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ImportanceAlthough dopamine is implicated in the pathophysiology of bipolar disorder (BD), the precise alterations in the dopaminergic system remain unknown.ObjectiveTo assess dopamine transporter (DAT) density in the striatum in patients with BD with current and recently remitted mania in comparison to healthy control individuals and its correlation with severity of manic symptoms.Design, Setting, and ParticipantsThis cross-sectional study conducted in a tertiary care referral center for mood disorders in Vancouver, British Columbia, Canada, recruited 26 patients with BD (9 with current mania; 17 with recently remitted mania) and 21 matched healthy control individuals. DAT density was measured using positron emission tomography with [11C]d-threo-methylphenidate (MP). The differences between the groups in nondisplaceable binding potential (BPND) for DAT was assessed using statistical parametric mapping. The study was conducted from November 2001 to February 2007 and the data were analyzed from November 2020 to December 2021.Main Outcomes and MeasuresDAT density as indexed by BPND for MP across groups; manic symptom severity as measured with the Young Mania Rating Scale (YMRS) and correlated with BPND values in patients with BD.ResultsOf 47 total participants (mean [SD] age, 37.8 [14.4] years), 27 (57.4%) were female; 26 individuals had BD (9 with current mania and 17 with recently remitted mania) and there were 21 healthy control individuals. MP BPND was significantly lower in patients with BD in the right putamen and nucleus accumbens (mean reduction [MR] = 22%; cluster level familywise error [FWE]–corrected P P P P = .005) but not in the left striatum in either group.Conclusions and RelevanceThese findings indicate that mania was associated with reduced DAT density and remitted mania was associated with DAT levels that approximated those present in individuals without BD. These results have potential implications for drug development for mania.

The main applications of 188Re in radionuclide therapies include trans-arterial liver radioembolization and palliation of painful bone-metastases. In order to optimize 188Re therapies, the accurate determination of radiation dose delivered to tumors and organs at risk is required. Single photon emission computed tomography (SPECT) can be used to perform such dosimetry calculations. However, the accuracy of dosimetry estimates strongly depends on the accuracy of activity quantification in 188Re images. In this study, we performed a series of phantom experiments aiming to investigate the accuracy of activity quantification for 188Re SPECT using high-energy and medium-energy collimators. Objects of different shapes and sizes were scanned in Air, non-radioactive water (Cold-water) and water with activity (Hot-water). The ordered subset expectation maximization algorithm with clinically available corrections (CT-based attenuation, triple-energy window (TEW) scatter and resolution recovery was used). For high activities, the dead-time corrections were applied. The accuracy of activity quantification was evaluated using the ratio of the reconstructed activity in each object to this object's true activity. Each object's activity was determined with three segmentation methods: a 1% fixed threshold (for cold background), a 40% fixed threshold and a CT-based segmentation. Additionally, the activity recovered in the entire phantom, as well as the average activity concentration of the phantom background were compared to their true values. Finally, Monte-Carlo simulations of a commercial -camera were performed to investigate the accuracy of the TEW method. Good quantification accuracy (errors 15%), mostly due to partial-volume effects. The Monte-Carlo simulations confirmed that TEW-scatter correction applied to 188Re, although practical, yields only approximate estimates of the true scatter.

Symmetries play an important role in modern theories of gravity. The strong equivalence principle (SEP) constitutes a collection of gravitational symmetries which are all implemented by general relativity. Alternative theories, however, are generally expected to violate some aspects of SEP. We test three aspects of SEP using observed change rates in the orbital period and eccentricity of binary pulsar J1713+0747: 1. the gravitational constant's constancy as part of locational invariance of gravitation; 2. the post-Newtonian parameter $\hat{\alpha}_3$ in gravitational Lorentz invariance; 3. the universality of free fall (UFF) for strongly self-gravitating bodies. Based on the pulsar timing result of the combined dataset from the North American Nanohertz Gravitational Observatory (NANOGrav) and the European Pulsar Timing Array (EPTA), we find $\dot{G}/G = (-0.1 \pm 0.9) \times 10^{-12}\,{\rm yr}^{-1}$, which is weaker than Solar system limits, but applies for strongly self-gravitating objects. Furthermore, we obtain the constraints $|\Delta|< 0.002$ for the UFF test and $-3\times10^{-20} < \hat{\alpha}_3 < 4\times10^{-20}$ at 95% confidence. These are the first direct UFF and $\hat{\alpha}_3$ tests based on pulsar binaries, and they overcome various limitations of previous tests., Comment: 11 pages, 6 figures, and 1 table; submitted to MNRAS

Purpose: In the nuclear medicine department, the activity of radiopharmaceuticals is measured using dose calibrators (DCs) prior to patient injection. The DC consists of an ionization chamber that measures current generated by ionizing radiation (emitted from the radiotracer). In order to obtain an activity reading, the current is converted into units of activity by applying an appropriate calibration factor (also referred to as DC dial setting). Accurate determination of DC dial settings is crucial to ensure that patients receive the appropriate dose in diagnostic scans or radionuclide therapies. The goals of this study were (1) to describe a practical method to experimentally determine dose calibrator settings using a thyroid-probe (TP) and (2) to investigate the accuracy, reproducibility, and uncertainties of the method. As an illustration, the TP method was applied to determine 188Re dial settings for two dose calibrator models: Atomlab 100plus and Capintec CRC-55tR. Methods: Using the TP to determine dose calibrator settings involved three measurements. First, the energy-dependent efficiency of the TP was determined from energy spectra measurements of two calibration sources (152Eu and 22Na). Second, the gamma emissions from the investigated isotope (188Re) were measured using the TP and its activity was determined using γ-ray spectroscopy methods. Ambient background, scatter, and source-geometry corrections were applied during the efficiency and activity determination steps. Third, the TP-based 188Re activity was used to determine the dose calibrator settings following the calibration curve method [B. E. Zimmerman et al., J. Nucl. Med. 40, 1508–1516 (1999)]. The interobserver reproducibility of TP measurements was determined by the coefficient of variation (COV) and uncertainties associated to each step of the measuring process were estimated. The accuracy of activity measurements using the proposed method was evaluated by comparing the TP activity estimates of 99mTc, 188Re, 131I, and 57Co samples to high purity Ge (HPGe) γ-ray spectroscopy measurements. Results: The experimental 188Re dial settings determined with the TP were 76.5 ± 4.8 and 646 ± 43 for Atomlab 100plus and Capintec CRC-55tR, respectively. In the case of Atomlab 100plus, the TP-based dial settings improved the accuracy of 188Re activity measurements (confirmed by HPGe measurements) as compared to manufacturer-recommended settings. For Capintec CRC-55tR, the TP-based settings were in agreement with previous results [B. E. Zimmerman et al., J. Nucl. Med. 40, 1508–1516 (1999)] which demonstrated that manufacturer-recommended settings overestimate 188Re activity by more than 20%. The largest source of uncertainty in the experimentally determined dial settings was due to the application of a geometry correction factor, followed by the uncertainty of the scatter-corrected photopeak counts and the uncertainty of the TP efficiency calibration experiment. When using the most intense photopeak of the sample's emissions, the TP method yielded accurate (within 5% errors) and reproducible (COV = 2%) measurements of sample's activity. The relative uncertainties associated with such measurements ranged from 6% to 8% (expanded uncertainty at 95% confidence interval, k = 2). Conclusions: Accurate determination/verification of dose calibrator dial settings can be performed using a thyroid-probe in the nuclear medicine department.

Purpose Beta particles emitted by radioisotopes used in targeted radionuclide therapies (TRT) create Bremsstrahlung (BRS) which may affect SPECT quantification when imaging these isotopes. The purpose of the current study was to investigate the characteristics of Bremsstrahlung produced in tissue by three β-emitting radioisotopes used in TRT. Methods Monte Carlo simulations of 177 Lu, 188 Re, and 90 Y sources placed in water filled cylinders were performed. BRS yields, mean energies and energy spectra for (a) all photons generated in the decays, (b) photons that were not absorbed and leave the cylinder, and (c) photons detected by the camera were analyzed. Next, the results of simulations were compared with those from experiments performed on a clinical SPECT camera using same acquisition conditions and phantom configurations as in simulations. Results Simulations reproduced relatively well the shapes of the measured spectra, except for 90 Y which showed an overestimation in the low energy range. Detailed analysis of the results allowed us to suggest best collimators and imaging conditions for each of the investigated isotopes. Finally, our simulations confirmed that the BRS contribution to the energy spectra in quantitative imaging of 177 Lu and 188 Re could be ignored. Conclusions For 177 Lu and 188 Re, BRS contributes only marginally to the total spectra recorded by the camera. Our analysis shows that MELP and HE collimators are the best for imaging these two isotopes. For 90 Y, HE collimator should be used.

We analyse the stochastic properties of the 49 pulsars that comprise the first International Pulsar Timing Array (IPTA) data release. We use Bayesian methodology, performing model selection to determine the optimal description of the stochastic signals present in each pulsar. In addition to spin-noise and dispersion-measure (DM) variations, these models can include timing noise unique to a single observing system, or frequency band. We show the improved radio-frequency coverage and presence of overlapping data from different observing systems in the IPTA data set enables us to separate both system and band-dependent effects with much greater efficacy than in the individual PTA data sets. For example, we show that PSR J1643$-$1224 has, in addition to DM variations, significant band-dependent noise that is coherent between PTAs which we interpret as coming from time-variable scattering or refraction in the ionised interstellar medium. Failing to model these different contributions appropriately can dramatically alter the astrophysical interpretation of the stochastic signals observed in the residuals. In some cases, the spectral exponent of the spin noise signal can vary from 1.6 to 4 depending upon the model, which has direct implications for the long-term sensitivity of the pulsar to a stochastic gravitational-wave (GW) background. By using a more appropriate model, however, we can greatly improve a pulsar's sensitivity to GWs. For example, including system and band-dependent signals in the PSR J0437$-$4715 data set improves the upper limit on a fiducial GW background by $\sim 60\%$ compared to a model that includes DM variations and spin-noise only., Comment: 29 pages. 16 figures. Accepted for publication in MNRAS

The highly stable spin of neutron stars can be exploited for a variety of (astro-)physical investigations. In particular arrays of pulsars with rotational periods of the order of milliseconds can be used to detect correlated signals such as those caused by gravitational waves. Three such "Pulsar Timing Arrays" (PTAs) have been set up around the world over the past decades and collectively form the "International" PTA (IPTA). In this paper, we describe the first joint analysis of the data from the three regional PTAs, i.e. of the first IPTA data set. We describe the available PTA data, the approach presently followed for its combination and suggest improvements for future PTA research. Particular attention is paid to subtle details (such as underestimation of measurement uncertainty and long-period noise) that have often been ignored but which become important in this unprecedentedly large and inhomogeneous data set. We identify and describe in detail several factors that complicate IPTA research and provide recommendations for future pulsar timing efforts. The first IPTA data release presented here (and available online) is used to demonstrate the IPTA's potential of improving upon gravitational-wave limits placed by individual PTAs by a factor of ~2 and provides a 2-sigma limit on the dimensionless amplitude of a stochastic GWB of 1.7x10^{-15} at a frequency of 1 yr^{-1}. This is 1.7 times less constraining than the limit placed by (Shannon et al. 2015), due mostly to the more recent, high-quality data they used., 25 pages, 6 tables, 5 figures. Accepted for publication in MNRAS

Background: Camera calibration, which translates reconstructed count map into absolute activity map, is a prerequisite procedure for quantitative SPECT imaging. Both planar and tomographic scans using different phantom geometries have been proposed for the determination of the camera calibration factor (CF). However, there is no consensus on which approach is the best. The aim of this study is to evaluate all these calibration methods, compare their performance, and propose a practical and accurate calibration method for SPECT quantitation of therapeutic radioisotopes. Twenty-one phantom experiments (Siemens Symbia SPECT/CT) and 12 Monte Carlo simulations (GATE v6.1) using three therapy isotopes (131I, 177Lu, and 188Re) have been performed. The following phantom geometries were used: (1) planar scans of point source in air (PS), (2) tomographic scans of insert(s) filled with activity placed in non-radioactive water (HS + CB), (3) tomographic scans of hot insert(s) in radioactive water (HS + WB), and (4) tomographic scans of cylinders uniformly filled with activity (HC). Tomographic data were reconstructed using OSEM with CT-based attenuation correction and triple energy window (TEW) scatter correction, and CF was determined using total counts in the reconstructed image, while for planar scans, the photopeak counts, corrected for scatter and background with TEW, were used. Additionally, for simulated data, CF obtained from primary photons only was analyzed. Results: For phantom experiments, CF obtained from PS and HS + WB agreed to within 6% (below 3% if experiments performed on the same day are considered). However, CF from HS + CB exceeded those from PS by 4–12%. Similar trend was found in simulation studies. Analysis of CFs from primary photons helped us to understand this discrepancy. It was due to underestimation of scatter by the TEW method, further enhanced by attenuation correction. This effect becomes less important when the source is distributed over the entire phantom volume (HS + WB and HC). Conclusions: Camera CF could be determined using planar scans of a point source, provided that the scatter and background contributions are removed, for example using the clinically available TEW method. This approach is simple and yet provides CF with sufficient accuracy (~ 5%) to be used in clinics for radiotracer quantification.

Background: The aim of this study was to investigate the deadtime (DT) effects that are present in 177Lu images acquired after radionuclide therapy injection, assess differences in DT based on the full spectrum and the photopeak-only measurements, and design a method to correct for the deadtime losses. A Siemens SymbiaT SPECT/CT camera with a medium energy collimator was used. A 295-mL bottle was placed off-center inside a large cylinder filled with water, and 177Lu activity was sequentially added up to a maximum of 9.12 GBq. The true count rates vs. observed count rates were plotted and fitted to the DT paralyzable model. This analysis was performed using counts recorded in the full spectrum and in other energy windows. The DT correction factors were calculated using the percentage difference between the true and the observed count rates. Results: The DT values of 5.99 ± 0.02 μs, 4.60 ± 0.052 μs, and 0.19 ± 0.18 μs were obtained for the primary photons (PP) recorded in the 113- and 208-keV photopeaks and for the full spectrum, respectively. For the investigated range of count rates, the DT correction factors of up to 23% were observed for PP corresponding to the 113-keV photopeak, while for the 208-keV photopeak values of up to 20% were obtained. These values were almost three times higher than the deadtime correction factors derived from the full spectrum. Conclusions: The paralyzable model showed to be appropriate for the investigated range of counts, which were five to six times higher than those observed in the patient post-therapy imaging. Our results suggest that the deadtime corrections should be based on count losses in the scatter-corrected photopeak window and not on the deadtime determined from the full spectrum. Finally, a general procedure that can be followed to correct patient images for deadtime is presented.

Pulsar-timing analyses are sensitive to errors in the solar-system ephemerides (SSEs) that timing models utilise to estimate the location of the solar-system barycentre, the quasi-inertial reference frame to which all recorded pulse times-of-arrival are referred. Any error in the SSE will affect all pulsars, therefore pulsar timing arrays (PTAs) are a suitable tool to search for such errors and impose independent constraints on relevant physical parameters. We employ the first data release of the International Pulsar Timing Array to constrain the masses of the planet-moons systems and to search for possible unmodelled objects (UMOs) in the solar system. We employ ten SSEs from two independent research groups, derive and compare mass constraints of planetary systems, and derive the first PTA mass constraints on asteroid-belt objects. Constraints on planetary-system masses have been improved by factors of up to 20 from the previous relevant study using the same assumptions, with the mass of the Jovian system measured at 9.5479189(3)$\times10^{-4}$ $M_{\odot}$. The mass of the dwarf planet Ceres is measured at 4.7(4)$\times10^{-10}$ $M_{\odot}$. We also present the first sensitivity curves using real data that place generic limits on the masses of UMOs, which can also be used as upper limits on the mass of putative exotic objects. For example, upper limits on dark-matter clumps are comparable to published limits using independent methods. While the constraints on planetary masses derived with all employed SSEs are consistent, we note and discuss differences in the associated timing residuals and UMO sensitivity curves., Comment: Accepted for publication by the Monthly Notices of the Royal Astronomical Society

Positron emission tomography (PET) data related to neurodegeneration are most often quantified using methods based on tracer kinetic modeling. In contrast, here we investigate the ability of geometry and texture-based metrics that are independent of kinetic modeling to convey useful information on disease state. The study was performed using data from Parkinson’s disease subjects imaged with 11C-dihydrotetrabenazine and 11C-raclopride. The pattern of the radiotracer distribution in the striatum was quantified using image-based metrics evaluated over multiple regions of interest that were defined on co-registered PET and MRI images. Regression analysis showed a significant degree of correlation between several investigated metrics and clinical evaluations of the disease ( p 2 = 0.94). These results demonstrate that there is clinically relevant quantitative information in the tracer distribution pattern that can be captured using geometric and texture descriptors. Such metrics may provide an alternate and complementary data analysis approach to traditional kinetic modeling.

Background: The aim of the study is to assess accuracy of activity quantification of 177Lu studies performed according to recommendations provided by the committee on Medical Internal Radiation Dose (MIRD) pamphlets 23 and 26. The performances of two scatter correction and three segmentation methods were compared. Additionally, the accuracy of tomographic and planar methods for determination of the camera normalization factor (CNF) was evaluated. Eight phantoms containing inserts of different sizes and shapes placed in air, water, and radioactive background were scanned using a Siemens SymbiaT SPECT/CT camera. Planar and tomographic scans with 177Lu sources were used to measure CNF. Images were reconstructed with our SPEQToR software using resolution recovery, attenuation, and two scatter correction methods (analytical photon distribution interpolated (APDI) and triple energy window (TEW)). Segmentation was performed using a fixed threshold method for both air and cold water scans. For hot water experiments three segmentation methods were compared as folows: a 40% fixed threshold, segmentation based on CT images, and our iterative adaptive dual thresholding (IADT). Quantification error, defined as the percent difference between experimental and true activities, was evaluated. Results: Quantification error for scans in air was better for TEW scatter correction (100 ml) were obtained when APDI and IADT were used for scatter correction and segmentation, respectively. Additionally, we showed that planar acquisitions with scatter correction and tomographic scans provide similar CNF values. This is an important finding because planar acquisitions are easier to perform than tomographic scans. TEW and APDI resulted in similar quantification errors with APDI showing a small advantage for objects placed in medium with non-uniform density. Conclusions: Following the MIRD recommendations for data acquisition and reconstruction resulted in accurate activity quantification (errors

We present a novel analysis method for positron emission tomography (PET) data that uses the spatial characteristics of the radiotracer's distribution within anatomically-defined regions of interest (ROIs) to provide an independent feature that may aid in characterizing pathological and normal states. The analysis of PET data for research purposes traditionally involves kinetic modeling of the concentration of the radiotracer over time within a ROI to derive parameters related to the uptake/binding of the radiotracer in the body. Here we describe an analysis method to quantify the spatial changes present in PET images based on 3D shape descriptors that are invariant to translation, scaling, and rotation, called 3D moment invariants (3DMIs). An ROI can therefore be characterized not only by the radiotracer's uptake rate constant or binding potential within the ROI, but also the 3D spatial shape and distribution of the radioactivity throughout the ROI. This is particularly relevant in Parkinson's disease (PD), where both the kinetic and the spatial distribution of the tracer are known to change due to disease: the posterior parts of the striatum (in particular in the putamen) are affected before the anterior parts. Here we show that 3DMIs are able to quantify the spatial distribution of PET radiotracer images allowing for discrimination between healthy controls and PD subjects. More importantly, 3DMIs are found to be well correlated with subjects' scores on the United Parkinson's Disease Rating Scale (a clinical measure of disease severity) in all anatomical regions studied here (putamen, caudate and ventral striatum). On the other hand, kinetic parameters only show significant correlation to clinically-assessed PD severity in the putamen. We also find that 3DMI-characterized changes in spatial patterns of dopamine release in response to l-dopa medication are significantly correlated with PD severity. These findings suggest that quantitative studies of a radiotracer's spatial distribution may provide complementary information to kinetic modeling that is relatively robust to intersubject variability and may contribute novel information in PET neuroimaging studies.

In the nuclear medicine department, the activity of radiopharmaceuticals is measured using dose calibrators (DCs) prior to patient injection. The DC consists of an ionization chamber that measures current generated by ionizing radiation (emitted from the radiotracer). In order to obtain an activity reading, the current is converted into units of activity by applying an appropriate calibration factor (also referred to as DC dial setting). Accurate determination of DC dial settings is crucial to ensure that patients receive the appropriate dose in diagnostic scans or radionuclide therapies. The goals of this study were (1) to describe a practical method to experimentally determine dose calibrator settings using a thyroid-probe (TP) and (2) to investigate the accuracy, reproducibility, and uncertainties of the method. As an illustration, the TP method was applied to determineUsing the TP to determine dose calibrator settings involved three measurements. First, the energy-dependent efficiency of the TP was determined from energy spectra measurements of two calibration sources (The experimentalAccurate determination/verification of dose calibrator dial settings can be performed using a thyroid-probe in the nuclear medicine department.

We analyze 24 binary radio pulsars in the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) nine-year data set. We make fourteen significant measurements of Shapiro delay, including new detections in four pulsar-binary systems (PSRs J0613$-$0200, J2017+0603, J2302+4442, and J2317+1439), and derive estimates of the binary-component masses and orbital inclination for these MSP-binary systems. We find a wide range of binary pulsar masses, with values as low as $m_{\rm p} = 1.18^{+0.10}_{-0.09}\text{M}_{\odot}$ for PSR J1918$-$0642 and as high as $m_{\rm p} = 1.928^{+0.017}_{-0.017}\text{M}_{\odot}$ for PSR J1614$-$2230 (both 68.3\% credibility). We make an improved measurement of the Shapiro timing delay in the PSR J1918$-$0642 and J2043+1711 systems, measuring the pulsar mass in the latter system to be $m_{\rm p} = 1.41^{+0.21}_{-0.18}\text{M}_{\odot}$ (68.3\% credibility) for the first time. We measure secular variations of one or more orbital elements in many systems, and use these measurements to further constrain our estimates of the pulsar and companion masses whenever possible. In particular, we used the observed Shapiro delay and periastron advance due to relativistic gravity in the PSR J1903+0327 system to derive a pulsar mass of $m_{\rm p} = 1.65^{+0.02}_{-0.02}\text{M}_{\odot}$ (68.3\% credibility). We discuss the implications that our mass measurements have on the overall neutron-star mass distribution, and on the "mass/orbital-period" correlation due to extended mass transfer., Comment: Fixed typos, added Table 5 and analysis of PSR J2145-0750. Accepted by ApJ on 24 September 2016

Gravitational wave astronomy using a pulsar timing array requires high-quality millisecond pulsars, correctable interstellar propagation delays, and high-precision measurements of pulse times of arrival. Here we identify noise in timing residuals that exceeds that predicted for arrival time estimation for millisecond pulsars observed by the North American Nanohertz Observatory for Gravitational Waves. We characterize the excess noise using variance and structure function analyses. We find that 26 out of 37 pulsars show inconsistencies with a white-noise-only model based on the short timescale analysis of each pulsar and we demonstrate that the excess noise has a red power spectrum for 15 pulsars. We also decompose the excess noise into chromatic (radio-frequency-dependent) and achromatic components. Associating the achromatic red-noise component with spin noise and including additional power-spectrum-based estimates from the literature, we estimate a scaling law in terms of spin parameters (frequency and frequency derivative) and data-span length and compare it to the scaling law of Shannon \& Cordes (2010). We briefly discuss our results in terms of detection of gravitational waves at nanohertz frequencies., 20 pages, 16 figures, to be published in ApJ

We present the polarization pulse profiles for 28 pulsars observed with the Arecibo Observatory by the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) timing project at 2.1 GHz, 1.4 GHz, and 430 MHz. These profiles represent some of the most sensitive polarimetric millisecond pulsar profiles to date, revealing the existence of microcomponents (that is, pulse components with peak intensities much lower than the total pulse peak intensity). Although microcomponents have been detected in some pulsars previously, we present microcomponents for PSRs B1937+21, J1713+0747, and J2234+0944 for the first time. These microcomponents can have an impact on pulsar timing, geometry, and flux density determination. We present rotation measures for all 28 pulsars, determined independently at different observation frequencies and epochs, and find the Galactic magnetic fields derived from these rotation measures to be consistent with current models. These polarization profiles were made using measurement equation template matching, which allows us to generate the polarimetric response of the Arecibo Observatory on an epoch-by-epoch basis. We use this method to describe its time variability, and find that the polarimetric responses of the Arecibo Observatory's 1.4 and 2.1 GHz receivers vary significantly with time., Comment: 41 pages, 20 figures

Objectives Bipolar I disorder (BD-I) is associated with gray matter volume (GMV) alterations in neural regions important for emotional regulation. Reductions found in patients with multiple episodes are not seen at illness onset, suggesting that changes occur with illness progression, although no prospective studies to date have examined this. In the present study, we assessed GMV at baseline and one year following a first manic episode, examining the impact of episode recurrence on the trajectory of change. Methods A total of 41 recently remitted first manic episode patients with BD-I and 25 healthy subjects (HS) underwent 3T magnetic resonance imaging at baseline and one year later. Using voxel-based morphometry, we compared GMV change between HS, patients who experienced a recurrence of a mood episode (BDrecurr), and patients in sustained remission (BDwell). Results The GMV change from baseline to one year did not differ significantly between HS and the full BD-I group or BDwell and HS. However, the BDrecurr group had greater GMV loss than HS in left frontal and bilateral temporal regions, and BDwell patients involving bilateral frontal, temporal and left parietal regions. Conclusions GMV change early in the course of BD-I is associated with clinical outcome, such that neuroprogression found in patients who experience a recurrence of a mood episode is not seen in those with sustained remission. These findings have important implications for the treatment of BD-I as they suggest that prevention of recurrence might minimize neuroprogression of the disease, possibly requiring a multipronged early intervention approach to achieve this goal.

We report 21-yr timing of one of the most precise pulsars: PSR J1713+0747. Its pulse times of arrival are well modeled by a comprehensive pulsar binary model including its three-dimensional orbit and a noise model that incorporates correlated noise such as jitter and red noise. Its timing residuals have weighted root mean square $\sim 92$ ns. The new dataset allows us to update and improve previous measurements of the system properties, including the masses of the neutron star ($1.31\pm0.11$ $M_{\odot}$) and the companion white dwarf ($0.286\pm0.012$ $M_{\odot}$) and the parallax distance $1.15\pm0.03$ kpc. We measured the intrinsic change in orbital period, $\dot{P}^{\rm Int}_{\rm b}$, is $-0.20\pm0.17$ ps s$^{-1}$, which is not distinguishable from zero. This result, combined with the measured $\dot{P}^{\rm Int}_{\rm b}$ of other pulsars, can place a generic limit on potential changes in the gravitational constant $G$. We found that $\dot{G}/G$ is consistent with zero [$(-0.6\pm1.1)\times10^{-12}$ yr$^{-1}$, 95\% confidence] and changes at least a factor of $31$ (99.7\% confidence) more slowly than the average expansion rate of the Universe. This is the best $\dot{G}/G$ limit from pulsar binary systems. The $\dot{P}^{\rm Int}_{\rm b}$ of pulsar binaries can also place limits on the putative coupling constant for dipole gravitational radiation $\kappa_D=(-0.9\pm3.3)\times10^{-4}$ (95\% confidence). Finally, the nearly circular orbit of this pulsar binary allows us to constrain statistically the strong-field post-Newtonian parameters $\Delta$, which describes the violation of strong equivalence principle, and $\hat{\alpha}_3$, which describes a breaking of both Lorentz invariance in gravitation and conservation of momentum. We found, at 95\% confidence, $\Delta, Comment: 14 pages, 6 figures. Published on ApJ, 809, 41 (2015)

The use of pulsars as astrophysical clocks for gravitational wave experiments demands the highest possible timing precision. Pulse times of arrival (TOAs) are limited by stochastic processes that occur in the pulsar itself, along the line of sight through the interstellar medium, and in the measurement process. On timescales of seconds to hours, the TOA variance exceeds that from template-fitting errors due to additive noise. We assess contributions to the total variance from two additional effects: amplitude and phase jitter intrinsic to single pulses and changes in the interstellar impulse response from scattering. The three effects have different dependencies on time, frequency, and pulse signal-to-noise ratio. We use data on 37 pulsars from the North American Nanohertz Observatory for Gravitational Waves to assess the individual contributions to the overall intraday noise budget for each pulsar. We detect jitter in 22 pulsars and estimate the average value of RMS jitter in our pulsars to be $\sim 1\%$ of pulse phase. We examine how jitter evolves as a function of frequency and find evidence for evolution. Finally, we compare our measurements with previous noise parameter estimates and discuss methods to improve gravitational wave detection pipelines., Comment: 22 pages, 11 figures, published in ApJ

Using the nine-year radio-pulsar timing data set from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav), collected at Arecibo Observatory and the Green Bank Telescope, we have measured the positions, proper motions, and parallaxes for 37 millisecond pulsars. We report twelve significant parallax measurements and distance measurements, and eighteen lower limits on distance. We compare these measurements to distances predicted by the NE2001 interstellar electron density model and find them to be in general agreement. We use measured orbital-decay rates and spin-down rates to confirm two of the parallax distances and to place distance upper limits on other sources; these distance limits agree with the parallax distances with one exception, PSR J1024-0719, which we discuss at length. Using the proper motions of the 37 NANOGrav pulsars in combination with other published measurements, we calculate the velocity dispersion of the millisecond pulsar population in Galactocentric coordinates. We find the radial, azimuthal, and perpendicular dispersions to be 46, 40, and 24 km s-1, respectively, in a model that allows for high-velocity outliers; or 81, 58, and 62 km s-1 for the full population. These velocity dispersions are far smaller than those of the canonical pulsar population, and are similar to older Galactic disk populations. This suggests that millisecond pulsar velocities are largely attributable to their being an old population rather than being artifacts of their birth and evolution as neutron star binary systems. The components of these velocity dispersions follow similar proportions to other Galactic populations, suggesting that our results are not biased by selection effects., Comment: Accepted by ApJ

We present observations with the Chandra Advanced CCD Imaging Spectrometer (ACIS-S) of the western interior of the supernova remnant (SNR) G292.2-0.5 associated with the high magnetic field pulsar (PSR) J1119-6127. Chandra's excellent resolution revealed 18 point sources on the S3 chip and allowed the study of the diffuse emission from G292.2-0.5 independently from these point sources. The diffuse emission from G292.2-0.5 can be adequately fitted with nonequilibrium ionization models; however, these fits result in an unrealistically high temperature (kT > 3 keV), indicating the presence of a hard nonthermal component. By performing a spatially resolved spectroscopic study of the remnant, we identify the nonthermal emission as originating from the region closer to the pulsar. Its spectrum is well described with a power law with a photon index of Γ ~ 1-2. As a result of the flat spectrum and location close to the pulsar, we propose that this nonthermal emission arises from the injection of high-energy particles originating from PSR J1119-6127 and its pulsar wind nebula (PWN) into the SNR shell. As for the 18 point sources revealed by Chandra, only 3 sources have previously known counterparts at other wavelengths. Two of these sources exhibit enough counts to extract a spectrum, one being a new source CXOU J111911.8-613026 and the other being the X-ray counterpart of PSR J1119-6127 studied by us in a previous work. The spectrum of the new source CXOU J111911.8-613026 is soft (power-law photon index Γ ~ 3.6-4.6 or blackbody temperature kT ~ 0.2-0.36 keV) with a luminosity comparable to that of faint radio-quiet neutron stars. The nature of CXOU J111911.8-613026, however, cannot be determined with the present data and has to await further observations.

Texture and shape analysis applied to positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging is a technique based on the characterization of the spatial distribution of a radio tracer using texture and shape descriptors. It has been shown in recent studies to provide functional disease related information. Applied to high resolution PET images of patients suffering from Parkinson's disease (PD), a good correlation has been found between 3D moment invariants (3DMI) which are shape metrics and Parkinson's disease severity. Given the wide availability of SPECT cameras in clinical environments, could texture and shape analysis provide comparable results on lower resolution images to those obtained with state-of-the-art PET cameras? The aim of the present study is to investigate the applicability and robustness of the texture and shape analysis in the specific context of images displaying localized spatial distribution of the tracer with disease induced spatial abnormalities. Applicability and robustness of the method was tested against: i) the choice of the texture and shape descriptors, ii) the image spatial resolution, iii) the image noise level and iv) the definition of the region of interest (ROI). Methods: a magnetic resonance imaging (MRI) scan to provide anatomical information for ROIs placement and a high resolution PET scan providing a dynamic sequence of [11C]dihydrotetrabenazine (DTBZ) images were acquired for 13 PD patients and 6 healthy controls. To simulate the lower spatial resolutions, the reconstructed PET images were smoothed with a 3D Gaussian filter with a full width at half maximum (FWHM) ranging from 2 mm to 20 mm. As an evaluation criterion, Spearman's correlation was calculated between texture and shape metrics and disease severity assessed either by the unified Parkinson's disease rating scale (UPDRS) scores or by the disease duration. Results and conclusion: this study has shown that texture and shape analysis can provide relevant disease related information when applied to images of tracers displaying a localized spatial distribution with disease dependent heterogeneity and/or shape characteristics. In the specific case of Parkinson's disease imaged with the PET tracer [11C]DTBZ, we have shown that the MEAN intensity metric and the 3D moment invariant metrics are strongly correlated with disease severity and that the strength of the correlation persisted on images ranging from the highest spatial resolutions achievable by state-of-the-art PET cameras to the lowest resolutions achievable by any modern clinical SPECT camera.

The objective of this work was to investigate if geometry and texture-based metrics contain brain disease-related information similar to measures typically derived from kinetic modeling- based approaches. Using co-registered PET and MRI images from an ongoing Parkinson's disease imaging study, the shape, size and texture of the striatal regions containing high tracer concentration were estimated, and regressed against the subject's disease duration. A novel inter-modality region fusion method was used for a systematic metric characterization and evaluation. It was established that several regional measures such as the region volume, surface area, moment invariants, and others were very good predictors of the clinical disease duration. Interestingly, some metrics revealed good correlation with the disease duration only when evaluated on the fused inter-modality PET-MRI regions. These results demonstrate that geometric features that do not rely on kinetic modeling may be used for disease characterization.

Objective: In this prospective cohort study, we investigated cerebral glucose metabolism reductions on [ 18 F]-fluorodeoxyglucose (FDG)-PET in progranulin ( GRN ) mutation carriers prior to frontotemporal dementia (FTD) onset. Methods: Nine mutation carriers (age 51.5 ± 13.5 years) and 11 noncarriers (age 52.7 ± 9.5 years) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI and clinical evaluation. Normalized FDG uptake values were calculated with reference to the pons. PET images were analyzed with regions of interest (ROI) and statistical parametric mapping (SPM) approaches. Results: Compared with noncarriers, GRN mutation carriers had a lowered anterior-to-posterior (AP) ratio of FDG uptake (0.86 ± 0.09 vs 0.92 ± 0.05) and less left-right asymmetry, consistent with an overall pattern of right anterior cerebral hypometabolism. This pattern was observed regardless of whether they were deemed clinically symptomatic no dementia or asymptomatic. Individual ROIs with lowered FDG uptake included right anterior cingulate, insula, and gyrus rectus. SPM analysis supported and extended these findings, demonstrating abnormalities in the right and left medial frontal regions, right insular cortex, right precentral and middle frontal gyri, and right cerebellum. Right AP ratio was correlated with cognitive and clinical scores (modified Mini-Mental State Examination r = 0.74; Functional Rating Scale r = −0.73) but not age and years to estimated onset in mutation carriers. Conclusion: The frontotemporal lobar degenerative process associated with GRN mutations appears to begin many years prior to the average age at FTD onset (late 50s–early 60s). Right medial and ventral frontal cortex and insula may be affected in this process but the specific regional patterns associated with specific clinical variants remain to be elucidated.

Kinetic parameter estimation at the individual voxel level has the powerful ability to represent both spatial distributions and quantitative physiological parameters of interest. In practice, parametric images are commonly quantified by computing mean values for specified ROIs. Nonetheless, the mean operator vastly oversimplifies the available spatial uptake information. It may be hypothesized that a given tracer will exhibit increasingly differential or heterogeneous uptake due to disease: subsequently, we have implemented and explored a comprehensive texture and shape analysis framework wherein extensive information is generated from parametric PET images, through: (1) 3D moment invariants analysis, (2) intensity histogram analysis, (3) gray-level spatial-dependence (GLSD) analysis, and (4) neighborhood gray tone difference (NGTD) analysis. In the present work, we applied this approach to imaging of 11C-DPA-713, a novel PET ligand with high binding to the translocator protein (TSPO), a marker of neuroinflammation. In particular, for tracers such as DPA with relatively wide-spread uptake, where a reliable reference tissue does not exist, quantification of heterogeneity may provide additional valuable information. Our center has been the first to perform DPA PET studies in humans, and is gathering a large collection of PET studies; e.g. subjects with systemic lupus erythematosus (SLE), traumatic brain injury (TBI; former NFL players), along with young and elderly controls. Our preliminary analysis has revealed that, compared to conventional mean ROI analysis, a number of metrics in the proposed framework yield enhanced discrimination (as measured using AVC) between patients vs. controls in a range of ROIs, in TBI as well as SLE vs. controls, consistent with increased heterogeneity of uptake with disease, though in the case of SLE this can be, at least partly, attributed to changes in ROI shapes. Overall, the proposed framework has the potential to bring about a new quantification paradigm in parametric imaging.

Different imaging modalities sample different properties of the tissue, and thus the tissue may appear different depending on the imaging technique. As a consequence, the shapes of organs and homogenous regions in tissues often have different shapes depending on the type of imaging. This presents a problem for ROI-based multi-modality quantitative imaging studies, since it is not clear what modality should be used for data segmentation. An example of such study is the quantitative PET imaging of Parkinson's disease subjects, which often present functional atrophy without an anatomical atrophy. A choice must be made between anatomical (MRI) and radioactivity-based (PET) ROIs. In addition manual ROI placement can be very time consuming and may lack consistency. In this work, we propose a new approach to multi-modality image segmentation. The proposed method generates so-called mixed ROIs that can be computed in a fully automated mode from single modality-based pure ROIs. The computation of the mixed ROIs is based on the fusion of probability images. The use of the fusion principles made it possible to transition between the pure ROI shapes in a smooth fashion. The mixed ROIs were found to be better aligned with the high activity regions than the pure MR ROIs, and had higher anatomical fidelity compared to the pure PET ROIs. Using the method, it is possible to generate a multitude of ROI sets for a particular study starting from one or more previously defined regions.

We present an analysis of high-precision pulsar timing data taken as part of the North American Nanohertz Observatory for Gravitational waves (NANOGrav) project. We have observed 17 pulsars for a span of roughly five years using the Green Bank and Arecibo radio telescopes. We analyze these data using standard pulsar timing models, with the addition of time-variable dispersion measure and frequency-variable pulse shape terms. Sub-microsecond timing residuals are obtained in nearly all cases, and the best root-mean-square timing residuals in this set are ~30-50 ns. We present methods for analyzing post-fit timing residuals for the presence of a gravitational wave signal with a specified spectral shape. These optimally take into account the timing fluctuation power removed by the model fit, and can be applied to either data from a single pulsar, or to a set of pulsars to detect a correlated signal. We apply these methods to our dataset to set an upper limit on the strength of the nHz-frequency stochastic supermassive black hole gravitational wave background of h_c (1 yr^-1) < 7x10^-15 (95%). This result is dominated by the timing of the two best pulsars in the set, PSRs J1713+0747 and J1909-3744., To be submitted to ApJ

The International Pulsar Timing Array project combines observations of pulsars from both Northern and Southern hemisphere observatories with the main aim of detecting ultra-low frequency (~10^-9 to 10^-8 Hz) gravitational waves. Here we introduce the project, review the methods used to search for gravitational waves emitted from coalescing supermassive binary black-hole systems in the centres of merging galaxies and discuss the status of the project., accepted by Classical and Quantum Gravity. Review talk for the Amaldi8 conference series

We present spatially resolved spectroscopy of the supernova remnant (SNR) G292.0+1.8 with the Chandra X-ray observatory. This SNR contains the 135 ms pulsar, J1124-5916. We apply non-equilibrium ionization (NEI) models to the data. By comparing the derived abundances with those predicted from nucleosynthesis models, we estimate a progenitor mass of 30-40 solar masses. We also derive the intrinsic parameters of the supernova explosion such as its energy, the age of the SNR, the blast wave velocity, and the swept-up mass. In the Sedov interpretation, our estimated SNR age of 2,600 years is close to the pulsar's characteristic age of 2,900 years. This confirms the pulsar/SNR association and relaxes the need for the pulsar to have a non-canonical value for the braking index, a large period at birth or a large transverse velocity. We discuss the properties of the pulsar wind nebula (PWN) in the light of the Kennel and Coroniti model and estimate the pulsar wind magnetization parameter. We also report the first evidence for steepening of the power law spectral index with increasing radius from the pulsar., Comment: 5 pages, 3 figures. To appear in ApJL, Feb 1 2003 (submitted Oct 9 2002, accepted Dec 19 2002)

High-magnetic-field radio pulsars are important transition objects for understanding the connection between magnetars and conventional radio pulsars. We present a detailed study of the young radio pulsar J1119-6127, which has a characteristic age of 1900yr and a spin-down-inferred magnetic field of 4.1e13G, and its associated supernova remnant G292.2-0.5, using deep XMM-Newton and Chandra X-ray Observatory exposures of over 120ks from each telescope. The pulsar emission shows strong modulation below 2.5keV, with a single-peaked profile and a large pulsed fraction of 0.48+/-0.12. Employing a magnetic, partially ionized hydrogen atmosphere model, we find that the observed pulse profile can be produced by a single hot spot of temperature 0.13keV covering about one third of the stellar surface, and we place an upper limit of 0.08keV for an antipodal hot spot with the same area. The nonuniform surface temperature distribution could be the result of anisotropic heat conduction under a strong magnetic field, and a single-peaked profile seems common among high-B radio pulsars. For the associated remnant G292.2-0.5, its large diameter could be attributed to fast expansion in a low-density wind cavity, likely formed by a Wolf-Rayet progenitor, similar to two other high-B radio pulsars., Comment: 11 pages, 4 figures, accepted for publication in ApJ

We present the first detailed imaging and spatially resolved spectroscopic study of the Galactic supernova remnant G292.2-0.5, associated with the high-magnetic field radio pulsar J1119-6127, using Chandra and XMM-Newton. The high-resolution X-ray images reveal a partially limb-brightened morphology in the west, with diffuse emission concentrated towards the interior of the remnant unlike the complete shell-like morphology observed at radio wavelengths. The spectra of most of the diffuse emission regions within the remnant are best described by a thermal+non-thermal model. The thermal component is described by a plane-parallel, non-equilibrium ionization plasma model with a temperature ranging from 1.3 keV in the western side of the remnant to 2.3 keV in the east, a column density increasing from 1.0e22 cm^-2 in the west to 1.8e22 cm^-2 in the east, and a low ionization timescale ranging from 5.7e9 cm^-3 s in the SNR interior to 3.6e10 cm^-3 s in the western side - suggestive of expansion of a young remnant in a low-density medium. The spatial and spectral differences across the SNR are consistent with the presence of a dark cloud in the eastern part of the SNR, absorbing the soft X-ray emission. The spectra from some of the regions also show slightly enhanced metal abundances from Ne, Mg and Si, hinting at the first evidence for ejecta heated by the reverse shock. Comparing our inferred metal abundances to core-collapse nucleosynthesis models yields, we estimate a high progenitor mass of ~30 solar mass suggesting a type Ib/c supernova. We confirm the presence of non-thermal hard X-ray emission from regions close to the pulsar. We estimate an SNR age range between 4.2 kyr (free expansion phase) and 7.1 kyr (Sedov phase), a factor of a few higher than the measured pulsar's age upper limit of 1.9 kyr., 17 pages, 7 figures, 4 tables; Abstract abridged. Accepted for publication in the Astrophysical Journal

Purpose: We propose to characterize the spatial distribution of PET‐derived voxel statistics within anatomically‐defined Regions Of Interest (ROIs) as a means to characterize disease‐related changes. Methods: We used 3D moment invariants (3DMIs) to characterize the spatial distribution of PET data ([11C]Raclopride, [11C]Tetrabenazine and [18F]Fluorodopa) recorded from subjects with Parkinson's Disease (PD) and healthy controls. 3DMIs are mathematical spatial descriptors designed to be invariant to scaling, translation and rotation. In fMRI studies, assessing the spatialcharacteristics of voxel‐based statistics has recently been shown to utilized be a powerful and sensitive method to characterize brain activation. Crucially, this allows characterization of the spatialcharacteristics of activation without the need to warp brainimages to a common brain template. Analogously, we propose characterizing the spatial distribution of PET‐derived voxel statistics within anatomically‐defined ROIs using 3DMIs. The 3DMIs used here were a combination of terms describing spatial variance, skewness and kurtosis. Subjects also underwent MRI scans so that the T1‐weighted MRI data could be used to anatomically delineate basal ganglia ROIs to act as binary masks on the PET data. Results: 3DMIs were found to accurately describe the “3D texture” of PETimages despite changes in the size and orientation of these regions across subjects. In addition, we were able to find differences in the 3DMIs of PD patients distinct from those of healthy volunteers. These changes suggest that disease‐related variations in the spatial distribution measured using PET can be quantitatively described with the proposed method Conclusions: This method shows great promise to extract additional information from PET data with a wealth of potential applications to disease diagnosis, staging, treatment assessment and more. The quantification of the observed disease‐related changes for PD subjects is currently under way.

We report on an effort to extract and monitor interstellar scintillation parameters in regular timing observations collected for the NANOGrav pulsar timing array. Scattering delays are measured by creating dynamic spectra for each pulsar and observing epoch of wide-band observations centered near 1500 MHz and carried out at the Green Bank Telescope and the Arecibo Observatory. The ~800-MHz wide frequency bands imply dramatic changes in scintillation bandwidth across the bandpass, and a stretching routine has been included to account for this scaling. For most of the 10 pulsars for which the scaling has been measured, the bandwidths scale with frequency less steeply than expected for a Kolmogorov medium. We find estimated scattering delay values that vary with time by up to an order of magnitude. The mean measured scattering delays are similar to previously published values and slightly higher than predicted by interstellar medium models. We investigate the possibility of increasing the timing precision by mitigating timing errors introduced by the scattering delays. For most of the pulsars, the uncertainty in the time of arrival of a single timing point is much larger than the maximum variation of the scattering delay, suggesting that diffractive scintillation remains only a negligible part of their noise budget., 14 pages, 5 figures, 3 tables. Accepted for publication in ApJ