Publications by authors named "Nathaniel M Alpert"

55 Publications

Quantification of Myocardial Mitochondrial Membrane Potential Using PET.

Curr Cardiol Rep 2021 05 10;23(6):70. Epub 2021 May 10.

Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St., Boston, MA, 02114, USA.

Purpose Of Review: To present a method enabling in vivo quantification of tissue membrane potential (ΔΨ), a proxy of mitochondrial membrane potential (ΔΨ), to review the origin and role of ΔΨ, and to highlight potential applications of myocardial ΔΨ imaging.

Recent Findings: Radiolabelled lipophilic cations have been used for decades to measure ΔΨ in vitro. Using similar compounds labeled with positron emitters and appropriate compartment modeling, this technique now allows in vivo quantification of ΔΨ with positron emission tomography. Studies have confirmed the feasibility of measuring myocardial ΔΨ in both animals and humans. In addition, ΔΨ 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 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.
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http://dx.doi.org/10.1007/s11886-021-01500-8DOI Listing
May 2021

In vivo quantitative mapping of human mitochondrial cardiac membrane potential: a feasibility study.

Eur J Nucl Med Mol Imaging 2021 02 27;48(2):414-420. Epub 2020 Jul 27.

Department of Radiology, Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua Street, #6604, Boston, MA, 02114, USA.

Purpose: Alteration in mitochondrial membrane potential (ΔΨ) 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 in the myocardium of normal human subjects.

Methods: Thirteen healthy subjects were imaged using [F]-triphenylphosphonium ([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) 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), a proxy of ΔΨ, 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), representing the sum of cellular membrane potential (ΔΨ) and ΔΨ, 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.
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http://dx.doi.org/10.1007/s00259-020-04878-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839097PMC
February 2021

PET imaging of neurotransmission using direct parametric reconstruction.

Neuroimage 2020 11 15;221:117154. Epub 2020 Jul 15.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

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) 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 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 computed using DPR had substantially improved bias and variance properties. Application of the method in human subjects was demonstrated using C-raclopride dynamic scans and a reward task, confirming the improved quality of the estimated parametric images using the proposed approach.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800040PMC
November 2020

In vivo quantification of mitochondrial membrane potential.

Nature 2020 Jul 8;583(7815):E17-E18. Epub 2020 Jul 8.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41586-020-2366-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357846PMC
July 2020

Imaging of Mitochondrial Depolarization of Myocardium With Positron Emission Tomography and a Proton Gradient Uncoupler.

Front Physiol 2020 15;11:491. Epub 2020 May 15.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Background: We recently reported a method using positron emission tomography (PET) and the tracer F-labeled tetraphenylphosphonium (F-TPP) for mapping the tissue (i.e., cellular plus mitochondrial) membrane potential (ΔΨ) 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 F-TPP and mitochondrial membrane potential (ΔΨ).

Methods: We tested these hypotheses by measuring decreases of 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 F-TPP concentration. More definitive experiments were performed in two additional pigs, in which we administered an intravenous bolus plus infusion of F-TPP to reach secular equilibrium followed by an intracoronary infusion of BAM15.

Results: Intracoronary BAM15 infusion led to a clear decrease in F-TPP concentration, falling to a lower level, and then recovering. A second BAM15 infusion reduced the 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 F-TPP PET is sensitive to temporal changes in mitochondrial membrane potential.
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http://dx.doi.org/10.3389/fphys.2020.00491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243673PMC
May 2020

Preclinical Validation of a Single-Scan Rest/Stress Imaging Technique for N-Ammonia Positron Emission Tomography Cardiac Perfusion Studies.

Circ Cardiovasc Imaging 2020 01 21;13(1):e009407. Epub 2020 Jan 21.

Department of Radiology, Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston (N.J.G., M.P.-G., D.W.W., J.L.G., M.D.N., G.E.F., N.M.A.).

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 F-Flurpiridaz with adenosine as a pharmacological stressor. The aim of the present work is to validate our technique for NH.

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, NH 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·cc, limits of agreement: [-0.070 to 0.204] mL·min·cc), 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·cc, limits of agreement: [-0.103 to 0.035] mL·min·cc) and stress (mean difference: 0.057±0.361 mL·min·cc, limits of agreement: [-0.651 to 0.765] mL·min·cc) 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 NH measurements. The NH rest/stress myocardial perfusion imaging procedure can be compressed into a single positron emission tomography scan session lasting less than 15 minutes.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.009407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205554PMC
January 2020

Body motion detection and correction in cardiac PET: Phantom and human studies.

Med Phys 2019 Nov 8;46(11):4898-4906. Epub 2019 Oct 8.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, 02114, USA.

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.
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http://dx.doi.org/10.1002/mp.13815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842053PMC
November 2019

Quantitative in vivo mapping of myocardial mitochondrial membrane potential.

PLoS One 2018 16;13(1):e0190968. Epub 2018 Jan 16.

Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190968PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770041PMC
February 2018

Frontostriatal and Dopamine Markers of Individual Differences in Reinforcement Learning: A Multi-modal Investigation.

Cereb Cortex 2018 12;28(12):4281-4290

Department of Psychiatry, Harvard Medical School, and Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, MA, USA.

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.
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http://dx.doi.org/10.1093/cercor/bhx281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454484PMC
December 2018

Rapid computation of single PET scan rest-stress myocardial blood flow parametric images by table look up.

Med Phys 2017 Sep 18;44(9):4643-4651. Epub 2017 Jul 18.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114-1107, USA.

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 ) and right (f ) 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 ) and stress (K ) 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  = 1.019 × K  + 0.019, R  = 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.
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http://dx.doi.org/10.1002/mp.12398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603217PMC
September 2017

Single-scan rest/stress imaging: validation in a porcine model with F-Flurpiridaz.

Eur J Nucl Med Mol Imaging 2017 Aug 1;44(9):1538-1546. Epub 2017 Apr 1.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: F-labeled myocardial flow agents are becoming available for clinical application but the ∼2 hour half-life of 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 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 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.
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http://dx.doi.org/10.1007/s00259-017-3684-6DOI Listing
August 2017

Impact of motion and partial volume effects correction on PET myocardial perfusion imaging using simultaneous PET-MR.

Phys Med Biol 2017 01 20;62(2):326-343. Epub 2016 Dec 20.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA. Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.

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 F-Flurpiridaz, a novel F-labeled perfusion tracer. Two dynamic 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.
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http://dx.doi.org/10.1088/1361-6560/aa5087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241952PMC
January 2017

Validation of Bayesian analysis of compartmental kinetic models in medical imaging.

Phys Med 2016 Oct 28;32(10):1252-1258. Epub 2016 Sep 28.

Massachusetts General Hospital and Harvard Medical School, Radiology Department, 55 Fruit Street, Boston, MA 02114, USA.

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.
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http://dx.doi.org/10.1016/j.ejmp.2016.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720163PMC
October 2016

National Electrical Manufacturers Association and Clinical Evaluation of a Novel Brain PET/CT Scanner.

J Nucl Med 2016 Apr 23;57(4):646-52. Epub 2015 Dec 23.

The Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts

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.
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http://dx.doi.org/10.2967/jnumed.115.159723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818715PMC
April 2016

Mapping (15)O production rate for proton therapy verification.

Int J Radiat Oncol Biol Phys 2015 Jun 25;92(2):453-9. Epub 2015 Mar 25.

Center for Advanced Radiological Sciences, Nuclear Medicine and Molecular Imaging, Radiology Department, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ijrobp.2015.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431894PMC
June 2015

Direct reconstruction of cardiac PET kinetic parametric images using a preconditioned conjugate gradient approach.

Med Phys 2013 Oct;40(10):102501

Center for Advanced Medical Imaging Sciences, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Boston, Massachusetts 02114 and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114.

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.
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http://dx.doi.org/10.1118/1.4819821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779266PMC
October 2013

Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI.

Proc Natl Acad Sci U S A 2013 Jul 30;110(27):11169-74. Epub 2013 May 30.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA.

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.
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http://dx.doi.org/10.1073/pnas.1220512110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703969PMC
July 2013

Dual-tracer PET using generalized factor analysis of dynamic sequences.

Mol Imaging Biol 2013 Dec;15(6):666-74

Center for Advanced Medical Imaging Sciences NMMI, Radiology Department, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA,

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.
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http://dx.doi.org/10.1007/s11307-013-0631-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812387PMC
December 2013

A receptor-based model for dopamine-induced fMRI signal.

Neuroimage 2013 Jul 1;75:46-57. Epub 2013 Mar 1.

Division of Nuclear Medicine, Massachusetts General Hospital, Boston, MA, USA.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2013.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683121PMC
July 2013

MRI-based nonrigid motion correction in simultaneous PET/MRI.

J Nucl Med 2012 Aug 28;53(8):1284-91. Epub 2012 Jun 28.

Center for Advanced Radiological Sciences, Nuclear Medicine and Molecular Imaging, Radiology Department, Massachusetts General Hospital, Boston, MA 02114, USA.

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.
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http://dx.doi.org/10.2967/jnumed.111.092353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077320PMC
August 2012

Parametric imaging with Bayesian priors: a validation study with (11)C-Altropane PET.

Neuroimage 2012 May 9;61(1):131-8. Epub 2012 Mar 9.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2012.03.003DOI Listing
May 2012

Dopamine release during human emotional processing.

Neuroimage 2009 Oct 11;47(4):2041-5. Epub 2009 Jun 11.

Division of Nuclear Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2009.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740985PMC
October 2009

A general method of Bayesian estimation for parametric imaging of the brain.

Neuroimage 2009 May 14;45(4):1183-9. Epub 2009 Jan 14.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, 50 Fruit Street, Boston, MA 02114, USA.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2008.12.064DOI Listing
May 2009

Explicit motor memory activates the striatal dopamine system.

Neuroreport 2008 Mar;19(4):409-12

Division of Nuclear Medicine (White 427), Massachusetts General Hospital, Boston, MA 02114, USA.

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.
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http://dx.doi.org/10.1097/WNR.0b013e3282f6435fDOI Listing
March 2008

Striatal dopamine release in sequential learning.

Neuroimage 2007 Nov 15;38(3):549-56. Epub 2007 Aug 15.

Division of Nuclear Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2007.07.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077859PMC
November 2007

PET/CT imaging for treatment verification after proton therapy: a study with plastic phantoms and metallic implants.

Med Phys 2007 Feb;34(2):419-35

Department of Radiation Oncology, Massachusetts General Hospital, 30 Fruit Street, Boston, Massachusetts 02114, USA.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292642PMC
http://dx.doi.org/10.1118/1.2401042DOI Listing
February 2007

A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder.

J Neurosurg 2006 Apr;104(4):558-65

Division of Psychiatric Neuroscience Research and Neurotherapeutics, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.

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.
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http://dx.doi.org/10.3171/jns.2006.104.4.558DOI Listing
April 2006

Decreased striatal D1 binding as measured using PET and [11C]SCH 23,390 in patients with major depression with anger attacks.

Depress Anxiety 2006 ;23(3):175-7

Department of Psychiatry, Massachusetts General Hospital, Boston, USA.

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.
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http://dx.doi.org/10.1002/da.20168DOI Listing
November 2006

Optimization of dynamic measurement of receptor kinetics by wavelet denoising.

Neuroimage 2006 Apr 27;30(2):444-51. Epub 2005 Oct 27.

Division of Nuclear Medicine, Massachusetts General Hospital, 50 Fruit Street, Boston, MA 02129, USA.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2005.09.031DOI Listing
April 2006

Accelerated triacylglycerol turnover kinetics in hearts of diabetic rats include evidence for compartmented lipid storage.

Am J Physiol Endocrinol Metab 2006 Mar 18;290(3):E448-55. Epub 2005 Oct 18.

Program in Integrative Cardiac Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA.

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.
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http://dx.doi.org/10.1152/ajpendo.00139.2005DOI Listing
March 2006
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