A DOI Detector With Crystal Scatter Identification Capability for High Sensitivity and High Spatial Resolution PET Imaging.

A new phoswich detector is being developed at the Crump Institute, aiming to provide improvements in sensitivity, and spatial resolution for PET. The detector configuration is comprised of two layers of pixelated scintillator crystal arrays, a glass light guide and a light detector. The annihilation photon entrance (top) layer is a 48 × 48 array of 1.01 × 1.01 × 7 mm3 LYSO crystals. The bottom layer is a 32 × 32 array of 1.55 × 1.55 × 9 mm3 BGO crystals. A tapered, multiple-element glass lightguide is used to couple the exit end of the BGO crystal array (52 × 52 mm2) to the photosensitive area of the Position Sensitive Photomultiplier Tube (46 × 46 mm2), allowing the creation of flat panel detectors without gaps between the detector modules. Both simulations and measurements were performed to evaluate the characteristics and benefits of the proposed design. The GATE Monte Carlo simulation indicated that the total fraction of the cross layer crystal scatter (CLCS) events in singles detection mode for this detector geometry is 13.2%. The large majority of these CLCS events (10.1% out of 13.2%) deposit most of their energy in a scintillator layer other than the layer of first interaction. Identification of those CLCS events for rejection or correction may lead to improvements in data quality and imaging performance. Physical measurements with the prototype detector showed that the LYSO, BGO and CLCS events were successfully identified using the delayed charge integration (DCI) technique, with more than 95% of the LYSO and BGO crystal elements clearly resolved. The measured peak-to-valley ratios (PVR) in the flood histograms were 3.5 for LYSO and 2.0 for BGO. For LYSO, the energy resolution ranged from 9.7% to 37.0% full width at half maximum (FWHM), with a mean of 13.4 ± 4.8%. For BGO the energy resolution ranged from 16.0% to 33.9% FWHM, with a mean of 18.6 ± 3.2%. In conclusion, these results demonstrate that the proposed detector is feasible and can potentially lead to a high spatial resolution, high sensitivity and DOI PET system.

A semi-automated vascular access system for preclinical models.

Murine models are used extensively in biological and translational research. For many of these studies it is necessary to access the vasculature for the injection of biologically active agents. Among the possible methods for accessing the mouse vasculature, tail vein injections are a routine but critical step for many experimental protocols. To perform successful tail vein injections, a high skill set and experience is required, leaving most scientists ill-suited to perform this task. This can lead to a high variability between injections, which can impact experimental results. To allow more scientists to perform tail vein injections and to decrease the variability between injections, a vascular access system (VAS) that semi-automatically inserts a needle into the tail vein of a mouse was developed. The VAS uses near infrared light, image processing techniques, computer controlled motors, and a pressure feedback system to insert the needle and to validate its proper placement within the vein. The VAS was tested by injecting a commonly used radiolabeled probe (FDG) into the tail veins of five mice. These mice were then imaged using micro-positron emission tomography to measure the percentage of the injected probe remaining in the tail. These studies showed that, on average, the VAS leaves 3.4% of the injected probe in the tail. With these preliminary results, the VAS system demonstrates the potential for improving the accuracy of tail vein injections in mice.

Betabox: a beta particle imaging system based on a position sensitive avalanche photodiode.

A beta camera has been developed that allows planar imaging of the spatial and temporal distribution of beta particles using a 14 × 14 mm(2) position sensitive avalanche photodiode (PSAPD). This camera system, which we call Betabox, can be directly coupled to microfluidic chips designed for cell incubation or other biological applications. Betabox allows for imaging the cellular uptake of molecular imaging probes labeled with charged particle emitters such as (18)F inside these chips. In this work, we investigate the quantitative imaging capabilities of Betabox for (18)F beta particles, in terms of background rate, efficiency, spatial resolution, and count rate. Measurements of background and spatial resolution are considered both at room temperature (21 °C ± 1 °C) and at an elevated operating temperature (37 °C ± 1 °C), as is often required for biological assays. The background rate measured with a 4 keV energy cutoff is below 2 cph mm(-2) at both 21 and 37 °C. The absolute efficiency of Betabox for the detection of (18)F positron sources in contact with a PSAPD with the surface passivated from ambient light and damage is 46% ± 1%. The lower detection limit is estimated using the Rose Criterion to be 0.2 cps mm(-2) for 1 min acquisitions and a 62 × 62 µm(2) pixel size. The upper detection limit is approximately 21 000 cps. The spatial resolution at both 21 and 37 °C ranges from 0.4 mm FWHM at the center of the field of view (FOV), and degrades to 1 mm at a distance of 5 mm away from center yielding a useful FOV of approximately 10 × 10 mm(2). We also investigate the effects on spatial resolution and sensitivity that result from the use of a polymer based microfluidic chip. For these studies we place varying layers of low-density polyethylene (LDPE) between the detector and the source and find that the spatial resolution degrades by ∼180 µm for every 100 µm of LDPE film. Sensitivity is reduced by half with the inclusion of ∼200 µm of additional LDPE film. Lastly, we demonstrate the practical utilization of Betabox, with an imaging test of its linearity, when coupled to a polydimethylsiloxane microfluidic chip designed for cell based assays.

NEMA NU-4 performance evaluation of PETbox4, a high sensitivity dedicated PET preclinical tomograph.

PETbox4 is a new, fully tomographic bench top PET scanner dedicated to high sensitivity and high resolution imaging of mice. This manuscript characterizes the performance of the prototype system using the National Electrical Manufacturers Association NU 4-2008 standards, including studies of sensitivity, spatial resolution, energy resolution, scatter fraction, count-rate performance and image quality. The PETbox4 performance is also compared with the performance of PETbox, a previous generation limited angle tomography system. PETbox4 consists of four opposing flat-panel type detectors arranged in a box-like geometry. Each panel is made by a 24 × 50 pixelated array of 1.82 × 1.82 × 7 mm bismuth germanate scintillation crystals with a crystal pitch of 1.90 mm. Each of these scintillation arrays is coupled to two Hamamatsu H8500 photomultiplier tubes via a glass light guide. Volumetric images for a 45 × 45 × 95 mm field of view (FOV) are reconstructed with a maximum likelihood expectation maximization algorithm incorporating a system model based on a parameterized detector response. With an energy window of 150-650 keV, the peak absolute sensitivity is approximately 18% at the center of FOV. The measured crystal energy resolution ranges from 13.5% to 48.3% full width at half maximum (FWHM), with a mean of 18.0%. The intrinsic detector spatial resolution is 1.5 mm FWHM in both transverse and axial directions. The reconstructed image spatial resolution for different locations in the FOV ranges from 1.32 to 1.93 mm, with an average of 1.46 mm. The peak noise equivalent count rate for the mouse-sized phantom is 35 kcps for a total activity of 1.5 MBq (40 µCi) and the scatter fraction is 28%. The standard deviation in the uniform region of the image quality phantom is 5.7%. The recovery coefficients range from 0.10 to 0.93. In comparison to the first generation two panel PETbox system, PETbox4 achieves substantial improvements on sensitivity and spatial resolution. The overall performance demonstrates that the PETbox4 scanner is suitable for producing high quality images for molecular imaging based biomedical research.

Performance Characteristics of BGO Detectors for a Low Cost Preclinical PET Scanner.

PETbox is a low-cost benchtop PET scanner dedicated to high throughput preclinical imaging that is currently under development at our institute. This paper presents the design and characterization of the detectors that are used in the PETbox system. In this work, bismuth germanate scintillator was used for the detector, taking advantage of its high stopping power, high photoelectric event fraction, lack of intrinsic background radiation and low cost. The detector block was segmented into a pixelated array consisting of 20 × 44 elements, with a crystal pitch of 2.2 mm and a crystal cross section of 2 mm × 2 mm. The effective area of the array was 44 mm × 96.8 mm. The array was coupled to two Hamamatsu H8500 position sensitive photomultiplier tubes, forming a flat-panel type detector head with a sensitive area large enough to cover the whole body of a typical laboratory mouse. Two such detector heads were constructed and their performance was characterized. For one detector head, the energy resolution ranged from 16.1% to 38.5% full width at half maximum (FWHM), with a mean of 20.1%; for the other detector head, the energy resolution ranged from 15.5% to 42.7% FWHM, with a mean of 19.6%. The intrinsic spatial resolution was measured to range from 1.55 mm to 2.39 mm FWHM along the detector short axis and from 1.48 mm to 2.33 mm FWHM along the detector long axis, with an average of 1.78 mm. Coincidence timing resolution for the detector pair was measured to be 4.1 ns FWHM. These measurement results show that the detectors are suitable for our specific application.

Dual-energy attenuation coefficient decomposition with differential filtration and application to a microCT scanner.

Dual-energy x-ray computed tomography (DECT) has the capability to decompose attenuation coefficients using two basis functions and has proved its potential in reducing beam-hardening artifacts from reconstructed images. The method typically involves two successive scans with different x-ray tube voltage settings. This work proposes an approach to dual-energy imaging through x-ray beam filtration that requires only one scan and a single tube voltage setting. It has been implemented in a preclinical microCT tomograph with minor modifications. Retrofitting of the microCT scanner involved the addition of an automated filter wheel and modifications to the acquisition and reconstruction software. Results show that beam-hardening artifacts are reduced to noise level. Acquisition of a mu-Compton image is well suited for attenuation-correction of PET images while dynamic energy selection (4D viewing) offers flexibility in image viewing by adjusting contrast and noise levels to suit the task at hand. All dual-energy and single energy reference scans were acquired at the same soft tissue dose level of 50 mGy.

Readout of the Optical PET (OPET) Detector.

The design of an imaging system capable of detecting both high-energy γ-rays and optical wavelength photons is underway at the Crump Institute for Molecular Imaging. This system will noninvasively image small animal models in vivo for the presence of positron emission tomographic (PET) and optical signals. The detector will consist of modules of multichannel photomultiplier tubes (MC-PMT) coupled to arrays of scintillator crystals. The MC-PMT will detect both the photons produced due to bioluminescence and the photons generated by the interaction of γ-rays within the crystals. The long wavelength photons produced through bioluminescence are only slightly attenuated by these crystals and are detected directly at the photocathode of the MC-PMT, resulting in signals of small (5-10 mV) short (~15 ns) pulses. In contrast, annihilation (511 keV) γ-rays interacting in the scintillator crystal send large bursts of photons to the PMT, and result in pulses that can be as large as 500 mV and > 200 ns duration. The processing of pulses with such different characteristics in a single circuit requires significant alteration of the standard pulse processing circuitry used in PET scanners. In this paper, we discuss the requirements of such a circuit and show the results of implementation of one design using single and multiple channel PMTs.

Performance measurements of a depth-encoding PET detector module based on position-sensitive avalanche photodiode read-out.

We are developing a high-resolution, high-efficiency positron emission tomography (PET) detector module with depth of interaction (DOI) capability based on a lutetium oxyorthosilicate (LSO) scintillator array coupled at both ends to position-sensitive avalanche photodiodes (PSAPDs). In this paper we present the DOI resolution, energy resolution and timing resolution results for complete detector modules. The detector module consists of a 7 x 7 matrix of LSO scintillator crystals (1 x 1 x 20 mm3 in dimension) coupled to 8 x 8 mm2 PSAPDs at both ends. Flood histograms were acquired and used to generate crystal look-up tables. The DOI resolution was measured for individual crystals within the array by using the ratio of the signal amplitudes from the two PSAPDs on an event-by-event basis. A measure of the total scintillation light produced was obtained by summing the signal amplitudes from the two PSAPDs. This summed signal was used to measure the energy resolution. The DOI resolution was measured to be 3-4 mm FWHM irrespective of the position of the crystal within the array, or the interaction location along the length of the crystal. The total light signal and energy resolution was almost independent of the depth of interaction. The measured energy resolution averaged 14% FWHM. The coincidence timing resolution measured using a pair of identical detector modules was 4.5 ns FWHM. These results are consistent with the design goals and the performance required of a compact, high-resolution and high-efficiency PET detector module for small animal and breast imaging applications.

Detector Concept for OPET-A Combined PET and Optical Imaging System.

The design of an imaging system capable of detecting both high-energy γ-rays and optical wavelength photons is underway at the UCLA Crump Institute for Molecular Imaging. This system, which we call optical PET (OPET), will be capable of non-invasively and repeatedly imaging small animal models in vivo for the presence of PET and optical signals. In this study, we describe the physical principles behind the operation of the OPET imaging system and discuss the design concept for one of the detector modules. Additionally, we demonstrate the operation of an initial prototype detector module for simultaneous detection and imaging of annihilation radiation and single optical photons emanating from separate sources. These results indicate that the construction of an imaging system based on this detector technology is feasible.

Design and evaluation of an LSO PET detector for breast cancer imaging.

Functional imaging with positron emission tomography (PET) may be a promising technique in conjunction with x-ray mammography for breast cancer patient management. Conventional whole body PET scanners provide metabolic images of breast cancer patients with several shortcomings related to the general-purpose nature of these systems. In whole body scanners, the detectors are typically 20-30 cm away from the breast or axilla, reducing sensitivity, and these scanners have relatively large detector elements (> 4 mm), limiting spatial resolution. Dedicated PET systems for breast imaging aim to overcome these limitations and improve the overall diagnostic quality of the images by bringing the detectors closer to the area to be imaged, thereby improving sensitivity, and by using smaller detector elements to improve the spatial resolution. We have designed and developed a modular PET detector that is composed of a 9x9 array of 3x3x20 mm3 lutetium oxyorthosilicate (LSO) scintillator crystals coupled to an optical fiber taper, which in turn is coupled to a Hamamatsu R5900-C8 position-sensitive photomultiplier tube. These detectors can be tiled together without gaps to construct large area detector arrays to form a dedicated PET breast cancer imaging system. Two complete detector modules have been built and tested. All detector elements are clearly visualized upon flood irradiation of the module. The intrinsic spatial resolution (full-width at half-maximum) was measured to be 2.26 mm (range 1.8-2.6 mm). The average energy resolution was 19.5% (range 17%-24%) at 511 keV. The coincidence time resolution was measured to be 2.4 ns. The detector efficiency for 511 keV gamma rays was 53% using a 350 keV energy threshold. These promising results support the feasibility of developing a high resolution, high sensitivity dedicated PET scanner for breast cancer applications.

Performance evaluation of microPET: a high-resolution lutetium oxyorthosilicate PET scanner for animal imaging.

UNLABELLED: A new dedicated PET scanner, microPET, was designed and developed at the University of California, Los Angeles, for imaging small laboratory animals. The goal was to provide a compact system with superior spatial resolution at a fraction of the cost of a clinical PET scanner. METHODS: The system uses fiberoptic readout of individually cut lutetium oxyorthosilicate (LSO) crystals to achieve high spatial resolution. Each microPET detector consists of an 8 x 8 array of 2 x 2 x 10-mm LSO scintillation crystals that are coupled to a 64-channel photomultiplier tube by optical fibers. The tomograph consists of 30 detectors in a continuous ring with a 17.2-cm diameter and fields of view (FOVs) of 11.25 cm in the transaxial direction and 1.8 cm in the axial direction. The system has eight crystal rings and no interplane septa. It operates exclusively in the three-dimensional mode and has an electronically controlled bed that is capable of wobbling with a radius of 300 microm. We describe the performance of the tomograph in terms of its spatial, energy and timing resolution, as well as its sensitivity and counting-rate performance. We also illustrate its overall imaging performance with phantom and animal studies that demonstrate the potential applications of this device to biomedical research. RESULTS: Images reconstructed with three-dimensional filtered backprojection show a spatial resolution of 1.8 mm at the center of the FOV (CFOV), which remains <2.5 mm for the central 5 cm of the transaxial FOV. The resulting volumetric resolution of the system is <8 microL. The absolute system sensitivity measured with a 0.74 MBq (20 microCi) 68Ge point source at the CFOV is 5.62 Hz/kBq. The maximum noise equivalent counting rate obtained with a 6.4-cm diameter cylinder spanning the central 56% of the FOV is 10 kcps, whereas the scatter fraction is 37% at the CFOV for an energy window of 250-650 keV and the same diameter cylinder. CONCLUSION: This is the first PET scanner to use the new scintillator LSO and uses a novel detector design to achieve high volumetric spatial resolution. The combination of imaging characteristics of this prototype system (resolution, sensitivity, counting-rate performance and scatter fraction) opens up new possibilities in the study of animal models with PET.

Simultaneous PET and MR imaging.

We have developed a prototype PET detector which is compatible with a clinical MRI system to provide simultaneous PET and MR imaging. This single-slice PET system consists of 48 2 x 2 x 10 mm3 LSO crystals in a 38 mm diameter ring configuration that can be placed inside the receiver coil of the MRI system, coupled to three multi-channel photomultipliers housed outside the main magnetic field via 4 m long and 2 mm diameter optical fibres. The PET system exhibits 2 mm spatial resolution, 41% energy resolution at 511 keV and 20 ns timing resolution. Simultaneous PET and MR phantom images were successfully acquired.

PET and NMR dual acquisition (PANDA): applications to isolated, perfused rat hearts.

Positron emission tomography and nuclear magnetic resonance spectroscopy are non-invasive techniques that allow serial metabolic measurements to be obtained in a single subject. Significant advantages could be obtained if both types of scans could be acquired with a single machine. A small-scale PET scanner, designed to operate in a high magnetic field, was therefore constructed and inserted into the top half of a 7.3 cm bore, 9.4 T NMR magnet and its performance characterized. The magnetic field did not significantly affect either the sensitivity (approximately 3 kcps/MBq) or the spatial resolution (2.0 mm full width at half maximum, measured using a 0.25 mm diameter line source) of the scanner. However, the presence of the PET scanner resulted in a small decrease in field homogeneity. The first, simultaneous 31P NMR spectra (200, 80 degrees pulses collected at 6 s intervals) and PET images (transverse, mid-ventricular slices at the level of the mitral value) from isolated, perfused rat hearts were acquired using a specially designed NMR probe inserted into the bottom half of the magnet. The PET images were of excellent quality, enabling the left ventricular wall and interventricular septum to be clearly seen. In conclusion, we have demonstrated the simultaneous acquisition of PET and NMR data from perfused rat hearts; we believe that the combination of these two powerful techniques has tremendous potential in both the laboratory and the clinic.

An automated method for studying drug effects on problem solving by small laboratory animals.

The design and construction details of a method for studying problem solving by small animals is described. The form of motivation is escape from water in a T-shaped apparatus, thus eliminating possible confounding effects involved when food or water intake is restricted below normal. The arm of the T in which escape is possible is alternated from trial to trial. Two levels of problem solving are evaluated: an animal can minimize escape time during a series of trials by alternating its responses, i.e., 100% reinforcement; alternatively, it may choose the same alley on each trial, which results in only 50% reinforcement. The time to make the decision and the total time are automatically recorded. We have demonstrated the sensitivity of the method to hypofunctioning of the cholinergic neurotransmitter system, an analogy to behavioral changes accompanying progressive degenerative dementia. Two effects of the hypocholinergic state were especially notable: animals in this state have significantly greater difficulty in shifting from the "primitive" position habit to the more complex alternation solution, and preliminary experiments suggest that certain pharmacological treatments may be effective in overcoming this deficiency.

A device to evoke acetylcholine release electrically in the guinea pig myenteric plexus/longitudinal muscle preparation through mass electrodes.

A stimulator was developed to evoke acetylcholine release in the myenteric plexus-longitudinal muscle preparation from the guinea pig ileum. A power output stage was devised to allow a conventional stimulator to drive the low impedance presented by this type of preparation. To eliminate electrode polarization, the polarity of the stimulus is alternated. A peak reading ammeter is included which allows the investigator to monitor the stimulus.

Monitoring the pathophysiological correlates of post-menopausal hot flushes.

Clinical assessment of the severity and frequency of post-menopausal hot flushes can be made objectively by measuring the associated changes in skin conductance and skin and core temperature. Such measurements provide a more reliable index of the response to therapy than does subjective reporting which has been employed in the past. The design and use of a working analyzer is presented that is sufficiently simple, rugged, safe and portable to be used under normal clinical conditions to provide a permanent record of the attacks.

Transmural nerve stimulation of blood vessels in vitro: a critical examination.

Use of the method of transmural nerve stimulation depends on the assumption that stimulation parameters can be chosen to selectively and maximally activate nerves without stimulating vascular smooth muscle directly. When commercial stimulators are used with low impedance electrodes, it may not be possible to validate this assumption, due to the limited current output in this situation. To circumvent this limitation a coupling device which provides a very low source impedance to the electrodes is described. Using this device in experiments on preparations of rabbit ear artery, we have demonstrated that it is possible to selectively activate nerves, without stimulating smooth muscle directly. Adrenergic nerve activation was blocked with guanethidine, phentolamine or tetrodotoxin, while responses to direct smooth muscle activation persist in the presence of these drugs. Appropriate parameters for supramaximal nerve stimulation vary with the type of preparation and electrode arrangement. The possibility of variation with tissue and species is also discussed.