Direct comparison of activation maps during galvanic vestibular stimulation: A hybrid H2[15 O] PET-BOLD MRI activation study.

Previous unimodal PET and fMRI studies in humans revealed a reproducible vestibular brain activation pattern, but with variations in its weighting and expansiveness. Hybrid studies minimizing methodological variations at baseline conditions are rare and still lacking for task-based designs. Thus, we applied for the first time hybrid 3T PET-MRI scanning (Siemens mMR) in healthy volunteers using galvanic vestibular stimulation (GVS) in healthy volunteers in order to directly compare H215O-PET and BOLD MRI responses. List mode PET acquisition started with the injection of 750 MBq H215O simultaneously to MRI EPI sequences. Group-level statistical parametric maps were generated for GVS vs. rest contrasts of PET, MR-onset (event-related), and MR-block. All contrasts showed a similar bilateral vestibular activation pattern with remarkable proximity of activation foci. Both BOLD contrasts gave more bilateral wide-spread activation clusters than PET; no area showed contradictory signal responses. PET still confirmed the right-hemispheric lateralization of the vestibular system, whereas BOLD-onset revealed only a tendency. The reciprocal inhibitory visual-vestibular interaction concept was confirmed by PET signal decreases in primary and secondary visual cortices, and BOLD-block decreases in secondary visual areas. In conclusion, MRI activation maps contained a mixture of CBF measured using H215O-PET and additional non-CBF effects, and the activation-deactivation pattern of the BOLD-block appears to be more similar to the H215O-PET than the BOLD-onset.

[18F]Fluciclovine PET/CT: joint EANM and SNMMI procedure guideline for prostate cancer imaging-version 1.0.

The aim of this guideline is to provide standards for the recommendation, performance, interpretation, and reporting of [18F]Fluciclovine PET/CT for prostate cancer imaging. These recommendations will help to improve accuracy, precision, and repeatability of [18F]Fluciclovine PET/CT for prostate cancer essentially needed for implementation of this modality in science and routine clinical practice.

18F-Fluciclovine PET/MRI for preoperative lymph node staging in high-risk prostate cancer patients.

OBJECTIVE: To investigate the diagnostic potential of simultaneous 18F-fluciclovine PET/MRI for pelvic lymph node (LN) staging in patients with high-risk prostate cancer. METHODS: High-risk prostate cancer patients (n=28) underwent simultaneous 18F-fluciclovine PET/MRI prior to surgery. LNs were removed according to a predefined template of eight regions. PET and MR images were evaluated for presence of LN metastases according to these regions. Sensitivity/specificity for detection of LN metastases were calculated on patient and region basis. Sizes of LN metastases in regions with positive and negative imaging findings were compared with linear mixed models. Clinical parameters of PET-positive and -negative stage N1 patients were compared with the Mann-Whitney U test. RESULTS: Patient- and region-based sensitivity/specificity for detection of pelvic LN metastases was 40 %/87.5 % and 35 %/95.7 %, respectively, for MRI and 40 %/100 % and 30 %/100 %, respectively, for PET. LN metastases in true-positive regions were significantly larger than metastases in false-negative regions. PET-positive stage N1 patients had higher metastatic burden than PET-negative N1 patients. CONCLUSION: Simultaneous 18F-fluciclovine PET/MRI provides high specificity but low sensitivity for detection of LN metastases in high-risk prostate cancer patients. 18F-Fluciclovine PET/MRI scan positive for LN metastases indicates higher metastatic burden than negative scan. KEY POINTS: • 18F-Fluciclovine PET/MRI has high specificity for detection of lymph node metastasis. • 18F-Fluciclovine PET/MRI lacks sensitivity to replace ePLND. • 18F-Fluciclovine PET/MRI may be used to aid surgery and select adjuvant therapy. • 18F-Fluciclovine PET-positive patients have more extensive disease than PET-negative patients. • Size of metastatic lymph nodes is an important factor for detection.

Opioid Modulation of Value-Based Decision-Making in Healthy Humans.

Modifying behavior to maximize reward is integral to adaptive decision-making. In rodents, the µ-opioid receptor (MOR) system encodes motivation and preference for high-value rewards. Yet it remains unclear whether and how human MORs contribute to value-based decision-making. We reasoned that if the human MOR system modulates value-based choice, this would be reflected by opposite effects of agonist and antagonist drugs. In a double-blind pharmacological cross-over study, 30 healthy men received morphine (10 mg), placebo, and the opioid antagonist naltrexone (50 mg). They completed a two-alternative decision-making task known to induce a considerable bias towards the most frequently rewarded response option. To quantify MOR involvement in this bias, we fitted accuracy and reaction time data with the drift-diffusion model (DDM) of decision-making. The DDM analysis revealed the expected bidirectional drug effects for two decision subprocesses. MOR stimulation with morphine increased the preference for the stimulus with high-reward probability (shift in starting point). Compared to placebo, morphine also increased, and naltrexone reduced, the efficiency of evidence accumulation. Since neither drug affected motor-coordination, speed-accuracy trade-off, or subjective state (indeed participants were still blinded after the third session), we interpret the MOR effects on evidence accumulation efficiency as a consequence of changes in effort exerted in the task. Together, these findings support a role for the human MOR system in value-based choice by tuning decision-making towards high-value rewards across stimulus domains.

Multisite Experience of the Safety, Detection Rate and Diagnostic Performance of Fluciclovine (18F) Positron Emission Tomography/Computerized Tomography Imaging in the Staging of Biochemically Recurrent Prostate Cancer.

PURPOSE: Sensitive detection of cancer foci in men experiencing biochemical recurrence following initial treatment of prostate cancer is of great clinical significance with a possible impact on subsequent treatment choice. We describe a multisite experience of the efficacy and safety of the positron emission tomography/computerized tomography agent fluciclovine (18F) after biochemical recurrence. MATERIALS AND METHODS: A total of 596 patients underwent fluciclovine (18F) positron emission tomography/computerized tomography at 4 clinical sites. Detection rate determinations were stratified by the baseline prostate specific antigen value. Diagnostic performance was assessed against a histological reference standard in 143 scans. RESULTS: The subject level fluciclovine (18F) positron emission tomography/computer tomography detection rate was 67.7% (403 of 595 scans). Positive findings were detected in the prostate/bed and pelvic lymph node regions in 38.7% (232 of 599) and 32.6% of scans (194 of 596), respectively. Metastatic involvement outside the pelvis was detected in 26.2% of scans (155 of 591). The subject level detection rate in patients in the lowest quartile for baseline prostate specific antigen (0.79 ng/ml or less) was 41.4% (53 of 128). Of these patients 13 had involvement in the prostate/bed only, 16 had pelvic lymph node involvement without distant disease and 24 had distant metastases. The positive predictive value of fluciclovine (18F) positron emission tomography/computerized tomography scanning for all sampled lesions was 62.2%, and it was 92.3% and 71.8% for extraprostatic and prostate/bed involvement, respectively. Fluciclovine (18F) was well tolerated and the safety profile was not altered following repeat administration. CONCLUSIONS: Fluciclovine (18F) is well tolerated and able to detect local and distant prostate cancer recurrence across a wide range of prostate specific antigen values.

The µ-opioid system promotes visual attention to faces and eyes.

Paying attention to others' faces and eyes is a cornerstone of human social behavior. The µ-opioid receptor (MOR) system, central to social reward-processing in rodents and primates, has been proposed to mediate the capacity for affiliative reward in humans. We assessed the role of the human MOR system in visual exploration of faces and eyes of conspecifics. Thirty healthy males received a novel, bidirectional battery of psychopharmacological treatment (an MOR agonist, a non-selective opioid antagonist, or placebo, on three separate days). Eye-movements were recorded while participants viewed facial photographs. We predicted that the MOR system would promote visual exploration of faces, and hypothesized that MOR agonism would increase, whereas antagonism decrease overt attention to the information-rich eye region. The expected linear effect of MOR manipulation on visual attention to the stimuli was observed, such that MOR agonism increased while antagonism decreased visual exploration of faces and overt attention to the eyes. The observed effects suggest that the human MOR system promotes overt visual attention to socially significant cues, in line with theories linking reward value to gaze control and target selection. Enhanced attention to others' faces and eyes represents a putative behavioral mechanism through which the human MOR system promotes social interest.

Sweet taste pleasantness is modulated by morphine and naltrexone.

BACKGROUND: Rodent models highlight the key role of µ-opioid receptor (MOR) signaling in palatable food consumption. In humans, however, the effects of MOR stimulation on eating and food liking remain unclear. OBJECTIVES: Here, we tested sweet pleasantness experience in humans following MOR drug manipulations. We hypothesized that behaviors regulated by the endogenous MOR system would be enhanced by MOR agonism and decreased by antagonism. In line with rodent findings, we expected the strongest drug effects for the sweetest (high-calorie) sucrose stimuli. As very sweet stimuli are considered aversive by many people (called sweet dislikers), we also assessed whether MOR manipulations affect pleasantness ratings of sucrose-water stimuli differently depending on subjective and objective value. METHODS: In a bidirectional psychopharmacological cross-over study, 49 healthy men underwent a sweet taste paradigm following double-blind administration of the MOR agonist morphine, placebo, and the opioid antagonist naltrexone. RESULTS: As hypothesized, MOR stimulation with morphine increased pleasantness of the sweetest of five sucrose solutions, without enhancing pleasantness of the lower-sucrose solutions. For opioid antagonism, an opposite pattern was observed for the sweetest drink only. The observed drug effects on pleasantness of the sweetest drink did not differ between sweet likers and dislikers. CONCLUSIONS: The bidirectional effect of agonist and antagonist treatment aligns with rodent findings showing that MOR manipulations most strongly affect the highest-calorie foods. We speculate that the MOR system promotes survival in part by increasing concordance between the objective (caloric) and subjective (hedonic) value of food stimuli, so that feeding behavior becomes more focused on the richest food available.

Synthesis and evaluation of three structurally related ¹8F-labeled orvinols of different intrinsic activities: 6-O-[¹8F]fluoroethyl-diprenorphine ([¹8F]FDPN), 6-O-[¹8F]fluoroethyl-buprenorphine ([¹8F]FBPN), and 6-O-[¹8F]fluoroethyl-phenethyl-orvinol ([¹8F]FPEO).

We report the synthesis and biological evaluation of a triplet of 6-O-(18)F-fluoroethylated derivatives of structurally related orvinols that span across the full range of intrinsic activities, the antagonist diprenorphine, the partial agonist buprenorphine, and the full agonist phenethyl-orvinol. [(18)F]fluoroethyl-diprenorphine, [(18)F]fluoroethyl-buprenorphine, and [(18)F]fluoroethyl-phenethyl-orvinol were prepared in high yields and quality from their 6-O-desmethyl-precursors. The results indicate suitable properties of the three 6-O-(18)F-fluoroethylated derivatives as functional analogues to the native carbon-11 labeled versions with similar pharmacological properties.

A fully automated radiosynthesis of [18F]fluoroethyl-diprenorphine on a single module by use of SPE cartridges for preparation of high quality 2-[18F]fluoroethyl tosylate.

We have developed a new method for automated production of 2-[18F]fluoroethyl tosylate ([18F]FETos) that enables 18F-alkylation to provide PET tracers with high chemical purity. The method is based on the removal of excess ethylene glycol bistosylate precursor by precipitation and subsequent filtration and purification of the filtrate by means of solid phase extraction cartridges (SPE). The method is integrated to a single synthesis module and thereby provides the advantage over previous methods of not requiring HPLC purification, as demonstrated by the full radiosynthesis of the potent opioid receptor PET tracer [18F]fluoroethyldiprenorphine.

Correction of partial volume effect in (18)F-FDG PET brain studies using coregistered MR volumes: voxel based analysis of tracer uptake in the white matter.

A voxel-based algorithm to correct for partial volume effect in PET brain volumes is presented. This method (named LoReAn) is based on MRI based segmentation of anatomical regions and accurate measurements of the effective point spread function of the PET imaging process. The objective is to correct for the spill-out of activity from high-uptake anatomical structures (e.g. grey matter) into low-uptake anatomical structures (e.g. white matter) in order to quantify physiological uptake in the white matter. The new algorithm is presented and validated against the state of the art region-based geometric transfer matrix (GTM) method with synthetic and clinical data. Using synthetic data, both bias and coefficient of variation were improved in the white matter region using LoReAn compared to GTM. An increased number of anatomical regions doesn't affect the bias (<5%) and misregistration affects equally LoReAn and GTM algorithms. The LoReAn algorithm appears to be a simple and promising voxel-based algorithm for studying metabolism in white matter regions.

Anatomical standardization of small animal brain FDG-PET images using synthetic functional template: experimental comparison with anatomical template.

Anatomical standardization (also called spatial normalization) of positron emission tomography (PET) small animal brain images is required to make statistical comparisons across individuals. Frequently, PET images are co-registered to an individual MR or CT image of the same subject in order to transform the functional images to an anatomical space. In the present work, we evaluate the normalization of synthetic PET (synPET) images to a synthetic PET template. To provide absolute error in terms of pixel misregistration, we created a synthetic PET image from the individual MR image through segmentation of the brain into gray and white matter which produced functional and anatomical images in the same space. When comparing spatial normalization of synPET images to a synPET template with the gold standard (MR images to an MR template), a mean translation error of 0.24mm (±0.20) and a maximal mean rotational error of 0.85° (±0.91) were found. Significant decrease in misregistration error was measured when achieving spatial normalization of functional images to a functional template instead of an anatomical template. This accuracy strengthens the use of standardization methods where individual PET images are registered to a customized PET template in order to statistically assess physiological changes in rat brains.

Spinal long-term potentiation is associated with reduced opioid neurotransmission in the rat brain.

INTRODUCTION: Neuronal events leading to development of long-term potentiation (LTP) in the nociceptive pathways may be a cellular mechanism underlying hyperalgesia. In the present study, we examine if induction of spinal LTP may be associated with functional changes in the supraspinal opioidergic system. The opioid receptors (ORs) play a key role in nociceptive processing and controlling the descending modulatory system to the spinal cord. METHODS: Spinal LTP was induced by electrical high-frequency stimulation (HFS) conditioning applied to the sciatic nerve, and the excitability at spinal level was verified by spinal field potential recordings. To study supraspinal changes in opioid neurotransmission following the same HFS conditioning, we used small animal positron emission tomography (PET) and [(11)C]Phenethyl-Orvinol ([(11)C]PEO). All rats included in the PET study were scanned at baseline and 150 min after HFS, and specific binding was calculated with a reference tissue model. RESULTS: A clear C-fibre LTP, i.e. increased C-fibre response and reduced C-fibre threshold, was observed 150 min after HFS conditioning (t-test, P<0.05, n = 6). Moreover, increased OR binding, relative to baseline, was observed after the same type of HFS conditioning ipsilaterally in the amygdala, hippocampus, somatosensory cortex and superior colliculus, and bilaterally in the nucleus accumbens, caudate putamen and hypothalamus (paired t-test, HFS>baseline, P<0.05, n = 8). CONCLUSIONS: HFS conditioning of the sciatic nerve resulted in both spinal LTP and functional changes in supraspinal opioidergic signalling. Our findings suggest that induction of spinal LTP may be associated with reduced opioid neurotransmission in brain regions involved in pain modulation and affective-emotional responses.

Evaluation of the kappa-opioid receptor-selective tracer [(11)C]GR103545 in awake rhesus macaques.

PURPOSE: The recent development in radiosynthesis of the (11)C-carbamate function increases the potential of [(11)C]GR103545, which for the last decade has been regarded as promising for imaging the kappa-opioid receptor (kappa-OR) with PET. In the present study, [(11)C]GR103545 was evaluated in awake rhesus macaques. Separate investigations were performed to clarify the OR subtype selectivity of this compound. METHODS: Regional brain uptake kinetics of [(11)C]GR103545 was studied 0-120 min after injection. The binding affinity and opioid subtype selectivity of [(11)C]GR103545 was determined in cells transfected with cloned human opioid receptors. RESULTS: In vitro binding assays demonstrated a high affinity of GR103545 for kappa-OR (K(i) = 0.02 +/- 0.01 nM) with excellent selectivity over mu-OR (6 x 10(2)-fold) and) delta-OR (2 x 10(4)-fold). PET imaging revealed a volume of distribution (V(T)) pattern consistent with the known distribution of kappa-OR, with striatum = temporal cortex > cingulate cortex > frontal cortex > parietal cortex > thalamus > cerebellum. CONCLUSION: [(11)C]GR103545 is selective for kappa-OR and holds promise for use to selectively depict and quantify this receptor in humans by means of PET.

Synthesis and evaluation of a full-agonist orvinol for PET-imaging of opioid receptors: [11C]PEO.

Antagonist radiotracers have shown only a low sensitivity for detecting competition from high-efficacy agonists at opioid receptors (ORs) in vivo. We report that [(11)C]PEO binds with high affinity to mu and kappa-opioid receptors, is a full agonist, and concentrates in brain regions of rats with a high density of the mu-OR after intravenous injection. Blocking studies with mu and kappa-OR selective compounds demonstrated that the binding of [(11)C]PEO is saturable and selective to the mu-OR in rat brain.

Metabolic plasticity in the supraspinal pain modulating circuitry after noxious stimulus-induced spinal cord LTP.

It has been suggested that spinal cord long-term potentiation (LTP) may contribute to hypersensitivity and hyperalgesia. We have investigated if noxious stimulus-induced spinal cord LTP might have a long lasting effect on supraspinal neuronal activity. First, we verified that spinal LTP was induced by electrical high frequency stimuli (HFS) conditioning applied to the sciatic nerve. The C-fibre response in the dorsal horn reached a twofold increase 150 min after HFS (t-test, p<0.01, n=6). Then, to study the metabolic supraspinal activity following the same stimulation protocol, we used small animal positron emission tomography (PET) and the glucose analog [(18)F]-fluorodeoxyglucose (FDG). With this combined approach we measured changes in regional supraspinal activity at two time points in HFS conditioned and in sham animals; acute (immediately after HFS/sham, n=4) and late phase (150 min after HFS/sham, n=10). Comparisons between HFS and sham groups revealed that induction of spinal LTP was followed by an acute metabolic response in the primary somatosensory cortex (S1), but also various slower metabolic adaptations in brain regions involved in modulation of nociceptive signaling and descending inhibition, i.e., amygdala, periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT) (t-test, p<0.05). The study demonstrates that PET may be used as an in vivo method to study regional brain metabolic activity between different conditions. It is concluded that noxious sciatic stimuli which induce spinal cord LTP also affect supraspinal metabolic activity. We suggest that these changes might illustrate a supraspinal maladaptive dysfunction involved in pain hypersensitivity and hyperalgesia.

Positron emission tomography ligand activation studies in the sports sciences: measuring neurochemistry in vivo.

Functional neuroimaging with magnetic resonance imaging (fMRI) or positron emission tomography (PET) provides the methodology to unravel some of the fascinating, but hitherto largely unresolved interactions between physical exercise and brain function. Phenomena such as raised mood, pain modulation, and sport addiction associated with physical exercise are highly interesting psychophysical models that require further in depth understanding at the neurotransmitter level. PET ligand displacement studies allow in vivo monitoring of endogenous transmitter trafficking in the entire brain and, thereby, to identify the link between exercise-induced behavioral measures and the endogenous neurotransmitter release. This review focuses on the methodology of ligand displacement in the opioidergic system, which together with the dopaminergic system has been considered as a central neurotransmitter system underlying diverse sport-induced psychophysical effects. Understanding the basic principles of exercise-induced transmitter release in the brain will potentially aid clinical applications of endurance training, both as a preventative or therapeutic intervention.

Imaging of opioid receptors in the central nervous system.

In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of mu-, kappa and delta-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation--mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs--have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging.

Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil.

BACKGROUND: Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used O-water and positron emission tomography to investigate dose-dependent effects of the short-acting mu-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers. METHODS: Positron emission tomography measurements were performed with injection of 7 mCi O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 microg x kg x min remifentanil, and 0.15 microg x kg x min remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach. RESULTS: During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray. CONCLUSIONS: Remifentanil induced regional cerebral blood flow increases in the cingulofrontal cortex and periaqueductal gray during pain stimulation, indicating that mu-opioidergic activation modulates activity in pain inhibitory circuitries. This provides direct evidence that opioidergic analgesia is mediated by activation of established descending antinociceptive pathways.