Biomedical Engineering; Nuclear Medicine; Physiology; Radiology; Positron-Emission Tomography
Dr. Richard Carson's research uses Positron Emission Tomography (PET) as a tool to noninvasively measure a wide range of in vivo physiology in human beings and laboratory animals. His focus is on the development and applications of new tracer kinetic modeling methods and algorithms and on research in PET image reconstruction and image quantification. These quantitative techniques are then applied in clinical populations and preclinical models of disease. Application areas include neuropsychiatric populations, diabetes, cardiology, and oncology. A primary focus of his more biological applications is the measurement of synaptic density in a wide range of neuropsychiatric disorders.
Specialized Terms: Positron emission tomography (PET) modeling and physics; Tracer kinetic modeling methods and parametric imaging techniques for PET tracers; Application of receptors ligands to assess neurotransmitter dynamic; 3D and 4D PET image reconstruction; Medical imaging
Extensive Research Description
Following administration of a positron-emitting radiopharmaceutical (tracer), PET permits the direct measurement of the four-dimensional radioactivity profile throughout a 3D object over time. Depending on the characteristics of the tracer, physiological parameters can be estimated, such as blood flow, metabolism, and receptor concentration. These measurements can be made with subjects in different states (e.g., stimulus or drug activation), used to compare patient groups to controls, or to assess the efficacy of drug treatment.
Tracer Kinetic Modeling
The goal of PET tracer kinetic modeling is to devise a biologically validated, quantitatively reliable, and logistically practical method for use in human PET studies. Animal studies are typically performed to characterize the tracers, followed by initially complex human studies, typically leading to the development of simplified methods, e.g., using continuous tracer infusion. These techniques are also applied on a pixel-by-pixel level to produce images of PET physiological and pharmacological parameters, such as blood flow and receptor binding. Mathematical methodology includes linear and non-linear differential equations, statistical estimation theory, methods to avoid the needs for arterial blood measurements (the input function) such as blind deconvolution, plus the development of novel rapid computational algorithms.
PET Physics and Reconstruction.
Proper characterization of the PET image data is essential for modeling studies. This requires accurate and carefully characterized corrections for the physics and electronics of coincident event acquisition. Studies of these effects are performed with phantom measurements made on the scanner.
A critical component in the application to real data is the correction for subject motion, particularly as the resolution of modern machines has improved (better than 3-mm in human brain machines). Both hardware and software approaches are employed to address these issues. To produce accurate images with minimum noise, a statistically-based iterative reconstruction algorithm is necessary. Developments in this area include the mathematical aspects of algorithm development, the computer science issues associated with a large cluster-based algorithm, the incorporation of the physics and motion correction, the use of prior information provided from MR images, and the tuning and characterization necessary for practical application for biological studies. The ultimate goal is the combination of the tracer kinetic modeling and image reconstruction to directly process a 4D dataset into parametric images of the physiological parameters of interest. When applied in the thorax, respiratory and cardiac motion must be included, raising the problem to 5D and 6D analysis.
PET studies are performed in human subjects and preclinical models of a wide variety of diseases. Examples of interest include:
- Synaptic density imaging in the living human brain (See Science Translational Medicine, 2016)
- Measuring beta cells in the pancreas for diabetes with novel tracers including ligands for the vesicular monoamine transporter
- Using PET to measure drug delivery in cancer
- Neuroreceptor studies have focused on determining changes in receptor concentration as a function of disease or measurement of receptor occupancy by drugs. Such changes have been successfully demonstrated in the dopaminergic, muscarinic, and serotonergic systems.
- Measurement of the relationship between dopamine receptors and impulsivity
- New methods for quantification of myocardial blood flow
- Hypoxia assessment in tumors before and after radiation treatment
- Differentiation of radiation necrosis vs. tumor recurrence
- 4D/5D Image reconstruction for PET
- Mathematical model development for novel radiopharmaceuticals
- Imaging of beta cells in the pancreas
- Neuroinflammation imaging in a wide variety of disorders
- Novel preclinical and clinical applications in oncology
- Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, Dhaher R, Matuskey D, Baum E, Holden D, Spencer DD, Mercier J, Hannestad J, Huang Y, Carson RE, Imaging synaptic density in the living human brain, Sci Transl Med, 8:348ra96, 2016 (cover).
- Nabulsi N, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, Lin SF, Deo A, Price N, Lara-Jaine T, Montel F, Laruelle M, Carson RE, Hannestad J, Huang Y, Synthesis and preclinical evaluation of 11C‑UCB‑J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain, J Nucl Med, 57:777-784, 2016
- Pittenger C, Adams TG, Gallezot JD, Crowley MJ, Nabulsi N, Ropchan J, Gao H, Kichuk SA, Simpson R, Billingslea E, Bloch M, Mayes L, Bhagwagar Z, Carson RE, OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5‑HT1B receptor binding, J Aff Dis, 196:87-96, 2016.
- Naganawa M, Dickinson G, Zheng MQ, Henry S, Vandenhende F, Witcher J, Bell R, Nabulsi N, Lin SF, Ropchan J, Neumeister A, Ranganathan M, Tauscher J, Huang Y, Carson RE, Receptor occupancy of the kappa opioid antagonist LY2456302 using the novel PET radiotracer 11C‑LY2795050, J Phar Exp Ther, 356:260-266 2016.
- Xia Y, Zheng M-Q, Holden D, Lin S-F, Kapinos M, Ropchan J, Gallezot J-D, Huang Y, Carson RE, Measurement of Bmax and Kd with the glycine transporter 1 radiotracer 18F MK6577 using a novel multi-infusion paradigm, J Cereb Blood Flow Metabol, 35:2001-2009, 2015.
- Park E, Sullivan J, Planeta P, Gallezot J-D, Lim K-P, Lin S-F, Ropchan J, McCarthy T, Ding Y-S, Morris ED, Williams WA, Huang Y, Carson RE, Test/retest reproducibility of the metabotropic glutamate receptor ligand [18F]FPEB with bolus plus constant infusion in human, Eur J Nuc Med Mol Imag, 42:570-577, 2015.
- Park E, Gallezot JD, Delgadillo A, Liu S, Planeta B, Lin SF, O’Connor K, Lim K, Lee J-Y, Chastre A, Chen, MK, Seneca N, Leppert D, Huang Y, Carson RE, Pelletier D, 11C PBR28 imaging in multiple sclerosis patients and healthy controls: Test-retest reproducibility and visualization of focal activation, Eur J Nucl Med Mol Imag, 42:1081-1092, 2015.
- DeLorenzo C, DellaGioia N, Bloch M, Sanacora G, Nabulsi N, Abdallah C, Man JJ, Krystal J, Parsey RV, Carson RE, Esterlis I, In vivo ketamine-induced changes in [11C]ABP688 binding to brain mGluR5 receptors in humans, Biol Psych, 77:266-275, 2015.
- Jian Y, Yao R, Mulnix T, Jin X, Carson RE, Application of line-of-response probability density function resolution models in list mode reconstruction for PET, Phys Med Biol, 60:253-278, 2015.
- Naganawa M, Zheng M-Q, Nabulsi N, Tomasi G, Henry S, Lin S-F, Ropchan J, Labaree D, Tauscher J, Neumeister A, Carson RE, Huang Y, Kinetic modeling of 11C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans, J Cereb Blood Flow Metab, 34:1818-1825, 2014.
- Naganawa M, Jacobsen LK, Zheng M-Q, Lin S-F, Banerjee A, Byon W, Weinzimmer D, Tomasi G, Grimwood S, Badura LL, Carson RE, McCarthy TJ, Huang Y, Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptors in humans: kinetic model selection, test-retest reproducibility, and receptor occupancy by the antagonist PF-04455242, Neuroimage, 99:69-79, 2014.
- Gallezot J-D, Zheng M-Q, Lim K, Lin SF, Labaree D, Matuskey D, Huang Y, Ding Y-S, Carson RE, Malison RT, Parametric imaging and test-retest variability of [11C]-(+)-PHNO binding to D2/D3 dopamine receptors in humans on the HRRT PET scanner, J Nucl Med, 14:960-966, 2014.
- Matuskey D, Gallezot J-D, Pittman B, Williams W, Wanyiri J, Gaiser E, Lee DE, Lim K, Zheng M-Q, Lin S-F, Labaree D, Potenza M, Carson RE, Malison RT, Ding Y-S, Dopamine D3 Receptor Alterations in Cocaine-Dependent Humans Imaged with the PET Ligand [11C](+)PHNO, Drug Alc Dep, 139:100-105, 2014.
- Li CR, Potenza MM, Lee DE, Planeta B, Gallezot J-D, Labaree D, Henry S, Nabulsi N, Sinha R, Ding, Y-S, Carson RE, Neumeister A, Decreased norepinephrine transporter availability in obesity: PET imaging with [11C]MRB, Neuroimage, 86:306-310, 2014
- Jin X, Mulnix T, Gallezot J-D, Carson RE, Evaluation of motion correction methods in human brain PET imaging - a simulation study based on human motion data, Med Phys, 40:102503, 2013.
- Matuskey D, Bhagwagar Z, Planeta B, Pittman B, Gallezot J-D, Chen J, Wanyiri J, Geha P, Potenza MN, Neumeister A, Carson RE, Malison RT, Reductions in Brain 5-HT1B Receptor Availability in Primarily Cocaine-Dependent Humans, Biol Psych, 76:816-822,2014
- Sandiego CM, Jin X, Mulnix T, Fowles K, Wells L, Labaree D, Ropchan J, Huang Y, Rabiner EA, Cosgrove K, Castner SA, Williams GV, Carson RE, Awake nonhuman primate brain PET imaging with minimal head restraint: Evaluation of GABAA, benzodiazepine binding with [11C]flumazenil in awake and anesthetized animals, J Nucl Med, 54:1962-1968, 2013.
- Sirianni RW, Zheng M-Q, Schafbauer T, Patel T, Zhou J, Saltzman WM, Huang Y, Carson RE, A non-invasive imaging technique for measuring the distribution of drugs and polymers after direct delivery to the brain, Mol Imag Biol, 15:596-605, 2013.
- Hannestad J, DellaGioia N, Gallezot J-D, Lim K, Nabulsi N, Esterlis I, Pittman B, Lee J-Y, O’Connor KC, Pelletier D, Carson RE, The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: A [11C]PBR28 PET study, Brain Beh Immun, 33:131-138, 2013.
- Jin X, Chan C, Mulnix T, Panin V, Casey ME, Liu C, Carson RE, List mode reconstruction for the Biograph mCT with probabilistic LOR positioning and event-by-event motion correction, Phys Med Biol, 58:5567-5591, 2013
- Fung EK, Carson RE, Cerebral blood flow with [15O]water PET using image-derived input functions and MR-defined carotid centerlines, Phys Med Biol, 58:1903-1923, PMC3626495, 2013
- Yan J, Planeta-Wilson B, Carson RE, Direct 4D PET list mode parametric reconstruction with a novel EM algorithm, IEEE Trans Med Imag, 31:2213-2223, PMC3660152, 2012
- Normandin M, Petersen KF, Ding, Y-S, Lin, S-F, Naik S, Skrovonsky DM, Herold KC, McCarthy TJ, Calle RA, Carson RE, Treadway JL, Cline GW, In vivo imaging of endogenous pancreatic ß cell mass in healthy and type 1 diabetic subjects using [18F](+)-FP-DTBZ and PET, J Nucl Med, 53: 908-916, 2012.
- Cosgrove KP, Kloczynski T, Nabulsi N, Weinzimmer D, Lin S-F, Staley JK, Bhagwagar Z, Carson RE, Assessing the sensitivity of [11C]P943, a novel 5 HT1B PET radioligand, to endogenous serotonin release, Synapse, 65:1113-1117, 2011
- Gallezot J-D, Nabulsi N, Neumeister A, Planeta-Wilson B, Williams WA, Singhal T, Kim S, Maguire RP, McCarthy T, Frost JJ, Huang Y, Ding Y-S, Carson RE, Kinetic modeling of the serotonin 5 HT1B receptor radioligand [11C]P943 in humans, J Cereb Blood Flow Metab, 30: 196-210, 2010
- Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, and Carson RE, Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab, 2007. 27(9): p. 1533-9 PMCID 17519979.
- Carson RE, Breier A, de Bartolomeis A, Saunders RC, Su TP, Schmall B, Der MG, Pickar D, Eckelman WC, Quantification of amphetamine-induced changes in [11C]-raclopride binding with continuous infusion, J Cereb Blood Flow Metab, 17:437-447, 1997
- Carson RE, Channing MA, Blasberg RG, Dunn BB, Cohen RM, Rice KC, Herscovitch P, Comparison of bolus and infusion methods for receptor quantitation: Application to [18F]-cyclofoxy and positron emission tomography, J Cereb Blood Flow Metab, 13:24-42, 1993.
- Lange K, Carson RE, EM reconstruction algorithms for emission and transmission tomography, J Comput Assist Tomogr, 8:306-316, 1984