Marlies C Goorden

Optical imaging of contrast agent microbubbles in an ultrasound field with a 100-MHz camera

Ultrasound (US) contrast agents, used in the field of medical diagnosis, contain small microbubbles of a mean diameter of about 3 microm. The acoustic behavior of these bubbles in US field has been subject to many investigations. In this study, we propose a method to visualize the behavior of the bubbles in a 0.5-MHz US field under a microscope with a frame rate of 4 MHz. For low acoustic pressures (peak negative pressure of 0.12 MPa), the radius-time curve as measured from the optical images is in agreement with the theory. For higher acoustic pressures (peak negative pressure of 0.6 MPa), the recorded radius is significantly larger than predicted by theory and sudden change in the bubbles shapes has been noticed. The proposed method enables the study and characterization of individual bubbles and their encapsulation. It is expected that this will open new areas for quality control, US contrast imaging and US-guided drug delivery.

Theoretical analysis of full-ring multi-pinhole brain SPECT

Presently used clinical brain SPECT suffers from limited spatio-temporal resolution. Here we investigate the feasibility of high-resolution and high-sensitivity full-ring multi-pinhole brain SPECT (MP-SPECT). Using an analytical model we optimized pinhole-detector geometries of MP-SPECT for different detector intrinsic resolutions R(i). System resolution and sensitivity of optimized MP-SPECT were compared to conventional clinical SPECT. The comparison of the system resolution of different systems was done at matched sensitivity, which was achieved by tuning pinhole diameters. Similarly, sensitivities were compared at matched system resolution. For MP-SPECT that uses detectors with intrinsic resolutions of 4 mm > R(i) 0.5 mm a sensitivity can be achieved that is 6.0 times higher than the sensitivity of conventional dual-head SPECT systems with parallel-hole collimators (DualPar), while system resolution can be improved by a factor of 2.4. To achieve these improvements a large detector-to-collimator distance is needed. In contrast, for detectors with intrinsic resolutions <0.2 mm, it is beneficial to place the detectors close to the pinholes, resulting in a high number of de-magnified projections. For a detector intrinsic resolution of 0.05 mm, a 14.5-fold improvement in sensitivity and a 3.8-fold improvement in system resolution compared to DualPar is predicted. Furthermore, we found that for optimized MP-SPECT the sensitivity scales proportionally to system resolution squared, with the proportionality constant depending on R(i). From our sensitivity-system resolution trade-off equations we deduced that MP-SPECT with an ideal detector (R(i) --> 0) can have a system resolution that is 2.0 times better than optimized MP-SPECT with a conventional detector (R(i) approximately 3 mm). The high performance of optimized MP-SPECT may open up completely new molecular imaging applications.

VECTor: A Preclinical Imaging System for Simultaneous Submillimeter SPECT and PET

Today, PET and SPECT tracers cannot be imaged simultaneously at high resolutions but require 2 separate imaging systems. This paper introduces a Versatile Emission Computed Tomography system (VECTor) for radionuclides that enables simultaneous submillimeter imaging of single-photon and positron-emitting radiolabeled molecules. Methods: γ-photons produced both by electron–positron annihilation and by single-photon emitters are projected onto the same detectors by means of a novel cylindric high-energy collimator containing 162 narrow pinholes that are grouped in clusters. This collimator is placed in an existing SPECT system (U-SPECT-II) with 3 large-field-of-view γ-detectors. From the acquired projections, PET and SPECT images are obtained using statistical image reconstruction that corrects for energy-dependent system blurring. Results: For PET tracers, the tomographic resolution obtained with a Jaszczak hot rod phantom was less than 0.8 mm, and 0.5-mm resolution images of SPECT tracers were acquired simultaneously. SPECT images were barely degraded by the simultaneous presence of a PET tracer, even when the activity concentration of the PET tracer exceeded that of the SPECT tracer by up to a factor of 2.5. Furthermore, we simultaneously acquired fully registered 3- and 4-dimensional multiple functional images from living mice that, in the past, could be obtained only sequentially. Conclusion: High-resolution complementary information about tissue function contained in SPECT and PET tracer distributions can now be obtained simultaneously using a fully integrated imaging device. These combined unique capabilities pave the way for new perspectives in imaging the biologic systems of rodents.

High-resolution tomography of positron emitters with clustered pinhole SPECT

State-of-the-art small-animal single photon emission computed tomography (SPECT) enables sub-half-mm resolution imaging of radio-labelled molecules. Due to severe photon penetration through pinhole edges, current multi-pinhole SPECT is not suitable for high-resolution imaging of photons with high energies, such as the annihilation photons emitted by positron emitting tracers (511 keV). To deal with this edge penetration, we introduce here clustered multi-pinhole SPECT (CMP): each pinhole in a cluster has a narrow opening angle to reduce photon penetration. Using simulations, CMP is compared with (i) a collimator with traditional pinholes that is currently used for sub-half-mm imaging of SPECT isotopes (U-SPECT-II), and (ii), like (i) but with collimator thickness adapted to image high-energy photons (traditional multi-pinhole SPECT, TMP). At 511 keV, U-SPECT-II is able to resolve the 0.9 mm rods of an iteratively reconstructed Jaszczak-like capillary hot rod phantom, and while TMP only leads to small improvements, CMP can resolve rods as small as 0.7 mm. Using a digital tumour phantom, we show that CMP resolves many details not assessable with standard USPECT-II and TMP collimators. Furthermore, CMP makes it possible to visualize uptake of positron emitting tracers in sub-compartments of a digital mouse striatal brain phantom. This may open up unique possibilities for analysing processes such as those underlying the function of neurotransmitter systems. Additional potential of CMP may include (i) the imaging of other high-energy single-photon emitters (e.g. I-131) and (ii) localized imaging of positron emitting tracers simultaneously with single photon emitters, with an even better resolution than coincidence PET.

Fast Spiral SPECT with Stationary γ-Cameras and Focusing Pinholes

Small-animal SPECT systems with stationary detectors and focusing multiple pinholes can achieve excellent resolution–sensitivity trade-offs. These systems are able to perform fast total-body scans by shifting the animal bed through the collimator using an automated xyz stage. However, so far, a large number of highly overlapping central fields of view have been used, at the cost of overhead time needed for animal repositioning and long image reconstruction times due to high numbers of projection views. Methods: To improve temporal resolution and reduce image reconstruction time for such scans, we have developed and tested spiral trajectories (STs) of the animal bed requiring fewer steps. In addition, we tested multiplane trajectories (MPTs) of the animal bed, which is the standard acquisition method of the U-SPECT-II system that is used in this study. Neither MPTs nor STs require rotation of the animal. Computer simulations and physical phantom experiments were performed for a wide range of numbers of bed positions. Furthermore, we tested STs in vivo for fast dynamic mouse scans. Results: We found that STs require less than half the number of bed positions of MPTs to achieve sufficient sampling. The reduced number of bed positions made it possible to perform a dynamic total-body bone scan and a dynamic hepatobiliary scan with time resolutions of 60 s and 15 s, respectively. Conclusion: STs open up new possibilities for high throughput and fast dynamic radio-molecular imaging.

Multi-scale algorithm for improved scintillation detection in a CCD-based gamma camera

Gamma cameras based on charge-coupled devices (CCDs) and micro-columnar CsI scintillators can reach high spatial resolutions. However, the gamma interaction probability of these scintillators is low (typically <30% at 141 keV) due to the limited thickness of presently available micro-columnar scintillators. Continuous scintillators can improve the interaction probability but suffer from increased light spread compared to columnar scintillators. In addition, for both types of scintillators, gamma photons incident at an oblique angle reduce the spatial resolution due to the variable depth of interaction (DOI). To improve the spatial resolution and spectral characteristics of these detectors, we have developed a fast analytic scintillation detection algorithm that makes use of a depth-dependent light spread model and as a result is able to estimate the DOI in the scintillator. This algorithm, performing multi-scale frame analysis, was tested for an electron multiplying CCD (EM-CCD) optically coupled to CsI(Tl) scintillators of different thicknesses. For the thickest scintillator (2.6 mm) a spatial resolution of 148 microm full width half maximum (FWHM) was obtained with an energy resolution of 46% FWHM for perpendicularly incident gamma photons (interaction probability 61% at 141 keV). The multi-scale algorithm improves the spatial resolution up to 11%, the energy resolution up to 36% and the signal-to-background counts ratio up to 46% compared to a previously implemented algorithm that did not model the depth-dependent light spread. In addition, the multi-scale algorithm can accurately estimate DOI. As a result, degradation of the spatial resolution due to the variable DOI for gamma photons incident at a 45 degrees angle was improved from 2.0 10(3) to 448 microm FWHM. We conclude that the multi-scale algorithm significantly improves CCD-based gamma cameras as can be applied in future SPECT systems.

Comparison of pinhole collimator materials based on sensitivity equivalence

Pinhole SPECT often provides an excellent resolution sensitivity trade-off for radionuclide imaging compared to SPECT with parallel holes, particularly when imaging small experimental animals like rodents. High absorption pinhole materials are often chosen because of their low edge penetration and therefore good system resolution. Capturing more photons in the edges however results in decreased system sensitivity if the pinhole diameter remains the same, which may partly undo the beneficial effect on the resolution. In the search for an optimal trade-off we have compared pinhole projection data and reconstructed images of different materials with pinhole aperture diameters adjusted to obtain equal sensitivity. Monte Carlo calculations modeling the transmission, penetration and scattering of gamma radiation in single pinholes of uranium, gold, tungsten and lead were performed for a range of pinhole opening angles, diameters and gamma ray energies. In addition, reconstructed images of a hot rod phantom were determined for a multipinhole SPECT system and for a system that can image the 511 keV annihilation photons of positron emitting tracers with clustered pinholes. Our results indicate that, under the condition of equal sensitivity, tungsten and for SPECT also lead pinholes perform just as well as gold and uranium ones, indicating that a significant cost reduction can be achieved in pinhole collimator manufacturing while the use of rare or impractical materials can be avoided.

An efficient simulator for pinhole imaging of PET isotopes

Today, small-animal multi-pinhole single photon emission computed tomography (SPECT) can reach sub-half-millimeter image resolution. Recently we have shown that dedicated multi-pinhole collimators can also image PET tracers at sub-mm level. Simulations play a vital role in the design and optimization of such collimators. Here we propose and validate an efficient simulator that models the whole imaging chain from emitted positron to detector signal. This analytical simulator for pinhole positron emission computed tomography (ASPECT) combines analytical models for pinhole and detector response with Monte Carlo (MC)-generated kernels for positron range. Accuracy of ASPECT was validated by means of a MC simulator (MCS) that uses a kernel-based step for detector response with an angle-dependent detector kernel based on experiments. Digital phantom simulations with ASPECT and MCS converge to almost identical images. However, ASPECT converges to an equal image noise level three to four orders of magnitude faster than MCS. We conclude that ASPECT could serve as a practical tool in collimator design and iterative image reconstruction for novel multi-pinhole PET.

An enhanced high-resolution EMCCD-based gamma camera using SiPM side detection

Electron-multiplying charge-coupled devices (EMCCDs) coupled to scintillation crystals can be used for high-resolution imaging of gamma rays in scintillation counting mode. However, the detection of false events as a result of EMCCD noise deteriorates the spatial and energy resolution of these gamma cameras and creates a detrimental background in the reconstructed image. In order to improve the performance of an EMCCD-based gamma camera with a monolithic scintillation crystal, arrays of silicon photon-multipliers (SiPMs) can be mounted on the sides of the crystal to detect escaping scintillation photons, which are otherwise neglected. This will provide a priori knowledge about the correct number and energies of gamma interactions that are to be detected in each CCD frame. This information can be used as an additional detection criterion, e.g. for the rejection of otherwise falsely detected events. The method was tested using a gamma camera based on a back-illuminated EMCCD, coupled to a 3 mm thick continuous CsI:Tl crystal. Twelve SiPMs have been mounted on the sides of the CsI:Tl crystal. When the information of the SiPMs is used to select scintillation events in the EMCCD image, the background level for (99m)Tc is reduced by a factor of 2. Furthermore, the SiPMs enable detection of (125)I scintillations. A hybrid SiPM-/EMCCD-based gamma camera thus offers great potential for applications such as in vivo imaging of gamma emitters.

Ultra-High-Sensitivity Submillimeter Mouse SPECT

SPECT with submegabecquerel amounts of tracer or subsecond time resolution would enable a wide range of new imaging protocols such as screening tracers with initially low yield or labeling efficiency, imaging low receptor densities, or even performing SPECT outside regular radiation laboratories. To this end we developed dedicated ultra-high-sensitivity pinhole SPECT. Methods: A cylindric collimator with 54 focused 2.0-mm-diameter conical pinholes was manufactured and mounted in a stationary small-animal SPECT system. The system matrix for image reconstruction was calculated via a hybrid method based on both 99mTc point source measurements and ray-tracing analytic modeling. SPECT images were reconstructed using pixel-based ordered-subsets expectation maximization. Performance was evaluated with phantoms and low-dose bone, dynamic kidney, and cardiac mouse scans. Results: The peak sensitivity reached 1.3% (13,080 cps/MBq). The reconstructed spatial resolution (rod visibility in a micro-Jaszczak phantom) was 0.85 mm. Even with only a quarter megabecquerel of activity, 30-min bone SPECT scans provided surprisingly high levels of detail. Dynamic dual-isotope kidney and 99mTc-sestamibi cardiac scans were acquired with a time-frame resolution down to 1 s. Conclusion: The high sensitivity achieved increases the range of mouse SPECT applications by enabling in vivo imaging with less than a megabecquerel of tracer activity or down to 1-s frame dynamics.