Integrable Atomtronic Interferometry.

High sensitivity quantum interferometry requires more than just access to entangled states. It is achieved through the deep understanding of quantum correlations in a system. Integrable models offer the framework to develop this understanding. We communicate the design of interferometric protocols for an integrable model that describes the interaction of bosons in a four-site configuration. Analytic formulas for the quantum dynamics of certain observables are computed. These expose the system's functionality as both an interferometric identifier, and producer, of NOON states. Being equivalent to a controlled-phase gate acting on 2 hybrid qudits, this system also highlights an equivalence between Heisenberg-limited interferometry and quantum information. These results are expected to open new avenues for integrability-enhanced atomtronic technologies.

Estimation of dynamic time activity curves from dynamic cardiac SPECT imaging.

Whole-heart coronary flow reserve (CFR) may be useful as an early predictor of cardiovascular disease or heart failure. Here we propose a simple method to extract the time-activity curve, an essential component needed for estimating the CFR, for a small number of compartments in the body, such as normal myocardium, blood pool, and ischemic myocardial regions, from SPECT data acquired with conventional cameras using slow rotation. We evaluated the method using a realistic simulation of (99m)Tc-teboroxime imaging. Uptake of (99m)Tc-teboroxime based on data from the literature were modeled. Data were simulated using the anatomically-realistic 3D NCAT phantom and an analytic projection code that realistically models attenuation, scatter, and the collimator-detector response. The proposed method was then applied to estimate time activity curves (TACs) for a set of 3D volumes of interest (VOIs) directly from the projections. We evaluated the accuracy and precision of estimated TACs and studied the effects of the presence of perfusion defects that were and were not modeled in the estimation procedure.The method produced good estimates of the myocardial and blood-pool TACS organ VOIs, with average weighted absolute biases of less than 5% for the myocardium and 10% for the blood pool when the true organ boundaries were known and the activity distributions in the organs were uniform. In the presence of unknown perfusion defects, the myocardial TAC was still estimated well (average weighted absolute bias <10%) when the total reduction in myocardial uptake (product of defect extent and severity) was ≤ 5%. This indicates that the method was robust to modest model mismatch such as the presence of moderate perfusion defects and uptake nonuniformities. With larger defects where the defect VOI was included in the estimation procedure, the estimated normal myocardial and defect TACs were accurate (average weighted absolute bias ≈ 5% for a defect with 25% extent and 100% severity).

Evaluation of simultaneous 201Tl/99mTc dual-isotope cardiac SPECT imaging with model-based crosstalk compensation using canine studies.

BACKGROUND: Simultaneous (201)Tl/(99m)Tc-sestamibi dual-isotope myocardial perfusion SPECT imaging can reduce imaging time and produce perfectly registered rest/stress images. However, crosstalk from (99m)Tc into (201)Tl images can significantly reduce (201)Tl image quality. We have developed a model-based compensation (MBC) method to compensate for this crosstalk. The method has previously been validated with phantom and simulation studies. In this study, we evaluated the MBC method using a canine model. METHODS: Left anterior descending or left circumflex coronary artery stenoses were created in 50 adult mongrel dogs weighing 20-30 kg. The dogs were injected with 111 MBq (3 mCi) of (201)Tl at rest, and a SPECT study acquired. Stress was induced by administering adenosine to the dog, followed by injection of 740 MBq (20 mCi) of (99m)Tc-sestamibi at peak stress. A second SPECT study was performed with data acquired in both (201)Tl and (99m)Tc energy windows to provide simultaneous dual-isotope projection data. The images were reconstructed using the ordered-subsets expectation-maximization reconstruction algorithm with compensation for attenuation, scatter, and detector response. For simultaneously acquired (201)Tl data, we also applied the MBC method to compensate for crosstalk contamination from (99m)Tc. RESULTS: Without compensation, (99m)Tc crosstalk increased the estimated (201)Tl activity concentration in the rest images and reduced defect contrast. After MBC, the (201)Tl images were in good agreement with the registered single-isotope images and ex vivo count data. The ischemic (IS) to non-ischemic (NIS) region (201)Tl activity concentration ratios were computed for single-isotope and dual-isotope studies. The correlation with ex vivo IS-NIS ratios was 0.815 after MBC, compared to the 0.495 from data without compensation. In addition, the regression line for the IS-NIS ratios with MBC was almost parallel to the line of identity with a slope of 0.93, compared to a slope of 0.45 without compensation. CONCLUSIONS: These results demonstrate that model-based crosstalk compensation can provide substantial reduction of crosstalk effects in simultaneously acquired myocardial perfusion SPECT images in living biological systems.

Measurement-based teleportation along quantum spin chains.

We examine the teleportation of an unknown spin-1/2 quantum state along a quantum spin chain with an even number of sites. Our protocol, using a sequence of Bell measurements, may be viewed as an iterated version of the 2-qubit protocol of C. H. Bennett et al. [Phys. Rev. Lett. 70, 1895 (1993)]. A decomposition of the Hilbert space of the spin chain into 4 vector spaces, called Bell subspaces, is given. It is established that any state from a Bell subspace may be used as a channel to perform unit fidelity teleportation. The space of all spin-0 many-body states, which includes the ground states of many known antiferromagnetic systems, belongs to a common Bell subspace. A channel-dependent teleportation parameter [symbol: see text] is introduced, and a bound on the teleportation fidelity is given in terms of [symbol: see text].

BrainImageJ: a Java-based framework for interoperability in neuroscience, with specific application to neuroimaging.

The Human Brain Project consortium continues to struggle with effective sharing of tools. To facilitate reuse of its tools, the Stanford Psychiatry Neuroimaging Laboratory (SPNL) has developed BrainImageJ, a new software framework in Java. The framework consists of two components-a set of four programming interfaces and an application front end. The four interfaces define extension pathways for new data models, file loaders and savers, algorithms, and visualization tools. Any Java class that implements one of these interfaces qualifies as a BrainImageJ plug-in-a self-contained tool. After automatically detecting and incorporating new plug-ins, the application front end transparently generates graphical user interfaces that provide access to plug-in functionality. New plug-ins interoperate with existing ones immediately through the front end. BrainImageJ is used at the Stanford Psychiatry Neuroimaging Laboratory to develop image-analysis algorithms and three-dimensional visualization tools. It is the goal of our development group that, once the framework is placed in the public domain, it will serve as an interlaboratory platform for designing, distributing, and using interoperable tools.

Ladder operator for the one-dimensional Hubbard model.

The one-dimensional Hubbard model is integrable in the sense that it has an infinite family of conserved currents. We explicitly construct a ladder operator which can be used to iteratively generate all of the conserved current operators. This construction is different from that used for Lorentz invariant systems such as the Heisenberg model. The Hubbard model is not Lorentz invariant, due to the separation of spin and charge excitations. The ladder operator is obtained by a very general formalism which is applicable to any model that can be derived from a solution of the Yang-Baxter equation.

Characterization of toxicokinetics and toxicodynamics with linear systems theory: application to lead-associated cognitive decline.

We present a theoretical approach to analysis of toxicokinetics and toxicodynamics using linear systems theory. In our approach, we define two impulse response functions that characterize the kinetic behavior of an environmental agent in the body and the dynamic time-course behavior of its effect on the body. This approach provides a formalism for understanding the relation among exposure, dose, and cumulative biologically effective dose and for understanding the implications of an effect time-course on cross-sectional and longitudinal data analyses. We use lead-associated cognitive decline as a specific example where the approach may be applied.

Past adult lead exposure is associated with longitudinal decline in cognitive function.

OBJECTIVE: To determine whether adults with past exposure to neurotoxicants have progressive declines in cognitive function years after exposure has ceased, and whether tibia lead is a predictor of the magnitude of change. METHODS: A total of 535 former organolead manufacturing workers with a mean age of 55.6 years, a mean duration of 16 years since last occupational lead exposure, and low blood lead levels at the first study visit and 118 controls were evaluated with neurobehavioral tests two to four times over 4 years. "Peak" tibia lead levels, estimated from current levels measured by X-ray fluorescence, were used to predict changes in cognitive function over time. RESULTS: In former lead workers, peak tibia lead ranged from -2.2 to 98.7 microg Pb/g bone mineral. Compared to controls, former lead workers performed worse over time for three tests of visuo-constructive ability and verbal memory and learning (p < 0.05). In former lead workers, peak tibia lead predicted declines for six tests of verbal memory and learning, visual memory, executive ability, and manual dexterity (p < 0.05 for four tests and < 0.10 for two additional tests). On average, for these six tests, an increase of 15.7 microg/g of peak tibia lead was equivalent in its effects on annual test decline to 5 more years of age at baseline. CONCLUSIONS: These are the first data to suggest that cognitive function can progressively decline due to past occupational exposures to a neurotoxicant.

Combined corrections for attenuation, depth-dependent blur, and motion in cardiac SPECT: a multicenter trial.

BACKGROUND: The diagnostic accuracy of cardiac single photon emission computed tomography (SPECT) is limited by image-degrading factors, such as heart or subject motion, depth-dependent blurring caused by the collimator, and photon scatter and attenuation. We developed correction approaches for motion, depth-dependent blur, and attenuation and performed a multicenter validation. METHODS AND RESULTS: Motion was corrected both transversely and axially with a cross-correlation technique. Depth-dependent blurring was corrected by first back-projecting each projection and then applying a depth-dependent Wiener filter row by row. Attenuation was corrected with an iterative, nonuniform Chang algorithm, based on a transmission scan-generated attenuation map. We validated these approaches in 112 subjects, including 36 women (20 healthy volunteers, 8 angiographically normal patients, and 8 patients with coronary artery disease [CAD] found by means of angiography) and 76 men (23 healthy volunteers, 10 angiographically normal patients, and 43 patients with CAD found by means of angiography). Either technetium 99m or thallium 201 was used for emission; either gadolinium 153 or Tc-99m was used for transmission. Images were reconstructed and blindly interpreted with a 5-point scale for receiver operating characteristic analysis in 2 ways: motion correction plus a Butterworth filter, and combined motion and blur and attenuation corrections. The interpretation by means of consensus was for the overall presence of CAD and vascular territory. The receiver operating characteristic curves for overall presence and each of the 3 main coronary arteries were all shifted upward and to the left and had larger areas under the curve, for combined corrections compared with motion correction and Butterworth. Sensitivity/specificity for motion correction and Butterworth were 84/69, 64/71, 32/94, and 71/81 overall for the left anterior descending, the right coronary artery, and circumflex territories, respectively, compared with 88/92, 77/93, 50/97, and 74/95, respectively, for the combined corrections. CONCLUSIONS: The proposed combined corrections for motion, depth-dependent blur, and attenuation significantly improve diagnostic accuracy, when compared with motion correction alone.

6-[18F]fluoro-A-85380, a novel radioligand for in vivo imaging of central nicotinic acetylcholine receptors.

A novel positron emission tomography (PET) radiotracer, 6-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[18F]fluoro-A-85380, 6-[18F]FA) was synthesized by a no-carrier-added fluorination. In vitro 6-[18F]FA bound to nicotinic acetylcholine receptors (nAChRs), with very high affinity (Kd 28 pM). In PET studies, 6-[18F]FA specifically labeled central nAChRs in the brain of the Rhesus monkey and demonstrated highest levels of accumulation of radioactivity in brain regions enriched with the alpha4beta2 subtype of nAChR. 6-[18F]FA exhibited a target-to-non-target ratio (estimated as radioactivity in the thalamus to that in the cerebellum) of binding in primate brain similar to that previously determined for a labeled analog of epibatidine, [18F]FPH. In contrast to [18F]FPH, the novel tracer is expected to exhibit substantially less toxicity. Thus, the novel radioligand, 6-[18F]FA, appears to be a suitable candidate for imaging nAChRs in human brain.

Validation of an analytic method of calculating cerebral glucose metabolism using PET.

UNLABELLED: Quantitative modeling of cerebral metabolic rate for glucose (CMRglc) using PET with the FDG method requires calculation of the integral of the time course of radioactivity in arterial plasma. Numeric integration has typically been used but requires 30 or more blood samples taken between 15 s and 100 min after injection of the radiotracer. Our laboratory has developed an alternative integration method that fits the values of the plasma samples to an analytically integrable function using only 4-6 samples taken between 40 and 110 min after radiotracer injection. METHODS: The plasma integrals were calculated by both the analytic and the numeric methods with data from FDG PET studies that were not used in the development of the analytic method. In 39 PET studies from 22 healthy volunteers, 30 plasma samples were taken over 110 min. RESULTS: The plasma integrals determined by the analytic and numeric methods yielded a within-subject correlation coefficient of >0.95 and differences of <10%. CONCLUSION: Because the analytic method requires less blood sampling and does not require sampling immediately after radiotracer injection, the experimental procedure is simplified without loss of accuracy in CMRglc computation, and the effect of missing or incorrect samples is reduced.

Associations of tibial lead levels with BsmI polymorphisms in the vitamin D receptor in former organolead manufacturing workers.

We evaluated associations of tibial lead levels with polymorphisms in the vitamin D receptor (VDR) in 504 former organolead manufacturing workers with past exposure to lead. In this cross-sectional study, we measured tibial lead by (109)Cd K-shell X-ray fluorescence. Tibial lead was evaluated in subjects with different VDR genotypes defined using the BsmI restriction enzyme, adjusting for confounding variables. Study participants had a mean age +/- SD of 57.4 +/- 7.6 years. A total of 169 (33.5%) subjects were homozygous for the BsmI restriction site (designated bb), 251 (49.8%) were heterozygous (Bb), and 84 (16.7%) were homozygous for the absence of the restriction site (BB). Among all of the study subjects, tibial lead concentrations were low, with a mean +/- SD of 14.4 +/- 9.3 microg Pb/g bone mineral. There were only small differences in tibial lead concentrations by VDR genotype, with mean +/- SD tibial lead concentrations of 13.9 +/- 7.9, 14.3 +/- 9.5, and 15.5 +/- 11.1 in subjects with bb, Bb, and BB, respectively. In a multiple linear regression model of tibial lead concentrations, the VDR genotype modified the relation between age and tibial lead concentrations; subjects with the B allele had larger increases in tibial lead concentrations with increasing age (0.37, 0.48, and 0.67 microg/g per year of age in subjects with bb, Bb, and BB, respectively; the adjusted p-value for trend in slopes = 0.04). The VDR genotype also modified the relation between years since last exposure to lead and tibial lead concentrations. Subjects with bb evidenced an average decline in tibial lead concentrations of 0.10 microg/g per year since their last exposure to lead, whereas subjects with Bb and BB evidenced average increases of 0.03 and 0.11 microg/g per year, respectively (the adjusted p-value for trend in slopes = 0.01). Polymorphisms in the vitamin D receptor modified the relations of age and years since the last exposure to lead with tibial lead concentrations. Although controversy remains on the influence of the VDR genotype on bone mineral density, the data suggest that variant VDR alleles modify lead concentrations in bone, either by influencing lead content or calcium content or both.

2-[18F]F-A-85380: a PET radioligand for alpha4beta2 nicotinic acetylcholine receptors.

2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380), a ligand for nicotinic acetylcholine receptors (nAChRs) was evaluated in an in vitro binding assay with membranes of rat brain and in vivo by PET in Rhesus monkey brain. The ligand has high affinity for alpha4beta2 nAChRs (K(D)=50 pM), crosses the blood-brain barrier, and distributes in the monkey brain in a pattern consistent with that of alpha4beta2 nAChRs. The specific/non-specific binding ratio increased steadily, reaching a value of 3.3 in the thalamus at 4 h. The specific binding of 2-[18F]F-A-85380 was reversed by cytisine. These results, in combination with the data demonstrating low toxicity of 2-[18F]F-A-85380, indicate that this ligand shows promise for use with PET in human subjects.

Predictors of dimercaptosuccinic acid chelatable lead and tibial lead in former organolead manufacturing workers.

OBJECTIVES: To identify predictors of tibial and dimercaptosuccinic acid (DMSA) chelatable lead in 543 organolead manufacturing workers with past exposure to organic and inorganic lead. METHODS: In this cross sectional study, tibial lead (by 109Cd K-shell x ray fluorescence), DMSA chelatable lead (4 hour urinary lead excretion after oral administration of 10 mg/kg), and several exposure measures were obtained on study participants, mean (SD) age 57.6 (7.6) years. RESULTS: Tibial lead concentrations ranged from -1.6 to 52.0 micrograms lead/g bone mineral, with a mean (SD) of 14.4 (9.3) micrograms/g. DMSA chelatable lead ranged from 1.2 to 136 micrograms, with a mean (SD) of 19.3 (17.2) micrograms. In a multiple linear regression model of tibial lead, age (p < 0.01), duration of exposure (p < 0.01), current (p < 0.01) and past (p = 0.05) cigarette smoking, and diabetes (p = 0.01) were all independent positive predictors, whereas height (p = 0.03), and exercise inducing sweating (p = 0.04) were both negative predictors. The final regression model accounted for 31% of the variance in tibial lead concentrations; 27% was explained by age and duration of exposure alone. DMSA chelatable lead was directly associated with tibial lead (p = 0.01), cumulative exposure to inorganic lead (y.microgram/m3, p = 0.01), current smoking (p < 0.01), and weight (p < 0.01), and negatively associated with diabetes (p = 0.02). The final model accounted for 11% of the variance in chelatable lead. When blood lead was added to this model of DMSA chelatable lead, tibial lead, cumulative exposure to inorganic lead, and diabetes were no longer significant; blood lead accounted for the largest proportion of variance (p < 0.001); and the total model r2 increased to 19%. CONCLUSIONS: The low proportions of variance explained in models of both tibial and chelatable lead suggest that other factors are involved in the deposition of lead in bone and soft tissue. In epidemiological studies of the health effects of lead, evaluation of associations with both these measures may allow inferences to be made about whether health effects are likely to be recent, and thus potentially reversible, or chronic, and thus possibly irreversible. The data also provide direct evidence that in men the total amount of lead in the body that is bioavailable declines with age.

Neurobehavioral function and tibial and chelatable lead levels in 543 former organolead workers.

OBJECTIVE: To evaluate the associations between tibial lead, dimercaptosuccinic acid (DMSA)-chelatable lead, and neurobehavioral function in former organolead manufacturing workers with past exposure to organic and inorganic lead. METHODS: Data were collected from 543 subjects with a mean age of 58 years and an average of 17.8 years since last lead exposure. Years since last exposure to lead was used to estimate tibial lead levels in the year of last occupational lead exposure, termed "peak tibial lead." Current tibial lead levels, measured by x-ray fluorescence, were extrapolated back using a clearance half-time of lead in tibia of 27 years, assuming first-order clearance from tibia. RESULTS: Peak tibial lead levels ranged from -2.2 to 105.9 microg Pb/g bone mineral, and DMSA-chelatable lead levels were between 1.2 and 136 microg. After adjustment for confounding variables, peak tibial lead was a significant negative predictor of performance on the Wechsler Adult Intelligence Scale-Revised vocabulary subtest (p = 0.02), serial digit learning test (p = 0.04), Rey Auditory-Verbal Learning Test (immediate recall and recognition, p = 0.03 for each), Trail Making Test B (p = 0.03), finger tapping (dominant hand [p = 0.02] and nondominant hand [p < 0.01]), Purdue pegboard (dominant hand, nondominant hand, both hands, and assembly, p < 0.01 for each), and Stroop Test (p < 0.01). Moreover, with one exception, average neurobehavioral test scores were poorer at higher peak tibial lead levels. DMSA-chelatable lead was only significantly associated with choice reaction time (p = 0.01). CONCLUSION: Peak tibial lead was consistently associated with poorer neurobehavioral test scores, particularly in the domains of manual dexterity, executive ability, verbal intelligence, and verbal memory.

In vivo imaging of brain nicotinic acetylcholine receptors with 5-[123I]iodo-A-85380 using single photon emission computed tomography.

The distribution and kinetics of 5-[123I]iodo-A-85380, a novel ligand for brain nicotinic acetylcholine receptors (nAChRs), were evaluated in the Rhesus monkey using single photon emission computed tomography (SPECT). Peak levels of radioactivity were measured in brain at 90 min after injection of the tracer. Accumulation of radioactivity was highest in the thalamus, intermediate in the frontal cortex and basal ganglia, and lowest in the cerebellum. The ratio of specific to nonspecific binding (V3") in the thalamus, estimated from the (thalamic-cerebellar)/cerebellar radioactivity ratio, reached a value of 6 at 4 h post-injection. Specific binding was reduced by subcutaneous injection of 1 mg/kg cytisine at 2.25 h after injection of radiotracer. At 2.5 h after cytisine administration, radioactivity in the thalamus was reduced by 84%, in the frontal cortex, by 76%, and in the basal ganglia, by 57% of the level measured at the time of cytisine administration, demonstrating that the binding was reversible. On the basis of these findings, together with other data indicating high affinity, receptor subtype selectivity, low nonspecific binding and lack of toxicity in animals, 5-[123I]iodo-A-85380 appears to be a promising ligand for SPECT imaging of nAChRs in the human brain.

Advances in nuclear medicine instrumentation: considerations in the design and selection of an imaging system.

Nuclear medicine remains a vibrant and dynamic medical specialty because it so adeptly marries advances in basic science research, technology, and medical practice in attempting to solve patients' problems. As a physicist, it is my responsibility to identify or design new instrumentation and techniques, and to implement, validate, and help apply these new approaches in the practice of nuclear medicine. At Johns Hopkins, we are currently in the process of purchasing both a single-photon/coincidence tomographic imaging system and a dedicated positron emission tomography (PET) scanner. Given the exciting advances that have been made, but the conflicting opinions of manufacturers and colleagues alike regarding "best" choices, it seemed useful to review what is new now, and what is on the horizon, to help identify all of the important considerations in the design and selection of an imaging system. It is important to note that many of the "advances" described here are in an early stage of development, and may never make it to routine clinical practice. Further, not all of the advances are of equal importance, or have the same degree of general clinical applicability. Please also note that the references contained herein are for illustrative purposes and are not all-inclusive; no implication that those chosen are "better" than others not mentioned is intended.

Special issues in quantitation of brain receptors and related markers by emission computed tomography.

Emission computed tomography provides an opportunity to quantify neurotransmitter-neuroreceptor systems in vivo. In order to do so, very high image quality and quantitative accuracy are required. Quantitation of receptor systems involves considerations of physical effects (such as finite spatial resolution, scatter, and attenuation), instrumentation design (such as spatial sampling), image processing (such as filtering), and data analysis (such as kinetic modeling). Appropriate application of these considerations can lead to useful results, but emerging approaches promise even greater levels of accuracy and precision.