Olivier Rousset

Increased Occupancy of Dopamine Receptors in Human Striatum during Cue-Elicited Cocaine Craving

In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [11C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET

Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D2 receptors (D2-Rs), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DArel) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DArel was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D2-R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS-OCD). In three subjects with TS+OCD, in whom D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DArel and 5-HT2A BP, when compared with TS–OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DArel is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT2AR in individuals with TS who had increased DArel, suggest a condition of increased phasic DArel modulated by low 5-HT in concomitant OCD.

Partial Volume Correction Strategies in PET

In the early days of PET, the partial volume effect (PVE) was identified as a serious factor affecting image quality and limiting the accuracy of quantitative analysis. Because of the limited spatial resolution of clinical PET systems, the images are blurred by the system response so that smaller objects appear larger. Although the total number of counts is preserved, they are distributed over a larger volume. This article describes the various partial volume correction strategies used in PET and summarizes their clinical and research applications.

Accurate Event-Driven Motion Compensation in High-Resolution PET Incorporating Scattered and Random Events

With continuing improvements in spatial resolution of positron emission tomography (PET) scanners, small patient movements during PET imaging become a significant source of resolution degradation. This work develops and investigates a comprehensive formalism for accurate motion-compensated reconstruction which at the same time is very feasible in the context of high-resolution PET. In particular, this paper proposes an effective method to incorporate presence of scattered and random coincidences in the context of motion (which is similarly applicable to various other motion correction schemes). The overall reconstruction framework takes into consideration missing projection data which are not detected due to motion, and additionally, incorporates information from all detected events, including those which fall outside the field-of-view following motion correction. The proposed approach has been extensively validated using phantom experiments as well as realistic simulations of a new mathematical brain phantom developed in this work, and the results for a dynamic patient study are also presented.

Strategies for Motion Tracking and Correction in PET

With the arrival of increasingly higher-resolution PET systems, small amounts of motion can cause significant blurring in the resulting images compared with the intrinsic resolution of the PET scanner. The authors review advanced correction methods for unwanted patient motion and for motion due to cardiac and respiratory cycles. A general theme in motion correction methods is the use of increasingly sophisticated software to make use of existing advanced hardware. In this sense, the field is open to future novel ideas (hardware and especially software) aimed at improving motion detection, characterization, and compensation.

Design and Implementation of an Automated Partial Volume Correction in PET: Application to Dopamine Receptor Quantification in the Normal Human Striatum

The considerable effort and potential lack of reproducibility of human-driven PET quantification and partial volume correction (PVC) can be alleviated by use of atlas-based automatic analysis. The present study examined the application of a new algorithm designed to automatically define 3-dimensional regions of interest (ROIs) and their effect on dopamine receptor quantification in the normal human brain striatum, both without and with PVC. Methods: A total of 90 healthy volunteers (age range, 18–46 y) received a single injection of 11C-raclopride, and automatic segmentation of concomitant structural MR images was performed using a maximum-probability atlas in combination with a trained neural network. For each identified tissue segment considered homogeneous for the tracer (or volumes of interest [VOIs]), an a priori criterion based on minimum axial recovery coefficient (RCzmin = 50%, 75%, and 90%) was used to constrain the extent of each ROI. Results: With ROIs essentially overlapping the entire VOI volume (obtained with RCzmin = 50%), the binding potential (BPND) of 11C-raclopride was found to be around 2.2 for caudate and 2.9 for putamen, an underestimation by 35% and 28%, respectively, according to PVC values. At increased RCzmin, BPND estimates of 11C-raclopride were increased by 12% and 21% for caudate and 8% and 15% for putamen when the associated ROIs decreased to around 65% and 43% of total tissue volume (VOI) for caudate and 67% and 31% for putamen. After PVC, we observed relative increases in BPND variance of 12% for caudate and 20% for putamen, whereas estimated BPND values all increased to 3.4 for caudate and 4.0 for putamen, regardless of ROI size. Dopamine receptor concentrations appeared less heterogeneous in the normal human striatum after PVC than they did without PVC: the 25%–30% difference in BPND estimates observed between caudate and putamen remained significant after PVC but was reduced to slightly less than 20%. Furthermore, the results were comparable with those obtained with a manual method currently in use in our laboratory. Conclusion: The new algorithm allows for traditional PET data extraction and PVC in an entirely automatic fashion, thus avoiding labor-intensive analyses and potential intra- or interobserver variability. This study also offers the first, to our knowledge, large-scale application of PVC to dopamine D2/D3 receptor imaging with 11C-raclopride in humans.

System matrix modelling of externally tracked motion.

In high resolution emission tomography imaging, even small patient movements can considerably degrade image quality. This work investigates an approach to motion compensated reconstruction of motion-contaminated data, thus applicable to any scanner in the field (e.g. without list-mode acquisition capability), assuming externally-tracked motion information; it involves incorporation of the measured motion information into the system matrix of the EM algorithm. Furthermore, it is shown that the effect of motion-contamination of the attenuation factors should also be modeled and taken into account in the reconstruction task.

Pixel- versus Region-Based Partial Volume Correction in PET

Partial volume correction (PVC) methods require precise determination of structural information from anatomy-oriented devices such as magnetic resonance imaging and the incorporation of positron emission tomography physical characteristics. The primary goal of this work was to study the error introduced by a heterogeneous tracer distribution within a particular tissue component assumed to be homogeneous. Two different approaches were compared: (i) a pixel-based method (PIX-PVC), which is a successive elimination–substitution method that yields corrected tissue maps (Meltzer et al., 1996), and (ii) a region-of-interest-based technique (ROI-PVC), which is a direct method of solving a system of simultaneous linear algebraic equations (Rousset et al., 1993b). To simulate a heterogeneous tracer distribution, the left insula region (lINS) was identified as a distinct volume of interest, and PVC was performed considering three pure tissue components: white matter, cortical gray matter, and basal ganglia. The relative errors made on regional measurements after PVC were found to be very similar between PIX–PVC and ROI-PVC for simulated data of the tracer [18F]fluoro-L-dopa uptake. In addition, both methods were applied to a real data set for this tracer and provided comparable results. However, this study cannot predict the amount of error propagation in the case of a more heterogeneous tracer distribution. In particular, the PIX–PVC method will encounter increasing difficulties to fulfill the assumption of tracer distribution homogeneity. However, the ROI-PVC method appears more flexible, does not require a priori knowledge of some tracer concentration, and is easier and faster to implement.Partial volume correction (PVC) methods require precise determination of structural information from anatomy-oriented devices such as magnetic resonance imaging and the incorporation of positron emission tomography physical characteristics. The primary goal of this work was to study the error introduced by a heterogeneous tracer distribution within a particular tissue component assumed to be homogeneous. Two different approaches were compared: (i) a pixel-based method (PIX-PVC), which is a successive elimination–substitution method that yields corrected tissue maps (Meltzer et al., 1996), and (ii) a region-of-interest-based technique (ROI-PVC), which is a direct method of solving a system of simultaneous linear algebraic equations (Rousset et al., 1993b). To simulate a heterogeneous tracer distribution, the left insula region (lINS) was identified as a distinct volume of interest, and PVC was performed considering three pure tissue components: white matter, cortical gray matter, and basal ganglia. The relative errors made on regional measurements after PVC were found to be very similar between PIX–PVC and ROI-PVC for simulated data of the tracer [18F]fluoro-L-dopa uptake. In addition, both methods were applied to a real data set for this tracer and provided comparable results. However, this study cannot predict the amount of error propagation in the case of a more heterogeneous tracer distribution. In particular, the PIX–PVC method will encounter increasing difficulties to fulfill the assumption of tracer distribution homogeneity. However, the ROI-PVC method appears more flexible, does not require a priori knowledge of some tracer concentration, and is easier and faster to implement.

Single photon emission computed tomography experience with (S)-5-[ 123I]iodo-3-(2-azetidinylmethoxy)pyridine in the living human brain of smokers and nonsmokers

(S)‐5‐[123I]iodo‐3‐(2‐azetidinylmethoxy)pyridine (5‐[123I]IA), a novel potent radioligand for high‐affinity α4β2* neuronal nicotinic acetylcholine receptors (nAChRs), provides a means to evaluate the density and the distribution of nAChRs in the living human brain. We sought in healthy adult smokers and nonsmokers to (1) evaluate the safety, tolerability, and efficacy of 5‐[123I]IA in an open nonblind trial and (2) to estimate the density and the distribution of α4β2* nAChRs in the brain. Single photon emission computed tomography (SPECT) was performed for 5 h after the i.v. administration of ∼0.001 μg/kg (∼10 mCi) 5‐[123I]IA. Blood pressure, heart rate, and neurobehavioral status were monitored before, during, and after the administration of 5‐[123I]IA to 12 healthy adults (8 men and 4 women) (6 smokers and 6 nonsmokers) ranging in age from 19 to 46 years (mean = 28.25, standard deviation = 8.20). High plasma‐nicotine level was significantly associated with low 5‐[123I]IA binding in: (1) the caudate head, the cerebellum, the cortex, and the putamen, utilizing both the Sign and Mann–Whitney U‐tests; (2) the fusiform gyrus, the hippocampus, the parahippocampus, and the pons utilizing the Mann–Whitney U‐test; and (3) the thalamus utilizing the Sign test. We conclude that 5‐[123I]IA is a safe, well‐tolerated, and effective pharmacologic agent for human subjects to estimate high‐affinity α4/β2 nAChRs in the living human brain. Synapse 63:339–358, 2009.

3D simulations of radiotracer uptake in deep nuclei of human brain

The accuracy of Positron Emission Tomography (PET) for measuring in vivo concentrations of radiolabelled pharmaceuticals is affected by the limited tomograph resolution. Using computer simulations, we developed a model reproducing the distribution of the tracer [18F]fluoroDOPA which is specifically taken up in the normal human striatum. Validation of the model was performed by comparing the simulated images with real PET scans of the same brain. The simulation was used to examine the effect of axial displacement of the brain relative to the PET imaging planes, and that of image contrast on signal recovery (partial volume effects).