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Efforts to build the next generation of brain PET scanners are underway. It is expected that a new scanner (NS) will offer an order-of-magnitude improvement in sensitivity to counts compared to the current state-of-the-art, Siemens HRRT. Our goal was to explore the use of the anticipated increased sensitivity in combination with the linear-parametric neurotransmitter PET (lp-ntPET) model to improve detection and classification of transient dopamine (DA) signals. We simulated striatal [11C]raclopride PET data to be acquired on a future NS which will offer ten times the sensitivity of the HRRT. The simulated PET curves included the effects of DA signals that varied in start-times, peak-times, and amplitudes. We assessed the detection sensitivity of lp-ntPET to various shapes of DA signal. We evaluated classification thresholds for their ability to separate 'early'- versus 'late'-peaking, and 'low'- versus 'high'-amplitude events in a 4D phantom. To further refine the characterization of DA signals, we developed a weighted k-nearest neighbors (wkNN) algorithm to incorporate information from the neighborhood around each voxel to reclassify it, with a level of certainty. Our findings indicate that the NS would expand the range of detectable neurotransmitter events to 72%, compared to the HRRT (31%). Application of wkNN augmented the detection sensitivity to DA signals in simulated NS data to 92%. This work demonstrates that the ultra-high sensitivity expected from a new generation of brain PET scanner, combined with a novel classification algorithm, will make it possible to accurately detect and classify short-lived DA signals in the brain based on their amplitude and timing. [ABSTRACT FROM AUTHOR]

For radioligands without a reference region, the Lassen plot can be used to estimate receptor occupancy by an exogenous drug ( O Drug ). However, the Lassen plot is not well-suited for spatial variation in O Drug . To overcome this limitation, we introduce a Lassen plot filter, i.e. a Lassen plot applied to local neighborhoods in PET images. Image data were simulated with regional variation in V N D , O Drug , both, or neither and analyzed using the change in binding potential ( Δ B P N D ), the conventional Lassen plot, and the Lassen plot filter at the region of interest (ROI) and voxel level. All methods were also applied to a human [11C]flumazenil occupancy study using PF-06372865. This combination of a non-selective radioligand and selective drug should lead to varying O Drug provided the distribution of subtypes varies spatially. In contrast with Δ B P N D and the conventional Lassen plot, ROI-level and voxel-level Lassen plot filter estimates remained unbiased in the presence of regional variation in V N D or O Drug . In the [11C]flumazenil data-set, O Drug was shown to vary regionally in accordance with the distribution of binding sites for [11C]flumazenil and PF-06372865. We demonstrate that a local-neighborhood Lassen plot filter provides robust and unbiased estimates of O Drug and V N D without the need for any user intervention. [ABSTRACT FROM AUTHOR]

Linear parametric neurotransmitter PET (lp-ntPET) is a novel kinetic model that estimates the temporal characteristics of a transient neurotransmitter component in PET data. To preserve computational simplicity in estimation, the parameters of the nonlinear term that describe this transient signal are discretized, and only a limited set of values for each parameter are allowed. Thus, linear estimation can be performed. Linear estimation is implemented using predefined basis functions that incorporate the discretized parameters. The implementation of the model using discretized parameters poses unique challenges for significance testing. Significance testing employs model comparison metrics to determine the significance of the improvement of the fit accomplished by including a basis function, i.e. it determines the presence of a transient signal in the PET data. A false positive occurs when the bases overfit data that do not contain a transient component. The number of parameters in a model, p, is necessary to determine the degrees of freedom in the model. In turn, p is crucial for the calculation of model selection metrics and controlling the false positive rate (FPR). In this work, we first explore the effect of parameter discretization on FPR by fitting simulated null data with varying numbers of bases. We demonstrate the dependence of FPR on number of bases. Then, we propose a correction to the number of parameters in the model, ${p}^{{\textit {eff}}}$ , which adapts to the number of bases used. Implementing model selection with ${p}^{{\textit {eff}}}$ maintains a stable FPR independent of number of bases. [ABSTRACT FROM AUTHOR]

We examined the effect of 28 days of overload on mammalian target of rapamycin (mTOR) and extracellular signal–regulated kinase (ERK) signaling in young adult (Y; 6-month old) and aged (O; 30-month old) Fischer 344 × Brown Norway rats subjected to bilateral synergist ablation (SA) of two thirds of the gastrocnemius muscle or sham surgery (CON). Although plantaris (PLA) muscle hypertrophy was attenuated by aging, mTOR phosphorylation was 44% and 35% greater in Y SA and O SA compared with CON (p = .038). Ribosomal protein S6 phosphorylation was 114% and 24% higher in Y SA and O SA compared with CON (p = .009). Eukaryotic initiation factor 2Bε phosphorylation was 33% and 9% higher in Y SA and O SA compared with CON (p = .04). Translational signaling in young adult and aged plantaris muscle is equally responsive to chronic overload. [ABSTRACT FROM PUBLISHER]

Abstract: Ground conductivity meters such as the Geonics EM-31 and EM-38 are used to measure apparent soil conductivity. Various agriculturally useful soil properties can be estimated from these readings. For most surveys the instruments are placed as close to the ground as possible. One of the advantages of increasing the instrument height is that the depth of penetration of the instrument increases. However, increasing the height of the instruments also reduces the magnitude of the apparent conductivity readings. If conductivity varies in a field, the decrease in amplitude will decrease the size of the conductivity differences. This makes it harder to discriminate between soils with different conductivities when the conductivity differences are small. Creating a map of conductivity ratios which divide conductivity values throughout a field by a typical conductivity in one area of the field avoids this problem. Conductivity ratio maps make it easy to map spatial variations in conductivity. Increasing the instrument height has little effect on the ratio maps, even at heights of 1m. This technique is most useful under non-saline conditions when conductivity differences between soil types may be small. [Copyright &y& Elsevier]

Background: The mesolimbic dopamine (DA) system is implicated in the development and maintenance of alcohol drinking; however, the exact mechanisms by which DA regulates human alcohol consumption are unclear. This study assessed the distinct effects of alcohol-related cues and alcohol administration on striatal DA release in healthy humans. Methods: Subjects underwent 3 PET scans with [11C]raclopride (RAC). Subjects were informed that they would receive either an IV Ringer's lactate infusion or an alcohol (EtOH) infusion during scanning, with naturalistic visual and olfactory cues indicating which infusion would occur. Scans were acquired in the following sequence: (1) Baseline Scan: Neutral cues predicting a Ringer’s lactate infusion, (2) CUES Scan: Alcohol-related cues predicting alcohol infusion in a Ringer’s lactate solution, but with alcohol infusion after scanning to isolate the effects of cues, and (3) EtOH Scan: Neutral cues predicting Ringer's, but with alcohol infusion during scanning (to isolate the effects of alcohol without confounding expectation or craving). Results: Relative to baseline, striatal DA concentration decreased during CUES, but increased during EtOH. Conclusion: While the results appear inconsistent with some animal experiments showing dopaminergic responses to alcohol’s conditioned cues, they can be understood in the context of the hypothesized role of the striatum in reward prediction error, and of animal studies showing that midbrain dopamine neurons decrease and increase firing rates during negative and positive prediction errors, respectively. We believe that our data are the first in humans to demonstrate such changes in striatal DA during reward prediction error. [ABSTRACT FROM AUTHOR]

The article presents research on the effect of government fiscal policy, particularly the taxation of corporations, on the decisions of businesses to locate operations in a particular locality, region, or country. Competition for such businesses has become acute due to globalization. Economic indicators from five U.S. states strongly suggest that corporate taxation rates are but one of many factors determining a business's decision on location. Persistently higher wage rates in Ontario compared to U.S. states is primarily due to the foreign exchange rate between the U.S. and Canada rather than the province's taxation and labor laws.

Abstract: We recently introduced neurotransmitter PET (ntPET), an analysis technique that estimates the kinetics of stimulus-induced neurotransmitter (NT) release. Here, we evaluate two formulations of ntPET. The arterial (ART) approach measures the tracer input function (TIF) directly. The reference (REF) approach derives the TIF from reference region data. Arterial sampling is considered the gold standard in PET modeling but reference region approaches are preferred for reduced cost and complexity. If simulated PET data with unbiased TIFs were analyzed using ART or REF, temporal precision was better than 3 min provided NT concentration peaked less than 30 min into the scanning session. The consequences of biased TIFs or stimulus-induced changes in tracer delivery were also evaluated. ART TIFs were biased by the presence of uncorrected radiometabolites in the plasma whereas REF TIFs were biased by specific binding in the reference region. Simulated changes in tracer delivery emulated ethanol-induced blood flow alterations observed previously with PET. ART performance deteriorated significantly if metabolites amounted to 50% of plasma radioactivity by 60 min. The accuracy and precision of REF were preserved even if the reference region contained 40% of the receptor density of the target region. Both methods were insensitive to blood flow alterations (proportional changes in K 1 and k 2). Our results suggest that PET data contain information – heretofore not extracted – about the timing of NT release. The REF formulation of ntPET proved to be robust to many plausible model violations and under most circumstances is an appropriate alternative to ART. [Copyright &y& Elsevier]

There is great interest in positron emission tomography (PET) as a noninvasive assay of fluctuations in synaptic neurotransmitter levels, but questions remain regarding the optimal choice of tracer for such a task. A mathematical method is proposed for predicting the utility of any PET tracer as a detector of changes in the concentration of an endogenous competitor via displacement of the tracer (a.k.a., its ‘vulnerability’ to competition). The method is based on earlier theoretical work by Endres and Carson and by the authors. A tracer-specific predictor, the PET Displacement Sensitivity (PDS), is calculated from compartmental model simulations of the uptake and retention of dopaminergic radiotracers in the presence of transient elevations of dopamine (DA). The PDS predicts the change in binding potential (ΔBP) for a given change in receptor occupancy because of binding by the endogenous competitor. Simulations were performed using estimates of tracer kinetic parameters derived from the literature. For D2/D3 tracers, the calculated PDS indices suggest a rank order for sensitivity to displacement by DA as follows: raclopride (highest sensitivity), followed by fallypride, FESP, FLB, NMSP, and epidepride (lowest). Although the PDS takes into account the affinity constant for the tracer at the binding site, its predictive value cannot be matched by either a single equilibrium constant, or by any one rate constant of the model. Values for ΔBP have been derived from published studies that employed comparable displacement paradigms with amphetamine and a D2/D3 tracer. The values are in good agreement with the PDS-predicted rank order of sensitivity to displacement.Journal of Cerebral Blood Flow & Metabolism (2007) 27, 606–617. doi:10.1038/sj.jcbfm.9600359; published online 21 June 2006 [ABSTRACT FROM AUTHOR]

We present a new application of positron emission tomography ("ntPET" or "neurotransmitter PET") designed to recover temporal patterns of neurotransmitter release from dynamic data. Our approach employs an enhanced tracer kinetic model that describes uptake of a labeled dopamine D2/D3 receptor ligand in the presence of a time-varying rise and fall in endogenous dopamine. Data must be acquired during both baseline and stimulus (transient dopamine release) conditions. Data from a reference region in both conditions are used as an input function, which alleviates the need for any arterial blood sampling. We use simulation studies to demonstrate the ability of the method to recover the temporal characteristics of an increase in dopamine concentration that might be expected following a drug treatment. The accuracy and precision of the method--as well as its potential for false-positive responses due to noise or changes in blood flow--were examined. Finally, we applied the ntPET method to small-animal imaging data in order to produce the first noninvasive assay of the time-varying release of dopamine in the rat striatum following alcohol. Mol Imaging (2005) 4, 473-489. [ABSTRACT FROM AUTHOR]

Understanding the neurobiological effects of stress is critical for addressing the etiology of major depressive disorder (MDD). Using a dimensional approach involving individuals with differing degree of MDD risk, we investigated 1) the effects of acute stress on cortico-cortical and subcortical-cortical functional connectivity (FC) and 2) how such effects are related to gene expression and receptor maps. Across 115 participants (37 control, 39 remitted MDD, 39 current MDD), we evaluated the effects of stress on FC during the Montreal Imaging Stress Task. Using partial least squares regression, we investigated genes whose expression in the Allen Human Brain Atlas was associated with anatomical patterns of stress-related FC change. Finally, we correlated stress-related FC change maps with opioid and GABA A (gamma-aminobutyric acid A) receptor distribution maps derived from positron emission tomography. Results revealed robust effects of stress on global cortical connectivity, with increased global FC in frontoparietal and attentional networks and decreased global FC in the medial default mode network. Moreover, robust increases emerged in FC of the caudate, putamen, and amygdala with regions from the ventral attention/salience network, frontoparietal network, and motor networks. Such regions showed preferential expression of genes involved in cell-to-cell signaling (OPRM1 , OPRK1 , SST , GABRA3 , GABRA5), similar to previous genetic MDD studies. Acute stress altered global cortical connectivity and increased striatal connectivity with cortical regions that express genes that have previously been associated with imaging abnormalities in MDD and are rich in μ and κ opioid receptors. These findings point to overlapping circuitry underlying stress response, reward, and MDD. [ABSTRACT FROM AUTHOR]

Background: Drug occupancy studies with positron emission tomography imaging are used routinely in early phase drug development trials. Recently, our group introduced the Lassen Plot Filter, an extended version of the standard Lassen plot to estimate voxel-level occupancy images. Occupancy images can be used to create an EC50 image by applying an Emax model at each voxel. Our goal was to apply functional clustering of occupancy images via a clustering algorithm and produce a more precise EC50 image while maintaining accuracy. Method: A digital brain phantom was used to create 10 occupancy images (corresponding to 10 different plasma concentrations of drug) that correspond to a ground truth EC50 image containing two bilateral local "hot spots" of high EC50 (region-1: 25; region-2: 50; background: 6–10 ng/mL). Maximum occupancy was specified as 0.85. An established noise model was applied to the simulated occupancy images and the images were smoothed. Simple Linear Iterative Clustering, an existing k-means clustering algorithm, was modified to segment a series of occupancy images into K clusters (which we call "SLIC-Occ"). EC50 images were estimated by nonlinear estimation at each cluster (post SLIC-Occ) and voxel (no clustering). Coefficient of variation images were estimated at each cluster and voxel, respectively. The same process was also applied to human occupancy data produced for a previously published study. Results: Variability in EC50 estimates was reduced by more than 80% in the phantom data after application of SLIC-Occ to occupancy images with only minimal loss of accuracy. A similar, but more modest improvement was achieved in variability when SLIC-Occ was applied to human occupancy images. Conclusions: Our results suggest that functional segmentation of occupancy images via SLIC-Occ could produce more precise EC50 images and improve our ability to identify local "hot spots" of high effective affinity of a drug for its target(s). [ABSTRACT FROM AUTHOR]

Introduction Tobacco smoking is a major public health burden. The mesocortical dopamine system—including the dorsolateral prefrontal cortex (dlPFC)—plays an important role in cognitive function. Dysregulated dopamine signaling in dlPFC is associated with cognitive deficits such as impairments in attention, learning, working memory, and inhibitory control. We recently showed that dlPFC dopamine D2/3-type receptor (D2R) availability was significantly lower in people who smoke than in healthy-controls and that dlPFC amphetamine-induced dopamine release was lower in females who smoke relative to males who smoke and female healthy-controls. However, we did not examine whether the smoking-related dopamine deficits were related to cognitive deficits. Aims and Methods The goal of this study was to relate dopamine metrics to cognitive performance in people who smoke and healthy-controls. In total 24 (12 female) people who smoke cigarettes and 25 sex- and age-matched healthy-controls participated in two same-day [11C]FLB457 positron emission tomography (PET) scans before and after amphetamine administration. Two outcome measures were calculated—D2R availability (non-displaceable binding potential; BP ND ) and amphetamine-induced dopamine release (%Δ BP ND ). Cognition (verbal learning and memory) was assessed with a computerized test from the CogState battery (International Shopping List). Results People who smoke had significantly worse immediate (p =.04) and delayed (p =.03) recall than healthy-controls. Multiple linear regression revealed that for people who smoke only, lower D2R availability was associated with worse immediate (p =.04) and delayed (p <.001) recall. %Δ BP ND was not significantly related to task performance. Conclusion This study demonstrated that lower dlPFC D2R availability in people who smoke is associated with disruptions in cognitive function that may underlie difficulty with resisting smoking. Implications This is the first study to directly relate dopamine metrics in the prefrontal cortex to cognitive function in people who smoke cigarettes compared to healthy-controls. The current work included a well-characterized subject sample with regards to demographic and smoking variables, as well as a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature by relating dopamine metrics to cognition in people who smoke, providing a better understanding of brain-behavior relationships. [ABSTRACT FROM AUTHOR]

PF‐05212377 (SAM760) is a potent and selective 5‐HT6 antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF‐05212377 was determined to be a P‐gp/non‐BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF‐05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu/Cpu) of 0.05 in rat and 0.64 in non‐human primates (NHP). Based on pre‐clinical evidence, brain penetration and target engagement of PF‐05212377 was confirmed in NHP using positron emission tomography (PET) measured 5‐HT6 receptor occupancy (%RO). The NHP Cpu EC50 of PF‐05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki: 0.32 nM). P‐gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non‐human primates and human; brain penetration of PF‐05212377 in humans was postulated to be similar to that in non‐human primates. In humans, PF‐05212377 demonstrated dose and concentration dependent increases in 5‐HT6 RO; maximal 5‐HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding Ki 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF‐05212377, a P‐gp/non‐BCRP substrate. Clinical trial number: NCT01258751. [ABSTRACT FROM AUTHOR]

• Lipopolysaccharide (LPS)-induced systemic inflammation affects dopamine. • LPS enhanced methylphenidate-induced dopamine elevation in striatum in smokers. • This study translated this phenomenon from healthy individuals to smokers. • This may have implications for drug reinforcement, seeking, and treatment. Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [11C]raclopride positron emission tomography three times—at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [11C]raclopride binding potential (ΔBP ND) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment. [ABSTRACT FROM AUTHOR]

Introduction: Tobacco smoking is a major public health burden. The first-line pharmacological treatment for tobacco smoking is nicotine replacement therapy (eg, the nicotine patch (NIC)). Nicotine acts on nicotinic-acetylcholine receptors on dopamine terminals to release dopamine in the ventral and dorsal striatum encoding reward and habit formation, respectively.Aims and Methods: To better understand treatment efficacy, a naturalistic experimental design combined with a kinetic model designed to characterize smoking-induced dopamine release in vivo was used. Thirty-five tobacco smokers (16 female) wore a NIC (21 mg, daily) for 1-week and a placebo patch (PBO) for 1-week in a randomized, counter-balanced order. Following 1-week under NIC and then overnight abstinence, smokers participated in a 90-minute [11C]raclopride positron emission tomography scan and smoked a cigarette while in the scanner. Identical procedures were followed for the PBO scan. A time-varying kinetic model was used at the voxel level to model transient dopamine release peaking instantaneously at the start of the stimulus and decaying exponentially. Magnitude and spatial extent of dopamine release were estimated. Smokers were subcategorized by nicotine dependence level and nicotine metabolism rate.Results: Dopamine release magnitude was enhanced by NIC in ventral striatum and diminished by NIC in dorsal striatum. More-dependent smokers activated more voxels than the less-dependent smokers under both conditions. Under PBO, fast metabolizers activated more voxels in ventral striatum and fewer voxels in dorsal striatum compared to slow metabolizers.Conclusions: These findings demonstrate that the model captured a pattern of transient dopamine responses to cigarette smoking which may be different across smoker subgroup categorizations.Implications: This is the first study to show that NIC alters highly localized patterns of cigarette smoking-induced dopamine release and that levels of nicotine dependence and nicotine clearance rate contribute to these alterations. This current work included a homogeneous subject sample with regards to demographic and smoking variables, as well as a highly sensitive model capable of detecting significant acute dopamine transients. The findings of this study add support to the recent identification of biomarkers for predicting the effect of nicotine replacement therapies on dopamine function which could help refine clinical practice for smoking cessation. [ABSTRACT FROM AUTHOR]

Background: The relationship between alcohol and pain is complex. Associations between pain and alcohol use disorder (AUD) vary by race, but the underlying biological basis is not understood. We examined the association of the kappa opioid receptor (KOR) with responses to the cold‐pressor test (CPT), before and after treatment with the opioid antagonist naltrexone, among individuals with AUD who self‐identified as Black or White. Methods: Thirty‐seven individuals (12 Black, 24 White, and 1 Multiracial) with AUD participated in two CPTs, separated by 1 week during which they received naltrexone 100 mg daily. During each CPT, pain reporting threshold (PRT), average pain increase rate (APIR), relative pain recovery (RPR), and alcohol craving were recorded. KOR availability was measured using [11C]‐LY2795050 positron emission tomography (PET) prior to treatment with naltrexone. Results: Black participants reported higher PRT and APIR than White participants during the CPT before, but not after, naltrexone treatment. Among Black participants, KOR availability was positively associated with PRT and APIR before, but not after naltrexone. Greater KOR availability was associated with faster RPR for White, but not Black, participants. The CPT induced more alcohol craving in Black than White participants, particularly in individuals with low KOR availability, an effect that was not attenuated by naltrexone. Conclusions: KOR involvement and naltrexone effects on responses to the CPT were different between Black and White participants. These preliminary findings suggest that further exploration of the differences in the opioid system and pain among Black and White individuals with AUD and their relationship with naltrexone's effects is warranted. [ABSTRACT FROM AUTHOR]

Background: There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [11C]raclopride with older data. This typically means harmonizing data across different scanners. Previous harmonization studies have utilized either phantoms or human subjects, but the use of both phantoms and humans in one harmonization study is not common. The purpose herein was (1) to use phantom images to develop an inter-scanner harmonization technique and (2) to test the harmonization technique in human subjects. Methods: To develop the harmonization technique (Experiment 1), the Iida brain phantom was filled with F-18 solution and scanned on the two scanners in question (HRRT, HR+, Siemens/CTI). Phantom images were used to determine the optimal isotropic Gaussian filter to harmonize HRRT and HR+ images. To evaluate the harmonization on human images (Experiment 2), inter-scanner variability was calculated using [11C]raclopride scans of 3 human subjects on both the HRRT and HR+ using percent difference (PD) in striatal non-displaceable binding potential (BPND) between HR+ and HRRT (with and without Gaussian smoothing). Finally, (Experiment 3), PDT/RT was calculated for test–retest (T/RT) variability of striatal BPND for 8 human subjects scanned twice on the HR+. Results: Experiment 1 identified the optimal filter as a Gaussian with a 4.5 mm FWHM. Experiment 2 resulted in 13.9% PD for unfiltered HRRT and 3.71% for HRRT filtered with 4.5 mm. Experiment 3 yielded 5.24% PDT/RT for HR+. Conclusions: The PD results show that the variability of harmonized HRRT is less than the T/RT variability of the HR+. The harmonization technique makes it possible for BPND estimates from the HRRT to be compared to (and/or combined with) those from the HR+ without adding to overall variability. Our approach is applicable to all pairs of scanners still in service. [ABSTRACT FROM AUTHOR]

Abstract: The parametric ntPET model (p-ntPET) estimates the kinetics of neurotransmitter release from dynamic PET data with receptor–ligand radiotracers. Here we introduce a linearization (lp-ntPET) that is computationally efficient and can be applied to single scan data. lp-ntPET employs a non-invasive reference region input function and extends the LSRRM of Alpert et al. (2003) using basis functions to characterize the time course of neurotransmitter activation. In simulation studies, the temporal precision of neurotransmitter profiles estimated by lp-ntPET was similar to that of p-ntPET (standard deviation ~3min for responses early in the scan) while computation time was reduced by several orders of magnitude. Violations of model assumptions such as activation-induced changes in regional blood flow or specific binding in the reference tissue have negligible effects on lp-ntPET performance. Application of the lp-ntPET method is demonstrated on [11C]raclopride data acquired in rats receiving methamphetamine, which yielded estimated response functions that were in good agreement with simultaneous microdialysis measurements of extracellular dopamine concentration. These results demonstrate that lp-ntPET is a computationally efficient, linear variant of ntPET that can be applied to PET data from single or multiple scan designs to estimate the time course of neurotransmitter activation. [Copyright &y& Elsevier]

Abstract: [11C]Raclopride ([11C]RAC) is a selective dopamine D2/D3 antagonist that is commonly used in positron emission tomography (PET) studies to assess both basal levels of receptor availability and changes in availability caused by alterations in striatal dopamine concentration. When designing [11C]RAC studies, it is important to understand what variables may affect the results. Here, we examined differences in baseline striatal [11C]RAC binding potential (BPND) under two different “rest” conditions. Thirteen subjects received [11C]RAC scans. Eight subjects were aware prior to initiation of scanning that they would receive a “baseline” scan, and that no additional procedures would take place during the scan (“certain rest” group, CER). Five subjects were informed that they might or might not receive an IV alcohol infusion during the scan (“uncertain rest” group, UNC). This group was informed five min after scan start that they would not receive alcohol. Voxel-wise analyses of binding potential (BPND) images generated for both “rest” conditions indicated that receptor availability was higher in UNC than in CER. This result was confirmed by a region-of-interest analysis, which indicated that the average BPND in right and left putamen was statistically higher in UNC. There were no differences in groups with respect to age or raclopride mass dose that could account for the difference in D2/D3 receptor availability. Our findings suggest that even slight differences in cognitive states between groups can have an effect on BPND, presumably mediated by changes in endogenous dopamine concentration. [Copyright &y& Elsevier]

We have developed a nonparametric approach to the analysis of dynamic positron emission tomography (PET) data for extracting temporal characteristics of the change in endogenous neurotransmitter concentration in the brain. An algebraic method based on singular value decomposition (SVD) was applied to simulated data under both rest (neurotransmitter at baseline) and activated (transient neurotransmitter release) conditions. The resulting signals are related to the integral of the change in free neurotransmitter concentration in the tissue. Therefore, a specially designed minimum mean-square error (MMSE) filter must be applied to the signals to recover the desired temporal pattern of neurotransmitter change. To test the method, we simulated sets of realistic time activity curves representing uptake of [11C]raclopride, a dopamine (DA) receptor antagonist, in brain regions, under baseline and dopamine-release conditions. Our tests considered two scenarios: 1) a spatially homogeneous pattern with all voxels in the activated state presenting an identical DA signal; 2) a spatially heterogeneous pattern in which different DA signals were contained in different families of voxels. In the first case, we demonstrated that the timing of a single DA peak can be accurately identified to within 1 mm and that two distinct neurotransmitter peaks can be distinguished. In the second case, separate peaks of activation separated by as little as 5 mm can be distinguished. A decrease in blood flow during activation could not account for our findings. We applied the method to human PET data acquired with [11C]raclopride in the presence of transiently elevated DA due to intravenous (IV) alcohol. Our results for an area of the nucleus accumbens—a region relevant to alcohol consumption—agreed with a model-based method for estimating the DA response. SVD-based analysis of dynamic PET data promises a completely noninvasive and model-independent technique for determining the dynamics of a neurotransmitter response to cognitive or pharmacological stimuli. Our results indicate that the method is robust enough for application to voxel-by-voxel data. [ABSTRACT FROM AUTHOR]

Purpose : We recently introduced voxel-level images of drug occupancy from PET via our "Lassen plot filter." Occupancy images revealed clear dependence of 11C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC50 values. We introduce an "EC50 image" from human data to evaluate this hypothesis. Methods: Five healthy subjects were scanned with the nonselective GABAa tracer, 11C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an Emax model locally to create one EC50 image. We also performed simulations to confirm our observations of regional variation in EC50 and to identify the main source of variability in EC50. Results: As expected, the EC50 image revealed spatial variation in apparent drug affinity. High EC50 was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision. Conclusion: Our results argue for (a) confidence in the ability of the EC50 images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC50 throughout the brain. The EC50 image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials. [ABSTRACT FROM AUTHOR]

Striatal dopamine transporter (DAT) binding potential (BP) was compared between schizophrenic subjects with and without tardive dyskinesia and controls. Although the groups were not statistically different in striatal BP, tardive subjects had apparently lower DAT density than non-tardive schizophrenic subjects. Significant and trend-level inverse correlations were found between DAT BP in the striatum, and especially the severity of negative symptom scores, but also cognitive, and depression/anxiety scores on the PANSS. [Copyright &y& Elsevier]

Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans. We assessed decision making in adult male rats using a probabilistic reversal learning task and used positron emission tomography with the 11C]-(+)-PHNO and 18F]FPEB radioligands to quantify regional dopamine D 2/3 and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 days of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted. We found that self-administration of cocaine, but not of saline, disrupted behavior in the probabilistic reversal learning task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D 2/3 and, importantly, midbrain D 3 receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating. These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals. [ABSTRACT FROM AUTHOR]

Results from neuroimaging studies suggest that disruptions in flexible decision-making functions in substance-dependent individuals are a consequence of drug-induced neural adaptations. In addicted populations, however, the causal relationship between biobehavioral phenotypes of susceptibility and addiction consequence is difficult to dissociate. Indeed, evidence from animals suggests that poor decision making due to preexisting biological factors can independently enhance the risk for developing addiction-like behaviors. Neuroimaging studies in animals provide a unique translational approach for the identification of the neurobiological mechanisms that mediate susceptibility to addiction. We used positron emission tomography in rats to quantify regional dopamine D 2/3 receptors and metabotropic glutamate receptor 5 (mGluR5) and assessed decision making using a probabilistic reversal learning task. Susceptibility to self-administer cocaine was then quantified for 21 days followed by tests of motivation and relapse-like behaviors. We found that deficits specifically in reward-guided choice behavior on the probabilistic reversal learning task predicted greater escalation of cocaine self-administration behavior and greater motivation for cocaine and, critically, were associated with higher midbrain D 3 receptor availability. Additionally, individual differences in midbrain D 3 receptor availability independently predicted the rate of escalation in cocaine-taking behaviors. No differences in mGluR5 availability, responses during tests of extinction, or cue-induced reinstatement were observed between the groups. These findings indicate that our identified D 3 -mediated decision-making phenotype can be used as a behavioral biomarker for assessment of cocaine use susceptibility in human populations. [ABSTRACT FROM AUTHOR]

Naltrexone is a nonselective opioid receptor antagonist used as a treatment for alcohol use disorder. However, only modest clinical effects have been observed, possibly because of limited knowledge about the biological variables affecting the efficacy of naltrexone. We investigated the potential role of the kappa opioid receptor (KOR) in the therapeutic effect of naltrexone. A total of 48 non-treatment-seeking heavy drinkers (16 women) who met DSM-IV criteria for alcohol dependence participated in two alcohol drinking paradigms (ADPs) separated by a week of open-label naltrexone (100 mg daily). Craving, assessed with the Alcohol Urge Questionnaire and the Yale Craving Scale, and drinking behavior were recorded in each ADP. Prior to naltrexone initiation, KOR availability was determined in the amygdala, hippocampus, pallidum, striatum, cingulate cortex, and prefrontal cortex using positron emission tomography with [11C]LY2795050. Participants reported lower levels of craving (Yale Craving Scale: −11 ± 1, p <.0001; Alcohol Urge Questionnaire: −6 ± 0.6, p <.0001) and consumed fewer drinks (−3.7 ± 4, p <.0001) during the second ADP following naltrexone therapy. The observed reduction in drinking was negatively associated with baseline KOR availability in the striatum (p =.005), pallidum (p =.023), and cingulate cortex (p =.018). Voxelwise analysis identified clusters in the bilateral insula, prefrontal, and cingulate cortex associated with the reduction in drinking (p <.0001). In addition, KOR availability in all evaluated brain regions was associated with craving measured in both ADPs. The KOR is implicated in drinking and craving following naltrexone therapy in alcohol use disorder. [ABSTRACT FROM AUTHOR]

The evidence that dopamine function mediates the association between aging and cognition is one of the most cited findings in the cognitive neuroscience of aging. However, few and relatively small studies have directly examined these associations. Here we examined correlations among adult age, dopamine D2-like receptor (D2R) availability, and cognition in two cross-sectional studies of healthy human adults. Participants completed a short cognitive test battery and, on a separate day, a PET scan with either the high-affinity D2R tracer [18F]Fallypride (Study 1) or [11C]FLB457 (Study 2). Digit span, a measure of short-term memory maintenance and working memory, was the only cognitive test for which dopamine D2R availability partially mediated the age effect on cognition. In Study 1, age was negatively correlated with digit span. Striatal D2R availability was positively correlated with digit span controlling for age. The age effect on digit span was smaller when controlling for striatal D2R availability. Although other cognitive measures used here have individually been associated with age and D2R availability in prior studies, we found no consistent evidence for significant associations between low D2R availability and low cognitive performance on these measures. These results at best only partially supported the correlative triad of age, dopamine D2R availability, and cognition. While a wealth of other research in human and nonhuman animals demonstrates that dopamine makes critical contributions to cognition, the present studies suggest caution in interpreting PET findings as evidence that dopamine D2R loss is a primary cause of broad age-related declines in fluid cognition. (PsycINFO Database Record (c) 2019 APA, all rights reserved). [ABSTRACT FROM AUTHOR]

The relatively modest spatial resolution of positron emission tomography (PET) increases the likelihood of partial volume effects such that binding potential (BPND) may be underestimated. Given structural grey matter losses across adulthood, partial volume effects may be even more problematic in older age leading to overestimation of adult age differences. Here we examined the effects of partial volume correction (PVC) in two studies from different sites using different high-affinity D2-like radioligands (18 F-Fallypride, 11C-FLB457) and different PET camera resolutions (∼5 mm, 2.5 mm). Results across both data sets revealed that PVC increased estimated BPND and reduced, though did not eliminate, age effects on BPND. As expected, the effects of PVC were smaller in higher compared to lower resolution data. Analyses using uncorrected data that controlled for grey matter volume in each region of interest approximated PVC corrected data for some but not all regions. Overall, the findings suggest that PVC increases estimated BPND in general and reduces adult age differences especially when using lower resolution cameras. The findings suggest that the past 30 years of research on dopamine receptor availability, for which very few studies use PVC, may overestimate effects of aging on dopamine receptor availability. [ABSTRACT FROM AUTHOR]

Background and Purpose: Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the α1 subunit, there has been a concerted effort to develop α2/3 subtype-selective PAMs.Experimental Approach: In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits. In vivo receptor occupancy (RO) was conducted, prior to confirmation of in vivo α2/3 and α1 pharmacology through quantitative EEG (qEEG) beta frequency and zolpidem drug discrimination in rats respectively. PF-06372865 was then progressed to Phase 1 clinical trials.Key Results: PF-06372865 exhibited functional selectivity for those receptors containing α2/3/5 subunits, with significant positive allosteric modulation (90-140%) but negligible activity (≤20%) at GABAA receptors containing α1 subunits. PF-06372865 exhibited concentration-dependent occupancy of GABAA receptors in preclinical species. There was an occupancy-dependent increase in qEEG beta frequency and no generalization to a GABAA α1 cue in the drug-discrimination assay, clearly demonstrating the lack of modulation at the GABAA receptors containing an α1 subtype. In a Phase 1 single ascending dose study in healthy volunteers, evaluation of the pharmacodynamics of PF-06372865 demonstrated a robust increase in saccadic peak velocity (a marker of α2/3 pharmacology), increases in beta frequency qEEG and a slight saturating increase in body sway.Conclusions and Implications: PF-06372865 has a unique clinical pharmacology profile and a highly predictive translational data package from preclinical species to the clinical setting. [ABSTRACT FROM AUTHOR]

Many theories of cognitive aging are based on evidence that dopamine (DA) declines with age. Here, we performed a systematic meta-analysis of cross-sectional positron emission tomography and single-photon emission-computed tomography studies on the average effects of age on distinct DA targets (receptors, transporters, or relevant enzymes) in healthy adults (N = 95 studies including 2611 participants). Results revealed significant moderate to large, negative effects of age on DA transporters and receptors. Age had a significantly larger effect on D1- than D2-like receptors. In contrast, there was no significant effect of age on DA synthesis capacity. The average age reductions across the DA system were 3.7%–14.0% per decade. A meta-regression found only DA target as a significant moderator of the age effect. This study precisely quantifies prior claims of reduced DA functionality with age. It also identifies presynaptic mechanisms (spared synthesis capacity and reduced DA transporters) that may partially account for previously unexplained phenomena whereby older adults appear to use dopaminergic resources effectively. Recommendations for future studies including minimum required samples sizes are provided. [ABSTRACT FROM AUTHOR]

Introduction Erlotinib is a tyrosine kinase inhibitor prescribed for non-small cell lung cancer (NSCLC) patients bearing epidermal growth factor receptor mutations in the kinase domain. The objectives of this study were to (1) establish a human dosimetry profile of [ 11 C]erlotinib and (2) assess the consistency of calculated equivalent dose across species using the same dosimetry model. Methods Subjects examined in this multi-species study included: a stage IIIa NSCLC patient, 3 rhesus macaque monkeys, a landrace pig, and 4 athymic nude-Fox1nu mice. [ 11 C]erlotinib PET data of the whole body were acquired dynamically for up to 120 min. Regions of interest (ROIs) were manually drawn to extract PET time activity curves (TACs) from identifiable organs. TACs were used to calculate time-integrated activity coefficients (residence times) in each ROI, which were then used to calculate the equivalent dose in OLINDA. Subject data were used to predict the equivalent dose to the organs of a 73.7 kg human male. Results In three of four species, the liver was identified as the organ receiving the highest equivalent dose (critical organ). The mean equivalent doses per unit of injected activity to the liver based on human, monkey, and mouse data were 29.4 μSv/MBq, 17.4 ± 6.0 μSv/MBq, and 5.27 ± 0.25 μSv/MBq, respectively. The critical organ based on the pig data was the gallbladder wall (20.4 μSv/MBq) but the liver received a nearly identical equivalent dose (19.5 μSv/MBq). Conclusions (1) When designing PET studies using [ 11 C]erlotinib, the liver should be considered the critical organ. (2) In organs receiving the greatest equivalent dose, mouse data underestimated the dose in comparison to larger species. However, the effective dose of [ 11 C]erlotinib to the whole body of a 73.7 kg man was predicted with good consistency based on mice (3.14 ± 0.05 μSv/MBq) or the larger species (3.46 ± 0.25 μSv/MBq). [ABSTRACT FROM AUTHOR]

The “linear parametric neurotransmitter PET” (lp-ntPET) model was introduced to capture the time course of transient endogenous neurotransmitter response to drug stimulus from dynamic PET data. We previously used this novel analysis tool to probe the short-lived dopamine (DA) response induced by cigarette smoking in the PET scanner. It allowed us to find a sex difference in the DA signature of cigarette smoking. To make best use of this tool to characterize neurotransmitter response to drug stimulus, the sensitivity of lp-ntPET to detect such responses must be maximized. We designed a series of simulation studies to examine the impact of the following factors on the sensitivity of lp-ntPET using smoking-induced DA release as an example application: tracer delivery protocol, pre-processing for image denoising, timing of the smoking task, duration of the PET scan, and dose of the radiotracer. Our results suggest that a Bolus paradigm could replace a more difficult B/I paradigm without sacrificing the sensitivity of the method. Pre-processing the PET data with the de-noising algorithm HYPR could improve the sensitivity. The optimal timing to start the smoking task is 45min in a 90min scan and 35min in a 75min scan. A mild shortening of the scan time from 90mCi to 75min should be acceptable without loss of sensitivity. We suggest a lower dose limit of a bolus injection at 16mCi to limit underestimation of DA activation. This study established the framework to optimize the experimental design for reaching the full potential of lp-ntPET to detect neurotransmitter responses to drugs or even behavioral tasks. [ABSTRACT FROM AUTHOR]

Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [11C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel threechoice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [11C)-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [11C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders. [ABSTRACT FROM AUTHOR]

Purpose: [F]FPEB is a promising PET radioligand for the metabotropic glutamate receptor 5 (mGluR5), a potential target for the treatment of neuropsychiatric diseases. The purpose of this study was to evaluate the test-retest reproducibility of [F]FPEB in the human brain. Methods: Seven healthy male subjects were scanned twice, 3 - 11 weeks apart. Dynamic data were acquired using bolus plus infusion of 162 ± 32 MBq [F]FPEB. Four methods were used to estimate volume of distribution ( V): equilibrium analysis (EQ) using arterial (EQ) or venous input data (EQ), MA1, and a two-tissue compartment model (2 T). Binding potential ( BP) was also estimated using cerebellar white matter (CWM) or gray matter (CGM) as the reference region using EQ, 2 T and MA1. Absolute test-retest variability (aTRV) of V and BP were calculated for each method. Venous blood measurements ( C) were compared with arterial input ( C) to examine their usability in EQ analysis. Results: Regional V estimated by the four methods displayed a high degree of agreement ( r ranging from 0.83 to 0.99 among the methods), although EQ and EQ overestimated V by a mean of 9 % and 7 %, respectively, compared to 2 T. Mean values of aTRV of V were 11 % by EQ, 12 % by EQ, 14 % by MA1 and 14 % by 2 T. Regional BP also agreed well among the methods and mean aTRV of BP was 8 - 12 % (CWM) and 7 - 9 % (CGM). Venous and arterial blood concentrations of [F]FPEB were well matched during equilibrium ( C = 1.01 · C, r = 0.95). Conclusion: [F]FPEB binding shows good TRV with minor differences among analysis methods. Venous blood can be used as an alternative for input function measurement instead of arterial blood in EQ analysis. Thus, [F]FPEB is an excellent PET imaging tracer for mGluR5 in humans. [ABSTRACT FROM AUTHOR]

Detecting fluctuations in synaptic dopamine levels in extrastriatal brain regions with [11C]FLB 457 and positron emission tomography (PET) is a valuable tool for studying dopaminergic dysfunction in psychiatric disorders. The evaluation of reference region modeling approaches would eliminate the need to obtain arterial input function data. Our goal was to explore the use of reference region models to estimate amphetamine-induced changes in [11C]FLB 457 dopamine D2/D3 binding. Six healthy tobacco smokers were imaged with [11C]FLB 457 at baseline and at 3 hours after amphetamine (0.4 to 0.5 mg/kg, per os) administration. Simplified reference tissue models, SRTM and SRTM2, were evaluated against the 2-tissue compartmental model (2TC) to estimate [11C]FLB 457 binding in extrastriatal regions of interest (ROIs), using the cerebellum as a reference region. No changes in distribution volume were observed in the cerebellum between scan conditions. SRTM and SRTM2 underestimated binding, compared with 2TC, in ROIs by 26% and 9%, respectively, with consistent bias between the baseline and postamphetamine scans. Postamphetamine, [11C]FLB 457 binding significantly decreased across several brain regions as measured with SRTM and SRTM2; no significant change was detected with 2TC. These data support the sensitivity of [11C]FLB 457 for measuring amphetamine-induced dopamine release in extrastriatal regions with SRTM and SRTM2. [ABSTRACT FROM AUTHOR]

ABSTRACT Findings from clinical and preclinical studies converge to suggest that increased adiposity and/or exposure to a high fat diet are associated with alterations in dorsal striatal (DS) circuitry. In humans there is a reliable inverse relationship between body mass index (BMI) and response to palatable food consumption in the dorsal striatum (DS). Positron emission tomography (PET) studies also suggest altered DS dopamine type 2/3 receptor (D2R/D3R) availability in obesity; however, the direction of the association is unclear. It is also not clear whether dopamine receptor levels contribute to the lower blood oxygen level dependent (BOLD) response because PET studies have targeted the morbidly obese and, functional magnetic resonance imaging (fMRI) studies rarely include individuals with BMIs in this range. Therefore we examined whether the fMRI BOLD response in the DS to milkshake is associated with D2R/D3R availability measured with [11C]PHNO and PET in individuals with BMI ranging from healthy weight to moderately obese. Twenty-nine subjects participated in the fMRI study, 12 in the [11C]PHNO PET study, 8 of whom also completed the fMRI study. As predicted there was a significant negative association between DS BOLD response to milkshake and BMI. In contrast, BMI was positively associated with D2R/D3R availability. Dorsal striatal BOLD response was unrelated to D2R/D3R availability. Considered in the context of the larger literature our results suggest the existence of a non-linear relationship between D2R/D3R availability and BMI. Additionally, the altered BOLD responses to palatable food consumption observed in obesity are not clearly related to D2R/D3R receptor availability. Using [11C]PHNO and PET brain imaging techniques we show that body mass index was positively associated with D2R/D3R availability in the dorsal striatum, but that functional MR BOLD response was unrelated to D2R/D3R availability. These results suggest the existence of a nonlinear relationship between D2R/D3R availability and body mass index and that the altered BOLD responses to food consumption seen in obesity are not directly related to D2R/D3R availability. Synapse, 69:195-202, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Introduction [ 11 C]PBR28 is a high-affinity ligand for the Translocator Protein 18 kDa (TSPO), which is considered to be a marker for microglial activation. Volume of distribution (V T ) estimated with an arterial plasma input function is the gold standard for quantitation of [ 11 C]PBR28 binding. However, arterial sampling is impractical at many PET sites for multiple reasons. Reference region modeling approaches are not ideal for TSPO tracers, as the existence of a true reference region cannot be assumed. Given that it would be desirable to have a non-invasive index of [ 11 C]PBR28 binding, we elected to study the utility of the semi-quantitative metric, standardized uptake value (SUV) for use in brain [ 11 C]PBR PET studies. The primary goal of this study was to determine the relationship between SUV and V T . Methods We performed a retrospective analysis of data from sixteen [ 11 C]PBR28 PET scans acquired in baboons at baseline and at multiple time points after IV injection of lipopolysaccharide, an endotoxin that transiently induces neuroinflammation. For each scan, data from 14 brain regions of interest were studied. V T was estimated with the Logan plot, using metabolite-corrected input functions. SUV was calculated with data from 30 to 60 minutes after [ 11 C]PBR28 injection. Results Within individual PET studies, SUV tended to correlate well with V T . Across studies, the relationship between SUV and V T was variable. Conclusions From study to study, there was variability in the degree of correlation between [ 11 C]PBR28 V T and SUV. There are multiple physiological factors that may contribute to this variance. Advances in Knowledge As currently applied, the non-invasive measurement of SUV does not appear to be a reliable outcome variable for [ 11 C]PBR28. Additional work is needed to discover the source of the discrepancy in SUV between [ 11 C]PBR28 scans. Implications for Patient Care There is a need to develop alternatives to arterial plasma input functions for TSPO ligands in order to facilitate multi-center trials. [ABSTRACT FROM AUTHOR]

Cigarette smoking is a major public health danger. Women and men smoke for different reasons and cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. Earlier PET studies reported conflicting findings but were each hampered by experimental and/or analytical limitations. Our new image analysis technique, Ip-ntPET (Normandin et al., 2012; Morris et al., 2013; Kim et al., 2014), has been optimized for capturing brief (lasting only minutes) and highly localized dopaminergic events in dynamic PET data. We coupled our analysis technique with high-resolution brain scanning and high-frequency motion correction to create the optimal experiment for capturing and characterizing the effects of smoking on the mesolimbic dopamine system in humans. Our main finding is that male smokers smoking in the PET scanner activate dopamine in the right ventral striatum during smoking but female smokers do not. This finding--men activating more ventrally than women--is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. Ip-ntPET analysis produces a novel multidimensional endpoint: voxel-level temporal patterns of neurotransmitter release ("DA movies") in individual subjects. By examining these endpoints quantitatively, we demonstrate that the timing of dopaminergic responses to cigarette smoking differs between men and women. Men respond consistently and rapidly in the ventral striatum whereas women respond faster in a discrete subregion of the dorsal putamen. [ABSTRACT FROM AUTHOR]

The 'linear parametric neurotransmitter PET' (lp-ntPET) model estimates time variation in endogenous neurotransmitter levels from dynamic PET data. The pattern of dopamine (DA) change over time may be an important element of the brain's response to addictive substances such as cigarettes or alcohol. We have extended the lp-ntPET model from the original region of interest (ROI) - based implementation to be able to apply the model at the voxel level. The resulting endpoint is a dynamic image, or movie, of transient neurotransmitter changes. Simulations were performed to select threshold values to reduce the false positive rate when applied to real 11C-raclopride PET data. We tested the new voxelwise method on simulated data, and finally, we applied it to 11C-raclopride PET data of subjects smoking cigarettes in the PET scanner. In simulation, the temporal precision of neurotransmitter response was shown to be similar to that of ROI-based lp-ntPET (standard deviation ∼ 3 min). False positive rates for the voxelwise method were well controlled by combining a statistical threshold (the F-test) with a new spatial (cluster-size) thresholding operation. Sensitivity of detection for the new algorithm was greater than 80% for the case of short-lived DA changes that occur in subregions of the striatum as might be the case with cigarette smoking. Finally, in 11C-raclopride PET data, DA movies reveal for the first time that different temporal patterns of the DA response to smoking may exist in different subregions of the striatum. These spatiotemporal patterns of neurotransmitter change created by voxelwise lp-ntPET may serve as novel biomarkers for addiction and/or treatment efficacy. Hum Brain Mapp 35:4876-4891, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We have previously implemented the direct reconstruction of dense kinetic model parameter images (“parametric images”) from sinogram data, and compared it to conventional image domain kinetic parameter estimation methods refid="ref1"/refid="ref2"/ refid="ref3"/. Although it has been shown that the direct reconstruction algorithm estimates the kinetic model parameters with lower root mean squared error than the conventional image domain techniques, some theoretical obstacles remain. These obstacles include the difficulty of evaluating the accuracy and precision of the estimated parameters. In image domain techniques, the reconstructed time activity curve (TAC) and the model predicted TAC are compared, and the goodness-of-fit is evaluated as a measure of the accuracy and precision of the estimated parameters. This approach cannot be applied to the direct reconstruction technique as there are no reconstructed TACs. In this paper, we propose ways of evaluating the precision and goodness-of-fit of the kinetic model parameters estimated by the direct reconstruction algorithm. Specifically, precision of the estimates requires the calculation of variance images for each parameter, and goodness-of-fit is addressed by reconstructing the difference between the measured and the fitted sinograms. We demonstrate that backprojecting the difference from sinogram space to image space creates error images that can be examined for goodness-of-fit and model selection purposes. The presence of nonrandom structures in the error images may indicate an inadequacy of the kinetic model that has been incorporated into the direct reconstruction algorithm. We introduce three types of goodness-of-fit images. We propose and demonstrate a number-of-runs image as a means of quantifying the adequacy or deficiency of the model. We further propose and demonstrate images of the F statistic and the change in the Akaike Information Criterion as devices for identifying the statistical advantage of one model over another at each voxel. As direct reconstruction to parametric images proliferates, it will be essential for imagers to adopt methods such as those proposed herein to assess the accuracy and precision of their parametric images. [ABSTRACT FROM PUBLISHER]

The radiotracer [11C]PHNO may have advantages over other dopamine (DA) D2/D3 receptor ligands because, as an agonist, it measures high-affinity, functionally active D2/D3 receptors, whereas the traditionally used radiotracer [11C]raclopride measures both high- and low-affinity receptors. Our aim was to take advantage of the strength of [11C]PHNO for measuring the small DA signal induced by nicotine, which has been difficult to measure in preclinical and clinical neuroimaging studies. Nicotine- and amphetamine-induced DA release in non-human primates was measured with [11C]PHNO and [11C]raclopride positron emission tomography (PET) imaging. Seven adult rhesus monkeys were imaged on a FOCUS 220 PET scanner after injection of a bolus of [11C]PHNO or [11C]raclopride in three conditions: baseline; preinjection of nicotine (0.1 mg/kg bolus+0.08 mg/kg infusion over 30 min); preinjection of amphetamine (0.4 mg/kg, 5 min before radiotracer injection). DA release was measured as change in binding potential (BPND). Nicotine significantly decreased BPND in the caudate (7±8%), the nucleus accumbens (10±7%), and in the globus pallidus (13±15%) measured with [11C]PHNO, but did not significantly decrease BPND in the putamen or the substantia nigra or in any region when measured with [11C]raclopride. Amphetamine significantly reduced BPND in all regions with both radiotracers. In the striatum, larger amphetamine-induced changes were detected with [11C]PHNO compared with [11C]raclopride (52-64% vs 33-35%, respectively). We confirmed that [11C]PHNO is more sensitive than [11C]raclopride to nicotine- and amphetamine-induced DA release. [11C]PHNO PET may be more sensitive to measuring tobacco smoking-induced DA release in human tobacco smokers. [ABSTRACT FROM AUTHOR]

Activating mutations of the epidermal growth factor receptor (EGFR) occur in multiple tumor types, including non-small cell lung cancer (NSCLC) and malignant glioma, and have become targets for therapeutic intervention. The determination of EGFR mutation status using a noninvasive, molecular imaging approach has the potential for clinical utility. In this study, we investigated [11C]-erlotinib positron emission tomography (PET) imaging as a tool to identify activating mutations of EGFR in both glioma and NSCLC xenografts. Radiotracer specific binding was determined for high and low specific activity (SA) [C]-erlotinib PET scans in mice bearing synchronous human cancer xenografts with different EGFR expression profiles (PC9, HCC827, U87, U87 ΔEGFR, and SW620). Although xenograft immunohistochemistry demonstrated constitutive EGFR phosphorylation, PET scan analysis using the Simplified Reference Tissue Model showed that only kinase domain mutant NSCLC (HCC827 and PC9) had significantly greater binding potentials in high versus low SA scans. Xenografts with undetectable EGFR expression (SW620), possessing wild-type EGFR (U87), and expressing an activating extracellular domain mutation (U87 ΔEGFR) were indistinguishable under both high and low SA scan conditions. The results suggest that [C]-erlotinib is a promising radiotracer that could provide a novel clinical methodology for assessing EGFR and erlotinib interactions in patients with tumors that harbor EGFR-activating kinase domain mutations. [ABSTRACT FROM AUTHOR]

[18F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n=5) or bolus-plus-constant-infusion (n=5) of [18F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate VT and BPND. [18F]FPEB was well fitted by the two-tissue compartment model, MA1 (t*=30), and MRTM (using cerebellum white matter as a reference). Highest VT values were observed in the anterior cingulate and caudate, and lowest VT values were observed in the cerebellum and pallidum. For kinetic modeling studies, VT and BPND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [18F]FPEB reduced intersubject variability in VT and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90-120 minutes after the start of injection. [ABSTRACT FROM AUTHOR]

We examined the reproducibility of using the constant infusion paradigm for equilibrium measurement of D2/3 receptors using [11C]- (+)-propyl-hexahydro-naphtho-oxazin (PHNO) positron emission tomography (PET). Six subjects were scanned with a bolus plus constant infusion (Kbol 5 80 minutes) of [11C]-(+)-PHNO. Binding potential (BPND) was computed using the equilibrium approach and compared to a simplified reference tissue model (SRTM). The rate of change in the concentration-activity curve from 60 to 90 minutes was -5 ± 13%/h in the caudate, putamen, substantia nigra, thalamus, and cerebellum but was 15 ± 15%/h in the ventral striatum and pallidum. Test--retest variability was lower in striatal compared to extrastriatal regions (4 ± 8% vs 28 ± 22%, respectively) using the equilibrium approach, with comparable results with SRTM. The equilibrium ratio and SRTM yielded reliable BPND estimates (intraclass correlation coefficient 5 0.88 and 0.82, respectively). These studies support the reproducibility of the bolus plus constant infusion paradigm with [11C]-(+)-PHNO PET. [ABSTRACT FROM AUTHOR]

A custom designed markerless tracking system was demonstrated to be applicable for positron emission tomography (PET) brain imaging. Precise head motion registration is crucial for accurate motion correction (MC) in PET imaging. State-of-the-art tracking systems applied with PET brain imaging rely on markers attached to the patient's head. The marker attachment is the main weakness of these systems. A healthy volunteer participating in a cigarette smoking study to image dopamine release was scanned twice for 2 h with ^11C-racolopride on the high resolution research tomograph (HRRT) PET scanner. Head motion was independently measured, with a commercial marker-based device and the proposed vision-based system. A list-mode event-by-event reconstruction algorithm using the detected motion was applied. A phantom study with hand-controlled continuous random motion was obtained. Motion was time-varying with long drift motions of up to 18 mm and regular step-wise motion of 1–6 mm. The evaluated measures were significantly better for motion-corrected images compared to no MC. The demonstrated system agreed with a commercial integrated system. Motion-corrected images were improved in contrast recovery of small structures. [ABSTRACT FROM PUBLISHER]

Abstract: Microglia play an essential role in many brain diseases. Microglia are activated by local tissue damage or inflammation, but systemic inflammation can also activate microglia. An important clinical question is whether the effects of systemic inflammation on microglia mediate the deleterious effects of systemic inflammation in diseases such as Alzheimer''s dementia, multiple sclerosis, and stroke. Positron Emission Tomography (PET) imaging with ligands that bind to Translocator Protein (TSPO) can be used to detect activated microglia. The aim of this study was to evaluate whether the effect of systemic inflammation on microglia could be measured with PET imaging in nonhuman primates, using the TSPO ligand [11C]PBR28. Methods: Six female baboons (Papio anubis) were scanned before and at 1h and/or 4h and/or 22h after intravenous administration of E. coli lipopolysaccharide (LPS; 0.1mg/kg), which induces systemic inflammation. Regional time-activity data from regions of interest (ROIs) were fitted to the two-tissue compartmental model, using the metabolite-corrected arterial plasma curve as input function. Total volume of distribution (V T) of [11C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in V T from baseline. Serum levels of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) were used to assess correlations between systemic inflammation and microglial activation. In one baboon, immunohistochemistry was used to identify cells expressing TSPO. Results: LPS administration increased [11C]PBR28 binding (F(3,6)=5.1, p =.043) with a 29±16% increase at 1h (n =4) and a 62±34% increase at 4h (n =3) post-LPS. There was a positive correlation between serum IL-1β and IL-6 levels and the increase in [11C]PBR28 binding. TSPO immunoreactivity occurred almost exclusively in microglia and rarely in astrocytes. Conclusion: In the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO that is readily detected with [11C]PBR28 PET. The effect of LPS on [11C]PBR28 binding is likely mediated by inflammatory cytokines. Activation of microglia may be a mechanism through which systemic inflammatory processes influence the course of diseases such as Alzheimer''s, multiple sclerosis, and possibly depression. [Copyright &y& Elsevier]

Abstract: To reduce imaging costs, we designed a head holder for scanning two rats simultaneously in small animal PET scanners. Our goals were (i) to maintain high sensitivity and (ii) to minimize repositioning error between scans. Methods: A semi-stereotaxic dual rat head holder was designed and constructed for dual rat scanning in our IndyPET-II scanner and the commercial microPET P4. It was also used for single rat scanning in a small-bore, high-resolution animal scanner (“ISAP”). Positional repeatability was validated via multiple [11C]Raclopride scans of a single rat on different days. Accuracy of repositioning was determined by visual comparison of images, and by metrics derived through image alignment. Kinetic validation was assessed via analysis of [18F]Fluorodeoxyglucose ([18F]FDG) dynamic PET studies of six rats. Each rat was scanned twice: once individually, with brain positioned at the center of field of view (CFOV), and once with a partner, with brain away from CFOV. Both rats were injected with FDG during each dual rat session. Patlak uptake constants (Ki) were calculated from whole brain images. Effects of attenuation and scatter correction on single versus dual scan images were explored. Results: Image comparison and alignment metrics indicated excellent repositioning of rats. Scaled time-activity-curves from single and dual rat scans were indistinguishable. Average single and dual scan Ki values differed by only 6.3±7.5%. Conclusion: Dual rat scanning in a semi-stereotaxic holder is practical for economical small animal scanning and does not compromise kinetic accuracy of [18F]FDG dynamic scan data. [Copyright &y& Elsevier]