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Abstract. Two novel radioligands, N,N-dimethyl-2-(2amino-4-methoxyphenylthio)benzylamine (DAPP) and (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (DASB), were radiolabeled with carbon-11 and evaluated as in vivo probes of the serotonin transporter (SERT) using positron emission tomography (PET). Both compounds are highly selective, with nanomolar affinity for the serotonin transporter and micromolar affinity for the dopamine and norepinephrine transporters. Six volunteers were imaged twice, once with each of the two radioligands. Both ligands displayed very good brain penetration and selective retention in regions rich in serotonin reuptake sites. Both had similar brain uptake and kinetics, but the cyano analogue, [[sup 11]C]DASB, had a slightly higher brain penetration in all subjects. Plasma analysis revealed that both radiotracers were rapidly metabolized to give mainly hydrophilic species as determined by reverse-phase high-performance liquid chromatography. Inhibition of specific binding to the SERT was demonstrated in three additional subjects imaged with [[sup 11]C]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate that both these substituted phenylthiobenzylamines have highly suitable characteristics for probing the serotonin reuptake system with PET in humans. [ABSTRACT FROM AUTHOR]

Objective: The study examined the influence of losses in dopaminergic function on age-related cognitive deficits.Method: Eleven healthy subjects (21-68 years of age) completed a set of cognitive tasks used to assess perceptual speed and episodic memory. D(2) receptor binding was measured in the caudate and the putamen by using positron emission tomography.Results: A gradual age-related deterioration was found for all cognitive tasks and for D(2) binding in both striatal structures. Statistical control of D(2) binding eliminated the age-related cognitive variation, whereas residual effects of D(2) binding were seen after the analysis controlled for age.Conclusions: D(2) receptor binding is a more important factor than chronological age in accounting for variation in cognitive performance across the adult lifespan. Changes in dopaminergic neurotransmission play an important role in aging-related cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Impulsive action and risk-related decision-making (RDM) are associated with various psychiatric disorders, including drug abuse. Both behavioral traits have also been linked to reduced frontocortical activity and alterations in dopamine function in the ventral tegmental area (VTA). However, despite direct projections from the medial prefrontal cortex (mPFC) to the VTA, the specific role of the mPFC-to-VTA pathway in controlling impulsive action and RDM remains unexplored., Methods: We used positron emission tomography with [18F]-fluorodeoxyglucose to evaluate brain metabolic activity in Roman high- (RHA) and low-avoidance (RLA) rats, which exhibit innate differences in impulsive action and RDM. Notably, we used a viral-based double dissociation chemogenetic strategy to isolate, for the first time to our knowledge, the role of the mPFC-to-VTA pathway in controlling these behaviors. We selectively activated the mPFC-to-VTA pathway in RHA rats and inhibited it in RLA rats, assessing the effects on impulsive action and RDM in the rat gambling task., Results: Our results showed that RHA rats displayed higher impulsive action, less optimal decision-making, and lower cortical activity than RLA rats at baseline. Chemogenetic activation of the mPFC-to-VTA pathway reduced impulsive action in RHA rats, whereas chemogenetic inhibition had the opposite effect in RLA rats. However, these manipulations did not affect RDM. Thus, by specifically targeting the mPFC-to-VTA pathway in a phenotype-dependent way, we reverted innate patterns of impulsive action but not RDM., Conclusion: Our findings suggest a dissociable role of the mPFC-to-VTA pathway in impulsive action and RDM, highlighting its potential as a target for investigating impulsivity-related disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD) are characterized by exacerbated motor and risk-related impulsivities, which are associated with decreased cortical activity. In rodents, the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been separately implicated in impulsive behaviors, but studies on the specific role of the mPFC-NAc pathway in these behaviors are limited. Here, we investigated whether heightened impulsive behaviors are associated with reduced mPFC activity in rodents and determined the involvement of the mPFC-NAc pathway in motor and risk-related impulsivities. We used the Roman High- (RHA) and Low-Avoidance (RLA) rat lines, which display divergent phenotypes in impulsivity. To investigate alterations in cortical activity in relation to impulsivity, regional brain glucose metabolism was measured using positron emission tomography and [ 18 F]-fluorodeoxyglucose ([ 18 F]FDG). Using chemogenetics, the activity of the mPFC-NAc pathway was either selectively activated in high-impulsive RHA rats or inhibited in low-impulsive RLA rats, and the effects of these manipulations on motor and risk-related impulsivity were concurrently assessed using the rat gambling task. We showed that basal [ 18 F]FDG uptake was lower in the mPFC and NAc of RHA compared to RLA rats. Activation of the mPFC-NAc pathway in RHA rats reduced motor impulsivity, without affecting risk-related decision-making. Conversely, inhibition of the mPFC-NAc pathway had no effect in RLA rats. Our results suggest that the mPFC-NAc pathway controls motor impulsivity, but has limited involvement in risk-related decision-making in our current model. Our findings suggest that reducing fronto-striatal activity may help attenuate motor impulsivity in patients with impulse control dysregulation., (© 2024 The Author(s). Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Impulsive action and risk-related decision-making (RDM) are two facets of impulsivity linked to a hyperdopaminergic release in the striatum and an increased propensity to cocaine intake. We previously showed that with repeated cocaine exposure, this initial hyperdopaminergic release is blunted in impulsive animals, potentially signaling drug-induced tolerance. Whether such dopaminergic dynamics involve changes in dopamine (DA) synthesis as a function of impulsivity is currently unknown. Here, we investigated the predictive value of DA synthesis for impulsive action, RDM, and the propensity to take cocaine in a rat model of vulnerability to cocaine abuse. Additionally, we assessed the effects of cocaine intake on these variables. Rats were tested sequentially in the rat Gambling Task (rGT) and were scanned with positron emission tomography and [ 18 F]-FDOPA to respectively assess both impulsivity facets and striatal DA synthesis before and after cocaine self-administration (SA). Our results revealed that baseline striatal levels of DA synthesis did not significantly predict impulsive action, RDM, or a greater propensity to cocaine SA in impulsive animals. Besides, we showed that impulsive action, but not RDM, predicted higher rates of cocaine taking. However, chronic cocaine exposure had no impact on DA synthesis, nor affected impulsive action and RDM. These findings indicate that the hyper-responsive DA system associated with impulsivity and a propensity for cocaine consumption, along with the reduction in this hyper-responsive DA state in impulsive animals with a history of cocaine use, might not be mediated by dynamic changes in DA synthesis., (Copyright © 2024 Urueña-Méndez et al.)

Current research indicates that altered dopamine (DA) transmission in the striatum contributes to impulsivity and novelty-seeking, and it may mediate a link concerning a higher susceptibility to drug abuse. Whether increased susceptibility to drug abuse results from a hyperdopaminergic or hypodopaminergic state is still debated. Here, we simultaneously tracked changes in DA D 2/3 receptor (D 2/3 R) availability and amphetamine-(AMPH)-induced DA release in relation to impulsivity and novelty-seeking prior to, and following, cocaine self-administration (SA) in Roman high- (RHA) and low- (RLA) avoidance rats. We found that high-impulsive/high novelty-seeking RHA rats exhibited lower D 2/3 R availabilities and higher AMPH-induced DA release in the striatum that predicted higher levels of cocaine intake compared with RLAs. Cocaine SA did not alter striatal D 2/3 R availability or impulsivity in RHA or RLA rats. Critically, cocaine exposure led to a baseline-dependent blunting of stimulated DA release in high-impulsive/high novelty-seeking RHA rats only, and to a baseline-dependent increase in novelty-seeking in low-impulsive/low novelty-seeking RLA rats only. Altogether, we propose that susceptibility to drug abuse results from an innate hyper-responsive DA system, promoting impulsive action and novelty-seeking, and producing stronger initial drug-reinforcing effects that contribute to the initiation and perpetuation of drug use. However, with repeated cocaine use, a tolerance to drug-induced striatal DA elevations develops, leading to a compensatory increase in drug consumption to overcome the reduced reward effects.

Introduction: Motor impulsivity and risk-related impulsive choice have been proposed as vulnerability factors for drug abuse, due to their high prevalence in drug abusers. However, how these two facets of impulsivity are associated to drug abuse remains unclear. Here, we investigated the predictive value of both motor impulsivity and risk-related impulsive choice on characteristics of drug abuse including initiation and maintenance of drug use, motivation for the drug, extinction of drug-seeking behavior following drug discontinuation and, finally, propensity to relapse., Methods: We used the Roman High- (RHA) and Low- Avoidance (RLA) rat lines, which display innate phenotypical differences in motor impulsivity, risk-related impulsive choice, and propensity to self-administer drugs. Individual levels of motor impulsivity and risk-related impulsive choice were measured using the rat Gambling task. Then, rats were allowed to self-administer cocaine (0.3 mg/kg/infusion; 14 days) to evaluate acquisition and maintenance of cocaine self-administration, after which motivation for cocaine was assessed using a progressive ratio schedule of reinforcement. Subsequently, rats were tested for their resistance to extinction, followed by cue-induced and drug-primed reinstatement sessions to evaluate relapse. Finally, we evaluated the effect of the dopamine stabilizer aripiprazole on reinstatement of drug-seeking behaviors., Results: We found that motor impulsivity and risk-related impulsive choice were positively correlated at baseline. Furthermore, innate high levels of motor impulsivity were associated with higher drug use and increased vulnerability to cocaine-primed reinstatement of drug-seeking. However, no relationships were observed between motor impulsivity and the motivation for the drug, extinction or cue-induced reinstatement of drug-seeking. High levels of risk-related impulsive choice were not associated to any aspects of drug abuse measured in our study. Additionally, aripiprazole similarly blocked cocaine-primed reinstatement of drug-seeking in both high- and low-impulsive animals, suggesting that aripiprazole acts as a D 2/3 R antagonist to prevent relapse independently of the levels of impulsivity and propensity to self-administer drugs., Discussion: Altogether, our study highlights motor impulsivity as an important predictive factor for drug abuse and drug-primed relapse. On the other hand, the involvement of risk-related impulsive choice as a risk factor for drug abuse appears to be limited., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Arrondeau, Urueña-Méndez, Bellés, Marchessaux, Goutaudier and Ginovart.)

Purpose: Partial volume effect (PVE) is a consequence of the limited spatial resolution of PET scanners. PVE can cause the intensity values of a particular voxel to be underestimated or overestimated due to the effect of surrounding tracer uptake. We propose a novel partial volume correction (PVC) technique to overcome the adverse effects of PVE on PET images., Methods: Two hundred and twelve clinical brain PET scans, including 50 18 F-Fluorodeoxyglucose ( 18 F-FDG), 50 18 F-Flortaucipir, 36 18 F-Flutemetamol, and 76 18 F-FluoroDOPA, and their corresponding T1-weighted MR images were enrolled in this study. The Iterative Yang technique was used for PVC as a reference or surrogate of the ground truth for evaluation. A cycle-consistent adversarial network (CycleGAN) was trained to directly map non-PVC PET images to PVC PET images. Quantitative analysis using various metrics, including structural similarity index (SSIM), root mean squared error (RMSE), and peak signal-to-noise ratio (PSNR), was performed. Furthermore, voxel-wise and region-wise-based correlations of activity concentration between the predicted and reference images were evaluated through joint histogram and Bland and Altman analysis. In addition, radiomic analysis was performed by calculating 20 radiomic features within 83 brain regions. Finally, a voxel-wise two-sample t-test was used to compare the predicted PVC PET images with reference PVC images for each radiotracer., Results: The Bland and Altman analysis showed the largest and smallest variance for 18 F-FDG (95% CI: - 0.29, + 0.33 SUV, mean = 0.02 SUV) and 18 F-Flutemetamol (95% CI: - 0.26, + 0.24 SUV, mean =  - 0.01 SUV), respectively. The PSNR was lowest (29.64 ± 1.13 dB) for 18 F-FDG and highest (36.01 ± 3.26 dB) for 18 F-Flutemetamol. The smallest and largest SSIM were achieved for 18 F-FDG (0.93 ± 0.01) and 18 F-Flutemetamol (0.97 ± 0.01), respectively. The average relative error for the kurtosis radiomic feature was 3.32%, 9.39%, 4.17%, and 4.55%, while it was 4.74%, 8.80%, 7.27%, and 6.81% for NGLDM_contrast feature for 18 F-Flutemetamol, 18 F-FluoroDOPA, 18 F-FDG, and 18 F-Flortaucipir, respectively., Conclusion: An end-to-end CycleGAN PVC method was developed and evaluated. Our model generates PVC images from the original non-PVC PET images without requiring additional anatomical information, such as MRI or CT. Our model eliminates the need for accurate registration or segmentation or PET scanner system response characterization. In addition, no assumptions regarding anatomical structure size, homogeneity, boundary, or background level are required., (© 2023. The Author(s).)

Impulsivity is a multidimensional construct, but the relationships between its constructs and their respective underlying dopaminergic underpinnings in the general population remain unclear. A cohort of Roman high- (RHA) and low- (RLA) avoidance rats were tested for impulsive action and risky decision-making in the rat gambling task, and then for delay discounting in the delay-discounting task to concurrently measure the relationships among the three constructs of impulsivity using a within-subject design. Then, we evaluated the effects of dopaminergic drugs on the three constructs of impulsivity, considering innate differences in impulsive behaviors at baseline. Risky decision-making and delay-discounting were positively correlated, indicating that both constructs of impulsive choice are related. Impulsive action positively correlated with risky decision-making but not with delay discounting, suggesting partial overlap between impulsive action and impulsive choice. RHAs showed a more impulsive phenotype in the three constructs of impulsivity compared to RLAs, demonstrating the comorbid nature of impulsivity in a population of rats. Amphetamine increased impulsive action and had no effect on risky decision-making regardless of baseline levels of impulsivity, but it decreased delay discounting only in high impulsive RHAs. In contrast, while D 1 R and D 3 R agonism as well as D 2/3 R partial agonism decreased impulsive action regardless of baseline levels of impulsivity, D 2/3 R agonism decreased impulsive action exclusively in high impulsive RHAs. Irrespective of baseline levels of impulsivity, risky decision-making was increased by D 1 R and D 2/3 R agonism but not by D 3 R agonism or D 2/3 R partial agonism. Finally, while D 1 R and D 3 R agonism, D 2/3 R partial agonism and D 2 R blockade increased delay discounting irrespective of baseline levels of impulsivity, D 2/3 R agonism decreased it in low impulsive RLAs only. These findings indicate that the acute effects of dopamine drugs were partially overlapping across dimensions of impulsivity, and that only D 2/3 R agonism showed baseline-dependent effects on impulsive action and impulsive choice., Competing Interests: Declaration of competing interest The authors declare that there is not personal financial conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Current research indicates deficits in cognitive function together with widespread changes in brain activity following long-term cannabis use. In particular, cannabis use has been associated with excessive spectral power of the alpha rhythm (8-12 Hz), which is also known to be modulated during attentional states. Recent neuroimaging studies have linked heavy cannabis use with structural and metabolic changes in the brain; however, the functional consequences of these changes are still not fully characterized. This study investigated the electrophysiological and behavioral correlates of cannabis dependence by comparing patients with a cannabis use disorder (CUD; N = 24) with cannabis nonuser controls (N = 24), using resting state electroencephalogram (EEG) source-imaging. In addition to evaluating mean differences between groups, we also explored whether particular EEG patterns were associated with individual cognitive-behavioral measures. First, we replicated historical findings of elevated levels of (relative) alpha rhythm in CUD patients compared with controls and located these abnormalities to mainly prefrontal cortical regions. Importantly, we observed a significant negative correlation between alpha spectral power in several cortical regions and individual attentional performance in the Go/NoGo task. Because such relationship was absent in the nonuser control group, our results suggest that reduced prefrontal cortical activation (indexed by increased relative alpha power) could be partly responsible for the reported cognitive impairments in CUD. Our findings support the use of electroencephalography as a noninvasive and cost-effective tool for biomarker discovery in substance abuse and have the potential of directly informing future intervention strategies., (© 2022. The Author(s).)

Rationale: Risk factors for drug addiction include genetics, environment, and behavioral traits such as impulsivity and novelty preference (NP), which have been related to deficits in striatal dopamine (DA) D 2/3 -receptors (D 2/3 R) and heightened amphetamine (AMPH)-induced DA release. However, the influence of the early rearing environment on these behavioral and neurochemical variables is not clear., Objectives: We investigated the influence of early rearing environment on striatal D 2/3 R availabilities and AMPH-induced DA release in relation to impulsivity, NP, and propensity to drug self-administration (SA) in "addiction-prone" Roman high- (RHA) and "addiction-resistant" Roman low-avoidance (RLA) rats., Methods: Animals were reared post-weaning in either environmental enrichment (EE) or impoverishment (EI) and were assessed at adulthood for impulsivity, NP, and propensity to cocaine SA. EE and EI rats were also scanned using single-photon emission computed tomography to concurrently measure in vivo striatal D 2/3 R availability and AMPH-induced DA release., Results: EE vs. EI was associated with heightened impulsivity and a lack of NP in both rat lines. Higher dorsal striatal D 2/3 R densities were found in RHA EE and higher AMPH-induced DA release in RLA EE. Both impulsivity and NP were negatively correlated to dorsal striatal D 2/3 R availabilities and positively correlated with AMPH-induced DA release in EI but not in EE. EE vs. EI was related to a faster rate of cocaine intake and elevated active timeout responses in RHAs., Conclusion: Our results suggest non-monotonic, environment-dependent, relationships between impulsivity, NP, and D 2/3 R-mediated signaling, and suggest that EI vs. EE may decrease the reinforcing effects of psychostimulants in predisposed individuals., (© 2021. The Author(s).)

Purpose: We assess the performance of a recurrent frame generation algorithm for prediction of late frames from initial frames in dynamic brain PET imaging., Methods: Clinical dynamic 18 F-DOPA brain PET/CT studies of 46 subjects with ten folds cross-validation were retrospectively employed. A novel stochastic adversarial video prediction model was implemented to predict the last 13 frames (25-90 minutes) from the initial 13 frames (0-25 minutes). The quantitative analysis of the predicted dynamic PET frames was performed for the test and validation dataset using established metrics., Results: The predicted dynamic images demonstrated that the model is capable of predicting the trend of change in time-varying tracer biodistribution. The Bland-Altman plots reported the lowest tracer uptake bias (-0.04) for the putamen region and the smallest variance (95% CI: -0.38, +0.14) for the cerebellum. The region-wise Patlak graphical analysis in the caudate and putamen regions for eight subjects from the test and validation dataset showed that the average bias for K i and distribution volume was 4.3%, 5.1% and 4.4%, 4.2%, (P-value <0.05), respectively., Conclusion: We have developed a novel deep learning approach for fast dynamic brain PET imaging capable of generating the last 65 minutes time frames from the initial 25 minutes frames, thus enabling significant reduction in scanning time., (© 2021 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: Impulsivity and novelty preference are both associated with an increased propensity to develop addiction-like behaviors, but their relationship and respective underlying dopamine (DA) underpinnings are not fully elucidated., Methods: We evaluated a large cohort (n = 49) of Roman high- and low-avoidance rats using single photon emission computed tomography to concurrently measure in vivo striatal D2/3 receptor (D2/3R) availability and amphetamine (AMPH)-induced DA release in relation to impulsivity and novelty preference using a within-subject design. To further examine the DA-dependent processes related to these traits, midbrain D2/3-autoreceptor levels were measured using ex vivo autoradiography in the same animals., Results: We replicated a robust inverse relationship between impulsivity, as measured with the 5-choice serial reaction time task, and D2/3R availability in ventral striatum and extended this relationship to D2/3R levels measured in dorsal striatum. Novelty preference was positively related to impulsivity and showed inverse associations with D2/3R availability in dorsal striatum and ventral striatum. A high magnitude of AMPH-induced DA release in striatum predicted both impulsivity and novelty preference, perhaps owing to the diminished midbrain D2/3-autoreceptor availability measured in high-impulsive/novelty-preferring Roman high-avoidance animals that may amplify AMPH effect on DA transmission. Mediation analyses revealed that while D2/3R availability and AMPH-induced DA release in striatum are both significant predictors of impulsivity, the effect of striatal D2/3R availability on novelty preference is fully mediated by evoked striatal DA release., Conclusions: Impulsivity and novelty preference are related but mediated by overlapping, yet dissociable, DA-dependent mechanisms in striatum that may interact to promote the emergence of an addiction-prone phenotype., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Several studies suggested that 5-HT 2A receptor (5-HT 2A R) blockade may provide a more favorable efficacy and side-effect profile to antipsychotic treatment. We hypothesized that a combined haloperidol (a D 2/3 receptor (D 2/3 R) antagonist) and MDL-100,907 (a 5-HT 2A R antagonist) treatment would reverse the side effects and the neurochemical alterations induced by haloperidol alone and would potentialize its efficacy. We thus chronically treated male Mdr1a knock-out rats with several doses of haloperidol alone or in combination with a saturating dose of a MDL-100,907. Receptor occupancy at clinically relevant levels was validated with a dual-radiotracer in-vivo SPECT imaging of D 2/3 R and 5-HT 2A R occupancy. Experimental tests of efficacy (dizocilpine-disrupted prepulse inhibition (PPI) of the startle reflex) and side effects (catalepsy, vacuous chewing movements) were performed. Finally, a second dual-radiotracer in-vivo SPECT scan assessed the neurochemical changes induced by the chronic treatments. Chronic haloperidol failed to reverse PPI disruption induced by dizocilpine, whilst administration of MDL-100,907 along with haloperidol was associated with a reversal of the effect of dizocilpine. Haloperidol at 0.5 mg/kg/day and at 1 mg/kg/day induced catalepsy that was significantly alleviated (by ~50%) by co-treatment with MDL-100,907 but only at 0.5 mg/kg/day dose of haloperidol. Chronic haloperidol treatment, event at doses as low as 0.1 mg/kg/day induced a significant upregulation of the D 2/3 R in the striatum (by over 40% in the nucleus accumbens and over 20% in the caudate-putamen nuclei), that was not reversed by MDL-100,907. Finally, an upregulation of 5-HT 2A R after chronic haloperidol treatment at a moderate dose only (0.25 mg/kg/day) was demonstrated in frontal cortical regions and the ventral tegmental area. Overall, a partial contribution of a 5-HT 2A R antagonism to the efficacy and side-effect profile of antipsychotic agents is suggested.

Neurofeedback (NFB) is a brain-based training method that enables users to control their own cortical oscillations using real-time feedback from the electroencephalogram (EEG). Importantly, no investigations to date have directly explored the potential impact of NFB on the brain's key neuromodulatory systems. Our study's objective was to assess the capacity of NFB to induce dopamine release as revealed by positron emission tomography (PET). Thirty-two healthy volunteers were randomized to either EEG-neurofeedback (NFB) or EEG-electromyography (EMG), and scanned while performing self-regulation during a single session of dynamic PET brain imaging using the high affinity D 2/3 receptor radiotracer, [ 18 F]Fallypride. NFB and EMG groups down-regulated cortical alpha power and facial muscle tone, respectively. Task-induced effects on endogenous dopamine release were estimated in the frontal cortex, anterior cingulate cortex, and thalamus, using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in radiotracer binding following task initiation. Contrary to our hypothesis of a differential effect for NFB vs. EMG training, significant dopamine release was observed in both training groups in the frontal and anterior cingulate cortex, but not in thalamus. Interestingly, a significant negative correlation was observed between dopamine release in frontal cortex and pre-to-post NFB change in spontaneous alpha power, suggesting that intra-individual changes in brain state (i.e., alpha power) could partly result from changes in neuromodulatory tone. Overall, our findings constitute the first direct investigation of neurofeedback's effect on the endogenous release of a key neuromodulator, demonstrating its feasibility and paving the way for future studies using this methodology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ros, Kwiek, Andriot, Michela, Vuilleumier, Garibotto and Ginovart.)

PET attenuation correction (AC) on systems lacking CT/transmission scanning, such as dedicated brain PET scanners and hybrid PET/MRI, is challenging. Direct AC in image-space, wherein PET images corrected for attenuation and scatter are synthesized from nonattenuation corrected PET (PET-nonAC) images in an end-to-end fashion using deep learning approaches (DLAC) is evaluated for various radiotracers used in molecular neuroimaging studies. One hundred eighty brain PET scans acquired using 18 F-FDG, 18 F-DOPA, 18 F-Flortaucipir (targeting tau pathology), and 18 F-Flutemetamol (targeting amyloid pathology) radiotracers (40 + 5, training/validation + external test, subjects for each radiotracer) were included. The PET data were reconstructed using CT-based AC (CTAC) to generate reference PET-CTAC and without AC to produce PET-nonAC images. A deep convolutional neural network was trained to generate PET attenuation corrected images (PET-DLAC) from PET-nonAC. The quantitative accuracy of this approach was investigated separately for each radiotracer considering the values obtained from PET-CTAC images as reference. A segmented AC map (PET-SegAC) containing soft-tissue and background air was also included in the evaluation. Quantitative analysis of PET images demonstrated superior performance of the DLAC approach compared to SegAC technique for all tracers. Despite the relatively low quantitative bias observed when using the DLAC approach, this approach appears vulnerable to outliers, resulting in noticeable local pseudo uptake and false cold regions. Direct AC in image-space using deep learning demonstrated quantitatively acceptable performance with less than 9% absolute SUV bias for the four different investigated neuroimaging radiotracers. However, this approach is vulnerable to outliers which result in large local quantitative bias., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Roman high- (RHA) and low-avoidance (RLA) rats have been used as a model for drug-addiction, showing, respectively, high- and low-responding to psychostimulants, and low versus high dopamine D2/3 receptors (D2/3R) striatal density. Previous studies indicated a major involvement of D2/3R on reinstatement of cocaine seeking, although the respective role of the two receptor subtypes is not clear. Here, we investigated sensitivity to cocaine self-administration (SA) through a dose-response protocol in RHAs and RLAs, and reinstatement of drug-seeking behavior at 15 days and 5 weeks following withdrawal. Compared to RLAs, RHAs confirmed a higher vulnerability to cocaine SA that was not related to a difference in sensitivity to the drug, as highlighted by the dose-response analysis. Both at early and late withdrawal, RHAs showed higher susceptibility than RLAs to reinstatement of drug-seeking when cocaine was used as a primer, but the two sublines did not differ when primed with the D2/3R agonist quinpirole. Moreover, while the specific D2R antagonist L741,626 blocked, the specific D3R antagonist SB-277011A failed to impair cocaine-primed relapse. The higher vulnerability of RHA versus RLA rats to cocaine-primed relapse, which contrasts with their similar vulnerability to quinpirole-primed relapse, suggests that the different propensity of both sublines to relapse likely relies on presynaptic rather than postsynaptic mechanisms. Moreover, our study challenges the involvement of D3R in the mechanisms underlying relapse to cocaine addiction, at least in conditions that may involve high levels of dopaminergic stimulation, and supports a major role of postsynaptic D2R over D3R in the vulnerability to relapse. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Purpose: PET and SPECT voxel kinetics are highly noised. To our knowledge, no study has determined the effect of denoising on the ability to detect differences in binding at the voxel level using Statistical Parametric Mapping (SPM)., Methods: In the present study, groups of subject-images with a 10%- and 20%- difference in binding of [123I]iomazenil (IMZ) were simulated. They were denoised with Factor Analysis (FA). Parametric images of binding potential (BPND) were produced with the simplified reference tissue model (SRTM) and the Logan non-invasive graphical analysis (LNIGA) and analyzed using SPM to detect group differences. FA was also applied to [123I]IMZ and [11C]flumazenil (FMZ) clinical images (n = 4) and the variance of BPND was evaluated., Results: Estimations from FA-denoised simulated images provided a more favorable bias-precision profile in SRTM and LNIGA quantification. Simulated differences were detected in a higher number of voxels when denoised simulated images were used for voxel-wise estimations, compared to quantification on raw simulated images. Variability of voxel-wise binding estimations on denoised clinical SPECT and PET images was also significantly diminished., Conclusion: In conclusion, noise removal from dynamic brain SPECT and PET images may optimize voxel-wise BPND estimations and detection of biological differences using SPM., Competing Interests: The authors have declared that no competing interests exist.

Purpose: SPECT imaging with two radiotracers at the same time is feasible if two different radioisotopes are employed, given their distinct energy emission spectra. In the case of 123 I and 125 I, dual SPECT imaging is not straightforward: 123 I emits photons at a principal energy emission spectrum of 143.1-179.9 keV. However, it also emits at a secondary energy spectrum (15-45 keV) that overlaps with the one of 125 I and the resulting cross-talk of emissions impedes the accurate quantification of 125 I. In this paper, we describe three different methods for the correction of this cross-talk and the simultaneous in vivo [ 123 I]IBZM and [ 125 I]R91150 imaging of D 2/3 and 5-HT 2A receptors in the rat brain., Methods: Three methods were evaluated for the correction of the effect of cross-talk in a series of simultaneous, [ 123 I]IBZM and [ 125 I]R91150 in vivo and phantom SPECT scans. Method 1 employs a dual-energy window (DEW) approach, in which the cross-talk on 125 I is considered a stable fraction of the energy emitted from 123 I at the principal emission spectrum. The coefficient describing the relationship between the emission of 123 I at the principal and the secondary spectrum was estimated from a series of single-radiotracer [ 123 I]IBZM SPECT studies. In Method 2, spectral factor analysis (FA) is applied to separate the radioactivity from 123 I and 125 I on the basis of their distinct emission patterns across the energy spectrum. Method 3 uses a modified simplified reference tissue model (SRTM C ) to describe the kinetics of [ 125 I]R91150. It includes the coefficient describing the cross-talk on 125 I from 123 I in the model parameters. The results of the correction of cross-talk on [ 125 I]R91150 binding potential (BP ND ) with each of the three methods, using cerebellum as the reference region, were validated against the results of a series of single-radiotracer [ 123 I]R91150 SPECT studies. In addition, the DEW approach (Method 1), considered to be the most straightforward to apply of the three, was further applied in a dual-radiotracer SPECT study of the relationship between D 2/3 and 5-HT 2A receptor binding in the striatum, both at the voxel and at the regional level., Results: Average regional BP ND values of [ 125 I]R91150, estimated on the cross-talk corrected dual-radiotracer SPECT studies provided satisfactory correlations with the BP ND values for [ 123 I]R91150 from single-radiotracer studies: r = 0.92, p < 0.001 for Method 1, r = 0.92, p < 0.001 for Method 2, r = 0.92, p < 0.001, for Method 3. The coefficient describing the ratio of the 123 I-emitted radioactivity at the 125 I-emission spectrum to the radioactivity that it emits at its principal emission spectrum was 0.34 in vivo. Dual-radiotracer in vivo SPECT studies corrected with Method 1 demonstrated a positive correlation between D 2/3 and 5-HT 2A receptor binding in the rat nucleus accumbens at the voxel level. At the VOI-level, a positive correlation was confirmed in the same region (r = 0.78, p < 0.01)., Conclusion: Dual-radiotracer SPECT imaging using 123 I and 125 I-labeled radiotracers is feasible if the cross-talk of 123 I on the 125 I emission spectrum is properly corrected. The most straightforward approach is Method 1, in which a fraction (34%) of the radioactivity emitted from 123 I at its principal energy spectrum is subtracted from the measured radioactivity at the spectrum of 125 I. With this method, a positive correlation between the binding of [ 123 I]IBZM and [ 125 I]R91150 was demonstrated in the rat nucleus accumbens. This result highlights the interest of dual-radiotracer SPECT imaging to study multiple neurotransmitter systems at the same time and under the same biological conditions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Roman high (RHA)- and low (RLA)-avoidance rat sublines have been identified as an addiction-prone and addiction-resistant phenotype based on their high vs. low locomotor responsiveness to novelty and high vs. low ability to develop neurochemical and behavioral sensitization to psychostimulants, respectively. Most studies though have focused on psychostimulants and little is known about the neuroadaptive response of these two lines to cannabinoids. This study investigated the effects of chronic exposure to Δ 9 -tetrahydrocannabinol (THC) on dopamine D 2/3 receptor (D 2/3 R) availabilities and functional sensitivity in the mesostriatal system of RHA and RLA rats. At baseline, RLA rats exhibited higher densities of mesostriatal D2/3R but lower levels of striatal CB 1 R mRNA and displayed a lower locomotor response to acute THC as compared to RHAs. Following chronic THC treatment, striking changes in D 2/3 R signaling were observed in RLA but not in RHA rats, namely an increased availability and functional supersensitivity of striatal D 2/3 R, as evidenced by a supersensitive psychomotor response to the D 2/3 R agonist quinpirole. Moreover, in RLA rats, the lower was the locomotor response to acute THC, the higher was the psychomotor response to quinpirole following chronic THC. These results showing a greater neuroadaptive response of RLA vs. RHA rats to chronic THC thus contrast with previous studies showing a resistance to neuroadaptive response of RLAs to psychostimulants, This suggests that, contrasting with their low proneness to psychostimulant drug-seeking, RLAs may exhibit a heightened proneness to cannabinoid drug-seeking as compared to RHA rats., (© 2017 Wiley Periodicals, Inc.)

Purpose: Molecular imaging of the D 2/3 receptor is widely used in neuropsychiatric research. Non-displaceable binding potential (BP ND ) is a very popular quantitative index, defined as the product of the receptor concentration (B avail ) and the radiotracer affinity for the receptor (1/appK d ). As the appK d is influenced by parameters such as the endogenous neurotransmitter dynamics, it often constitutes a confounding factor in research studies. A simplified method for absolute quantification of both these parameters would be of great interest in this context. Here, we describe the use of a partial saturation protocol that permits to produce an in vivo Scatchard plot and thus estimate B avail and appK d separately , through a single dynamic SPECT session. To validate this approach, a multi-injection protocol is used for the full kinetic modeling of [ 123 I]IBZM using a 3-tissue compartment, 7-parameter model (3T-7k). Finally, more "classic" BP ND estimation methods are also validated against the results of the 3T-7k., Methods: Twenty-nine male rats were used. Binding parameters were estimated using the 3T-7k in a multi-injection protocol. A partial saturation protocol was applied at the region- and voxel-level and results were compared to those obtained with the 3T-7k model. The partial saturation protocol was applied after an adenovirus-mediated D 2 receptor striatal overexpression and in an amphetamine-induced dopamine release paradigm. The Simplified Reference Tissue Model (SRTM), the Logan's non-invasive graphical analysis (LNIGA) and a simple standardized uptake ratio (SUR) method were equally applied., Results: The partial saturation experiments gave similar values as the 3T-7k both at the regional and voxel-level. After adenoviral-mediated D 2 -receptor overexpression, an increase in B avail by approximately 18% was observed in the striatum. After amphetamine administration, a 16.93% decrease in B avail (p<0.05) and a 39.12% increase (p<0.01) in appK d was observed. BP ND derived from SRTM, LNIGA and SUR correlated well with the B avail values from the 3T-7k (r=0.84, r=0.84 and r=0.83, respectively, p<0.0001 for all correlations)., Conclusion: A partial saturation protocol permits the non-invasive and time-efficient estimation of B avail and appK d separately. Given the different biological phenomena that underlie these parameters, this method may be applied for the in-depth study of the dopaminergic system in translational molecular imaging studies. It can detect the biological variations in these parameters, dissociating the variations in receptor density (B avail ) from affinity (1/appK d ), which reflects the interactions of the receptor with its endogenous ligand., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This study examined the time-course of alterations in levels and functional sensitivities of dopamine D2/3 receptors (D2/3R) during the course and up to 6 weeks following cessation of chronic treatment with Delta(9)-Tetrahydrocannabinol (THC) in rats. THC treatment led to an increase in D2/3R levels in striatum, as assessed using [(3)H]-(+)-PHNO, that was readily observable after one week of treatment, remained stably elevated during the subsequent 2 weeks of treatment, but fully reversed within 2 weeks of THC discontinuation. THC-induced D2/3R alterations were more pronounced and longer lasting in the dopamine cell body regions of the midbrain, wherein [(3)H]-(+)-PHNO binding was still elevated at 2 weeks but back to control values at 6 weeks after THC cessation. Parallel analyses of the psychomotor effects of pre- and post-synaptic doses of quinpirole also showed a pattern of D2/3R functional supersensitivity indicative of more rapid subsidence in striatum than in midbrain following drug cessation. These results indicate that chronic THC is associated with a biochemical and functional sensitization of D2/3R signaling, that these responses show a region-specific temporal pattern and are fully reversible following drug discontinuation. These results suggest that an increased post-synaptic D2/3R function and a decreased DA presynaptic signaling, mediated by increased D2/3R autoinhibition, may predominate during distinct phases of withdrawal and may contribute both to the mechanisms leading to relapse and to cannabinoid withdrawal symptoms. The different rates of normalization of D2/3R function in striatum and midbrain may be critical information for the development of new pharmacotherapies for cannabis dependence., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Pharmacological P-glycoprotein (P-gp) inhibition with tariquidar (TQD) is considered a promising strategy for the augmentation of radiotracer brain uptake. However, a region-dependent effect may compromise the robustness of quantitative studies. For this reason, we studied the effect of a TQD pretreatment on 5-HT2A imaging with [(123)I]R91150 and compared results with those obtained in Mdr1a knock-out (KO) rats., Methods: Ex vivo autoradiography was performed in TQD (15 mg/kg) pretreated wild-type (WT-TQD), Mdr1a knock-out (KO) and untreated WT rats for Specific Binding Ratio (SBR) estimation. In vivo dynamic SPECT imaging with serial arterial blood sampling was performed in the former two groups of rats and kinetic analysis was performed with a one tissue-compartment (1TC) model and the Specific Uptake Ratio (SUR). Results were analyzed statistically using repeated measures ANOVA., Results: SBR values differed between WT-TQD, Mdr1a KO and WT rats in a region-dependent manner (p<0.0001). In vivo brain uptake of radiotracer did not differ between groups. Similarly, kinetic analysis provided distribution volume (V(T)) values that did not differ significantly between groups. SUR binding potential (BPND) values from both groups highly correlated with corresponding V(T) (r=0.970, p<0.0001 and r=0.962, p<0.0001, respectively). However, SUR measured over averaged images between 100 and 120 min, using cerebellum as reference region, demonstrated values that were, by average, 2.99±0.53 times higher in the WT-TQD group, with the difference between groups being region-dependent (p<0.001). In addition, coefficient of variation of the SUR BPND values across brain regions was significantly higher in the WT-TQD rats (41.25%±9.63% versus 11.13%±5.59%, p<0.0001)., Conclusion: P-gp inhibition with TQD leads to region-dependent effect in the rat brain, with probably sub-optimal effect in cerebellum. This warrants attention when it is used as a reference region for quantitative studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Our goal was to identify suitable image quantification methods to image 5-hydroxytryptamine2A (5-HT2A) receptors in vivo in Mdr1a knockout (KO) rats (i.e., P-glycoprotein KO) using 123I-R91150 single-photon emission computed tomography (SPECT). The 123I-R91150 binding parameters estimated with different reference tissue models (simplified reference tissue model [SRTM], Logan reference tissue model, and tissue ratio [TR] method) were compared to the estimates obtained with a comprehensive three-tissue/seven-parameter (3T/7k)-based model. The SRTM and Logan reference tissue model estimates of 5-HT2A receptor (5-HT2AR) nondisplaceable binding potential (BPND) correlated well with the absolute receptor density measured with the 3T/7k gold standard (r > .89). Quantification of 5-HT2AR using the Logan reference tissue model required at least 90 minutes of scanning, whereas the SRTM required at least 110 minutes. The TR method estimates were also highly correlated to the 5-HT2AR density (r > .91) and only required a single 20-minute scan between 100 and 120 minutes postinjection. However, a systematic overestimation of the BPND values was observed. The Logan reference tissue method is more convenient than the SRTM for the quantification of 5-HT2AR in Mdr1a KO rats using 123I-R91150 SPECT. The TR method is an interesting and simple alternative, despite its bias, as it still provides a valid index of 5-HT2AR density.

Cannabis produces cognitive dysfunctions that resemble those of schizophrenia; yet the neurobiological substrate of this similarity remains unclear. Schizophrenia patients show deficits in prepulse inhibition (PPI) of the acoustic startle reflex (ASR), an operational measure of the information-processing abnormalities that may underlie the cognitive and positive symptoms of the disease. However, the effect of cannabis on PPI remains poorly understood, as data are often contradictory. Here, we investigated the effect of acute and repeated treatment with ∆(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on PPI in rats, and the role of dopamine D₂/₃-receptor blockade in this effect. PPI and ASR were sequentially measured after the first and the last dose of a 21-days treatment with THC (1 mg/kg/day) or vehicle and at 1-week following discontinuation of treatment. The effect of haloperidol (0.1 mg/kg) on THC-induced PPI alteration was also evaluated. Chronic, but not acute, THC treatment produced significant reductions in PPI that were normalized back to control values within one-week of THC discontinuation. The THC-induced gating deficits were observed in the absence of ASR change and were reversed by the D₂/₃-receptor antagonist haloperidol. Chronic THC exposure induced PPI disruptions that emerged only following repeated administrations, suggesting that time-dependent neuroadaptations within the DA mesolimbic system are involved in the disruptive effects of THC on sensorimotor gating. These gating deficits were transient and appeared to be dependent on an overactivity of D₂/₃-receptor-mediated dopamine signaling, highlighting a potential role for D₂/₃-receptors in the propsychotic action of THC., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Purpose: In vivo imaging of GABAA receptors is essential for the comprehension of psychiatric disorders in which the GABAergic system is implicated. Small animal SPECT provides a modality for in vivo imaging of the GABAergic system in rodents using [(123)I]Iomazenil, an antagonist of the GABAA receptor. The goal of this work is to describe and evaluate different quantitative reference tissue methods that enable reliable binding potential (BP) estimations in the rat brain to be obtained., Methods: Five male Sprague-Dawley rats were used for [(123)I]Iomazenil brain SPECT scans. Binding parameters were obtained with a one-tissue compartment model (1TC), a constrained two-tissue compartment model (2TCc), the two-step Simplified Reference Tissue Model (SRTM2), Logan graphical analysis and analysis of delayed-activity images. In addition, we employed factor analysis (FA) to deal with noise in data., Results: BPND obtained with SRTM2, Logan graphical analysis and delayed-activity analysis was highly correlated with BPF values obtained with 2TCc (r=0.954 and 0.945 respectively, p<0.0001). Equally significant correlations were found between values obtained with 2TCc and SRTM2 in raw and FA-denoised images (r=0.961 and 0.909 respectively, p<0.0001). Scans of at least 100min are required to obtain stable BPND values from raw images while scans of only 70min are sufficient from FA-denoised images. These images are also associated with significantly lower standard errors of 2TCc and SRTM2 BP values., Conclusion: Reference tissue methods such as SRTM2 and Logan graphical analysis can provide equally reliable BPND values from rat brain [(123)I]Iomazenil SPECT. Acquisitions, however, can be much less time-consuming either with analysis of delayed activity obtained from a 20-minute scan 50min after tracer injection or with FA-denoising of images., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The pharmacokinetic properties of radiotracers are crucial for successful in vivo single-photon emission computed tomographic (SPECT) imaging. Our goal was to determine if MDR1A-deficient animals could allow better SPECT imaging outcomes than wild-type (WT) animals for a selection of serotoninergic radioligands. Thus, we compared the performances of 123I-p-MPPI, 123I-R91150, 123I-SB207710, and 123I-ADAM radioligands, for imaging of their respective targets (5-hydroxytryptamine [5-HT]1A, 5-HT2A, 5-HT4, and serotonin transporter [SERT]), in WT and Mdr1a knockout (KO) rats. With 123I-SB207710, virtually no SPECT signal was recorded in the brain of WT or KO animals. For 123I-p-MPPI, low nondisplaceable binding potentials (BPND, mean ± SD) were observed in WT (0.49 ± 0.25) and KO (0.89 ± 0.52) animals. For 123I-ADAM, modest imaging contrast was observed in WT (1.27 ± 0.02) and KO (1.31 ± 0.09) animals. For 123I-R91150, the BPND were significantly higher in Mdr1a KO (3.98 ± 0.65) animals compared to WT animals (1.22 ± 0.26). The pharmacokinetics of 123I-SB207710 and 123I-p-MPPI do not make them ideal tracers for preclinical SPECT neuroimaging. 123I-ADAM showed adequate brain uptake regardless of Mdr1a expression and appeared suitable for preclinical SPECT neuroimaging in both animal strains. The use of Mdr1a KO animals significantly improved the brain penetration of 123I-R91150, making this animal strain an interesting option when considering SPECT neuroimaging of 5-HT2A receptors in rat.

Defluorination of [18F]fallypride and accumulation of 18F in skull and glands leads to the contamination of brain structures with spillover activity due to partial volume effects, leading to considerable errors in binding potential estimations. Here we propose a modification of the simplified reference tissue model (SRTM) to take into account the contribution of skull activity to the radioactivity kinetic pattern in cerebellum and target regions. It consists of the introduction of an additional parameter for each volume of interest (sT) and one for the cerebellum (sR), corresponding to the fraction of skull activity contaminating these structures. Using five rat positron emission tomography experiments, we applied the modified SRTM (SRTMc), which resulted in excellent fits. As a relative means of comparison of results, we applied factor analysis (FA) to decompose dynamic data into images corresponding to brain and skull activity. With the skull factor images, we estimated the "true" sT and sR values, ultimately permitting us to fix the sR value. Parameters obtained with the SRTMc were closely correlated with values obtained from FA-corrected data. In conclusion, we propose an efficient method for reliable quantification of dopamine D2/3 receptors with single-injection [18F]fallypride scans that is potentially applicable to human studies where 18F skull accumulation compromises binding parameter estimation.

High novelty-seeking has been related to an increased risk for developing addiction, but the neurobiological mechanism underlying this relationship is unclear. We investigated whether differences in dopamine (DA) D2/3-receptor (D2/3R) function underlie phenotypic divergence in novelty-seeking and vulnerability to addiction. Measures of D2/3R availability using the D2R-preferring antagonist [18F]Fallypride, and the D3R-preferring agonist [3H]-(+)-PHNO and of DA-related gene expression and behaviours were used to characterize DA signalling in Roman high- (RHA) and low-avoidance (RLA) rats, which respectively display high and low behavioural responsiveness both to novelty and psychostimulant exposure. When compared to RLA rats, high novelty-responding RHAs had lower levels of D2R, but not D3R, binding and mRNA in substantia nigra/ventral tegmental area (SN/VTA) and showed behavioural evidence of D2-autoreceptor subsensitivity. RHA rats also showed a higher expression of the tyrosine hydroxylase gene in SN/VTA, higher levels of extracellular DA in striatum and augmentation of the DA-releasing effects of amphetamine (Amph), suggesting hyperfunctioning of midbrain DA neurons. RHA rats also exhibited lower availabilities and functional sensitivity of D2R, but not D3R, in striatum, which were inversely correlated with individual scores of novelty-seeking, which, in turn, predicted the magnitude of Amph-induced behavioural sensitization. These results indicate that innately low levels of D2R in SN/VTA and striatum, whether they are a cause or consequence of the concomitantly observed elevated DA tone, result in a specific pattern of DA signalling that may subserve novelty-seeking and vulnerability to drug use. This suggests that D2R deficits in SN/VTA and striatum could both constitute neurochemical markers of an addiction-prone phenotype.