Involvement of dopamine D3 receptor in impulsive choice decision-making in male rats.

Impulsive decision-making has been linked to impulse control disorders and substance use disorders. However, the neural mechanisms underlying impulsive choice are not fully understood. While previous PET imaging and autoradiography studies have shown involvement of dopamine and D2/3 receptors in impulsive behavior, the roles of distinct D1, D2, and D3 receptors in impulsive decision-making remain unclear. In this study, we used a food reward delay-discounting task (DDT) to identify low- and high-impulsive rats, in which low-impulsive rats exhibited preference for large delayed reward over small immediate rewards, while high-impulsive rats showed the opposite preference. We then examined D1, D2, and D3 receptor gene expression using RNAscope in situ hybridization assays. We found that high-impulsive male rats exhibited lower levels of D2 and D3, and particularly D3, receptor expression in the nucleus accumbens (NAc), with no significant changes in the insular, prelimbic, and infralimbic cortices. Based on these findings, we further explored the role of the D3 receptor in impulsive decision-making. Systemic administration of a selective D3 receptor agonist (FOB02-04) significantly reduced impulsive choices in high-impulsive rats but had no effects in low-impulsive rats. Conversely, a selective D3 receptor antagonist (VK4-116) produced increased both impulsive and omission choices in both groups of rats. These findings suggest that impulsive decision-making is associated with a reduction in D3 receptor expression in the NAc. Selective D3 receptor agonists, but not antagonists, may hold therapeutic potentials for mitigating impulsivity in high-impulsive subjects.

Validation of the Sexual Discounting Task for Use in Adolescents.

The Sexual Discounting Task (SDT) was developed to evaluate the effects of delay on decision making as it relates to sexual risk-taking behaviors. Though previously validated with other populations, including urban emerging adults, the current study sought to validate the SDT with adolescents. A sample of adolescents (N = 155; 61% female) between ages 14 and 21 (Mage = 19.5 years) was recruited to complete the SDT (involving choices between immediate unprotected sex and delayed sex with a condom with hypothetical sexual partners) and the Delay Discounting Task (a delay discounting task for money outcomes). Additionally, they completed several self-report measures assessing demographics, sexual behavior, and sexual history. If the condom was readily available, respondents were more likely to use a condom for partners who were judged "most likely to have an STI" and for those that participants were "least likely to have sex with." Moreover, when a condom was not immediately available, greater self-reported sexual risk-taking was related to greater sexual discounting (i.e., greater effects of delay on decreasing condom use). Furthermore, sexual discounting was greater among partners deemed more desirable and those judged "least likely to have an STI." Differences in sexual discounting were significant after controlling for immediately available condom use. Findings from the current study suggest that the SDT is clinically meaningful for adolescents and is sensitive to factors that influence real-world decisions to use condoms. Future treatment and prevention should consider delay discounting as an important variable affecting sexual risk behavior.

A Behavioral Economic Examination of Sexual Behaviors in the Era of Pre-exposure Prophylaxis via Explanatory Sequential Mixed Methods.

Pre-exposure prophylaxis (PrEP) use may be associated with condom use decisions. The current investigation examined sexual decision-making in the context of PrEP among young adult men who have sex with men (MSM) between 18 and 30 years old, using an explanatory sequential mixed methods design. For the quantitative aim, 99 MSM currently taking PrEP (i.e., PrEP-experienced) and 140 MSM not currently taking PrEP (i.e., PrEP-naive) completed an online survey, including the Sexual Delay Discounting Task (SDDT), which captures likelihood of condom use. For the qualitative aim, 15 people from each group were interviewed about their (1) conceptualizations of risky sex and (2) ways they manage their sexual risk. Participants were, on average, 25.69 years old (SD = 3.07) and 64% White. Results from the quantitative aim revealed, controlling for covariates, PrEP-experienced participants exhibited significantly lower likelihood of (1) using an immediately available condom and (2) waiting for a delayed condom (i.e., sexual delay discounting) compared to PrEP-naive participants. Qualitative themes explaining what young adult MSM consider to be risky sex included: (1) any sex as risky sex, (2) risky sex as "sex without a conversation," and (3) risky sex as sex with risk for physical harm. Themes on ways young adult MSM manage sexual risk were classified as proactive, reactive, and passive. Results suggest that PrEP use is related to condom use decisions. Taken together, quantitative differences in sexual delay discounting, but qualitatively similar conceptualizations and management of risky sex, suggest that the SDDT may be a useful tool in sex research to capture processes (i.e., delay discounting) underlying sexual decision-making that may be missed by traditional self-reports. Implications of results, including potentially providing (good quality) condoms with every PrEP prescription, and future research topics are discussed.

Patients with episodic migraine without aura have an increased rate of delayed discounting.

OBJECTIVE: This study aimed to explore decision-making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA). BACKGROUND: Previous evidence indicates increased impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear. METHODS: Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting-state function magnetic resonance imaging scans. Resting-state functional connectivity (RSFC) between the regions of interest and the entire brain was explored. RESULTS: Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p = .032), which was positively related to a history of migraines (r = .742, p < .001). RSFC among the ventral striatum (vSTR), ventromedial prefrontal cortex, and occipital cortex was lower in patients with EMoA than in control groups, which was correlated with history (r' = .294, p = .036) and subjective discount rate (r' = .380, p = .006). Additionally, discounting rates and RSFC between the vSTR and occipital regions were significantly abnormal in the triptan group than the non-triptan group. Mediating effect analysis indicated a significant mediating effect in the change in RSFC between the vSTR and occipital status, history of triptan use, and subjective discount rate. CONCLUSION: This study further elucidated that an increase in delayed discounting rate exists in patients with EMoA and is related to the abnormality of the value processing network.

Brain responses to decision-making in easy and hard choices in internet gaming disorder: Implications for irrepressible gaming behaviours.

BACKGROUND: Impaired decision-making was observed in internet gaming disorder (IGD), however, these studies did not differentiate 'hard' to 'easy' decisions, and only the 'hard' decision-making could reveal the mechanism underlying this issue. METHODS: We recruited forty-eight individuals with IGD and forty-six recreational internet game users (RGUs) as a control group in this study. fMRI data were collected when they were finishing a value-matching delayed discount task (DDT), which included easy and hard decisions judging based on the indifference points of every participant. The correlations between brain responses during DDT and IGD severity and the effective connectivity between brain regions were calculated. RESULTS: Compared to RGUs, IGD subjects showed enhanced activation in the orbitofrontal cortex (OFC) when facing hard choices, and this feature was associated with IGD severity. In addition, individuals with IGD showed increased effective connectivity from the OFC to the dorsolateral prefrontal cortex and the OFC to the occipital lobe and decreased effective connectivity from the occipital lobe to the OFC. CONCLUSION: The current study showed that the abnormal activation in the OFC was associated with IGD severity and higher OFC-DLPFC/OFC-occipital lobe effective connectivity and lower occipital lobe-OFC effective connectivity when individuals with IGD faced different choices in the DDT. These findings suggest the neural mechanisms of impulsive decision-making in individuals with IGD due to dysfunction with subjective evaluation and dysfunction of the connection with the executive control system.

Focusing on Safety or Pleasure Determine Condom Use Intentions Differently Depending on Condom Availability and STI Risk.

Objective: Regulatory Focus Theory suggests that goal pursuit is driven by two separate and fundamental motives. Being more focused on prevention motivates people to enact safer behaviors and avoid negative outcomes (e.g., to prevent diseases), whereas being more focused on promotion motivates people to take risks and pursue pleasurable experiences (e.g., condomless sex). Methods: A quasi-experimental study (N = 476) examined if differences in regulatory focus (i.e., prevention vs. promotion) determined condom use intentions with a prospective casual partner, depending on condom availability delay and STI risk cues. Results: Participants focused on prevention (vs. promotion) were less likely to consider having condomless sex across condom availability delays conditions. However, STI risk cues changed condom use intentions. When STI risk was lower, condom use intentions decreased as condom availability delays increased (particularly for participants focused on promotion). When STI risk was higher, condom use intentions were stronger and consistent across condom availability delays (particularly for participants focused on prevention). Conclusions: These findings highlight the importance of distinct sexual motives when examining sexual health practices.

Contrasting effects of DOM and lisuride on impul-sive decision-making in delay discounting task / 中国药理学与毒理学杂志

OBJECTIVE The 5-HT2A receptor is the major target of classic hallucinogens.Both DOM(2,5-dimethoxy-4-methylamphetamine)and lisuride act at 5-HT2A receptors,and lisuride shares comparable affinity with DOM and acts as a partial agonist at 5-HT2A recep-tors.However,not like DOM,lisuride lacks hallucinogenic properties.Impulsive decision-making refers to the prefer-ence for an immediate small reinforcer(SR)over a delayed large reinforcer(LR).The current study aims to compare the effects of DOM and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs.METHODS Impulsive decision-making was evaluated in male Sprague-Dawley rats by the percent-age of choice for the LR in delay discounting task(DDT).Delay to the LR changed in an ascending order(0,4,8,16,and 32 s)across one session.RESULTS DOM(0.3 and 0.5 mg·kg-1)increased impulsive decision-making,and the effects of DOM(0.5 mg·kg-1)was blocked by the 5-HT2A receptor antagonist ketanserin(1.0 mg·kg-1)rather than the 5-HT2C receptor antagonist SB-242084(1.0 mg·kg-1).Contrarily,lisuride(0.1,0.3 and 0.5 mg·kg-1)decreased impulsive decision-making.The effects of lisu-ride(0.3 mg·kg-1)were not antagonized by ketanserin(1.0 mg·kg-1),selective 5-HT1A antagonist WAY-100635(1.0 mg·kg-1)or selective dopamine D4 receptor antagonist L-745870(1.0 mg·kg-1),but were attenuated by the selec-tive dopamine D2/D3 receptor antagonist tiapride(40 mg·kg-1).CONCLUSION DOM and lisuride have contrasting effects on impulsive decision-making via distinct recep-tors.DOM-induced increase of impulsivity is mediated by the 5-HT2A receptor,while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor.

Contrasting effects of DOI and lisuride on impulsive decision-making in delay discounting task.

RATIONALE: The 5-HT2A receptor is the major target of classic hallucinogens. Both DOI (2,5-dimethoxy-4-iodoamphetamine) and lisuride act at 5-HT2A receptors, and lisuride shares comparable affinity with DOI and acts as a partial agonist at 5-HT2A receptors. However, not like DOI, lisuride lacks hallucinogenic properties. Impulsive decision-making refers to the preference for an immediate small reinforcer (SR) over a delayed large reinforcer (LR). OBJECTIVES: The current study aims to compare the effects of DOI and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs. METHODS: Impulsive decision-making was evaluated in male Sprague-Dawley rats by the percentage of choice for the LR in delay discounting task (DDT). Delay to the LR changed in an ascending order (0, 4, 8, 16, and 32 s) across one session. RESULTS: DOI (0.5 and 1.0 mg/kg) increased impulsive decision-making, and the effects of DOI (1.0 mg/kg) were blocked by the 5-HT2A receptor antagonist ketanserin (1.0 mg/kg) rather than the 5-HT2C receptor antagonist SB-242084 (1.0 mg/kg). Contrarily, lisuride (0.1, 0.3, and 0.5 mg/kg) decreased impulsive decision-making. The effects of lisuride (0.3 mg/kg) were not antagonized by ketanserin (1.0 mg/kg), selective 5-HT1A antagonist WAY-100635 (1.0 mg/kg), or selective dopamine D4 receptor antagonist L-745870 (1.0 mg/kg) but were attenuated by the selective dopamine D2/D3 receptor antagonist tiapride (40 mg/kg). CONCLUSIONS: DOI and lisuride have contrasting effects on impulsive decision-making via distinct receptors. DOI-induced increase of impulsivity is mediated by the 5-HT2A receptor, while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor.

One-year into COVID-19 pandemic: Decision-making and mental-health outcomes and their risk factors.

BACKGROUND: The COVID-19 pandemic represents an unprecedented worldwide crisis with serious socioeconomic, physical and mental health consequences. However, its long-lasting effects on both mental health and decision-making difficulties remain unexplored. This study aimed to determine the prevalence and severity of psychological disorders in Italy's populace one-year after the outbreak; further, we investigated potential risks impacting mental health and decision-making. METHODS: In March 2021, 586 individuals (18-73 years) completed an online-survey plus a computerized delay discounting task for hypothetical money rewards. RESULTS: Psychological symptoms prevalence exceeded the Italy's lockdown rates, with about one-third reporting moderate-to-extremely severe depression, another third anxiety, and the rest stress; mirrored by an increase of symptoms at clinically significant severity levels. One year into the pandemic, half of our sample presented at least one psychological problem, and one-third was at risk of developing a more clinically severe psychological outcome. Fear of job loss, loneliness and intolerance of uncertainty were among the major risk factors to mental health. Plus, social-relationships and financial uncertainty were key determinants of depression, while fear of COVID-19 infection predicted anxiety symptoms. For decision-making tendencies, elevated delay discounting rates, implying less future-oriented behaviors, were mostly predicted by increased job loss fear and older age (>35 years). LIMITATIONS: This study provides cross-sectional evidence. CONCLUSIONS: Depression, anxiety and stress levels were still alarming one-year into COVID-19. Individuals experiencing financial insecurity, loneliness and intolerance of uncertainty perhaps benefit most from early interventions. Governments need to implement timely recovery plans to reduce financial insecurity, given its significant mental health impact and decision-making outcomes.

Chronic early-life stress increases cognitive impulsivity and D2 immunoreactivity in the nucleus accumbens of adult rats.

Chronic early life stress (ECS) induced by limited bedding and nesting (LBN) material in rodents is a naturalistic stress model that mimics many of the behavioral and neural consequences of child abuse and neglect; however, the effect of ECS on adult impulsivity has never been studied. The aim of our work was to determine the effects of ECS on cognitive impulsivity and its relation to D2 immunoreactivity in the nucleus accumbens (NAc) and prefrontal cortex (PFC) of adult male rats. Sprague-Dawley rats were exposed to LBN from postnatal day 2 to 9. We evaluated dams' maternal behavior and offspring corticosterone levels. The rats' impulsive cognitive behavior was evaluated by a delay-discounting task (transitional bridge) on P70, and we evaluated D2 receptors by immunostaining. Our results indicated that ECS affected maternal behavior in the dams and increased pups' corticosterone levels at P9, but not in adults. ECS rats showed lower frequencies of choosing the delayed reinforcer and shorter latencies to cross on the delay-discounting task. In addition, ECS rats showed increased D2 immunoreactivity in the NAc when compared with controls. Our data suggest that ECS can cause impulsive behaviors in adult rats characterized by less convenient choices, likely related to an increase in D2 receptors in the NAc. These findings could contribute to our understanding of the effects of child abuse and neglect on impulsive behavior.

Discerning Mouse Trajectory Features With the Drift Diffusion Model.

Mouse tracking, a new action-based measure of behavior, has advanced theories of decision making with the notion that cognitive and social decision making is fundamentally dynamic. Implicit in this theory is that people's decision strategies, such as discounting delayed rewards, are stable over task design and that mouse trajectory features correspond to specific segments of decision making. By applying the hierarchical drift diffusion model and the Bayesian delay discounting model, we tested these assumptions. Specifically, we investigated the extent to which the "mouse-tracking" design of decision-making tasks (delay discounting task, DDT and stop-signal task, SST) deviate from the standard "keypress" design of decision making tasks. We found remarkable agreement in delay discounting rates (intertemporal impatience) obtained in the keypress and mouse-tracking versions of DDT (ρ = 0.90) even though these tasks were given about 1 week apart. Rates of evidence accumulation converged well in the two versions (DDT, ρ = .86; SST, ρ = .55). Omission/commission error in SST showed high agreement (ρ = .42, ρ = .53). Mouse-motion features such as maximum velocity and AUC (area under the curve) correlated well with nondecision time (ρ = -.42) and boundary separation (ρ = .44)-the amount of information needed to accumulate prior to making a response. These results indicate that the response time (RT) and motion-based decision tasks converge well at a fundamental level, and that mouse-tracking features such as AUC and maximum velocity do indicate the degree of decision conflict and impulsivity.

High impulsive choice is accompanied by an increase in dopamine release in rat dorsolateral striatum.

Dopamine neurotransmission has been consistently associated with individual differences in impulsive choice. Clinical and preclinical evidence suggests that low striatal dopamine D2 signaling predisposes to engage in impulsive behaviors. Although dopamine D2 signaling controls dopamine (DA) extracellular levels, the relationship between striatal dopamine extracellular levels and impulsive choice remains poorly understood. Using quantitative microdialysis, we investigated whether extracellular DA levels in rat dorsolateral striatum (DLS) correlates with preference for an immediate small reward or for a delayed larger reward. Rats were tested in a delay-discounting task and classified as high impulsive (HI) or low impulsive (LI) according to the area under the discounting curve (AUC). No-net flux microdialysis experiments, assessing basal DA release, DA-uptake, and DA extracellular concentration (DA Cext), were carried out in dorsolateral striatum (DLS) of urethane-anesthetized rats. Rats classified as HI showed a higher DA release compared with LI rats. Differences in DLS DA-uptake and DA Cext were non-significant. Importantly, a significant negative correlation was observed between AUC and DA release, indicating that the lower the AUC, the higher the DLS DA release. This finding shows that DA release is augmented in the DLS of rats classified as HI, suggesting that a hyper-activated nigro-striatal pathway contributes to impulsive choice.

Attention-Deficit/Hyperactivity Disorder Symptoms Are Associated with Greater Delay Discounting of Condom-Protected Sex and Money.

Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk of detrimental life outcomes. Recent research also indicates that ADHD is associated with sexual risk behavior, such as unprotected sex. Some risky sexual behaviors may be driven, in part, by preference for immediate rewards, referred to as delay discounting, which is prominent in etiological models of ADHD. Therefore, the present study examined the effect of delay on preference for both monetary and sexual outcomes in adults with many ADHD symptoms (both on and off medication) and with fewer ADHD symptoms. Online participants (N = 275; n = 161 males, n = 114 females) completed a monetary delay discounting task, assessing preference for smaller sooner versus larger delayed hypothetical money, and the Sexual Delay Discounting Task, assessing preference for condom use in hypothetical casual sex scenarios based on delay until condom availability. Those with greater ADHD symptoms discounted delayed monetary outcomes as well as delayed condom-protected sex (i.e., preferred sooner money rewards and immediate unprotected sex) significantly more than those with fewer symptoms; however, no effect of current medication use was found across monetary or sexual delay discounting among those with greater ADHD symptoms. This study is the first to demonstrate the relation between ADHD symptoms and reduced condom-use likelihood. Increased discounting of delayed condom-protected sex might constitute one mechanism of risky sexual behavior among individuals with ADHD symptoms. Interventions geared toward increasing condom use in situations in which condoms may otherwise be unavailable, may mitigate risky sexual behaviors and their associated harms in this population.

Increased vulnerability to impulsive behavior after streptococcal antigen exposure and antibiotic treatment in rats.

RATIONALE: The inflammation induced by Group A Streptococcus (GAS) infection has been viewed as a vulnerability factor in mental disorders characterized by inhibitory control deficits, such as attention-deficit/hyperactivity disorder or obsessive-compulsive disorder. Antibiotic treatment reduces GAS symptoms; however, its effects on impulsivity have not been fully assessed. OBJECTIVES: We investigated whether GAS exposure during early adolescence might be a vulnerability factor for adult impulsivity, if antibiotic treatment acts as a protective factor, and whether these differences are accompanied by changes in the inflammatory cytokine frontostriatal regions. METHODS: Male Wistar rats were exposed to the GAS antigen or to vehicle plus adjuvants at postnatal day (PND) 35 (with two boosts), and they received either ampicillin (supplemented in the drinking water) or water alone from PND35 to PND70. Adult impulsivity was assessed using two different models, the 5-choice serial reaction time task (5-CSRT task) and the delay discounting task (DDT). The levels of interleukin-6 (IL-6) and IL-17 were measured in the prefrontal cortex (PFc), and the tumor necrosis factor α levels (TNFα) were measured in the PFc and nucleus accumbens (NAcc). RESULTS: GAS exposure and ampicillin treatment increased the waiting impulsivity by a higher number of premature responses when the animals were challenged by a long intertrial interval during the 5-CSRT task. The GAS exposure revealed higher impulsive choices at the highest delay (40 s) when tested by DDT, while coadministration with ampicillin prevented the impulsive choice. GAS exposure and ampicillin reduced the IL-6 and IL-17 levels in the PFc, and ampicillin treatment increased the TNFα levels in the NAcc. A regression analysis revealed a significant contribution of GAS exposure and TNFα levels to the observed effects. CONCLUSIONS: GAS exposure and ampicillin treatment induced an inhibitory control deficit in a different manner depending on the form of impulsivity measured here, with inflammatory long-term changes in the PFc and NAcc that might increase the vulnerability to impulsivity-related neuropsychiatric disorders.

Behavioral and Neuroanatomical Account of Impulsivity in Parkinson's Disease.

Impulse control disorder (ICD) is a major non-motor complication of Parkinson's disease (PD) with often devastating consequences for patients' quality of life. In this study, we aimed to characterize the phenotype of impulsivity in PD and its neuroanatomical correlates. Methods: Thirty-seven PD patients (15 patients with ICD, 22 patients without ICD) and 36 healthy controls underwent a neuropsychological battery. The test battery consisted of anxiety and depression scales, self-report measures of impulsivity (Barratt scale and UPPS-P), behavioral measures of impulsive action (Go/No-Go task, Stop signal task) and impulsive choice (Delay discounting, Iowa gambling task), and measures of cognitive abilities (working memory, attention, executive function). Patients and controls underwent structural MRI scanning. Results: Patients with ICD had significantly higher levels of self-reported impulsivity (Barratt scale and Lack of perseverance from UPPS-P) in comparison with healthy controls and non-impulsive PD patients, but they performed similarly in behavioral tasks, except for the Iowa gambling task. In this task, patients with ICD made significantly less risky decisions than patients without ICD and healthy controls. Patients without ICD did not differ from healthy controls in self-reported impulsivity or behavioral measurements. Both patient groups were more anxious and depressive than healthy controls. MRI scanning revealed structural differences in cortical areas related to impulse control in both patient groups. Patients without ICD had lower volumes and cortical thickness of bilateral inferior frontal gyrus. Patients with ICD had higher volumes of right caudal anterior cingulate and rostral middle frontal cortex. Conclusions: Despite the presence of ICD as confirmed by both clinical follow-up and self-reported impulsivity scales and supported by structural differences in various neural nodes related to inhibitory control and reward processing, patients with ICD performed no worse than healthy controls in various behavioral tasks previously hypothesized as robust impulsivity measures. These results call for caution against impetuous interpretation of behavioral tests, since various factors may and will influence the ultimate outcomes, be it the lack of sensitivity in specific, limited ICD subtypes, excessive caution of ICD patients during testing due to previous negative experience rendering simplistic tasks insufficient, or other, as of now unknown aspects, calling for further research.

The role of the dorsal striatum in choice impulsivity.

It has long been recognized that the dorsal striatum is an essential brain region for control of action selection based on action-outcome contingency learning, particularly when the available actions are bound to rewarding outcomes. In principle, intertemporal choice in the delay-discounting task-a validated measure of choice impulsivity-involves reward-associated actions that require the recruitment of the dorsal striatum. Here, we conjecture about ways the dorsal striatum is involved in choice impulsivity. Based on a selective body of studies, we begin with a brief history of research on choice impulsivity and the dorsal striatum, and then provide a comprehensive summary of contemporary studies utilizing human neuroimaging and animal models to search for links between choice impulsivity and the dorsal striatum. In particular, we discuss in-depth the converging evidence for the associations of choice impulsivity with the reward valuation coded by the caudate, a ventral-to-dorsal gradient in the dorsal striatum, the origins of striatal afferents, and developmental maturation of frontostriatal connectivity during adolescence.

Archetypes of human cognition defined by time preference for reward and their brain correlates: An evolutionary trade-off approach.

Biological systems carry out multiple tasks in their lifetime, which, in the course of evolution, may lead to trade-offs. In fact phenotypes (different species, individuals within a species, circuits, bacteria, proteins, etc.) cannot be optimal at all tasks, and, according to Pareto optimality theory, lay into a well-defined geometrical distribution (polygons and/or polyhedrons) in the space of traits. The vertices of this distribution contain archetypes, namely phenotypes that are specialists at one of the tasks, whereas phenotypes toward the center of the geometrical distribution show average performance across tasks. We applied this theory to the variability of cognitive and behavioral scores measured in 1206 individuals from the Human Connectome Project. Among all possible combinations of pairs of traits, we found the best fit to Pareto optimality when individuals were plotted in the trait-space of time preferences for reward, evaluated with the Delay Discounting Task (DDT). The DDT measures subjects' preference in choosing either immediate smaller rewards or delayed larger rewards. Time preference for reward was described by a triangular distribution in which each of the three vertices included individuals who used a particular strategy to discount reward. These archetypes accounted for variability on many cognitive, personality, and socioeconomic status variables, as well as differences in brain structure and functional connectivity, with only a weak influence of genetics. In summary, time preference for reward reflects a core variable that biases human phenotypes via natural and cultural selection.

Disruption of Multiple Distinctive Neural Networks Associated With Impulse Control Disorder in Parkinson's Disease.

The phenomenon of impulsivity in Parkinson's disease appears as an arduous side effect of dopaminergic therapy with potentially detrimental consequences for the life of the patients. Although conceptualized as a result of non-physiologic chronic dopaminergic stimulation, recent advances speculate on combined disruption of other networks as well. In the search for neuroanatomical correlates of this multifaceted disturbance, this study employs two distinct, well-defined tasks of close association to motor inhibition and decision-making impulsivity, Go/No Go and Delay discounting. The fMRI and functional connectivity analysis in 21 Parkinson's disease patients, including 8 patients suffering from severe impulse control disorder, and 28 healthy controls, revealed in impulsive Parkinson's disease patients not only decreased fMRI activation in the dorsolateral prefrontal cortex and bilateral striatum, but also vast functional connectivity changes of both caudate nuclei as decreased connectivity to the superior parietal cortex and increased connectivity to the insular area, clearly beyond the commonly stated areas, which indicates that orbitofronto-striatal and mesolimbic functional disruptions are not the sole mechanisms underlying impulse control disorder in Parkinson's disease. Ergo, our results present a refinement and synthesis of gradually developing ideas about the nature of impulsive control disorder in Parkinson's disease-an umbrella term encompassing various behavioral deviations related to distinct neuronal networks and presumably neurotransmitter systems, which greatly exceed the previously envisioned dopaminergic pathways as the only culprit.

5-HT3 antagonists decrease discounting rate without affecting sensitivity to reward magnitude in the delay discounting task in mice.

RATIONALE: Impulsive choice has often been evaluated in rodents according to the proportion of choices for the delayed large magnitude reinforcer (%large choice) in a delay-discounting task (DDT). However, because %large choice is influenced by both sensitivity to reinforcer magnitude and sensitivity to delayed reinforcement (i.e., discounting rate), distinctively evaluating such discounting parameters represents a critical issue demanding methods to determine each parameter in rats. The serotonin (5-HT) system is well known to be involved in impulsive choice; nevertheless, only a few studies have distinguished discounting parameters and investigated how 5-HT modulators affect discounting rate. OBJECTIVE: Here, we performed a discounting parameter analysis in mice and examined the effects of various 5-HT modulators on discounting rate. METHODS: We set up DDTs with different delay schedules to determine which schedule could address delay-discounting rates in mice. We examined the effect of the following drugs on impulsive choice: a 5-HT reuptake inhibitor (paroxetine), a 5-HT1A receptor agonist (8-OH-DPAT), and two 5-HT3 receptor antagonists (granisetron and ondansetron). RESULTS: Mice showed typical delay discounting at the shorter delay schedules (up to 4 s delay). The %large choice under shorter, but not longer, schedules followed an exponential function and allowed us to derive discounting rates. We selected a DDT with a 4-s delay schedule for further experiments. Granisetron and ondansetron, but not paroxetine or 8-OH-DPAT, decreased discounting rates without affecting sensitivity to reinforcer magnitude. CONCLUSION: We found that a method to calculate discounting rates in rats is also applicable to mouse models. We also provided evidence that 5-HT3 antagonism controls impulsive choice in mice.

Nigrostriatal Dopaminergic Denervation Does Not Promote Impulsive Choice in the Rat: Implication for Impulse Control Disorders in Parkinson's Disease.

Impulse control disorders (ICDs) are frequent behavioral complications of dopaminergic (DA) replacement therapies (DRTs) in Parkinson's disease (PD). Impulsive choice, which refers to an inability to tolerate delays to reinforcement, has been identified as a core pathophysiological process of ICDs. Although impulsive choices are exacerbated in PD patients with ICDs under DRTs, some clinical and preclinical studies suggest that the DA denervation of the dorsal striatum induced by the neurodegenerative process as well as a pre-existing high impulsivity trait, may both contribute to the emergence of ICDs in PD. We therefore investigated in a preclinical model in rats, specifically designed to study PD-related non-motor symptoms, the effect of nigrostriatal DA denervation on impulsive choice, in relation to pre-existing levels of impulsivity, measured in a Delay Discounting Task (DDT). In this procedure, rats had the choice between responding for a small sucrose reinforcer delivered immediately, or a larger sucrose reinforcer, delivered after a 0, 5, 10 or 15 s delay. In two different versions of the task, the preference for the large reinforcer decreased as the delay increased. However, and in contrast to our initial hypothesis, this discounting effect was neither exacerbated by, or related to, the extent of the substantia nigra pars compacta (SNc) DA lesion, nor it was influenced by pre-existing variability in impulsive choice. These results therefore question the potential implication of the nigrostriatal DA system in impulsive choice, as well as the DA neurodegenerative process as a factor contributing significantly to the development of ICDs in PD.