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OBJECTIVE: The mediating neuroanatomy of human appetitive function is poorly understood. A state induction paradigm was employed, in conjunction with positron emission tomography, to test the hypothesis that limbic/paralimbic regions respond to the desirability of food stimuli. METHODS: Eight normal subjects were studied during each of three conditions, involving visual exposure to high-caloric food, low-caloric food, and nonfood stimuli. Subjective indices of hunger were measured via analog scales. RESULTS: Planned contrasts demonstrated significant increases in desire to eat and decreases in left temporoinsular cortical blood flow during the high-caloric versus control conditions. DISCUSSION: Results implicate the temporo-insular cortex in normal appetitive function, suggesting that activity within this region is associated with the desirability or valence of food stimuli, prior to ingestion. These data will provide a broad foundation for future studies of patients with eating disorders. Copyright 2000 by John Wiley Sons, Inc. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction plays a key role in doxorubicin-induced cardiotoxicity (DIC). In this proof-of-principle study, we investigated whether PET mapping of cardiac membrane potential, an indicator of mitochondrial function, could detect an acute cardiotoxic effect of doxorubicin (DOX) in a large animal model. Eight Yucatan pigs were imaged dynamically with [ 18 F](4-Fluorophenyl)triphenylphosphonium ([ 18 F]FTPP + ) PET/CT. Our experimental protocol included a control saline infusion into the left anterior descending coronary artery (LAD) followed by a DOX test infusion of either 1 mg/kg or 2 mg/kg during PET. We measured the change in total cardiac membrane potential (ΔΨ T ), a proxy for the mitochondrial membrane potential, ΔΨ m , after the saline and DOX infusions. We observed a partial depolarization of the mitochondria following the DOX infusions, which occurred only in myocardial areas distal to the intracoronary catheter, thereby demonstrating a direct association between the exposure of the mitochondria to DOX and a change in ΔΨ T . Furthermore, doubling the DOX dose caused a more severe depolarization of myocardium in the LAD territory distal to the infusion catheter. In conclusion, [ 18 F]FTPP + PET-based ΔΨ T mapping can measure partial depolarization of myocardial mitochondria following intracoronary DOX infusion in a large animal model., (© 2022. The Author(s).)

Purpose of Review: To present a method enabling in vivo quantification of tissue membrane potential (ΔΨ T ), a proxy of mitochondrial membrane potential (ΔΨ m ), to review the origin and role of ΔΨ m , and to highlight potential applications of myocardial ΔΨ T imaging., Recent Findings: Radiolabelled lipophilic cations have been used for decades to measure ΔΨ m in vitro. Using similar compounds labeled with positron emitters and appropriate compartment modeling, this technique now allows in vivo quantification of ΔΨ T with positron emission tomography. Studies have confirmed the feasibility of measuring myocardial ΔΨ T in both animals and humans. In addition, ΔΨ T showed very low variability among healthy subjects, suggesting that this method could allow detection of relatively small pathological changes. In vivo assessment of myocardial ΔΨ T provides a new tool to study the pathophysiology of cardiovascular diseases and has the potential to serve as a new biomarker to assess disease stage, prognosis, and response to therapy.

Purpose: Alteration in mitochondrial membrane potential (ΔΨ m ) is an important feature of many pathologic processes, including heart failure, cardiotoxicity, ventricular arrhythmia, and myocardial hypertrophy. We present the first in vivo, non-invasive, assessment of regional ΔΨ m in the myocardium of normal human subjects., Methods: Thirteen healthy subjects were imaged using [ 18 F]-triphenylphosphonium ([ 18 F]TPP+) on a PET/MR scanner. The imaging protocol consisted of a bolus injection of 300 MBq followed by a 120-min infusion of 0.6 MBq/min. A 60 min, dynamic PET acquisition was started 1 h after bolus injection. The extracellular space fraction (f ECS ) was simultaneously measured using MR T1-mapping images acquired at baseline and 15 min after gadolinium injection with correction for the subject's hematocrit level. Serial venous blood samples were obtained to calculate the plasma tracer concentration. The tissue membrane potential (ΔΨ T ), a proxy of ΔΨ m , was calculated from the myocardial tracer concentration at secular equilibrium, blood concentration, and fECS measurements using a model based on the Nernst equation., Results: In 13 healthy subjects, average tissue membrane potential (ΔΨ T ), representing the sum of cellular membrane potential (ΔΨ c ) and ΔΨ m , was - 160.7 ± 3.7 mV, in excellent agreement with previous in vitro assessment., Conclusion: In vivo quantification of the mitochondrial function has the potential to provide new diagnostic and prognostic information for several cardiac diseases as well as allowing therapy monitoring. This feasibility study lays the foundation for further investigations to assess these potential roles. Clinical trial identifier: NCT03265431.

Receptor ligand-based dynamic Positron Emission Tomography (PET) permits the measurement of neurotransmitter release in the human brain. For single-scan paradigms, the conventional method of estimating changes in neurotransmitter levels relies on fitting a pharmacokinetic model to activity concentration histories extracted after PET image reconstruction. However, due to the statistical fluctuations of activity concentration data at the voxel scale, parametric images computed using this approach often exhibit low signal-to-noise ratio, impeding characterization of neurotransmitter release. Numerous studies have shown that direct parametric reconstruction (DPR) approaches, which combine image reconstruction and kinetic analysis in a unified framework, can improve the signal-to-noise ratio of parametric mapping. However, there is little experience with DPR in imaging of neurotransmission and the performance of the approach in this application has not been evaluated before in humans. In this report, we present and evaluate a DPR methodology that computes 3-D distributions of ligand transport, binding potential (BP ND ) and neurotransmitter release magnitude (γ) from a dynamic sequence of PET sinograms. The technique employs the linear simplified reference region model (LSRRM) of Alpert et al. (2003), which represents an extension of the simplified reference region model that incorporates time-varying binding parameters due to radioligand displacement by release of neurotransmitter. Estimation of parametric images is performed by gradient-based optimization of a Poisson log-likelihood function incorporating LSRRM kinetics and accounting for the effects of head movement, attenuation, detector sensitivity, random and scattered coincidences. A 11 C-raclopride simulation study showed that the proposed approach substantially reduces the bias and variance of voxel-wise γ estimates as compared to standard methods. Moreover, simulations showed that detection of release could be made more reliable and/or conducted using a smaller sample size using the proposed DPR estimator. Likewise, images of BP ND computed using DPR had substantially improved bias and variance properties. Application of the method in human subjects was demonstrated using 11 C-raclopride dynamic scans and a reward task, confirming the improved quality of the estimated parametric images using the proposed approach., Competing Interests: Declaration of competing interest Over the past three years, D.A.P has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, and Takeda and an honorarium from Alkernes, for activities unrelated to the current paper. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. All other authors report no biomedical financial interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We recently reported a method using positron emission tomography (PET) and the tracer 18 F-labeled tetraphenylphosphonium ( 18 F-TPP + ) for mapping the tissue (i.e., cellular plus mitochondrial) membrane potential (ΔΨ T ) in the myocardium. The purpose of this work is to provide additional experimental evidence that our methods can be used to observe transient changes in the volume of distribution for 18 F-TPP + and mitochondrial membrane potential (ΔΨ m )., Methods: We tested these hypotheses by measuring decreases of 18 F-TPP + concentration elicited when a proton gradient uncoupler, BAM15, is administered by intracoronary infusion during PET scanning. BAM15 is the first proton gradient uncoupler shown to affect the mitochondrial membrane without affecting the cellular membrane potential. Preliminary dose response experiments were conducted in two pigs to determine the concentration of BAM15 infusate necessary to perturb the 18 F-TPP + concentration. More definitive experiments were performed in two additional pigs, in which we administered an intravenous bolus plus infusion of 18 F-TPP + to reach secular equilibrium followed by an intracoronary infusion of BAM15., Results: Intracoronary BAM15 infusion led to a clear decrease in 18 F-TPP + concentration, falling to a lower level, and then recovering. A second BAM15 infusion reduced the 18 F-TPP + level in a similar fashion. We observed a maximum depolarization of 10 mV as a result of the BAM15 infusion., Summary: This work provides evidence that the total membrane potential measured with 18 F-TPP + PET is sensitive to temporal changes in mitochondrial membrane potential., (Copyright © 2020 Alpert, Pelletier-Galarneau, Kim, Petibon, Sun, Ramos-Torres, Normandin and El Fakhri.)

Background: We previously proposed a technique for quantitative measurement of rest and stress absolute myocardial blood flow (MBF) using a 2-injection single-scan imaging session. Recently, we validated the method in a pig model for the long-lived radiotracer 18 F-Flurpiridaz with adenosine as a pharmacological stressor. The aim of the present work is to validate our technique for 13 NH 3 ., Methods: Nine studies were performed in 6 pigs; 5 studies were done in the native state and 4 after infarction of the left anterior descending artery. Each study consisted of 3 dynamic scans: a 2-injection rest-rest single-scan acquisition (scan A), a 2-injection rest/stress single-scan acquisition (scan B), and a conventional 1-injection stress acquisition (scan C). Variable doses of adenosine combined with dobutamine were administered to induce a wide range of MBF. The 2-injection single-scan measurements were fitted with our nonstationary kinetic model (MGH2). In 4 studies, 13 NH 3 injections were paired with microsphere injections. MBF estimates obtained with our method were compared with those obtained with the standard method and with microspheres. We used a model-based method to generate separate rest and stress perfusion images., Results: In the absence of stress (scan A), the MBF values estimated by MGH2 were nearly the same for the 2-radiotracer injections (mean difference: 0.067±0.070 mL·min -1 ·cc -1 , limits of agreement: [-0.070 to 0.204] mL·min -1 ·cc -1 ), showing good repeatability. Bland-Altman analyses demonstrated very good agreement with the conventional method for both rest (mean difference: -0.034±0.035 mL·min -1 ·cc -1 , limits of agreement: [-0.103 to 0.035] mL·min -1 ·cc -1 ) and stress (mean difference: 0.057±0.361 mL·min -1 ·cc -1 , limits of agreement: [-0.651 to 0.765] mL·min -1 ·cc -1 ) MBF measurements. Positron emission tomography and microsphere MBF measurements correlated closely. Very good quality perfusion images were obtained., Conclusions: This study provides in vivo validation of our single-scan rest-stress method for 13 NH 3 measurements. The 13 NH 3 rest/stress myocardial perfusion imaging procedure can be compressed into a single positron emission tomography scan session lasting less than 15 minutes.

Purpose: Patient body motion during a cardiac positron emission tomography (PET) scan can severely degrade image quality. We propose and evaluate a novel method to detect, estimate, and correct body motion in cardiac PET., Methods: Our method consists of three key components: motion detection, motion estimation, and motion-compensated image reconstruction. For motion detection, we first divide PET list-mode data into 1-s bins and compute the center of mass (COM) of the coincidences' distribution in each bin. We then compute the covariance matrix within a 25-s sliding window over the COM signals inside the window. The sum of the eigenvalues of the covariance matrix is used to separate the list-mode data into "static" (i.e., body motion free) and "moving" (i.e. contaminated by body motion) frames. Each moving frame is further divided into a number of evenly spaced sub-frames (referred to as "sub-moving" frames), in which motion is assumed to be negligible. For motion estimation, we first reconstruct the data in each static and sub-moving frame using a rapid back-projection technique. We then select the longest static frame as the reference frame and estimate elastic motion transformations to the reference frame from all other static and sub-moving frames using nonrigid registration. For motion-compensated image reconstruction, we reconstruct all the list-mode data into a single image volume in the reference frame by incorporating the estimated motion transformations in the PET system matrix. We evaluated the performance of our approach in both phantom and human studies., Results: Visually, the motion-corrected (MC) PET images obtained using the proposed method have better quality and fewer motion artifacts than the images reconstructed without motion correction (NMC). Quantitative analysis indicates that MC yields higher myocardium to blood pool concentration ratios. MC also yields sharper myocardium than NMC., Conclusions: The proposed body motion correction method improves image quality of cardiac PET., (© 2019 American Association of Physicists in Medicine.)

Prior studies have shown that dopamine (DA) functioning in frontostriatal circuits supports reinforcement learning (RL), as phasic DA activity in ventral striatum signals unexpected reward and may drive coordinated activity of striatal and orbitofrontal regions that support updating of action plans. However, the nature of DA functioning in RL is complex, in particular regarding the role of DA clearance in RL behavior. Here, in a multi-modal neuroimaging study with healthy adults, we took an individual differences approach to the examination of RL behavior and DA clearance mechanisms in frontostriatal learning networks. We predicted that better RL would be associated with decreased striatal DA transporter (DAT) availability and increased intrinsic functional connectivity among DA-rich frontostriatal regions. In support of these predictions, individual differences in RL behavior were related to DAT binding potential in ventral striatum and resting-state functional connectivity between ventral striatum and orbitofrontal cortex. Critically, DAT binding potential had an indirect effect on reinforcement learning behavior through frontostriatal connectivity, suggesting potential causal relationships across levels of neurocognitive functioning. These data suggest that individual differences in DA clearance and frontostriatal coordination may serve as markers for RL, and suggest directions for research on psychopathologies characterized by altered RL.

Background: Mitochondrial membrane potential (ΔΨm) arises from normal function of the electron transport chain. Maintenance of ΔΨm within a narrow range is essential for mitochondrial function. Methods for in vivo measurement of ΔΨm do not exist. We use 18F-labeled tetraphenylphosphonium (18F-TPP+) to measure and map the total membrane potential, ΔΨT, as the sum of ΔΨm and cellular (ΔΨc) electrical potentials., Methods: Eight pigs, five controls and three with a scar-like injury, were studied. Pigs were studied with a dynamic PET scanning protocol to measure 18F-TPP+ volume of distribution, VT. Fractional extracellular space (fECS) was measured in 3 pigs. We derived equations expressing ΔΨT as a function of VT and the volume-fractions of mitochondria and fECS. Seventeen segment polar maps and parametric images of ΔΨT were calculated in millivolts (mV)., Results: In controls, mean segmental ΔΨT = -129.4±1.4 mV (SEM). In pigs with segmental tissue injury, ΔΨT was clearly separated from control segments but variable, in the range -100 to 0 mV. The quality of ΔΨT maps was excellent, with low noise and good resolution. Measurements of ΔΨT in the left ventricle of pigs agree with previous in in-vitro measurements., Conclusions: We have analyzed the factors affecting the uptake of voltage sensing tracers and developed a minimally invasive method for mapping ΔΨT in left ventricular myocardium of pigs. ΔΨT is computed in absolute units, allowing for visual and statistical comparison of individual values with normative data. These studies demonstrate the first in vivo application of quantitative mapping of total tissue membrane potential, ΔΨT.

Purpose: We have recently reported a method for measuring rest-stress myocardial blood flow (MBF) using a single, relatively short, PET scan session. The method requires two IV tracer injections, one to initiate rest imaging and one at peak stress. We previously validated absolute flow quantitation in ml/min/cc for standard bull's eye, segmental analysis. In this work, we extend the method for fast computation of rest-stress MBF parametric images., Methods: We provide an analytic solution to the single-scan rest-stress flow model which is then solved using a two-dimensional table lookup method (LM). Simulations were performed to compare the accuracy and precision of the lookup method with the original nonlinear method (NLM). Then the method was applied to 16 single scan rest/stress measurements made in 12 pigs: seven studied after infarction of the left anterior descending artery (LAD) territory, and nine imaged in the native state. Parametric maps of rest and stress MBF as well as maps of left (f LV ) and right (f RV ) ventricular spill-over fractions were generated. Regions of interest (ROIs) for 17 myocardial segments were defined in bull's eye fashion on the parametric maps. The mean of each ROI was then compared to the rest (K 1r ) and stress (K 1s ) MBF estimates obtained from fitting the 17 regional TACs with the NLM., Results: In simulation, the LM performed as well as the NLM in terms of precision and accuracy. The simulation did not show that bias was introduced by the use of a predefined two-dimensional lookup table. In experimental data, parametric maps demonstrated good statistical quality and the LM was computationally much more efficient than the original NLM. Very good agreement was obtained between the mean MBF calculated on the parametric maps for each of the 17 ROIs and the regional MBF values estimated by the NLM (K 1map LM  = 1.019 × K 1 ROI NLM  + 0.019, R 2  = 0.986; mean difference = 0.034 ± 0.036 mL/min/cc)., Conclusions: We developed a table lookup method for fast computation of parametric imaging of rest and stress MBF. Our results show the feasibility of obtaining good quality MBF maps using modest computational resources, thus demonstrating that the method can be applied in a clinical environment to obtain full quantitative MBF information., (© 2017 American Association of Physicists in Medicine.)

Purpose: 18 F-labeled myocardial flow agents are becoming available for clinical application but the ∼2 hour half-life of 18 F complicates their clinical application for rest-stress measurements. The goal of this work is to evaluate in a pig model a single-scan method which provides quantitative rest-stress blood flow in less than 15 minutes., Methods: Single-scan rest-stress measurements were made using 18 F-Flurpiridaz. Nine scans were performed in healthy pigs and seven scans were performed in injured pigs. A two-injection, single-scan protocol was used in which an adenosine infusion was started 4 minutes after the first injection of 18 F-Flurpiridaz and followed either 3 or 6 minutes later by a second radiotracer injection. In two pigs, microsphere flow measurements were made at rest and during stress. Dynamic images were reoriented into the short axis view, and regions of interest (ROIs) for the 17 myocardial segments were defined in bull's eye fashion. PET data were fitted with MGH2, a kinetic model with time varying kinetic parameters, in which blood flow changes abruptly with the introduction of adenosine. Rest and stress myocardial blood flow (MBF) were estimated simultaneously., Results: The first 12-14 minutes of rest-stress PET data were fitted in detail by the MGH2 model, yielding MBF measurement with a mean precision of 0.035 ml/min/cc. Mean myocardial blood flow across pigs was 0.61 ± 0.11 mL/min/cc at rest and 1.06 ± 0.19 mL/min/cc at stress in healthy pigs and 0.36 ± 0.20 mL/min/cc at rest and 0.62 ± 0.24 mL/min/cc at stress in the ischemic area. Good agreement was obtained with microsphere flow measurement (slope = 1.061 ± 0.017, intercept = 0.051 ± 0.017, mean difference 0.096 ± 0.18 ml/min/cc)., Conclusion: Accurate rest and stress blood flow estimation can be obtained in less than 15 min of PET acquisition. The method is practical and easy to implement suggesting the possibility of clinical translation.

PET is an established modality for myocardial perfusion imaging (MPI) which enables quantification of absolute myocardial blood flow (MBF) using dynamic imaging and kinetic modeling. However, heart motion and partial volume effects (PVE) significantly limit the spatial resolution and quantitative accuracy of PET MPI. Simultaneous PET-MR offers a solution to the motion problem in PET by enabling MR-based motion correction of PET data. The aim of this study was to develop a motion and PVE correction methodology for PET MPI using simultaneous PET-MR, and to assess its impact on both static and dynamic PET MPI using 18 F-Flurpiridaz, a novel 18 F-labeled perfusion tracer. Two dynamic 18 F-Flurpiridaz MPI scans were performed on healthy pigs using a PET-MR scanner. Cardiac motion was tracked using a dedicated tagged-MRI (tMR) sequence. Motion fields were estimated using non-rigid registration of tMR images and used to calculate motion-dependent attenuation maps. Motion correction of PET data was achieved by incorporating tMR-based motion fields and motion-dependent attenuation coefficients into image reconstruction. Dynamic and static PET datasets were created for each scan. Each dataset was reconstructed as (i) Ungated, (ii) Gated (end-diastolic phase), and (iii) Motion-Corrected (MoCo), each without and with point spread function (PSF) modeling for PVE correction. Myocardium-to-blood concentration ratios (MBR) and apparent wall thickness were calculated to assess image quality for static MPI. For dynamic MPI, segment- and voxel-wise MBF values were estimated by non-linear fitting of a 2-tissue compartment model to tissue time-activity-curves. MoCo and Gating respectively decreased mean apparent wall thickness by 15.1% and 14.4% and increased MBR by 20.3% and 13.6% compared to Ungated images (P  <  0.01). Combined motion and PSF correction (MoCo-PSF) yielded 30.9% (15.7%) lower wall thickness and 82.2% (20.5%) higher MBR compared to Ungated data reconstructed without (with) PSF modeling (P  <  0.01). For dynamic PET, mean MBF across all segments were comparable for MoCo (0.72  ±  0.21 ml/min/ml) and Gating (0.69  ±  0.18 ml/min/ml). Ungated data yielded significantly lower mean MBF (0.59  ±  0.16 ml/min/ml). Mean MBF for MoCo-PSF was 0.80  ±  0.22 ml/min/ml, which was 37.9% (25.0%) higher than that obtained from Ungated data without (with) PSF correction (P  <  0.01). The developed methodology holds promise to improve the image quality and sensitivity of PET MPI studies performed using PET-MR.

Introduction: Kinetic compartmental analysis is frequently used to compute physiologically relevant quantitative values from time series of images. In this paper, a new approach based on Bayesian analysis to obtain information about these parameters is presented and validated., Materials and Methods: The closed-form of the posterior distribution of kinetic parameters is derived with a hierarchical prior to model the standard deviation of normally distributed noise. Markov chain Monte Carlo methods are used for numerical estimation of the posterior distribution. Computer simulations of the kinetics of F18-fluorodeoxyglucose (FDG) are used to demonstrate drawing statistical inferences about kinetic parameters and to validate the theory and implementation. Additionally, point estimates of kinetic parameters and covariance of those estimates are determined using the classical non-linear least squares approach., Results and Discussion: Posteriors obtained using methods proposed in this work are accurate as no significant deviation from the expected shape of the posterior was found (one-sided P>0.08). It is demonstrated that the results obtained by the standard non-linear least-square methods fail to provide accurate estimation of uncertainty for the same data set (P<0.0001)., Conclusions: The results of this work validate new methods for a computer simulations of FDG kinetics. Results show that in situations where the classical approach fails in accurate estimation of uncertainty, Bayesian estimation provides an accurate information about the uncertainties in the parameters. Although a particular example of FDG kinetics was used in the paper, the methods can be extended for different pharmaceuticals and imaging modalities., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Unlabelled: The aim of this study was to determine the performance of a novel mobile human brain/small-animal PET/CT system. The scanner has a 35.7-cm-diameter bore and a 22-cm axial extent. The detector ring has 7 modules each with 3 × 4 cerium-doped lutetium yttrium orthosilicate crystal blocks, each consisting of 22 × 22 outer-layer and 21 × 21 inner-layer crystals, each layer 1-cm thick. Light is collected by 12 × 12 silicon photomultipliers. The integrated CT can be used for attenuation correction and anatomic localization. The scanner was designed as a low-cost device that nevertheless produces high-quality PET images with the unique capability of battery-powered propulsion, enabling use in many settings., Methods: Spatial resolution, sensitivity, and noise-equivalent counting rate were measured based on the National Electrical Manufacturers Association NU2-2012 procedures. Reconstruction was done with tight energy and timing cuts-400-650 keV and 7 ns-and loose cuts-350-700 keV and 10 ns. Additional image quality measurements were made from phantom, human, and animal studies. Performance was compared with a reference scanner with comparable imaging properties., Results: The full width at half maximum transverse resolution at a 1-cm (10-cm) radius was 3.2 mm (5.2-mm radial, 3.1-mm tangential), and the axial resolution was 3.5 mm (4.0 mm). A sensitivity of 7.5 and 11.7 kcps/MBq at the center for tight and loose cuts, respectively, increased to 8.8 and 13.9 kcps/MBq, respectively, at a 10-cm radial offset. The maximum noise-equivalent counting rate of 19.5 and 22.7 kcps for tight and loose cuts, respectively, was achieved for an activity concentration of 2.9 kBq/mL. Contrast recovery for 4:1 hot cylinder to warm background was 76% for the 25-mm-diameter cylinder but decreased with decreasing cylinder size. The quantitation agreed within 2% of the known activity distribution and concentration. Brain phantom and human scans have shown agreement in SUVs and image quality with the reference scanner., Conclusion: We characterized the performance of the NeuroPET/CT and showed images from the first human studies. The study shows that this scanner achieves good performance when spatial resolution, sensitivity, counting rate, and image quality along with a low cost and unique mobile capabilities are considered., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: This work was a proof-of-principle study for the evaluation of oxygen-15 ((15)O) production as an imaging target through the use of positron emission tomography (PET), to improve verification of proton treatment plans and to study the effects of perfusion., Methods and Materials: Dynamic PET measurements of irradiation-produced isotopes were made for a phantom and rabbit thigh muscles. The rabbit muscle was irradiated and imaged under both live and dead conditions. A differential equation was fitted to phantom and in vivo data, yielding estimates of (15)O production and clearance rates, which were compared to live versus dead rates for the rabbit and to Monte Carlo predictions., Results: PET clearance rates agreed with decay constants of the dominant radionuclide species in 3 different phantom materials. In 2 oxygen-rich materials, the ratio of (15)O production rates agreed with the expected ratio. In the dead rabbit thighs, the dynamic PET concentration histories were accurately described using (15)O decay constant, whereas the live thigh activity decayed faster. Most importantly, the (15)O production rates agreed within 2% (P>.5) between conditions., Conclusions: We developed a new method for quantitative measurement of (15)O production and clearance rates in the period immediately following proton therapy. Measurements in the phantom and rabbits were well described in terms of (15)O production and clearance rates, plus a correction for other isotopes. These proof-of-principle results support the feasibility of detailed verification of proton therapy treatment delivery. In addition, (15)O clearance rates may be useful in monitoring permeability changes due to therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: With single-photon emission computed tomography, simultaneous imaging of two physiological processes relies on discrimination of the energy of the emitted gamma rays, whereas the application of dual-tracer imaging to positron emission tomography (PET) imaging has been limited by the characteristic 511-keV emissions., Procedures: To address this limitation, we developed a novel approach based on generalized factor analysis of dynamic sequences (GFADS) that exploits spatio-temporal differences between radiotracers and applied it to near-simultaneous imaging of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) (brain metabolism) and (11)C-raclopride (D2) with simulated human data and experimental rhesus monkey data. We show theoretically and verify by simulation and measurement that GFADS can separate FDG and raclopride measurements that are made nearly simultaneously., Results: The theoretical development shows that GFADS can decompose the studies at several levels: (1) It decomposes the FDG and raclopride study so that they can be analyzed as though they were obtained separately. (2) If additional physiologic/anatomic constraints can be imposed, further decomposition is possible. (3) For the example of raclopride, specific and nonspecific binding can be determined on a pixel-by-pixel basis. We found good agreement between the estimated GFADS factors and the simulated ground truth time activity curves (TACs), and between the GFADS factor images and the corresponding ground truth activity distributions with errors less than 7.3 ± 1.3 %. Biases in estimation of specific D2 binding and relative metabolism activity were within 5.9 ± 3.6 % compared to the ground truth values. We also evaluated our approach in simultaneous dual-isotope brain PET studies in a rhesus monkey and obtained accuracy of better than 6 % in a mid-striatal volume, for striatal activity estimation., Conclusions: Dynamic image sequences acquired following near-simultaneous injection of two PET radiopharmaceuticals can be separated into components based on the differences in the kinetics, provided their kinetic behaviors are distinct.

Purpose: Our research goal is to develop an algorithm to reconstruct cardiac positron emission tomography (PET) kinetic parametric images directly from sinograms and compare its performance with the conventional indirect approach., Methods: Time activity curves of a NCAT phantom were computed according to a one-tissue compartmental kinetic model with realistic kinetic parameters. The sinograms at each time frame were simulated using the activity distribution for the time frame. The authors reconstructed the parametric images directly from the sinograms by optimizing a cost function, which included the Poisson log-likelihood and a spatial regularization terms, using the preconditioned conjugate gradient (PCG) algorithm with the proposed preconditioner. The proposed preconditioner is a diagonal matrix whose diagonal entries are the ratio of the parameter and the sensitivity of the radioactivity associated with parameter. The authors compared the reconstructed parametric images using the direct approach with those reconstructed using the conventional indirect approach., Results: At the same bias, the direct approach yielded significant relative reduction in standard deviation by 12%-29% and 32%-70% for 50 × 10(6) and 10 × 10(6) detected coincidences counts, respectively. Also, the PCG method effectively reached a constant value after only 10 iterations (with numerical convergence achieved after 40-50 iterations), while more than 500 iterations were needed for CG., Conclusions: The authors have developed a novel approach based on the PCG algorithm to directly reconstruct cardiac PET parametric images from sinograms, and yield better estimation of kinetic parameters than the conventional indirect approach, i.e., curve fitting of reconstructed images. The PCG method increases the convergence rate of reconstruction significantly as compared to the conventional CG method.

This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine's effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET (11)C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3 dopamine receptor antagonist [(11)C]raclopride at varying specific activities to anesthetized nonhuman primates, we mapped associations between changes in receptor occupancy and hemodynamics [cerebral blood volume (CBV)] in the domains of space, time, and dose. Mass doses of raclopride above tracer levels caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system with an available PET tracer.

Unlabelled: Respiratory and cardiac motion is the most serious limitation to whole-body PET, resulting in spatial resolution close to 1 cm. Furthermore, motion-induced inconsistencies in the attenuation measurements often lead to significant artifacts in the reconstructed images. Gating can remove motion artifacts at the cost of increased noise. This paper presents an approach to respiratory motion correction using simultaneous PET/MRI to demonstrate initial results in phantoms, rabbits, and nonhuman primates and discusses the prospects for clinical application., Methods: Studies with a deformable phantom, a free-breathing primate, and rabbits implanted with radioactive beads were performed with simultaneous PET/MRI. Motion fields were estimated from concurrently acquired tagged MR images using 2 B-spline nonrigid image registration methods and incorporated into a PET list-mode ordered-subsets expectation maximization algorithm. Using the measured motion fields to transform both the emission data and the attenuation data, we could use all the coincidence data to reconstruct any phase of the respiratory cycle. We compared the resulting SNR and the channelized Hotelling observer (CHO) detection signal-to-noise ratio (SNR) in the motion-corrected reconstruction with the results obtained from standard gating and uncorrected studies., Results: Motion correction virtually eliminated motion blur without reducing SNR, yielding images with SNR comparable to those obtained by gating with 5-8 times longer acquisitions in all studies. The CHO study in dynamic phantoms demonstrated a significant improvement (166%-276%) in lesion detection SNR with MRI-based motion correction as compared with gating (P < 0.001). This improvement was 43%-92% for large motion compared with lesion detection without motion correction (P < 0.001). CHO SNR in the rabbit studies confirmed these results., Conclusion: Tagged MRI motion correction in simultaneous PET/MRI significantly improves lesion detection compared with respiratory gating and no motion correction while reducing radiation dose. In vivo primate and rabbit studies confirmed the improvement in PET image quality and provide the rationale for evaluation in simultaneous whole-body PET/MRI clinical studies.

It has been suggested that Bayesian estimation methods may be used to improve the signal-to-noise ratio of parametric images. However, there is little experience with the method and some of the underlying assumptions and performance properties of Bayesian estimation remain to be investigated. We used a sample population of 54 subjects, studied previously with (11)C-Altropane, to empirically evaluate the assumptions, performance and some practical issues in forming parametric images. By using normality tests, we showed that the underpinning normality assumptions of data and parametric distribution apply to more than 80% of voxels. The standard deviation of the binding potential can be reduced 30-50% using Bayesian estimation, without introducing substantial bias. The sample size required to form the a priori information was found to be modest; as little as ten subjects may be sufficient and the choice of specific subjects has little effect on Bayesian estimation. A realistic simulation study showed that detection of localized differences in parametric images, e.g. by statistical parametric mapping (SPM), could be made more reliable and/or conducted with smaller sample size using Bayesian estimation. In conclusion, Bayesian estimation can improve the SNR of parametric images and better detect localized changes in cohorts of subjects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Neuroimaging research has demonstrated medial prefrontal cortex (mPFC) hyporesponsivity and amygdala hyperresponsivity to trauma-related or emotional stimuli in post-traumatic stress disorder (PTSD). Relatively few studies have examined brain responses to the recollection of stressful, but trauma-unrelated, personal events in PTSD. In the current study, we sought to determine whether regional cerebral blood flow (rCBF) abnormalities in mPFC and amygdala in PTSD could be observed during the recollection of trauma-unrelated stressful personal events., Method: Participants were 35 right-handed male combat veterans (MCVs) and female nurse veterans (FNVs) who served in Vietnam: 17 (seven male, 10 female) with current military-related PTSD and 18 (nine male, nine female) with no current or lifetime PTSD. We used positron emission tomography (PET) and script-driven imagery to study rCBF during the recollection of trauma-unrelated stressful versus neutral and traumatic events., Results: Voxelwise tests revealed significant between-group differences for the trauma-unrelated stressful versus neutral comparison in mPFC, specifically in the anterior cingulate cortex (ACC). Functional region of interest (ROI) analyses demonstrated that this interaction in mPFC represented greater rCBF decreases in the PTSD group during trauma-unrelated stressful imagery relative to neutral imagery compared to the non-PTSD group. No differential amygdala activation was observed between groups or in either group separately., Conclusions: Veterans with PTSD, compared to those without PTSD, exhibited decreased rCBF in mPFC during mental imagery of trauma-unrelated stressful personal experiences. Functional neuroanatomical models of PTSD must account for diminished mPFC responses that extend to emotional stimuli, including stressful personal experiences that are not directly related to PTSD.

Purpose: We propose a novel approach for PET respiratory motion correction using tagged-MRI and simultaneous PET-MRI acquisitions., Methods: We use a tagged-MRI acquisition followed by motion tracking in the phase domain to estimate the nonrigid deformation of biological tissues during breathing. In order to accurately estimate motion even in the presence of noise and susceptibility artifacts, we regularize the traditional HARP tracking strategy using a quadratic roughness penalty on neighboring displacement vectors (R-HARP). We then incorporate the motion fields estimated with R-HARP in the system matrix of an MLEM PET reconstruction algorithm formulated both for sinogram and list-mode data representations. This approach allows reconstruction of all detected coincidences in a single image while modeling the effect of motion both in the emission and the attenuation maps. At present, tagged-MRI does not allow estimation of motion in the lungs and our approach is therefore limited to motion correction in soft tissues. Since it is difficult to assess the accuracy of motion correction approaches in vivo, we evaluated the proposed approach in numerical simulations of simultaneous PET-MRI acquisitions using the NCAT phantom. We also assessed its practical feasibility in PET-MRI acquisitions of a small deformable phantom that mimics the complex deformation pattern of a lung that we imaged on a combined PET-MRI brain scanner., Results: Simulations showed that the R-HARP tracking strategy accurately estimated realistic respiratory motion fields for different levels of noise in the tagged-MRI simulation. In simulations of tumors exhibiting increased uptake, contrast estimation was 20% more accurate with motion correction than without. Signal-to-noise ratio (SNR) was more than 100% greater when performing motion-corrected reconstruction which included all counts, compared to when reconstructing only coincidences detected in the first of eight gated frames. These results were confirmed in our proof-of-principle PET-MRI acquisitions, indicating that our motion correction strategy is accurate, practically feasible, and is therefore ready to be tested in vivo., Conclusions: This work shows that PET motion correction using motion fields measured with tagged-MRI in simultaneous PET-MRI acquisitions can be made practical for clinical application and that doing so has the potential to remove motion blur in whole-body PET studies of the torso.

Involvement of dopamine neurotransmission in human emotional processing is unclear but animal studies have indicated that it is critical for processing of fear response. In this experiment we examined dopaminergic involvement in the processing of human emotions. We used a novel dynamic molecular imaging technique to detect and map dopamine released during presentation of emotional stimuli. The technique exploited the competition between endogenously released dopamine and its ligand for receptor occupancy and involved dynamic voxel-wise measurement of the rate at which a dopamine receptor ligand ((18)F-Fallypride) was displaced from receptor sites during emotional processing. An increase in the rate indicated dopamine release. We found that the rate of ligand displacement increased significantly in the left amygdala, left medial temporal lobe (MTL) and left inferior frontal gyrus. The results provide the first direct evidence of dopaminergic modulation of human emotional processing and suggest that the modulation occurs at multiple levels of processing. This finding indicates that the neurocognitive models of human emotion should take into account dopaminergic effects, and that, there is a need to investigate whether manipulation of the dopaminergic system could be an alternate strategy for treatment of conditions in which emotional processing is impaired.

We report a general method of Bayesian estimation that uses prior measurements to improve the signal-to-noise ratio of parametric images computed from dynamic PET scanning. In our method, the ordinary weighted least squares cost function is augmented by a penalty term to yield Phi(K,S)=minK{(C-f(K))(T)Omega(C)(-1)(C-f(K))+SPhi(K,S=0)(K-K;)(T)Omega(K)(-1)(K-K;)}, where C is a PET concentration history and Omega(C) is its variance, f is the model of the concentration history, K=[k(1),k(2),...,k(m)](T) is the parameter vector, K; is the vector of population means for the model parameters, Omega(K) is its covariance, Phi(K)(K,S=0) is the conventional weighted sum of squares. S>0 is chosen to control the balance between the prior and new data. Data from a prior population of subjects are analyzed with standard methods to provide maps of the mean parameter values and their variances. As an example of this approach we used the dynamic image data of 10 normal subjects who had previously been studied with (11)C-raclopride to estimate the prior distribution. The dynamic data were transformed to stereotactic coordinates and analyzed by standard methods. The resulting parametric maps were used to compute the voxel-wise sample statistics. Then the cohort of priors was analyzed as a function of S, using nonlinear least squares estimation and the cost function shown above. As S is increased the standard error in estimating BP in single subjects was substantially reduced allowing measurement in BP in thalamus, cortex, brain stem, etc. Additional studies demonstrate that a range of S values exist for which the bias is not excessive, even when parameter values differ markedly from the sample mean. This method can be used with any kinetic model so long as it is possible to compute a map of a priori mean parameters and their variances.

We studied the pattern of striatal dopamine release during performance of an explicit motor memory task in healthy volunteers. The release was estimated by dynamically measuring concentration of a dopamine ligand using a positron emission tomography camera. An increased release of endogenous dopamine in the dorsomedial aspect of posterior putamen and in the anterior part of the caudate bilaterally was observed, during task performance. As we have earlier observed dopamine release in all of these areas, except the right putamen, in an implicit motor memory task, it seems that the striatal dopaminergic network for implicit and explicit motor memories are essentially similar.

Sequential learning is an important aspect of cognitive processing. Neuropharmacological evidence acquired in laboratory animals suggests that striatal dopaminergic mechanisms may be important for processing of this form of learning. However, because experiments conducted on dopamine deficient patients have reported contradictory evidence, the role of dopamine and the striatum remains unclear in human sequential learning. We used a newly developed dynamic molecular imaging technique to determine whether striatal dopamine is released during performance of a sequential learning task. In this study we localized striatal regions where dopamine receptor ligand (11C-raclopride) was displaced from receptor sites, during performance of a motor sequence learning (serial reaction time) task. The results suggest that the task induces release of endogenous dopamine in the posterior two-third of dorsomedial aspect of left putamen and the anterior part of the body of caudate bilaterally. The activations of the left putamen and the right caudate coincided with the activations observed earlier during performance of a motor planning task. Since these activations are associated with the selection and execution of a response, the activation in the left caudate, which was not observed in motor planning, is probably associated with the detection of a change in the 'context', and in the formulation of a new 'rule'. Thus, the results suggest that sequential learning involves two striatal dopaminergic mechanisms, one for the detection of a change in context, and the other for selection and execution of the response.

The feasibility of off-line positron emission tomography/computed tomography (PET/CT) for routine three dimensional in-vivo treatment verification of proton radiation therapy is currently under investigation at Massachusetts General Hospital in Boston. In preparation for clinical trials, phantom experiments were carried out to investigate the sensitivity and accuracy of the method depending on irradiation and imaging parameters. Furthermore, they addressed the feasibility of PET/CT as a robust verification tool in the presence of metallic implants. These produce x-ray CT artifacts and fluence perturbations which may compromise the accuracy of treatment planning algorithms. Spread-out Bragg peak proton fields were delivered to different phantoms consisting of polymethylmethacrylate (PMMA), PMMA stacked with lung and bone equivalent materials, and PMMA with titanium rods to mimic implants in patients. PET data were acquired in list mode starting within 20 min after irradiation at a commercial luthetium-oxyorthosilicate (LSO)-based PET/CT scanner. The amount and spatial distribution of the measured activity could be well reproduced by calculations based on the GEANT4 and FLUKA Monte Carlo codes. This phantom study supports the potential of millimeter accuracy for range monitoring and lateral field position verification even after low therapeutic dose exposures of 2 Gy, despite the delay between irradiation and imaging. It also indicates the value of PET for treatment verification in the presence of metallic implants, demonstrating a higher sensitivity to fluence perturbations in comparison to a commercial analytical treatment planning system. Finally, it addresses the suitability of LSO-based PET detectors for hadron therapy monitoring. This unconventional application of PET involves countrates which are orders of magnitude lower than in diagnostic tracer imaging, i.e., the signal of interest is comparable to the noise originating from the intrinsic radioactivity of the detector itself. In addition to PET alone, PET/CT imaging provides accurate information on the position of the imaged object and may assess possible anatomical changes during fractionated radiotherapy in clinical applications.

The most important technical limitation affecting dynamic measurements with PET is low signal-to-noise ratio (SNR). Several reports have suggested that wavelet processing of receptor kinetic data in the human brain can improve the SNR of parametric images of binding potential (BP). However, it is difficult to fully assess these reports because objective standards have not been developed to measure the tradeoff between accuracy (e.g. degradation of resolution) and precision. This paper employs a realistic simulation method that includes all major elements affecting image formation. The simulation was used to derive an ensemble of dynamic PET ligand (11C-raclopride) experiments that was subjected to wavelet processing. A method for optimizing wavelet denoising is presented and used to analyze the simulated experiments. Using optimized wavelet denoising, SNR of the four-dimensional PET data increased by about a factor of two and SNR of three-dimensional BP maps increased by about a factor of 1.5. Analysis of the difference between the processed and unprocessed means for the 4D concentration data showed that more than 80% of voxels in the ensemble mean of the wavelet processed data deviated by less than 3%. These results show that a 1.5x increase in SNR can be achieved with little degradation of resolution. This corresponds to injecting about twice the radioactivity, a maneuver that is not possible in human studies without saturating the PET camera and/or exposing the subject to more than permitted radioactivity.

Object: Deep brain stimulation (DBS) of the ventral [anterior internal] capsule/ventral striatum (VC/VS) is under investigation as an alternative to anterior capsulotomy for severe obsessive-compulsive disorder (OCD). In neuroimaging studies of patients with OCD, dysfunction in the orbitofrontal and anterior cingulate cortex, striatum, and thalamus has been identified; and modulation of activity in this circuit has been observed following successful nonsurgical treatment. The purpose of the current study was to test hypotheses regarding changes in regional cerebral blood flow (rCBF) during acute DBS at the VC/VS target in patients with OCD who were participating in a clinical DBS trial., Methods: Six patients enrolled in a DBS trial for OCD underwent positron emission tomography to measure rCBF; the rCBF measured during acute DBS at high frequency was then compared with those measured during DBS at low frequency and off (control) conditions. On the basis of neuroanatomical knowledge about the VC/VS and neuroimaging data on OCD, the authors predicted that acute DBS at this target would result in modulation of activity within the implicated frontal-basal ganglia-thalamic circuit. Data were analyzed using statistical parametric mapping. In a comparison of acute high-frequency DBS with control conditions, the authors found significant activation of the orbitofrontal cortex, anterior cingulate cortex, striatum, globus pallidus, and thalamus., Conclusions: Acute DBS at the VC/VS target is associated with activation of the circuitry implicated in OCD. Further studies will be necessary to replicate these findings and to determine the neural effects associated with chronic VC/VS DBS. Moreover, additional data are needed to investigate whether pretreatment imaging profiles can be used to predict a patient's subsequent clinical response to chronic DBS.

Triacylglycerol (TAG) storage and turnover rates in the intact, beating rat heart were determined for the first time using dynamic mode (13)C- NMR spectroscopy to elucidate profound differences between hearts from diabetic rats (DR, streptozotocin treatment) and normal rats (NR). The incorporation of [2,4,6,8,10,12,14,16-(13)C(8)]palmitate into the TAG pool was monitored in isolated hearts perfused with physiological (0.5 mM palmitate, 5 mM glucose) and elevated substrate levels (1.2 mM palmitate, 11 mM glucose) characteristic of the diabetic condition. Surprisingly, although the normal hearts were enriched at a near-linear profile for >or=2 h before exponential characterization, exponential enrichment of TAG in diabetic hearts reached steady state after only 45 min. Consequently, TAG turnover rate was determined by fitting an exponential model to enrichment data rather than conventional two-point linear analysis. In the high-substrate group, both turnover rate (DR 820+/- 330, NR 190 +/-150 nmol.min(-1).g(-1) dry wt; P< 0.001) and [TAG] content (DR 78 +/-10, NR 32+/- 4 micromol/g dry wt; P< 0.001) were greater in the diabetic group. At lower substrate concentrations, turnover was greater in diabetics (DR 530+/-300, NR 160+/- 30; P<0.05). However, this could not be explained by simple mass action, because [TAG] content was similar between groups [DR 34+/- 7, NR 39+/- 9 micromol/g dry wt; not significant (NS)]. Consistent with exponential enrichment data, (13)C fractional enrichment of TAG was lower in diabetics (low- substrate groups: DR 4+/-1%, NR 10+/- 4%, P<0.05; high-substrate groups: DR 8+/- 3%, NR 14+/- 9%, NS), thereby supporting earlier speculation that TAG is compartmentalized in the diabetic heart.

This study assessed striatal dopamine 1 (D1) receptor binding in patients with major depressive disorder and anger attacks (MDD+A) and healthy volunteers. We used positron emission tomography with [(11)C]SCH 23,390 to compare 10 patients with MDD+A to 10 healthy volunteers. [(11)C]SCH 23,390 binding in bilateral striata was significantly lower in the MDD+A group when compared to healthy volunteers. These results implicate striatal D1 receptor dysfunction in MDD+A and further suggest an association between dopaminergic transmission and anger or aggression.

Objectives: We investigated the acute effect of orally administered high-dose folic acid on coronary dilator function in humans., Background: Folic acid and its active metabolite, 5-methyltetrahydrofolate, increase endothelium-dependent vasodilation in human peripheral circulation. However, the acute effect on coronary circulation is not known., Methods: Fourteen patients with ischemic heart disease, age 62 +/- 12 years (mean +/- SD), were enrolled in a double-blind, placebo-controlled crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) were determined by positron emission tomography, and myocardial flow reserve was calculated. Each patient was studied after ingestion of placebo and after ingestion of 30 mg folic acid. Myocardial zones were prospectively defined physiologically as "normal" versus "abnormal" on the basis of MBF response to adenosine 140 microg/kg/min (normal = MBF >1.65 ml/min/g). Abnormal and normal zones were analyzed separately in a patient-based analysis., Results: Folate was associated with a reduction in mean arterial pressure (100 +/- 12 mm Hg vs. 96 +/- 11 mm Hg, placebo vs. folate, p < 0.03). Despite the fall in mean arterial pressure, folic acid significantly increased the MBF dose response to adenosine (p < 0.001 using analysis of variance) in abnormal zones, whereas MBF in normal zones did not change. In abnormal segments, folic acid increased peak MBF by 49% (1.45 +/- 0.59 ml/min/g vs. 2.16 +/- 1.01 ml/min/g, p < 0.02). Furthermore, folate increased dilator reserve by 83% in abnormal segments (0.77 +/- 0.59 vs. ml/min/g 1.41 +/- 1.08 ml/min/g, placebo vs. folate, p < 0.05), whereas dilator reserve in normal segments remained unchanged (2.00 +/- 0.61 ml/min/g vs. 2.12 +/- 0.69 ml/min/g, placebo vs. folate, p = NS)., Conclusions: The data demonstrate that high-dose oral folate acutely lowers blood pressure and enhances coronary dilation in patients with coronary artery disease.

Is there more than one method whereby people can generate visual mental images? Participants generated images after learning patterns in two ways. In one condition, they memorized descriptions of how segments are arranged to form patterns; in another, they memorized segments and mentally amalgamated them into patterns. In both conditions, identical stimuli cued them to form images while brain activation was monitored using PET. Comparison of the two imagery conditions revealed different activation between hemispheres when images were formed after patterns were learned by mentally combining segments versus when images were formed from stored verbal descriptions. Thus, images can be generated in at least two ways. However, this laterality difference was subtle; the majority of brain areas were activated in common across conditions. This overall similarity is counter to what would be expected if image generation is simply perceptual exploration in the absence of appropriate stimuli, as is posited by perceptual activity theory.

Context: Although a variety of functional neuroimaging studies have used emotion induction paradigms to investigate the neural basis of anger in control subjects, no functional neuroimaging studies using anger induction have been conducted in patient populations., Objective: To study the neural basis of anger in unmedicated patients with major depressive disorder with anger attacks (MDD + A), unmedicated patients with MDD without anger attacks (MDD - A), and controls., Design: We used positron emission tomography, psychophysiologic measures, and autobiographical narrative scripts in the context of an anger induction paradigm., Setting: Academic medical center., Participants: Thirty individuals, evenly divided among the 3 study groups., Interventions: In separate conditions, participants were exposed to anger and neutral autobiographical scripts during the positron emission tomography study. Subjective self-report and psychophysiologic data were also collected., Main Outcome Measures: Voxelwise methods were used for analyses of regional cerebral blood flow changes for the anger vs neutral contrast within and between groups., Results: Controls showed significantly (P<.001) greater regional cerebral blood flow increases in the left ventromedial prefrontal cortex during anger induction than patients with MDD + A, whereas these differences were not present in other between-group analyses. Also, in controls, an inverse relationship was demonstrated between regional cerebral blood flow changes during anger induction in the left ventromedial prefrontal cortex and left amygdala, whereas in patients with MDD + A there was a positive correlation between these brain regions during anger induction. There was no significant relationship between these brain regions during anger induction in patients with MDD - A., Conclusion: These results suggest a pathophysiology of MDD + A that is distinct from that of MDD - A and that may be responsible for the unique clinical presentation of patients with MDD + A.

Context: Theoretical neuroanatomic models of posttraumatic stress disorder (PTSD) and the results of previous neuroimaging studies of PTSD highlight the potential importance of the amygdala and medial prefrontal regions in this disorder. However, the functional relationship between these brain regions in PTSD has not been directly examined., Objective: To examine the relationship between the amygdala and medial prefrontal regions during symptom provocation in male combat veterans (MCVs) and female nurse veterans (FNVs) with PTSD., Design: Case-control study., Setting: Academic medical center., Participants: Volunteer sample of 17 (7 men and 10 women) Vietnam veterans with PTSD (PTSD group) and 19 (9 men and 10 women) Vietnam veterans without PTSD (control group)., Main Outcome Measures: We used positron emission tomography and the script-driven imagery paradigm to study regional cerebral blood flow (rCBF) during the recollection of personal traumatic and neutral events. Psychophysiologic and emotional self-report data also were obtained to confirm the intended effects of script-driven imagery., Results: The PTSD group exhibited rCBF decreases in medial frontal gyrus in the traumatic vs neutral comparison. When this comparison was conducted separately by subgroup, MCVs and FNVs with PTSD exhibited these medial frontal gyrus decreases. Only MCVs exhibited rCBF increases in the left amygdala. However, for both subgroups with PTSD, rCBF changes in medial frontal gyrus were inversely correlated with rCBF changes in the left amygdala and the right amygdala/periamygdaloid cortex. Furthermore, in the traumatic condition, for both subgroups with PTSD, symptom severity was positively related to rCBF in the right amygdala and negatively related to rCBF in medial frontal gyrus., Conclusions: These results suggest a reciprocal relationship between medial prefrontal cortex and amygdala function in PTSD and opposing associations between activity in these regions and symptom severity consistent with current functional neuroanatomic models of this disorder.

Recent studies have reported memory deficits and reduced hippocampal volumes in posttraumatic stress disorder (PTSD). The goal of the current research was to use functional neuroimaging and a validated explicit memory paradigm to examine hippocampal function in PTSD. We used positron emission tomography (PET) and a word-stem completion task to study regional cerebral blood flow (rCBF) in the hippocampus in 16 firefighters: 8 with PTSD (PTSD group) and 8 without PTSD (Control group). During PET scanning, participants viewed three-letter word stems on a computer screen and completed each stem with a word they had previously encoded either deeply (High Recall condition) or shallowly (Low Recall condition). Relative to the Control group, the PTSD group exhibited significantly smaller rCBF increases in the left hippocampus in the High vs Low Recall comparison. However, this finding reflected relatively elevated rCBF in the Low Recall condition in the PTSD group. Collapsing across High and Low Recall conditions, (1) the PTSD group had higher rCBF in bilateral hippocampus and left amygdala than the Control group, and (2) within the PTSD group, symptom severity was positively associated with rCBF in hippocampus and parahippocampal gyrus. The groups did not significantly differ with regard to accuracy scores on the word-stem completion task. The PTSD group had significantly smaller right (and a trend for smaller left) hippocampal volumes than the Control group. The results suggest an abnormal rCBF response in the hippocampus during explicit recollection of nonemotional material in firefighters with PTSD, and that this abnormal response appears to be driven by relatively elevated hippocampal rCBF in the comparison condition.

Cognitive properties of associative priming are different from those of the non-associative priming. We examined areas associated with associative priming to understand its cortical processing. After subjects had studied pairs of unrelated words, they were shown one of the studied words and a 3-letter word-stem that could be completed using either the word that was paired with the presented studied word (same context), or with a different word (different context). As compared to the fixation, both conditions elicited increased activations in the left prefrontal and decreased activation in the extrastriate cortex. Medial temporal lobe was activated only in the same-context condition. This finding helps to understand why associative priming is impaired in some amnesic patients.

Object: Neurosurgical procedures are a viable intervention for severe, treatment-refractory major depression, although they have been associated with only modest rates of efficacy. The purpose of this study was to identify possible neuroimaging predictors of treatment response to anterior cingulotomy in patients with major depression., Methods: Thirteen patients underwent stereotactic anterior cingulotomy for treatment-refractory major depression. Symptom severity was measured using the Beck Depression Inventory (BDI) both before and approximately 12 months after surgery. The authors performed [18F]fluorodeoxyglucose-positron emission tomography (PET) studies in all patients preoperatively. Statistical parametric mapping methods were used to test for loci of significant correlation between preoperative regional cerebral metabolism and postoperative reduction in BDI scores. The mean (+/- standard deviation) change in the BDI score from the preoperative period (43.7 +/- 7.8) to the postoperative period (30.5 +/- 21.3) was 33.1 +/- 45.4%. Two loci--the left subgenual prefrontal cortex and left thalamus--were identified as sites at which preoperative metabolism was significantly correlated with subsequent improvement in depressive symptom severity following cingulotomy. Specifically, higher preoperative rates of metabolism at these loci were associated with better postoperative results., Conclusions: Possible PET scanning predictors of treatment response were identified in patients with major depression who had undergone anterior cingulotomy. Further research will be necessary to determine the reproducibility of this finding. If confirmed, the availability of an index for noninvasively predicting a patient's response to cingulotomy for the treatment of major depression would be of great clinical value.

Summary: Striatal dopamine is associated with the processing of rewarded motor tasks. Its involvement in mediating unrewarded tasks is, however, unclear. We used a recently developed PET technique to dynamically measure the rate of displacement of a dopamine receptor ligand raclopride in healthy volunteers performing a finger opposition task. Rapid displacement of the ligand from the posterior putamen and the caudate immediately after the task initiation suggested striatal dopamine release during task performance. Since dopamine release was observed in the striatal areas that are implicated in unrewarded tasks by neuroimaging studies, the results demonstrate that the PET method can be used to extend the findings of conventional neuroimaging techniques, that do not provide information about signal transduction.

Over the last decade, it has become possible to study theories of cognition using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These methods yield statistical parametric maps of changes in cerebral blood flow (CBF) elicited by cognitive tasks. A limitation of these studies is that they provide no information about the underlying neurochemistry. However, it is possible to extend the concept of activation studies to include measurements targeting neurotransmitters and specific receptor populations. Cognitive activation increases neuronal firing rate, increasing the endogenous neurotransmitter level. The increased neurotransmitter level can be used to alter the kinetics of specifically bound radioligands. We describe a new approach to the design and analysis of neuromodulation experiments. This approach uses PET, a single-scan session design, and a linear extension of the simplified reference region model (LSSRM) that accounts for changes in ligand binding induced by cognitive tasks or drug challenge. In the LSSRM, an "activation" parameter is included that represents the presence or absence of change in apparent dissociation rate. Activation of the neurotransmitter is detected statistically when the activation parameter is shown to violate the null hypothesis. Simulation was used to explore the properties of the LSSRM with regard to model identifiability, effect of statistical noise, and confounding effects of CBF-related changes. Simulation predicted that it is possible to detect and map neuromodulatory changes in single-subject designs. A human study was conducted to confirm the predictions of simulation using (11)C-raclopride and a motor planning task. Parametric images of transport, binding potential, areas of significant dopamine release, and statistical parameters were computed. Examination of the kinetics of activation demonstrated that maximum dopamine release occurred immediately following task initiation and then decreased with a half-time of about 3 min. This method can be extended to explore neurotransmitter involvement in other behavioral and cognitive domains.

Purpose: To determine if volumetric nonlinear registration or registration of thoracic computed tomography (CT) and 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) datasets changes the detection of mediastinal and hilar nodal disease in patients undergoing staging for lung cancer and if it has any impact on radiologic lung cancer staging., Method: Computer-based image registration was performed on 45 clinical thoracic helical CT and FDG-PET scans of patients with lung cancer who were staged by mediastinoscopy and/or thoracotomy. Thoracic CT, FDG-PET, and registration datasets were each interpreted by 2 readers for the presence of metastatic nodal disease and were staged independently of each other. Results were compared with surgical pathologic findings., Results: One hundred and thirty lymph node stations in the mediastinum and hila were evaluated each on CT, PET, and registration datasets. Sensitivity, specificity, positive predictive value, and negative predictive value, respectively, for detecting metastatic nodal disease for CT were 74%, 78%, 55%, 88%; for PET with CT side by side, 59% to 76%, 77% to 89%, 48% to 68%, and 84% to 91%; and for CT-PET registration, 71% to 76%, 89% to 96%, 70% to 86%, and 90% to 91%. Registration images were significantly more sensitive in detecting nodal disease over PET for 1 reader (P = 0.0156) and were more specific than PET (P = 0.0107 and 0.0017) in identifying the absence of mediastinal disease for both readers. Registration was significantly more accurate for staging when compared with PET for both readers (P = 0.002 and 0.035)., Conclusion: Registration of CT and FDG-PET datasets significantly improved the specificity of detecting metastatic disease. In addition, registration improved the radiologic staging of lung cancer patients when compared with CT or FDG-PET alone.

Recent research indicates that motor areas are activated in some types of mental rotation. Many of these studies have required participants to perform egocentric transformations of body parts or whole bodies; however, motor activation also has been found with nonbody objects when participants explicitly relate the objects to their hands. The current study used positron emission tomography (PET) to examine whether such egocentric motor strategies can be transferred implicitly from one type of mental rotation to another. Two groups of participants were tested. In the Hand-Object group, participants performed imaginal rotations of pictures of hands; following this, they then made similar judgments of pictures of Shepard-Metzler objects. The Object-Object group performed the rotation task for two sets of Shepard-Metzler objects only. When the second condition in each group (which always required rotating Shepard-Metzler objects) was compared, motor areas (Area 6 and M1) were found to be activated only in the Hand-Object group. These findings suggest that motor strategies can be covertly transferred to imaginal transformations of nonbody objects.

Rationale and Objectives: The authors evaluated the clinical utility of image coregistration in the interpretation of follow-up computed tomographic (CT) studies of the head., Materials and Methods: Fourteen patients with 34 intracranial lesions underwent follow-up head CT. The images were coregistered automatically with proprietary software on a standard personal computer, and all patient demographic data were removed. A neuroradiologist read the coregistered images several days after first reading the nonregistered images. The reading was repeated some months later to assess intraobserver variability, and a second reader was recruited so that interobserver variability also could be assessed. The interpretations of nonregistered images served as controls for the interpretations of coregistered images. Readers were asked to assess changes in lesion size quantitatively and to record the time it took to evaluate each case. Differences in interpretation speed were evaluated with the t test. Univariate analysis was used to measure accuracy; interpretations were compared with those of a nonblinded senior neuroradiologist, which served as the diagnostic standard. Intra- and interindividual variability were assessed with the kappa statistic., Results: The time needed to read the studies decreased by an average of 65.6% (P < .05), with statistically significant reductions for each reader. Coregistration also changed the interpretation results in 21.9% of cases. Coregistration increased the accuracy of reading, but not significantly. Intraobserver variability improved from 0.3554 to 0.7328 with coregistration, and interobserver variability improved from 0.2670 to 0.3309., Conclusion: Image coregistration is technically feasible and accurate. Coregistration of follow-up studies significantly reduces the time needed for comparison and interpretation. It does not detract from the accuracy of interpretation of follow-up studies and tends to decrease intra- and interobserver variability.

Background: Patients with schizophrenia demonstrate poor verbal memory, ascribed to impaired prefrontal and hippocampal function. Healthy adults can increase recall accuracy following encoding interventions, such as item repetition and the formation of semantic associations. We examined the effects of these interventions on both memory performance and retrieval-related hippocampal activity in healthy adults and patients with schizophrenia., Methods: Twelve patients with schizophrenia and twelve healthy control subjects participated. During study, subjects counted either the number of meanings or T-junctions in words seen only once or repeated four times. At test, O15-positron emission tomography scans were acquired while subjects completed word-stems with previously studied items., Results: Control subjects recalled more words overall, but both groups demonstrated similar performance benefits following deeper encoding. Both item repetition and the use of a semantic encoding task were associated with memory retrieval-related hippocampal recruitment in control but not schizophrenic participants. Patients with schizophrenia demonstrated greater activation of prefrontal cortical areas during word retrieval., Conclusions: Despite a lack of hippocampal recruitment, patients with schizophrenia showed intact modulation of memory performance following both encoding interventions. Impaired hippocampal recruitment, in concert with greater prefrontal activation, may reflect a specific deficit in conscious recollection in schizophrenia.