Irina Vitcu

Separate brain regions code for salience vs. valence during reward prediction in humans

Predicting rewards and avoiding aversive conditions is essential for survival. Recent studies using computational models of reward prediction implicate the ventral striatum in appetitive rewards. Whether the same system mediates an organisms response to aversive conditions is unclear. We examined the question using fMRI blood oxygen level‐dependent measurements while healthy volunteers were conditioned using appetitive and aversive stimuli. The temporal difference learning algorithm was used to estimate reward prediction error. Activations in the ventral striatum were robustly correlated with prediction error, regardless of the valence of the stimuli, suggesting that the ventral striatum processes salience prediction error. In contrast, the orbitofrontal cortex and anterior insula coded for the differential valence of appetitive/aversive stimuli. Given its location at the interface of limbic and motor regions, the ventral striatum may be critical in learning about motivationally salient stimuli, regardless of valence, and using that information to bias selection of actions. Inc. Hum Brain Mapp, 2007.

An automated method for the extraction of regional data from PET images

Manual drawing of regions of interest (ROIs) on brain positron emission tomography (PET) images is labour intensive and subject to intra- and inter-individual variations. To standardize analysis and improve the reproducibility of PET measures, we have developed image analysis software for automated quantification of PET data. The method is based on the individualization of a set of standard ROIs using a magnetic resonance (MR) image co-registered with the PET image. To evaluate the performance of this automated method, the software-based quantification has been compared with conventional manual quantification of PET images obtained using three different PET radiotracers: [(11)C]-WAY 100635, [(11)C]-raclopride and [(11)C]-DASB. Our results show that binding potential estimates obtained using the automated method correlate highly with those obtained by trained raters using manual delineation of ROIs for frontal and temporal cortex, thalamus, and striatum (global intraclass correlation coefficient >0.8). For the three radioligands, the software yields time-activity data that are similar (within 8%) to those obtained by manual quantification, eliminates investigator-dependent variability, considerably shortens the time required for analysis and thus provides an alternative method for accurate quantification of PET data.

Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response-a double-blind PET study in schizophrenia

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.

Temporal Difference Modeling of the Blood-Oxygen Level Dependent Response During Aversive Conditioning in Humans: Effects of Dopaminergic Modulation

BACKGROUND The prediction error (PE) hypothesized by the temporal difference model has been shown to correlate with the phasic activity of dopamine neurons during reward learning and the blood-oxygen level dependent (BOLD) response during reward and aversive conditioning tasks. We hypothesized that dopamine would modulate the PE related signal in aversive conditioning and that haloperidol would reduce PE related activity, while an acute dose of amphetamine would increase PE related activity in the ventral striatum. METHODS Healthy participants took an acute dose of amphetamine, haloperidol, or placebo. We used functional magnetic resonance imaging (fMRI) to measure the BOLD signal while they carried out an aversive conditioning task, using cutaneous electrical stimulation as the unconditioned stimulus (US) and yellow and blue circles as conditioned stimulus (CS+ and CS-, respectively). RESULTS Prediction error related BOLD activity was seen only in the ventral striatum in the placebo subjects. The subjects given amphetamine showed a wider network of PE related BOLD activity, including the ventral striatum, globus pallidus, putamen, insula, anterior cingulate, and substantia nigra/ventral tegmental area. Haloperidol subjects did not show PE related activity in any of these regions. CONCLUSIONS Our results provide the first demonstration that the modulation of dopamine transmission affects both the physiological correlates and PE related BOLD activity during aversive learning.

First human evidence of d-amphetamine induced displacement of a D2/3 agonist radioligand: A [11C]-(+)-PHNO positron emission tomography study

Imaging the competition between D2/3 radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D2 receptor exists in a high (D2high) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D2high only. [11C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D2/3 agonist radioligand for positron emission tomography (PET) imaging in humans. Since [11C]-(+)-PHNO is expected to bind preferentially to D2high, it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [11C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [11C]-(+)-PHNO BPs in caudate (−13.2%), putamen (−20.8%), and ventral striatum (−24.9%), but not in globus pallidus (−6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D2/3 agonist radioligand in humans. [11C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D2/3 antagonist radioligands.

Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humans.

The D2 receptors exist in either the high‐ or low‐affinity state with respect to agonists, and while agonists bind preferentially to the high‐affinity state, antagonists do not distinguish between the two states. [11C]‐(+)‐PHNO is a PET D2 agonist radioligand and therefore provides a preferential measure of the D2high receptors. In contrast, [11C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D2 high‐ and low‐affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [11C]‐(+)‐PHNO and [11C]raclopride in volunteers using a within‐subject design. Both radioligands accumulated in brain areas rich in D2/D3‐receptors. However, [11C]‐(+)‐PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [11C]raclopride showed preferential uptake in the dorsal striatum. Mean binding potentials were higher in the putamen (4.3 vs. 2.8) and caudate (3.4 vs 2.1) for [11C]raclopride, equal in the ventral‐striatum (3.4 vs. 3.3), and higher in the globus pallidus for [11C]‐(+)‐PHNO (1.8 vs. 3.3). Moreover [11C]‐(+)‐PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [11C]‐(+)‐PHNO in the globus pallidus and ventral‐striatum could be the presence of a greater proportion of high‐ vs. low‐affinity receptors in these areas. Alternatively, the observed distribution could also be explained by a preferential binding of D3‐over‐D2 with [11C]‐(+)‐PHNO. This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease. Hum Brain Mapp 2008.

Quantitation of Translocator Protein Binding in Human Brain with the Novel Radioligand [18F]-FEPPA and Positron Emission Tomography

This article describes the kinetic modeling of [18F]-FEPPA binding to translocator protein 18 kDa in the human brain using high-resolution research tomograph (HRRT) positron emission tomography. Positron emission tomography scans were performed in 12 healthy volunteers for 180 minutes. A two-tissue compartment model (2-CM) provided, with no exception, better fits to the data than a one-tissue model. Estimates of total distribution volume (VT), specific distribution volume (VS), and binding potential (BPND) demonstrated very good identifiability (based on coefficient of variation (COV)) for all the regions of interest (ROIs) in the gray matter (COV VT < 7%, COV VS < 8%, COV BPND < 11%). Reduction of the length of the scan to 2 hours is feasible as VS and VT showed only a small bias (6% and 7.5%, respectively). Monte Carlo simulations showed that, even under conditions of a 500% increase in specific binding, the identifiability of VT and VS was still very good with COV<10%, across high-uptake ROIs. The excellent identifiability of VT values obtained from an unconstrained 2-CM with data from a 2-hour scan support the use of VT as an appropriate and feasible outcome measure for [18F]-FEPPA.

Oligodontia Is Caused by Mutation in LTBP3, the Gene Encoding Latent TGF-β Binding Protein 3

We have identified a consanguineous Pakistani family where oligodontia is inherited along with short stature in an autosomal-recessive fashion. Increased bone density was present in the spine and at the base of the skull. Using high-density single-nucleotide polymorphism microarrays for homozygosity mapping, we identified a 28 Mb homozygous stretch shared between affected individuals on chromosome 11q13. Screening selected candidate genes within this region, we identified a homozygous nonsense mutation, Y774X, within LTBP3, the gene for the latent TGF-beta binding protein 3, an extracellular matrix protein believed to be required for osteoclast function.

Side Effects Profile in Humans of 11C-(+)-PHNO, a Dopamine D2/3 Agonist Ligand for PET

cation, and standard operating procedure protocols. Consequently, the solutions have to be prepared from highpurity batches, have to be kept in closed vials, and have to be refrigerated or stored at 220 C for a limited time only. If not, the sterility of the Millipore water and the saline solutions is not guaranteed, the composition of the acetone/HCl mixtures will change because of the low boiling points of the compounds, and the acetone in acidic media will undergo an aldol addition reaction forming 4-methyl-3-penten-2-on. We appreciate the effort of Petrik et al. to ‘‘finally’’ identify this well-known product, confirming the standard education of chemistry students (6). If it was the intention of the present letter to the editor to reflect the relevancy of creating and following standard operating procedures for the synthesis of radiopharmaceuticals, we completely agree. Regarding the nontoxic compound 4-methyl-3penten-2-on, Petrik et al. correctly state that its formation is negligible if acetone/HCl mixtures are stored with protection from light at 220 C or if freshly prepared mixtures are used.

Whole-Body Radiation Dosimetry of 11C-Carbonyl-URB694: A PET Tracer for Fatty Acid Amide Hydrolase

11C-carbonyl-URB694 (11C-CURB) is a novel 11C-labeled suicide irreversible radiotracer for PET developed as a surrogate measure of activity of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase. The aim of the study was to investigate the whole-body biodistribution and estimate the radiation dosimetry from 11C-CURB scans in humans. Methods: Six healthy volunteers (3 men and 3 women) completed a single whole-body scan (∼120 min, 9 time frames) on a PET/CT scanner after administration of 11C-CURB (∼350 MBq and ∼2 μg). Time–radioactivity curves were extracted in 11 manually delineated organs and corrected for injected activity, specific organ density, and volume to obtain normalized cumulated activities. OLINDA/EXM 1.1 was used to estimate standard internal dose exposure in each organ. The mean effective dose was calculated using the male and female models for the full sample and female-only sample, respectively. Results: 11C-CURB was well tolerated in all subjects, with no radiotracer-related adverse event reported. The mean effective dose (±SD) was estimated to be 4.6 ± 0.3 μSv/MBq for all subjects and 5.2 ± 0.3 μSv/MBq for the female sample. Organs with the highest normalized cumulated activities (in h) were the liver (0.117), gallbladder wall (0.046), and small intestine (0.033), and organs with the highest dose exposure (in μGy/MBq) were the gallbladder wall (111 ± 60) > liver (21 ± 7), kidney (14 ± 3), and small intestine (12 ± 2). Conclusion: Organ radiation exposure for the irreversible fatty acid amide hydrolase enzyme probe 11C-CURB is within the same range as other radiotracers labeled with 11C, thus allowing for safe, serial PET scans in the same individuals.