Positron range-free and multi-isotope tomography of positron emitters.

Despite improvements in small animal PET instruments, many tracers cannot be imaged at sufficiently high resolutions due to positron range, while multi-tracer PET is hampered by the fact that all annihilation photons have equal energies. Here we realize multi-isotope and sub-mm resolution PET of isotopes with several mm positron range by utilizing prompt gamma photons that are commonly neglected. A PET-SPECT-CT scanner (VECTor/CT, MILabs, The Netherlands) equipped with a high-energy cluster-pinhole collimator was used to image 124I and a mix of 124I and 18F in phantoms and mice. In addition to positrons (mean range 3.4 mm) 124I emits large amounts of 603 keV prompt gammas that-aided by excellent energy discrimination of NaI-were selected to reconstruct 124I images that are unaffected by positron range. Photons detected in the 511 keV window were used to reconstruct 18F images. Images were reconstructed iteratively using an energy dependent matrix for each isotope. Correction of 18F images for contamination with 124I annihilation photons was performed by Monte Carlo based range modelling and scaling of the 124I prompt gamma image before subtracting it from the 18F image. Additionally, prompt gamma imaging was tested for 89Zr that emits very high-energy prompts (909 keV). In Derenzo resolution phantoms 0.75 mm rods were clearly discernable for 124I, 89Zr and for simultaneously acquired 124I and 18F imaging. Image quantification in phantoms with reservoirs filled with both 124I and 18F showed excellent separation of isotopes and high quantitative accuracy. Mouse imaging showed uptake of 124I in tiny thyroid parts and simultaneously injected 18F-NaF in bone structures. The ability to obtain PET images at sub-mm resolution both for isotopes with several mm positron range and for multi-isotope PET adds to many other unique capabilities of VECTor's clustered pinhole imaging, including simultaneous sub-mm PET-SPECT and theranostic high energy SPECT.

Indicators to facilitate the early identification of patients with major depressive disorder in need of highly specialized care: A concept mapping study.

BACKGROUND: Early identification of the subgroup of patients with major depressive disorder (MDD) in need of highly specialized care could enhance personalized intervention. This, in turn, may reduce the number of treatment steps needed to achieve and sustain an adequate treatment response. The aim of this study was to identify patient-related indicators that could facilitate the early identification of the subgroup of patients with MDD in need of highly specialized care. METHODS: Initial patient indicators were derived from a systematic review. Subsequently, a structured conceptualization methodology known as concept mapping was employed to complement the initial list of indicators by clinical expertise and develop a consensus-based conceptual framework. Subject-matter experts were invited to participate in the subsequent steps (brainstorming, sorting, and rating) of the concept mapping process. A final concept map solution was generated using nonmetric multidimensional scaling and agglomerative hierarchical cluster analyses. RESULTS: In total, 67 subject-matter experts participated in the concept mapping process. The final concept map revealed the following 10 major clusters of indicators: 1-depression severity, 2-onset and (treatment) course, 3-comorbid personality disorder, 4-comorbid substance use disorder, 5-other psychiatric comorbidity, 6-somatic comorbidity, 7-maladaptive coping, 8-childhood trauma, 9-social factors, and 10-psychosocial dysfunction. CONCLUSIONS: The study findings highlight the need for a comprehensive assessment of patient indicators in determining the need for highly specialized care, and suggest that the treatment allocation of patients with MDD to highly specialized mental healthcare settings should be guided by the assessment of clinical and nonclinical patient factors.

Developing a decision tool to identify patients with personality disorders in need of highly specialized care.

BACKGROUND: Current guidelines recommend referral to highly specialized care for patients with severe personality disorders. However, criteria for allocation to highly specialized care are not clearly defined. The aim of the present study was to develop a decision tool that can support clinicians to identify patients with a personality disorder in need of highly specialized care. METHODS: Steps taken to develop a decision tool were a literature search, concept mapping, a meeting with experts and a validation study. RESULTS: The concept mapping method resulted in six criteria for the decision tool. The model used in concept mapping provided a good fit (stress value = 0.30) and reasonable reliability (ρ = 0.49). The bridging values were low, indicating homogeneity. The decision tool was subsequently validated by enrolling 368 patients from seven centers. A multilevel model with a Receiver Operating Characteristic Curve (ROC) was applied. In this way, an easily implementable decision tool with relatively high sensitivity (0.74) and specificity (0.69) was developed. CONCLUSIONS: A decision tool to identify patients with personality disorders for highly specialized care was developed using advanced methods to combine the input of experts with currently available scientific knowledge. The tool appeared to be able to accurately identify this group of patients. Clinicians can use this decision tool to identify patients who are in need of highly specialized treatment.

Similarity-regulation of OS-EM for accelerated SPECT reconstruction.

Ordered subsets expectation maximization (OS-EM) is widely used to accelerate image reconstruction in single photon emission computed tomography (SPECT). Speedup of OS-EM over maximum likelihood expectation maximization (ML-EM) is close to the number of subsets used. Although a high number of subsets can shorten reconstruction times significantly, it can also cause severe image artifacts such as improper erasure of reconstructed activity if projections contain few counts. We recently showed that such artifacts can be prevented by using a count-regulated OS-EM (CR-OS-EM) algorithm which automatically adapts the number of subsets for each voxel based on the estimated number of counts that the voxel contributed to the projections. While CR-OS-EM reached high speed-up over ML-EM in high-activity regions of images, speed in low-activity regions could still be very slow. In this work we propose similarity-regulated OS-EM (SR-OS-EM) as a much faster alternative to CR-OS-EM. SR-OS-EM also automatically and locally adapts the number of subsets, but it uses a different criterion for subset regulation: the number of subsets that is used for updating an individual voxel depends on how similar the reconstruction algorithm would update the estimated activity in that voxel with different subsets. Reconstructions of an image quality phantom and in vivo scans show that SR-OS-EM retains all of the favorable properties of CR-OS-EM, while reconstruction speed can be up to an order of magnitude higher in low-activity regions. Moreover our results suggest that SR-OS-EM can be operated with identical reconstruction parameters (including the number of iterations) for a wide range of count levels, which can be an additional advantage from a user perspective since users would only have to post-filter an image to present it at an appropriate noise level.

Cost-effectiveness of multidimensional family therapy compared to cognitive behavioral therapy for adolescents with a cannabis use disorder: Data from a randomized controlled trial.

OBJECTIVE: To evaluate the cost-effectiveness of Multidimensional Family Therapy (MDFT) for adolescents with a cannabis use disorder, compared to Cognitive Behavioural Therapy (CBT). METHODS: A parallel-group randomized controlled trial was performed. 109 adolescents with a DSM-IV cannabis use disorder (CBT n=54; MDFT n=55) were included. Assessments were conducted at baseline, and 3, 6, 9 and 12 months post-baseline, and included measures on cannabis and other substance use, delinquency, health care utilization, and general health related quality of life. RESULTS: Excluding those with missing cost-data, 96 participants (MDFT n=49; CBT n=47) were included. From a health care perspective, the average annual direct medical costs in the CBT group were €2015 (95%C.I. 1397-2714), compared to €5446 (95%C.I. 4159-7092) in the MDFT group. The average quality-adjusted life years (QALY's) gained were 0.06 QALY higher for the MDFT group, which led to an incremental cost-effectiveness ratio (ICER) of 54,308 Euro/QALY or €43,405 per recovered patient. Taking the costs of delinquency into account, the costs increased to €21,330 (95%C.I. 12,389-32,894) for the CBT group and to €21,915 (95%C.I. 16,273-28,181) for the MDFT group, which lead to an ICER of 9266 Euro/QALY or a cost per recovered patient of €7491. CONCLUSIONS: This is the first comprehensive CEA of MDFT compared to CBT and it demonstrated that when costs of delinquency were included, the ICERS were modest. The results underline the importance of adopting a broader perspective regarding cost effectiveness analyses in mental health care.

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.

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.

Superconductivity-induced macroscopic resonant tunneling.

We show analytically and by numerical simulations that the conductance through pi-biased chaotic Josephson junctions is enhanced by several orders of magnitude in the short-wavelength regime. We identify the mechanism behind this effect as macroscopic resonant tunneling through a macroscopic number of low-energy quasidegenerate Andreev levels.

Macroscopic resonant tunnelling through Andreev interferometers.

We investigate the conductance through and the spectrum of ballistic chaotic quantum dots attached to two s-wave superconductors, as a function of the phase difference phi between the two order parameters. A combination of analytical techniques-random matrix theory, Nazarov's circuit theory and the trajectory-based semiclassical theory-allows us to explore the quantum-to-classical crossover in detail. When the superconductors are not phase-biased, phi = 0, we recover known results that the spectrum of the quantum dot exhibits an excitation gap, while the conductance across two normal leads carrying N(N) channels and connected to the dot via tunnel contacts of transparency Gamma(N) is [Formula: see text]. In contrast, when phi = pi, the excitation gap closes and the conductance becomes [Formula: see text] in the universal regime. For [Formula: see text], we observe an order-of-magnitude enhancement of the conductance towards [Formula: see text] in the short-wavelength limit. We relate this enhancement to resonant tunnelling through a macroscopic number of levels close to the Fermi energy. Our predictions are corroborated by numerical simulations.

Two-particle scattering matrix of two interacting mesoscopic conductors.

We consider two quantum coherent conductors interacting weakly via long range Coulomb forces. We describe the interaction in terms of two-particle collisions described by a two-particle scattering matrix. As an example we determine the transmission probability and correlations in a two-particle scattering experiment and find that the results can be expressed in terms of the density-of-states matrices of the noninteracting scatterers.

Entanglement spectroscopy of a driven solid-state qubit and its detector.

We study the asymptotic dynamics of a driven quantum two-level system coupled via a quantum detector to the environment. We find multiphoton resonances which are due to the entanglement of the qubit and the detector. Different regimes are studied by employing a perturbative Floquet-Born-Markov approach for the qubit+detector system, as well as nonperturbative real-time path integral schemes for the driven spin-boson system. We find analytical results for the resonances, including the red and the blue sidebands. They agree well with those of exact ab initio calculations.

Adiabatic quantization of Andreev quantum billiard levels.

We identify the time T between Andreev reflections as a classical adiabatic invariant in a ballistic chaotic cavity (Lyapunov exponent lambda), coupled to a superconductor by an N-mode constriction. Quantization of the adiabatically invariant torus in phase space gives a discrete set of periods T(n), which in turn generate a ladder of excited states epsilon (nm)=(m+1/2)pi(h) /T(n). The largest quantized period is the Ehrenfest time T(0)=lambda(-1)ln(N). Projection of the invariant torus onto the coordinate plane shows that the wave functions inside the cavity are squeezed to a transverse dimension W/sqrt[N], much below the width W of the constriction.

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.