm for processing raw event data is also proposed that has more degrees of freedom in data processing and can discriminate against a special kind of noise present in some low-cost intensifiers. The results show that in comparison with a 450 μm-thickness columnar CsI(Tl) scintillator, the 1650 μm thick CsI(Tl) scintillator provides more than twice the sensitivity at the expense of some spatial resolution degradation. The depth-of-interaction study also shows that event size and amplitude vary with scintillator thickness, which can assist in future detector simulations and 3D-interaction-position estimation.
• Li, X., & Furenlid, L. R. (2014). A SPECT system simulator built on the SolidWorks (TM) 3D-Design package. Proceedings of SPIE--the International Society for Optical Engineering, 9214.
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  We have developed a GPU-accelerated SPECT system simulator that integrates into instrument-design workflow [1]. This simulator includes a gamma-ray tracing module that can rapidly propagate gamma-ray photons through arbitrary apertures modeled by SolidWorks (TM) -created stereolithography (.STL) representations with a full complement of physics cross sections [2, 3]. This software also contains a scintillation detector simulation module that can model a scintillation detector with arbitrary scintillation crystal shape and light-sensor arrangement. The gamma-ray tracing module enables us to efficiently model aperture and detector crystals in SolidWorks (TM) and save them as STL file format, then load the STL-format model into this module to generate list-mode results of interacted gamma-ray photon information (interaction positions and energies) inside the detector crystals. The Monte-Carlo scintillation detector simulation module enables us to simulate how scintillation photons get reflected, refracted and absorbed inside a scintillation detector, which contributes to more accurate simulation of a SPECT system.
• Miller, B. W., Gregory, S. J., Fuller, E. S., Barrett, H. H., Barber, H. B., & Furenlid, L. R. (2014). The iQID camera: An ionizing-radiation quantum imaging detector. Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment, 767, 146-152.
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  We have developed and tested a novel, ionizing-radiation Quantum Imaging Detector (iQID). This scintillation-based detector was originally developed as a high-resolution gamma-ray imager, called BazookaSPECT, for use in single-photon emission computed tomography (SPECT). Recently, we have investigated the detector's response and imaging potential with other forms of ionizing radiation including alpha, neutron, beta, and fission fragment particles. The confirmed response to this broad range of ionizing radiation has prompted its new title. The principle operation of the iQID camera involves coupling a scintillator to an image intensifier. The scintillation light generated by particle interactions is optically amplified by the intensifier and then re-imaged onto a CCD/CMOS camera sensor. The intensifier provides sufficient optical gain that practically any CCD/CMOS camera can be used to image ionizing radiation. The spatial location and energy of individual particles are estimated on an event-by-event basis in real time using image analysis algorithms on high-performance graphics processing hardware. Distinguishing features of the iQID camera include portability, large active areas, excellent detection efficiency for charged particles, and high spatial resolution (tens of microns). Although modest, iQID has energy resolution that is sufficient to discriminate between particles. Additionally, spatial features of individual events can be used for particle discrimination. An important iQID imaging application that has recently been developed is real-time, single-particle digital autoradiography. We present the latest results and discuss potential applications.
• Salçin, E., Barrett, H. H., Barber, H. B., Takeda, S., Watanabe, S., Takahashi, T., & Furenlid, L. R. (2014). Fisher Information Analysis of Depth-of-Interaction Estimation in Double-Sided Strip Detectors. IEEE transactions on nuclear science, 61(3), 1243-1251.
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  In very-high-spatial-resolution gamma-ray imaging applications, such as preclinical PET and SPECT, estimation of 3D interaction location inside the detector crystal can be used to minimize parallax error in the imaging system. In this work, we investigate the effect of bias voltage setting on depth-of-interaction (DOI) estimates for a semiconductor detector with a double-sided strip geometry. We first examine the statistical properties of the signals and develop expressions for likelihoods for given gamma-ray interaction positions. We use Fisher Information to quantify how well (in terms of variance) the measured signals can be used for DOI estimation with different bias-voltage settings. We performed measurements of detector response versus 3D position as a function of applied bias voltage by scanning with highly collimated synchrotron radiation at the Advanced Photon Source at Argonne National Laboratory. Experimental and theoretical results show that the optimum bias setting depends on whether or not the estimated event position will include the depth of interaction. We also found that for this detector geometry, the z-resolution changes with depth.
• Chaix, C., Kovalsky, S., Kosmider, M., Barrett, H. H., & Furenlid, L. R. (2013). Integration of AdaptiSPECT, a small-animal adaptive SPECT imaging system. Proceedings of SPIE--the International Society for Optical Engineering, 8853.
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  AdaptiSPECT is a pre-clinical adaptive SPECT imaging system under final development at the Center for Gamma-ray Imaging. The system incorporates multiple adaptive features: an adaptive aperture, 16 detectors mounted on translational stages, and the ability to switch between a non-multiplexed and a multiplexed imaging configuration. In this paper, we review the design of AdaptiSPECT and its adaptive features. We then describe the on-going integration of the imaging system.
• Dumas, C., Bernstein, A., Espinoza, A., Morgan, D., Lewis, K., Nipper, M., Barrett, H. H., Kupinski, M. A., & Furenlid, L. R. (2013). SmartCAM: An adaptive clinical SPECT camera. Proceedings of SPIE--the International Society for Optical Engineering, 8853.
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  An adaptive pinhole aperture that fits a GE MaxiCam Single-Photon-Emission Computed Tomography (SPECT) system has been designed, built, and is undergoing testing. The purpose of an adaptive aperture is to allow the imaging system to make adjustments to the aperture while imaging data are being acquired. Our adaptive pinhole aperture can alter several imaging parameters, including field of view, resolution, sensitivity, and magnification. The dynamic nature of such an aperture allows for imaging of specific regions of interest based on initial measurements of the patient. Ideally, this mode of data collection will improve the understanding of a patient's condition, and will facilitate better diagnosis and treatment. The aperture was constructed using aluminum and a low melting point, high-stopping-power metal alloy called Cerrobend. The aperture utilizes a rotating disk for the selection of a pinhole configuration; as the aluminum disk rotates, different pinholes move into view of the camera face and allow the passage of gamma rays through that particular pinhole. By controlling the angular position of the disk, the optical characteristics of the aperture can be modified, allowing the system to acquire data from controlled regions of interest. First testing was performed with a small radioactive source to prove the functionality of the aperture.
• Han, L., Barrett, H. H., Barber, H. B., & Furenlid, L. R. (2013). The effect of gain variation in micro-channel plates on gamma-ray energy resolution. Proceedings of SPIE--the International Society for Optical Engineering, 8853.
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  A Monte Carlo simulation of micro-channel plate (MCP) with particular interest in its effect on energy resolution performance is presented. Important physical processes occurring in MCP channels are described and modeled, including secondary electron (SE) yield, SE emission, and primary electron reflection. The effects causing channel saturation are also introduced. A two dimensional Monte Carlo simulation is implemented under the assumption of unsaturated channel. Simulation results about basic MCP performances and especially gain and energy resolution performances are presented and analyzed. It's found that energy resolution as an intrinsic property of MCP cannot be improved simply by adjusting system parameters; however it can be improved by increasing input signal or number of photoelectrons (PEs) in the context of image intensifier. An initial experiment with BazookaSPECT detector and CsI(Tl) scintillator is performed to validate and correlate with the simulation results and good agreement is achieved.
• Havelin, R. J., Miller, B. W., Barrett, H. H., Furenlid, L. R., Murphy, J. M., & Foley, M. J. (2013). A SPECT imager with synthetic collimation. Proceedings of SPIE--the International Society for Optical Engineering, 8853.
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  This work outlines the development of a multi-pinhole SPECT system designed to produce a synthetic-collimator image of a small field of view. The focused multi-pinhole collimator was constructed using rapid-prototyping and casting techniques. The collimator projects the field of view through forty-six pinholes when the detector is adjacent to the collimator. The detector is then moved further from the collimator to increase the magnification of the system. The amount of pinhole-projection overlap increases with the system magnification. There is no rotation in the system; a single tomographic angle is used in each system configuration. The maximum-likelihood expectation-maximization (MLEM) algorithm is implemented on graphics processing units to reconstruct the object in the field of view. Iterative reconstruction algorithms, such as MLEM, require an accurate model of the system response. For each system magnification, a sparsely-sampled system response is measured by translating a point source through a grid encompassing the field of view. The pinhole projections are individually identified and associated with their respective apertures. A 2D elliptical Gaussian model is applied to the pinhole projections on the detector. These coefficients are associated with the object-space location of the point source, and a finely-sampled system matrix is interpolated. Simulations with a hot-rod phantom demonstrate the efficacy of combining low-resolution non-multiplexed data with high-resolution multiplexed data to produce high-resolution reconstructions.
• Liu, Z., Barber, C., Wan, L., Liu, S., Hui, M. M., Furenlid, L. R., Xu, H., & Woolfenden, J. M. (2013). SPECT imaging of inflammatory response in ischemic-reperfused rat hearts using a 99mTc-labeled dual-domain cytokine ligand. Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 54(12), 2139-45.
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  Soluble tumor necrosis factor (TNF) receptor-2 (TNFR2) and interleukin-1 receptor antagonist (IL-1ra) were fused to the Fc portion of IgG1 using recombinant DNA technology. The resulting dual-domain cytokine ligand, TNFR2-Fc-IL-1ra, specifically binds to TNF and to the type I IL-1 receptor (IL-1RI). This study was designed to characterize the kinetic profile of (99m)Tc-labeled TNFR2-Fc-IL-1ra (TFI) for imaging inflammatory response in an ischemic-reperfused (IR) rat heart model.
• Zhang, Y., Stevenson, G. D., Barber, C., Furenlid, L. R., Barrett, H. H., Woolfenden, J. M., Zhao, M., & Liu, Z. (2013). Imaging of rat cerebral ischemia-reperfusion injury using(99m)Tc-labeled duramycin. Nuclear medicine and biology, 40(1), 80-8.
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  Prompt identification of necrosis and apoptosis in the infarct core and penumbra region is critical in acute stroke for delineating the underlying ischemic/reperfusion molecular pathologic events and defining therapeutic alternatives. The objective of this study was to investigate the capability of (99m)Tc-labeled duramycin in detecting ischemia-reperfusion injury in rat brain after middle cerebral artery (MCA) occlusion.
• Lawson, P. R., Poyneer, L., Barrett, H., Frazin, R., Caucci, L., Devaney, N., Furenlid, L., Gładysz, S., Guyon, O., Krist, J., Maire, J., Marois, C., Mawet, D., Mouillet, D., Mugnier, L., Pearson, I., Perrin, M., Pueyo, L., & Savransky, D. (2012). On Advanced Estimation Techniques for Exoplanet Detection and Characterization Using Ground-based Coronagraphs. Proceedings of SPIE--the International Society for Optical Engineering, 8447.
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  The direct imaging of planets around nearby stars is exceedingly difficult. Only about 14 exoplanets have been imaged to date that have masses less than 13 times that of Jupiter. The next generation of planet-finding coronagraphs, including VLT-SPHERE, the Gemini Planet Imager, Palomar P1640, and Subaru HiCIAO have predicted contrast performance of roughly a thousand times less than would be needed to detect Earth-like planets. In this paper we review the state of the art in exoplanet imaging, most notably the method of Locally Optimized Combination of Images (LOCI), and we investigate the potential of improving the detectability of faint exoplanets through the use of advanced statistical methods based on the concepts of the ideal observer and the Hotelling observer. We propose a formal comparison of techniques using a blind data challenge with an evaluation of performance using the Receiver Operating Characteristic (ROC) and Localization ROC (LROC) curves. We place particular emphasis on the understanding and modeling of realistic sources of measurement noise in ground-based AO-corrected coronagraphs. The work reported in this paper is the result of interactions between the co-authors during a week-long workshop on exoplanet imaging that was held in Squaw Valley, California, in March of 2012.
• Liu, Z., Wyffels, L., Barber, C., Wan, L., Xu, H., Hui, M. M., Furenlid, L. R., & Woolfenden, J. M. (2012). Characterization of 99mTc-labeled cytokine ligands for inflammation imaging via TNF and IL-1 pathways. Nuclear medicine and biology, 39(7), 905-15.
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  TNFR2-Fc and IL-1ra-Fc are recombinant cytokine ligands that target TNF and IL-1. TNFR2-Fc-IL-1ra, a dual-domain agent that incorporates both ligands, allows bifunctional binding of IL-1 receptors and TNF. This study was designed to characterize (99m)Tc-labeled forms of these ligands, (99m)Tc-IL-1ra-Fc (IF), (99m)Tc-TNFR2-Fc (TF), and (99m)Tc-TNFR2-Fc-IL-1ra (TFI), for inflammation imaging.
• Miller, B. W., Barber, H. B., Barrett, H. H., Liu, Z., Nagarkar, V. V., & Furenlid, L. R. (2012). Progress in BazookaSPECT: High-Resolution, Dynamic Scintigraphy with Large-Area Imagers. Proceedings of SPIE--the International Society for Optical Engineering, 8508.
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  We present recent progress in BazookaSPECT, a high-resolution, photon-counting gamma-ray detector. It is a new class of scintillation detector that combines columnar scintillators, image intensifiers, and CCD (charge-coupled device) or CMOS (complementary metal-oxide semiconductors) sensors for high-resolution imaging. A key feature of the BazookaSPECT paradigm is the capability to easily design custom detectors in terms of the desired intrinsic detector resolution and event detection rate. This capability is possible because scintillation light is optically amplified by the image intensifier prior to being imaging onto the CCD/CMOS sensor, thereby allowing practically any consumer-grade CCD/CMOS sensor to be used for gamma-ray imaging. Recent efforts have been made to increase the detector area by incorporating fiber-optic tapers between the scintillator and image intensifier, resulting in a 16× increase in detector area. These large-area BazookaSPECT detectors can be used for full-body imaging and we present preliminary results of their use as dynamic scintigraphy imagers for mice and rats. Also, we discuss ongoing and future developments in BazookaSPECT and the improved event-detection rate capability that is achieved using Graphics Processing Units (GPUs), multi-core processors, and new high-speed, USB 3.0 CMOS cameras.
• Miller, B. W., Van Holen, R., Barrett, H. H., & Furenlid, L. R. (2012). A System Calibration and Fast Iterative Reconstruction Method for Next-Generation SPECT Imagers. IEEE transactions on nuclear science, 59(5), 1990-1996.
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  Recently, high-resolution gamma cameras have been developed with detectors containing > 10(5)-10(6) elements. Single-photon emission computed tomography (SPECT) imagers based on these detectors usually also have a large number of voxel bins and therefore face memory storage issues for the system matrix when performing fast tomographic reconstructions using iterative algorithms. To address these issues, we have developed a method that parameterizes the detector response to a point source and generates the system matrix on the fly during MLEM or OSEM on graphics hardware. The calibration method, interpolation of coefficient data, and reconstruction results are presented in the context of a recently commissioned small-animal SPECT imager, called FastSPECT III.
• Furenlid, L., Lemieux, D. A., Baudet, C., Grim, G. P., Barber, H. B., Miller, B. W., Fasje, D., & Furenlid, L. R. (2011). Investigation of the possibility of gamma-ray diagnostic imaging of target compression at NIF. Proceedings - Society of Photo-Optical Instrumentation Engineers, 8144.
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  The National Ignition Facility at Lawrence Livermore National Laboratory is the world's leading facility to study the physics of igniting plasmas. Plasmas of hot deuterium and tritium, undergo d(t,n)α reactions that produce a 14.1 MeV neutron and 3.5 MeV a particle, in the center of mass. As these neutrons pass through the materials surrounding the hot core, they may undergo subsequent (n,x) reactions. For example, (12)C(n,n'γ)(12)C reactions occur in remnant debris from the polymer ablator resulting in a significant fluence of 4.44 MeV gamma-rays. Imaging of these gammas will enable the determination of the volumetric size and symmetry of the ablation; large size and high asymmetry is expected to correlate with poor compression and lower fusion yield. Results from a gamma-ray imaging system are expected to be complimentary to a neutron imaging diagnostic system already in place at the NIF. This paper describes initial efforts to design a gamma-ray imaging system for the NIF using the existing neutron imaging system as a baseline for study. Due to the cross-section and expected range of ablator areal densities, the gamma flux should be approximately 10(-3) of the neutron flux. For this reason, care must be taken to maximize the efficiency of the gamma-ray imaging system because it will be gamma starved. As with the neutron imager, use of pinholes and/or coded apertures are anticipated. Along with aperture and detector design, the selection of an appropriate scintillator is discussed. The volume of energy deposition of the interacting 4.44 MeV gamma-rays is a critical parameter limiting the imaging system spatial resolution. The volume of energy deposition is simulated with GEANT4, and plans to measure the volume of energy deposition experimentally are described. Results of tests on a pixellated LYSO scintillator are also presented.
• Furenlid, L., Miller, B. W., Moore, J. W., Barrett, H. H., Fryé, T., Adler, S., Sery, J., & Furenlid, L. R. (2011). 3D printing in X-ray and Gamma-Ray Imaging: A novel method for fabricating high-density imaging apertures. Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment, 659(1).
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  Advances in 3D rapid-prototyping printers, 3D modeling software, and casting techniques allow for cost-effective fabrication of custom components in gamma-ray and X-ray imaging systems. Applications extend to new fabrication methods for custom collimators, pinholes, calibration and resolution phantoms, mounting and shielding components, and imaging apertures. Details of the fabrication process for these components, specifically the 3D printing process, cold casting with a tungsten epoxy, and lost-wax casting in platinum are presented.
• Furenlid, L., Barrett, H. H., Hunter, W. C., Miller, B. W., Moore, S. K., Chen, Y., & Furenlid, L. R. (2009). Maximum-Likelihood Methods for Processing Signals From Gamma-Ray Detectors. IEEE transactions on nuclear science, 56(3).
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  In any gamma-ray detector, each event produces electrical signals on one or more circuit elements. From these signals, we may wish to determine the presence of an interaction; whether multiple interactions occurred; the spatial coordinates in two or three dimensions of at least the primary interaction; or the total energy deposited in that interaction. We may also want to compute listmode probabilities for tomographic reconstruction. Maximum-likelihood methods provide a rigorous and in some senses optimal approach to extracting this information, and the associated Fisher information matrix provides a way of quantifying and optimizing the information conveyed by the detector. This paper will review the principles of likelihood methods as applied to gamma-ray detectors and illustrate their power with recent results from the Center for Gamma-ray Imaging.
• Furenlid, L., Moore, J. W., Barrett, H. H., & Furenlid, L. R. (2009). Adaptive CT for High-Resolution, Controlled-Dose, Region-of-Interest Imaging. IEEE Nuclear Science Symposium conference record. Nuclear Science Symposium, 2009(5402313,).
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  We have developed a flexible x-ray micro-CT system, named FaCT, capable of changing its geometric configuration and acquisition protocol in order to best suit an object being imaged for a particular diagnostic task. High-performance computing technologies have been a major enabling factor for this adaptive CT system in terms of system control, fast reconstruction, and data analysis. In this work, we demonstrate an adaptive procedure in which a quick, sparse-projection pre-scan is performed, the data are reconstructed, and a region of interest is identified. Next, a diagnostic-quality scan is performed where, given the region of interest, the control computer calculates an illumination window for on-line control of an x-ray source masking aperture to transmit radiation only through the region of interest throughout the scan trajectory. Finally, the diagnostic scan data are reconstructed, with the region of interest being clearly resolved. We use a combination of a multi-core CPU and a pair of NVIDIA Tesla GPUs to perform these tasks.
• Furenlid, L., Clarkson, E., Kupinski, M. A., Barrett, H. H., & Furenlid, L. R. (2008). A Task-Based Approach to Adaptive and Multimodality Imaging: Computation techniques are proposed for figures-of-merit to establish feasibility and optimize use of multiple imaging systems for disease diagnosis and treatment-monitoring. Proceedings of the IEEE. Institute of Electrical and Electronics Engineers, 96(3).
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  Multimodality imaging is becoming increasingly important in medical imaging. Since the motivation for combining multiple imaging modalities is generally to improve diagnostic or prognostic accuracy, the benefits of multimodality imaging cannot be assessed through the display of example images. Instead, we must use objective, task-based measures of image quality to draw valid conclusions about system performance. In this paper, we will present a general framework for utilizing objective, task-based measures of image quality in assessing multimodality and adaptive imaging systems. We introduce a classification scheme for multimodality and adaptive imaging systems and provide a mathematical description of the imaging chain along with block diagrams to provide a visual illustration. We show that the task-based methodology developed for evaluating single-modality imaging can be applied, with minor modifications, to multimodality and adaptive imaging. We discuss strategies for practical implementing of task-based methods to assess and optimize multimodality imaging systems.

Proceedings Publications

• McLeod, E., Mansuripur, M., Lemon, C., Koshel, J., Jones, J. P., Jessen, P., Furenlid, L. R., Chalifoux, B. D., & Kim, D. (2023).

  Optical Sciences Winter School for enabling future students in optics society

  . In SPIE Conference on Education and Training in Optics and Photonics: ETOP, 12723, 127231D.
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  Optical Sciences and Photonics are areas of growing importance that are too often missing from traditional undergraduate science and engineering curricula. Often, aspects of optics and photonics are picked up as side topics in undergraduate and graduate courses along the way to obtaining more traditional STEM (Science, Technology, Engineering and Mathematics) degrees. Since 2016, the annual Optical Sciences Winter School has been held during the winter break of the University of Arizona’s academic calendar. Its annual participants are now approximately 50 – 60 undergraduate students (mostly juniors and seniors) from US (United States) Universities who demonstrate an aptitude and talent for science and research. These students participate in a three- to five-day immersion experience, learning the many opportunities and benefits that choosing optics and photonics for their graduate studies can offer. The Optical Sciences Winter School (OSWS) brings together a motivated group of undergraduate students for a series of overview lectures teaching foundational topics in optics and their relation to current research. It also provides a forum for faculty, alumni, and invited guests to share results, approaches and methodologies in optics and photonics research and education that are unique to the undergraduate setting. This event is not focused on a specific school’s program but tries to highlight the diverse optics programs in the US. Many sessions in the program are filled with various invited faculties and researchers’ presentations from prominent optical physics and engineering undergraduate or graduate institutions.
• Anderson, O., Bl"ackberg, L., Sajedi, S., Sabet, H., & Furenlid, L. R. (2021). A 5-Axis Calibration Stage for Depth-of-Interaction-Correcting Scintillation Crystals. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Auer, B., Kalluri, K. S., Abayazeed, A. H., De, B. J., Zeraatkar, N., Lindsay, C., Momsen, N. C., Richards, R. G., May, M., Kupinski, M. A., & others, . (2021). Aperture size selection for improved brain tumor detection and quantification in multi-pinhole 123I-CLINDE SPECT imaging. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Bl"ackberg, L., Sajedi, S., Anderson, O. A., Feng, Y., El, F. G., Furenlid, L., & Sabet, H. (2021). Dynamic Cardiac SPECT for diagnostic and theranostics applications: latest results. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Cronin, K. P., Kupinski, M. A., Woolfenden, J. M., Yabu, G., Kawamura, T., Takeda, S., Takahashi, T., & Furenlid, L. R. (2021). Design of a Multi-Technology Pre-Clinical SPECT System. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Doty, K. J., Li, X., Richards, R. G., King, M. A., Kuo, P. H., Kupinski, M. A., & Furenlid, L. R. (2021). Modular camera design study for human brain SPECT system. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Kalluri, K. S., Auer, B., Zeraatkar, N., Richards, R. G., May, M., Doty, K., Ruiz-Gonzalez, M., Momsen, N. C., Kuo, P. H., Furenlid, L. R., & others, . (2021). Investigation of Designs for a Stationary Adaptive Multi-Pinhole Brain SPECT Employing Flat-Square Detector Modules. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• May, M., Momsen, N. C., Richards, R. G., Kalluri, K. S., Zeraatkar, N., Auer, B., King, M. A., Kuo, P. H., & Furenlid, L. R. (2021). Design of adaptive pinhole SPECT collimators for improved spatial resolution and sensitivity. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Richards, R. G., Ruiz-Gonzalez, M., May, M., Doty, K. J., Kalluri, K. S., Zeraatkar, N., Auer, B., King, M. A., Kuo, P. H., & Furenlid, L. R. (2021). Hardware development of hybrid-sensor cameras and gantry for an adaptive SPECT system. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Ruiz-Gonzalez, M., & Furenlid, L. R. (2021). Comparison of Conventional and SDM-Based Read-Out Systems for Gamma-Ray Imaging. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Ruiz-Gonzalez, M., Richards, R. G., Doty, K. J., Kuo, P. H., King, M. A., & Furenlid, L. R. (2021). Design of an 81-Channel Read-Out System for a Hybrid PMT/SiPM Modular Gamma-Ray Camera. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Zeraatkar, N., Kalluri, K. S., Auer, B., Momsen, N. C., May, M., Richards, R. G., Furenlid, L. R., Kuo, P. H., & King, M. A. (2021). Demultiplexing of projection data in adaptive brain SPECT with multi-pinhole collimation. In 2020 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Auer, B., De, B. J., Zeraatkar, N., Kuo, P. H., Furenlid, L. R., & King, M. A. (2020). Performance of an Ideal Attenuation and Scatter Correction Strategy for a Next-Generation SPECT System Dedicated to Quantitative Clinical Brain Imaging. In 2019 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Momsen, N., & Furenlid, L. R. (2020). Calibration and Processing of a Waveform MDRF for a Clinical Gamma Camera. In 2019 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Ruiz-Gonzalez, M., & Furenlid, L. R. (2020). Characterization of Non-Uniform 2-bit Sigma-Delta Modulator for Gamma-Ray Detectors. In 2019 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Zeraatkar, N., Lindsay, C., Auer, B., Furenlid, L. R., Kuo, P. H., & King, M. A. (2020). Compensation of Head Motion in AdaptiSPECT-C Using a GPU-Based Iterative Reconstruction Algorithm: Initial Results. In 2019 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC).
• Kalluri, K. S., Zeraatkar, N., Auer, B., H., P., Furenlid, L. R., & King, M. A. (2019, 2019/5/28 DOI - 10.1117/12.2534885). Preliminary investigation of AdaptiSPECT-C designs with square or square and hexagonal detectors employing direct and oblique apertures. In Preliminary investigation of AdaptiSPECT-C designs with square or square and hexagonal detectors employing direct and oblique apertures, 11072.
• Zeraatkar, N., Auer, B., Kalluri, K., Furenlid, L. R., Kuo, P. H., & King, M. A. (2019, 2019/5/28 DOI - 10.1117/12.2534523). GPU-accelerated generic analytic simulation and image reconstruction platform for multi-pinhole SPECT systems. In GPU-accelerated generic analytic simulation and image reconstruction platform for multi-pinhole SPECT systems, 11072.
• , N., , G., & Furenlid, L. R. (2018, 2018/9/18 DOI - 10.1117/12.2326512). System integration for a SPECT system featuring digital waveform acquisition. In System integration for a SPECT system featuring digital waveform acquisition, 10763.
• Li, X., Tao, L., Levin, C. S., & Furenlid, L. R. (2018, 2018). Fast gamma-ray event interaction position estimation using k-d tree - a simulation study. In 2018 IEEE Nuclear Science Symposium and Medical Imaging Conference Proceedings (NSS/MIC), 1-7.
• Ruiz-Gonzalez, M., & Furenlid, L. R. (2018, 2018/9/11 DOI - 10.1117/12.2326393). Scintillator-specific optimization of 2-bit sigma-delta modulation A/D for gamma-ray pulse waveform capture. In Scintillator-specific optimization of 2-bit sigma-delta modulation A/D for gamma-ray pulse waveform capture, 10763.
• Han, L., Miller, B. W., Barrett, H. H., Barber, H. B., & Furenlid, L. R. (2017, 2017/9/15 DOI - 10.1117/12.2279302). Applications of iQID cameras. In Applications of iQID cameras, 10393.
• Levin, C. S., Innes, D., Hsu, D., Grim, G., Furenlid, L. R., Freese, D. L., & Barber, H. B. (2017). 3D position-sensitive scintillation detectors for a high-resolution loco-regional PET imaging system (Conference Presentation). In Radiation Detectors in Medicine, Industry, and National Security XVIII, 10393.
  More info

  We are building a dual-panel positron emission tomography (PET) system prototype that enables focused imaging of local regions of interest of the body with 1 mm3 spatial resolution, The detector panels are built from novel 3D position sensitive scintillation (3DPSS) detectors comprising arrays of 1x1x1 mm3 LYSO scintillation crystal elements coupled to position-sensitive avalanche photodiodes (PSAPD). At the present state of system construction, the measured energy resolution over 98,304 crystal elements coupled to 1,536 PSAPDs is 11.34%, and 76.2% (74,938) of the system LYSO crystal elements are found to have greater than 99% event positioning accuracy. Imaging studies performed with a high-resolution phantom demonstrate resolution of the smallest (1.2 mm diameter) features. Besides enabling 1 mm resolution clinical PET studies, we describe other novel ways we are planning to exploit the 3DPSS detector information.
• Ruiz-Gonzalez, M., & Furenlid, L. R. (2017, 2017). Pulse timing in edge-readout PET detectors. In Proc. SPIE, 10393, 103930Q-10393-8.
• , S., , T., , Y., , H., , R., , M., , G., , S., , H., , T., Furenlid, L. R., & Bradford, H. (2016, 2016). High-resolution CdTe detectors with application to various fields (Conference Presentation). In High-resolution CdTe detectors with application to various fields (Conference Presentation), 9969, 99690K-9969-1.
• Ruiz-Gonzalez, M., Caucci, L., & Furenlid, L. R. (2016, 2016). Joint amplitude and timing estimation for scintillation pulses in GPU. In 2016 IEEE Nuclear Science Symposium, Medical Imaging Conference and Room-Temperature Semiconductor Detector Workshop (NSS/MIC/RTSD), 1-3.
• Barrett, H. H., Alberts, D. S., Woolfenden, J. M., Liu, Z., Clarkson, E. W., Kupinski, M. A., Furenlid, L. R., & Hoppin, J. (2015, august). Quantifying and Reducing Uncertainties in Cancer Therapy. In Proceedings of SPIE, 9412, 9412N-4.
• Barrett, H. H., Alberts, D. S., Woolfenden, J. M., Liu, Z., Clarkson, E. W., Kupinski, M. A., Furenlid, L. R., Hoppin, J., Barrett, H. H., Alberts, D. S., Woolfenden, J. M., Liu, Z., Clarkson, E. W., Kupinski, M. A., Furenlid, L. R., & Hoppin, J. (2015, august). Quantifying and Reducing Uncertainties in Cancer Therapy. In Proceedings of SPIE, 9412, 9412N-4.
• Caucci, L., & Furenlid, L. R. (2015, August). Graphics Processing units for biomedical imaging. In SPIE, 9594, 95940G.
• Caucci, L., Barrett, H. H., Liu, Z., Han, H., & Furenlid, L. R. (2015, September). Towards Continuous-To-Continuous 3D Data Reconstruction. In 13th International Meeting on Fully Three-Dimensional Image Reconstruction in Radiology and Nuclear Medicine.
• Ghanbari, N., Kupinski, M. A., & Furenlid, L. R. (2015, August). Optimization of an adaptive SPECT system with the scanning linear estimator. In SPIE, 9594, 95940A.
• Ruiz-Gonzalez, M., & Furenlid, L. R. (2015, 2015). Fisher information analysis of digital pulse timing. In 2015 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC), 1-3.
• Ruiz-Gonzalez, M., & Furenlid, L. R. (2015, August). Fisher information analysis of digital pulse timing. In IEEE, 9594.
• Salçın, E., Barrett, H. H., Barber, H. B., Takeda, S., Watanabe, S., Takahashi, T., & Furenlid, L. R. (2013, 2013). Fisher information analysis of depth-of-interaction estimation in double-sided strip detectors. In 2013 IEEE Nuclear Science Symposium and Medical Imaging Conference (2013 NSS/MIC), 1-9.

Presentations

• Liu, Z., Gray, B. D., Barber, C., Wan, L., Furenlid, L. R., & Woolfenden, J. M. (2019, June). Comparative evaluation of TCP-1 molecular probes in colorectal and pancreatic cancer models. 2019 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging. Anaheim, CA: The Society of Nuclear Medicine and Molecular Imaging.
• Liu, Z., Wan, L., Barber, C., Han, L., Furenlid, L. R., & Woolfenden, J. M. (2019, May). Radioiodinated hyaluronan for imaging pancreatic stromal remodeling related to pancreatic cancer development. The 23rd International Symposium on Radiopharmaceutical Sciences. Beijing, China: The Society of Radiopharmaceutical Sciences.

Poster Presentations

• Gray, B., Barber, C., Wan, L., Pak, K. Y., Furenlid, L. R., & Liu, Z. (2020, October). Characterization of PEGylated TCP1 probes for molecular imaging of colorectal cancer. 2020 World Molecular Imaging Congress (WMIC) VirtualWorld Molecular Imaging Society.
• Furenlid, L. R., Zhao, M., Wan, L., Barber, C., & Liu, Z. (2018, September). Characterization of Tc-99m-duramycin bound to circulating extracellular vesicles as a predictor of atherosclerotic plaque destabilization. 2018 World Molecular Imaging Congress. Seattle, WA: The World Molecular Imaging Society.
• Liu, Z., Lerman, L., Woolfenden, J. M., Furenlid, L. R., Wan, L., Tang, H., & Barber, C. (2018, September). Detection of renal ischemia/reperfusion injury in mouse models by Tc-99m-duramycin SPECT imaging. 2018 World Molecular Imaging Congress. Seattle, WA: The World Molecular Imaging Society.
• Liu, Z., Woolfenden, J. M., Furenlid, L. R., Han, L., Barber, C., & Wan, L. (2018, September). Radioiodination and biodistribution of hyaluronan in mouse models. 2018 World Molecular Imaging Congress. Seattle, WA: The World Molecular Imaging Society.