D2/3 Agonist during Learning Potentiates Cued Risky Choice.

Impulse control and/or gambling disorders can be triggered by dopamine agonist therapies used to treat Parkinson's disease, but the cognitive and neurobiological mechanisms underlying these adverse effects are unknown. Recent data show that adding win-paired sound and light cues to the rat gambling task (rGT) potentiates risky decision-making and impulsivity via the dopamine system, and that changing dopaminergic tone has a greater influence on behavior while subjects are learning task contingencies. Dopamine agonist therapy may therefore be potentiating risk-taking by amplifying the behavioral impact of gambling-related cues on novel behavior. Here, we show that ropinirole treatment in male rats transiently increased motor impulsivity but robustly and progressively increased choice of the high-risk/high-reward options when administered during acquisition of the cued but not uncued rGT. Early in training, ropinirole increased win-stay behavior after large unlikely wins on the cued rGT, indicative of enhanced model-free learning, which mediated the drug's effect on later risk preference. Ex vivo cFos imaging showed that both chronic ropinirole and the addition of win-paired cues suppressed the activity of dopaminergic midbrain neurons. The ratio of midbrain:prefrontal cFos+ neurons was lower in animals with suboptimal choice patterns and tended to predict risk preference across all rats. Network analyses further suggested that ropinirole induced decoupling of the dopaminergic cells of the VTA and nucleus accumbens but only when win-paired cues were present. Frontostriatal activity uninformed by the endogenous dopaminergic teaching signal therefore appeared to perpetuate risky choice, and ropinirole exaggerated this disconnect in synergy with reward-paired cues.SIGNIFICANCE STATEMENT D2/3 receptor agonists, used to treat Parkinson's disease, can cause gambling disorder through an unknown mechanism. Ropinirole increased risky decision-making in rats, but only when wins were paired with casino-inspired sounds and lights. This was mediated by increased win-stay behavior after large unlikely wins early in learning, indicating enhanced model-free learning. cFos imaging showed that ropinirole suppressed activity of midbrain dopamine neurons, an effect that was mimicked by the addition of win-paired cues. The degree of risky choice rats exhibited was uniquely predicted by the ratio of midbrain dopamine:PFC activity. Depriving the PFC of the endogenous dopaminergic teaching signal may therefore drive risky decision-making on-task, and ropinirole acts synergistically with win-paired cues to amplify this.

Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.

BACKGROUND: The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far. METHODS: This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status. RESULTS: We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability. CONCLUSIONS: The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.

Effects of quinpirole in the ventral tegmental area on impulsive behaviour during performance on the five-choice serial reaction time task.

Impulsive behaviour on the five-choice serial reaction time task (5CSRTT), a task measuring attention and impulsivity in rodents, is known to depend on dopamine (DA) neurotransmission in the mesolimbic DA pathway. Previous research in our lab reported that systemic administration of the D2/3 agonist quinpirole, which decreases DA release in the striatum, reduced premature responses in rats performing the 5CSRTT. It is unclear, however, whether this effect is mediated by the activation of inhibitory somatodendritic receptors in the ventral tegmental area (VTA), which in turn leads to a reduction in DA release in the nucleus accumbens, a major terminal region of the mesolimbic DA pathway. In the present study, we investigated this possibility by infusing quinpirole directly into the VTA of rats during performance on the 5CSRTT. We found that quinpirole, at the highest dose, significantly reduced the frequency of premature responses on the 5CSRTT. Thus, the effects of quinpirole and other D2/3 receptor agonists to reduce this form of impulsive behaviour appear to depend on the activation of somatodendritic D2/3 receptors in the VTA.

New compounds with hepatoprotective effects from the stems of Sabia parviflora.

Three new compounds, (8S)-2,2,7,7-tetramethyl-8-hydroxymethyl-6H-indanone-(2,3-b)-2H-pyran-9-O-ß-d-glucopyranoside (1), (7S,8S)-2,2,7-trimethyl-7-hydroxymethyl-8-hydroxy-2,7,8,9-tetrahydro-6H-naphtho-(2,3-b)-pyran-10-O-ß-d-glucopyranoside (2), 1-deoxy-1-(3,4-dihydro-7-methyl-2,3-dioxo-1(2H)-quinoxalinyl)pentitol-6-carboxylic acid (3), as well as six known compounds (4-9), were obtained. Their structures were determined by spectroscopy and comparison with NMR data of related compounds. Absolute configurations were determined by ECD spectroscopy. The hepatoprotective effects of these compounds were investigated on HepG2 and LO2 cells lines; compounds 1, 2, and 4 displayed moderate activity.

Repeated Cocaine Intake Differentially Impacts Striatal D2/3 Receptor Availability, Psychostimulant-Induced Dopamine Release, and Trait Behavioral Markers of Drug Abuse.

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 D2/3 receptor (D2/3R) 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 D2/3R 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 D2/3R 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.

Extrastriatal Dopamine D2/3 Receptor Availability in Alcohol Use Disorder and Individuals at High Risk.

INTRODUCTION: Reduced striatal dopamine D2/3 receptor availability in alcohol use disorder (AUD) has been demonstrated in recent clinical studies and meta-analyses. However, only a limited number of studies investigated extrastriatal D2/3 availability in AUD or in at-risk populations. In line with a dimensional understanding of addiction, extrastriatal dopaminergic neuroadaptations have been suggested to be relevant from a pathobiological perspective. METHODS: We investigated D2/3 receptor availability via 18F-fallypride positron emission tomography applying a region of interest (ROI) approach. We selected ROIs for the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC). Our sample included 19 healthy controls (low risk [LR]), 19 individuals at high risk (HR) to develop addiction, and 20 recently detoxified AUD patients. RESULTS: We found significantly higher D2/3 receptor availability of HR compared to AUD in the left and right rostral ACC (rACC), as well as in the left ventrolateral PFC (vlPFC). We did not observe a significant difference between AUD and LR. After corrections for multiple comparisons none of the ROIs reached significance throughout the group comparison. The D2/3 receptor availability in the left rACC was inversely correlated with symptom severity assessed with the Alcohol Dependency Scale. DISCUSSION: To our knowledge, the present work is the first study investigating extrastriatal D2/3 receptor availabilities in individuals at HR and patients with AUD. The observation that D2/3 receptor availabilities are highest in HR might suggest that their pathobiology differs from subjects with AUD. Future studies are necessary to clarify the intraindividual course of this biomarker over different disease stages and its possible role as a risk or protective factor.

Modeling and optimal control of mutated COVID-19 (Delta strain) with imperfect vaccination.

As people around the world work to stop the COVID-19 pandemic, mutated COVID-19 (Delta strain) that are more contagious are emerging in many places. How to develop effective and reasonable plans to prevent the spread of mutated COVID-19 is an important issue. In order to simulate the transmission of mutated COVID-19 (Delta strain) in China with a certain proportion of vaccination, we selected the epidemic situation in Jiangsu Province as a case study. To solve this problem, we develop a novel epidemic model with a vaccinated population. The basic properties of the model is analyzed, and the expression of the basic reproduction number R 0 is obtained. We collect data on the Delta strain epidemic in Jiangsu Province, China from July 20, to August 5, 2021. The weighted nonlinear least square estimation method is used to fit the daily asymptomatic infected people, common infected people and severe infected people. The estimated parameter values are obtained, the approximate values of the basic reproduction number are calculated R 0 ≈ 1.378 . Through the global sensitivity analysis, we identify some parameters that have a greater impact on the prevalence of the disease. Finally, according to the evaluation results of parameter influence, we consider three control measures (vaccination, isolation and nucleic acid testing) to control the spread of the disease. The results of the study found that the optimal control measure is to dynamically adjust the three control measures to achieve the lowest number of infections at the lowest cost. The research in this paper can not only enrich theoretical research on the transmission of COVID-19, but also provide reliable control suggestions for countries and regions experiencing mutated COVID-19 epidemics.

Optimal control and cost-effectiveness analysis of a new COVID-19 model for Omicron strain.

Omicron, a mutant strain of COVID-19, has been sweeping the world since November 2021. A major characteristic of Omicron transmission is that it is less harmful to healthy adults, but more dangerous for people with underlying disease, the elderly, or children. To simulate the spread of Omicron in the population, we developed a new 9-dimensional mathematical model with high-risk and low-risk exposures. Then we analyzed its dynamic properties and obtain the basic reproduction number R 0 . With the data of confirmed cases from March 1, 2022 published on the official website of Shanghai, China, we used the weighted nonlinear least square estimation method to estimate the parameters, and get the basic reproduction number R 0 ≈ 1 . 5118 . Finally, we considered three control measures (isolation, detection and treatment), and studied the optimal control strategy and cost-effectiveness analysis of the model. The control strategy G is determined to be the optimal control strategy from the purpose of making fewer people infected. In strategy G, the three human control measures contain six control variables, and the control strength of these variables needs to be varied according to the pattern shown in Figure 11, so that the number of infections can be minimized and the percentage of reduction of infections can reach more than 95%.

TBC1 domain family member 23 interacts with Ras-related protein Rab-11A to promote poor prognosis of non-small-cell lung cancer via ß1-integrin.

Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer cases. TBC1D23, a member of the TBC/RABGAP family, is widely expressed in human tissues; however, its role in NSCLC is currently unknown. Immunohistochemical analysis was conducted on 173 paraffin-embedded lung tissue sections from patients with NSCLC from 2014 to 2018 at the First Affiliated Hospital of China Medical University. MTT, colony formation assay, cell cycle assay, scratch assay, transwell assay, Western blotting and real-time PCR were employed on multiple NSCLC cell lines modified to knock down or overexpress TBC1D23/RAB11A. Immunoprecipitation, immunoprecipitation-mass spectrometry, immunofluorescence and flow cytometry were performed to explore the interaction between TBC1D23 and RAB11A and TBC1D23 involvement in the interaction between RAB11A and ß1 integrin in the para-nucleus. TBC1D23 was correlated with tumour size, differentiation degree, metastasis, TNM stage and poor prognosis. TBC1D23 was involved in the interaction between RAB11A and ß1 integrin in the para-nucleus, thus activating the ß1 integrin/FAK/ERK signalling pathway to promote NSCLC. Furthermore, TBC1D23 promoted NSCLC progression by inducing cell proliferation, migration and invasion. This study indicated the relationship between TBC1D23 expression and the adverse clinicopathological characteristics of patients with NSCLC, suggesting that TBC1D23 may be an important target for NSCLC treatment.

Dopamine D2/3 Receptor Availabilities and Evoked Dopamine Release in Striatum Differentially Predict Impulsivity and Novelty Preference in Roman High- and Low-Avoidance Rats.

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.

Effectiveness, safety and acceptability of no-test medical abortion (termination of pregnancy) provided via telemedicine: a national cohort study.

OBJECTIVE: To compare outcomes before and after implementation of medical abortion (termination of pregnancy) without ultrasound via telemedicine. DESIGN: Cohort analysis. SETTING: The three main abortion providers. POPULATION OR SAMPLE: Medical abortions at home at ≤69 days' gestation in two cohorts: traditional model (in-person with ultrasound, n = 22 158) from January to March 2020 versus telemedicine-hybrid model (either in person or via telemedicine without ultrasound, n = 29 984, of whom 18 435 had no-test telemedicine) between April and June 2020. Sample (n = 52 142) comprises 85% of all medical abortions provided nationally. METHODS: Data from electronic records and incident databases were used to compare outcomes between cohorts, adjusted for baseline differences. MAIN OUTCOME MEASURES: Treatment success, serious adverse events, waiting times, gestation at treatment, acceptability. RESULTS: Mean waiting time from referral to treatment was 4.2 days shorter in the telemedicine-hybrid model and more abortions were provided at ≤6 weeks' gestation (40% versus 25%, P < 0.001). Treatment success (98.8% versus 98.2%, P > 0.999), serious adverse events (0.02% versus 0.04%, P = 0.557) and incidence of ectopic pregnancy (0.2% versus 0.2%, P = 0.796) were not different between models. In the telemedicine-hybrid model, 0.04% were estimated to be over 10 weeks' gestation at the time of the abortion; all were completed safely at home. Within the telemedicine-hybrid model, effectiveness was higher with telemedicine than in-person care (99.2% versus 98.1%, P < 0.001). Acceptability of telemedicine was high (96% satisfied) and 80% reported a future preference for telemedicine. CONCLUSIONS: A telemedicine-hybrid model for medical abortion that includes no-test telemedicine and treatment without an ultrasound is effective, safe, acceptable and improves access to care. TWEETABLE ABSTRACT: Compelling evidence from 52 142 women shows no-test telemedicine abortion is safe, effective and improves care.

Dopamine D2/3 receptor availability in alcohol use disorder and individuals at high risk: Towards a dimensional approach.

Alcohol use disorder (AUD) is the most common substance use disorder worldwide. Although dopamine-related findings were often observed in AUD, associated neurobiological mechanisms are still poorly understood. Therefore, in the present study, we investigate D2/3 receptor availability in healthy participants, participants at high risk (HR) to develop addiction (not diagnosed with AUD), and AUD patients in a detoxified stage, applying 18 F-fallypride positron emission tomography (18 F-PET). Specifically, D2/3 receptor availability was investigated in (1) 19 low-risk (LR) controls, (2) 19 HR participants, and (3) 20 AUD patients after alcohol detoxification. Quality and severity of addiction were assessed with clinical questionnaires and (neuro)psychological tests. PET data were corrected for age of participants and smoking status. In the dorsal striatum, we observed significant reductions of D2/3 receptor availability in AUD patients compared with LR participants. Further, receptor availability in HR participants was observed to be intermediate between LR and AUD groups (linearly decreasing). Still, in direct comparison, no group difference was observed between LR and HR groups or between HR and AUD groups. Further, the score of the Alcohol Dependence Scale (ADS) was inversely correlated with D2/3 receptor availability in the combined sample. Thus, in line with a dimensional approach, striatal D2/3 receptor availability showed a linear decrease from LR participants to HR participants to AUD patients, which was paralleled by clinical measures. Our study shows that a core neurobiological feature in AUD seems to be detectable in an early, subclinical state, allowing more individualized alcohol prevention programs in the future.

Mathematical modeling and analysis for controlling the spread of infectious diseases.

In this work, we present and discuss the approaches, that are used for modeling and surveillance of dynamics of infectious diseases by considering the early stage asymptomatic and later stage symptomatic infections. We highlight the conceptual ideas and mathematical tools needed for such infectious disease modeling. We compute the basic reproduction number of the proposed model and investigate the qualitative behaviours of the infectious disease model such as, local and global stability of equilibria for the non-delayed as well as delayed system. At the end, we perform numerical simulations to validate the effectiveness of the derived results.

Association of dopamine D2/3 receptor binding potential measured using PET and [11C]-(+)-PHNO with post-mortem DRD2/3 gene expression in the human brain.

Open access post-mortem transcriptome atlases such as the Allen Human Brain Atlas (AHBA) can inform us about mRNA expression of numerous proteins of interest across the whole brain, while in vivo protein binding in the human brain can be quantified by means of neuroreceptor positron emission tomography (PET). By combining both modalities, the association between regional gene expression and receptor distribution in the living brain can be approximated. Here, we compare the characteristics of D2 and D3 dopamine receptor distribution by applying the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and human gene expression data. Since [11C]-(+)-PHNO has a higher affinity for D3 compared to D2 receptors, we hypothesized that there is a stronger relationship between D2/3 non-displaceable binding potentials (BPND) and D3 mRNA expression. To investigate the relationship between D2/3 BPND and mRNA expression of DRD2 and DRD3 we performed [11C]-(+)-PHNO PET scans in 27 healthy subjects (12 females) and extracted gene expression data from the AHBA. We also calculated D2/D3 mRNA expression ratios to imitate the mixed D2/3 signal of [11C]-(+)-PHNO. In accordance with our a priori hypothesis, a strong correlation between [11C]-(+)-PHNO and DRD3 expression was found. However, there was no significant correlation with DRD2 expression. Calculated D2/D3 mRNA expression ratios also showed a positive correlation with [11C]-(+)-PHNO binding, reflecting the mixed D2/3 signal of the radioligand. Our study supports the usefulness of combining gene expression data from open access brain atlases with in vivo imaging data in order to gain more detailed knowledge on neurotransmitter signaling.

Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia.

Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.

Global analysis of a predator-prey model with variable predator search rate.

We consider a modified Holling-type II predator-prey model, based on the premise that the search rate of predators is dependent on the prey density, rather than constant. A complete analysis of the global behavior of the model is presented, and shows that the model exhibits a dichotomy similar to the classical Holling-type II model: either the coexistence steady state is globally stable; or it is unstable, and then a unique, globally stable limit cycle exists. We discuss the similarities, but also important differences between our model and the Holling-type II model. The main differences are that: 1. The paradox of enrichment which always occurs in the Holling-type II model, does not always occur here, and 2. Even when the paradox of enrichment occurs, predators can adapt by lowering their search rate, and effectively stabilize the system.

Dynamic analysis of a mathematical model with health care capacity for COVID-19 pandemic.

The fact that no there exists yet an absolute treatment or vaccine for COVID-19, which was declared as a pandemic by the World Health Organization (WHO) in 2020, makes very important spread out over time of the epidemic in order to burden less on hospitals and prevent collapsing of the health care system. This case is a consequence of limited resources and is valid for all countries in the world facing with this serious threat. Slowing the speed of spread will probably make that the outbreak last longer, but it will cause lower total death count. In this study, a new SEIR epidemic model formed by taking into account the impact of health care capacity has been examined and local and global stability of the model has been analyzed. In addition, the model has been also supported by some numerical simulations.

Relationship of self-transcendence traits with in vivo dopamine D2/3 receptor availability and functional connectivity: An [18 F]fallypride PET and fMRI study.

Genetic research has implicated dopamine neurotransmission in the expression of the self-transcendence trait in humans. However, molecular imaging of dopaminergic markers is undocumented in relation to this personality trait. In this multimodal imaging study, we first investigated the relationship between the self-transcendence trait and in vivo dopamine D2/3 receptor availability using [18 F]fallypride positron emission tomography (PET). We next conducted seed-based functional connectivity analyses using resting-state functional magnetic resonance imaging (rs-fMRI) data with regions derived from the PET analysis as seeds to explore the functional significance of D2/3 receptor availability foci associated with the self-transcendence trait. Twenty-one healthy subjects underwent high-resolution PET with [18 F]fallypride and a subset of 18 subjects also completed 3-Tesla rs-fMRI. The Temperament and Character Inventory was used to measure the self-transcendence trait. A voxel-based whole brain analysis revealed that the [18 F]fallypride binding potential (BPND ) within the cluster of the left insula was significantly positively correlated with self-transcendence trait scores. A region-of-interest analysis also showed a significant positive correlation between self-transcendence and [18 F]fallypride BPND in the left insula. The exploratory [18 F]fallypride BPND seed-based rs-fMRI analysis showed that the functional connectivity from the left insula seed to the prefrontal cortices (including the inferior frontal region) was negatively associated with self-transcendence trait scores. The results of the present study suggest that D2/3 receptor-mediated neurotransmission in the left insula may constitute a significant neurobiological factor in the self-transcendence trait. The negative associations between BPND seed-based functional connectivity and self-transcendence trait scores may suggest reduced prefrontal control in this personality trait.

Dual-radiotracer translational SPECT neuroimaging. Comparison of three methods for the simultaneous brain imaging of D2/3 and 5-HT2A receptors.

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 123I and 125I, dual SPECT imaging is not straightforward: 123I 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 125I and the resulting cross-talk of emissions impedes the accurate quantification of 125I. In this paper, we describe three different methods for the correction of this cross-talk and the simultaneous in vivo [123I]IBZM and [125I]R91150 imaging of D2/3 and 5-HT2A receptors in the rat brain. METHODS: Three methods were evaluated for the correction of the effect of cross-talk in a series of simultaneous, [123I]IBZM and [125I]R91150 in vivo and phantom SPECT scans. Method 1 employs a dual-energy window (DEW) approach, in which the cross-talk on 125I is considered a stable fraction of the energy emitted from 123I at the principal emission spectrum. The coefficient describing the relationship between the emission of 123I at the principal and the secondary spectrum was estimated from a series of single-radiotracer [123I]IBZM SPECT studies. In Method 2, spectral factor analysis (FA) is applied to separate the radioactivity from 123I and 125I on the basis of their distinct emission patterns across the energy spectrum. Method 3 uses a modified simplified reference tissue model (SRTMC) to describe the kinetics of [125I]R91150. It includes the coefficient describing the cross-talk on 125I from 123I in the model parameters. The results of the correction of cross-talk on [125I]R91150 binding potential (BPND) with each of the three methods, using cerebellum as the reference region, were validated against the results of a series of single-radiotracer [123I]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 D2/3 and 5-HT2A receptor binding in the striatum, both at the voxel and at the regional level. RESULTS: Average regional BPND values of [125I]R91150, estimated on the cross-talk corrected dual-radiotracer SPECT studies provided satisfactory correlations with the BPND values for [123I]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 123I-emitted radioactivity at the 125I-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 D2/3 and 5-HT2A 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 123I and 125I-labeled radiotracers is feasible if the cross-talk of 123I on the 125I emission spectrum is properly corrected. The most straightforward approach is Method 1, in which a fraction (34%) of the radioactivity emitted from 123I at its principal energy spectrum is subtracted from the measured radioactivity at the spectrum of 125I. With this method, a positive correlation between the binding of [123I]IBZM and [125I]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.