Contractile Force of Transplanted Cardiomyocytes Actively Supports Heart Function After Injury.

BACKGROUND: Transplantation of pluripotent stem cell-derived cardiomyocytes represents a promising therapeutic strategy for cardiac regeneration, and the first clinical studies in patients with heart failure have commenced. Yet, little is known about the mechanism of action underlying graft-induced benefits. Here, we explored whether transplanted cardiomyocytes actively contribute to heart function. METHODS: We injected cardiomyocytes with an optogenetic off-on switch in a guinea pig cardiac injury model. RESULTS: Light-induced inhibition of engrafted cardiomyocyte contractility resulted in a rapid decrease of left ventricular function in ≈50% (7/13) animals that was fully reversible with the offset of photostimulation. CONCLUSIONS: Our optogenetic approach demonstrates that transplanted cardiomyocytes can actively participate in heart function, supporting the hypothesis that the delivery of new force-generating myocardium can serve as a regenerative therapeutic strategy.

Congruence of Inherent and Acquired Values Facilitates Reward-Based Decision-Making.

UNLABELLED: Most real-life cues exhibit certain inherent values that may interfere with or facilitate the acquisition of new expected values during associative learning. In particular, when inherent and acquired values are congruent, learning may progress more rapidly. Here we investigated such an influence through a 2 × 2 factorial design, using attractiveness (high/low) of the facial picture as a proxy for the inherent value of the cue and its reward probability (high/low) as a surrogate for the acquired value. Each picture was paired with a monetary win or loss either congruently or incongruently. Behavioral results from 32 human participants indicated both faster response time and faster learning rate for value-congruent cue-outcome pairings. Model-based fMRI analysis revealed a fractionation of reinforcement learning (RL) signals in the ventral striatum, including a strong and novel correlation between the cue-specific decaying learning rate and BOLD activity in the ventral caudate. Additionally, we detected a functional link between neural signals of both learning rate and reward prediction error in the ventral striatum, and the signal of expected value in the ventromedial prefrontal cortex, showing a novel confirmation of the mathematical RL model via functional connectivity. SIGNIFICANCE STATEMENT: Most real-world decisions require the integration of inherent value and sensitivity to outcomes to facilitate adaptive learning. Inherent value is drawing increasing interest from decision scientists because it influences decisions in contexts ranging from advertising to investing. This study provides novel insight into how inherent value influences the acquisition of new expected value during associative learning. Specifically, we find that the congruence between the inherent value and the acquired reward influences the neural coding of learning rate. We also show for the first time that neuroimaging signals coding the learning rate, prediction error, and acquired value follow the multiplicative Rescorla-Wagner learning rule, a finding predicted by reinforcement learning theory.

Episodic Future Thinking Is Related to Impulsive Decision Making in Healthy Adolescents.

Delay discounting is a stable trait measure of impulsivity. Engaging in episodic future thinking (EFT) can reduce discounting, but whether individual differences in discounting are associated with differences in future thinking remains unclear. Here, this association was tested in healthy adolescents (n = 49, age range = 12-16 years, fluent German speakers, from a large German city). Data collection was between December 2011 and December 2012. Vividness of EFT (assessed via the Autobiographical Memory Interview) was negatively correlated with discounting (r = -.41, 95% CI [-.63, -.13], r(2) = .17). Regression analyses confirmed that this association was stable when controlling for additional variables, including hormonal measures of pubertal maturation and intelligence. EFT may attenuate impulsivity in young people at risk of engaging in problematic behavior.

Decomposition of Reinforcement Learning Deficits in Disordered Gambling via Drift Diffusion Modeling and Functional Magnetic Resonance Imaging.

Gambling disorder is associated with deficits in reward-based learning, but the underlying computational mechanisms are still poorly understood. Here, we examined this issue using a stationary reinforcement learning task in combination with computational modeling and functional resonance imaging (fMRI) in individuals that regular participate in gambling (n = 23, seven fulfilled one to three DSM 5 criteria for gambling disorder, sixteen fulfilled four or more) and matched controls (n = 23). As predicted, the gambling group exhibited substantially reduced accuracy, whereas overall response times (RTs) were not reliably different between groups. We then used comprehensive modeling using reinforcement learning drift diffusion models (RLDDMs) in combination with hierarchical Bayesian parameter estimation to shed light on the computational underpinnings of this performance deficit. In both groups, an RLDDM in which both non-decision time and decision threshold (boundary separation) changed over the course of the experiment accounted for the data best. The model showed good parameter and model recovery, and posterior predictive checks revealed that, in both groups, the model accurately reproduced the evolution of accuracies and RTs over time. Modeling revealed that, compared to controls, the learning impairment in the gambling group was linked to a more rapid reduction in decision thresholds over time, and a reduced impact of value-differences on the drift rate. The gambling group also showed shorter non-decision times. FMRI analyses replicated effects of prediction error coding in the ventral striatum and value coding in the ventro-medial prefrontal cortex, but there was no credible evidence for group differences in these effects. Taken together, our findings show that reinforcement learning impairments in disordered gambling are linked to both maladaptive decision threshold adjustments and a reduced consideration of option values in the choice process.

Dopamine regulates decision thresholds in human reinforcement learning in males.

Dopamine fundamentally contributes to reinforcement learning, but recent accounts also suggest a contribution to specific action selection mechanisms and the regulation of response vigour. Here, we examine dopaminergic mechanisms underlying human reinforcement learning and action selection via a combined pharmacological neuroimaging approach in male human volunteers (n = 31, within-subjects; Placebo, 150 mg of the dopamine precursor L-dopa, 2 mg of the D2 receptor antagonist Haloperidol). We found little credible evidence for previously reported beneficial effects of L-dopa vs. Haloperidol on learning from gains and altered neural prediction error signals, which may be partly due to differences experimental design and/or drug dosages. Reinforcement learning drift diffusion models account for learning-related changes in accuracy and response times, and reveal consistent decision threshold reductions under both drugs, in line with the idea that lower dosages of D2 receptor antagonists increase striatal DA release via an autoreceptor-mediated feedback mechanism. These results are in line with the idea that dopamine regulates decision thresholds during reinforcement learning, and may help to bridge action selection and response vigor accounts of dopamine.

Present bias in economic choice demonstrates increased cognitive fatigability of glioma patients.

Fatigue is a frequent symptom in many clinical conditions that is still poorly understood despite having a major impact on quality of life. Here, we propose a novel approach using model-based analysis of choice behaviour to extract fatigue markers. We applied this approach to the case of low-grade glioma, with the aim of testing the hypothesis that fatigability in this condition may manifest as limited control over choice impulsivity. Patients with intact or resected glioma (n = 29) and matched healthy controls (n = 27) performed a series of behavioural tasks included in a 4 h-long neuropsychological assessment. Intertemporal choices, opposing smaller-sooner to larger-later monetary rewards, were intermixed with tasks designed to test cognitive and motor performance and to assess perceived fatigue with subjective ratings. All dependent variables were analysed with generalised linear models testing the main effects of group and time-on-task, as well as their interaction. While absent in standard measures of fatigue (subjective rating and objective performance), a significant group-by-time interaction was observed in the rate of impulsive choices: contrary to controls, patients developed a preference for the smaller-sooner option in the course of neuropsychological assessment. This preference shift was captured by computational modelling as an increase in the present bias, a parameter that assigns an additive bonus to immediate rewards. Thus, choice impulsivity was the only reliable marker that reflected the enhanced fatigability of patients relative to controls. These results suggest that the impact of glioma (or its resection) on brain functioning limits the exertion of cognitive control during decision-making. More generally, they pave the way to using model-based analysis of choice behaviour for future investigations of the many clinical conditions plagued with cognitive fatigue.

A neuro-metabolic account of why daylong cognitive work alters the control of economic decisions.

Behavioral activities that require control over automatic routines typically feel effortful and result in cognitive fatigue. Beyond subjective report, cognitive fatigue has been conceived as an inflated cost of cognitive control, objectified by more impulsive decisions. However, the origins of such control cost inflation with cognitive work are heavily debated. Here, we suggest a neuro-metabolic account: the cost would relate to the necessity of recycling potentially toxic substances accumulated during cognitive control exertion. We validated this account using magnetic resonance spectroscopy (MRS) to monitor brain metabolites throughout an approximate workday, during which two groups of participants performed either high-demand or low-demand cognitive control tasks, interleaved with economic decisions. Choice-related fatigue markers were only present in the high-demand group, with a reduction of pupil dilation during decision-making and a preference shift toward short-delay and little-effort options (a low-cost bias captured using computational modeling). At the end of the day, high-demand cognitive work resulted in higher glutamate concentration and glutamate/glutamine diffusion in a cognitive control brain region (lateral prefrontal cortex [lPFC]), relative to low-demand cognitive work and to a reference brain region (primary visual cortex [V1]). Taken together with previous fMRI data, these results support a neuro-metabolic model in which glutamate accumulation triggers a regulation mechanism that makes lPFC activation more costly, explaining why cognitive control is harder to mobilize after a strenuous workday.

Study of the Kinetics of the Determinants of Performance During a Mountain Ultramarathon: Multidisciplinary Protocol of the First Trail Scientifique de Clécy 2021.

BACKGROUND: The growing interest of the scientific community in trail running has highlighted the acute effects of practice at the time of these races on isolated aspects of physiological and structural systems; biological, physiological, cognitive, and muscular functions; and the psychological state of athletes. However, no integrative study has been conducted under these conditions with so many participants and monitoring of pre-, per-, and postrace variables for up to 10 days over a distance close to 100 miles. OBJECTIVE: The aim of this study was to evaluate the kinetics of the performance parameters during a 156 km trail run and 6000 m of elevation gain in pre-, per-, and postrace conditions. The general hypothesis is based on significant alterations in the psychological, physiological, mechanical, biological, and cognitive parameters. METHODS: The Trail Scientifique de Clécy took place on November 11, 2021. This prospective experimental study provides a comprehensive exploration of the constraints and adaptations of psychophysiological and sociological variables assessed in real race conditions during a trail running of 156 km on hilly ground and 6000 m of elevation gain (D+). The study protocol allowed for repeatability of study measurements under the same experimental conditions during the race, with the race being divided into 6 identical loops of 26 km and 1000 m D+. Measurements were conducted the day before and the morning of the race, at the end of each lap, after a pit stop, and up to 10 days after the race. A total of 55 participants were included, 43 (78%) men and 12 (22%) women, who were experienced in ultra-trail-running events and with no contraindications to the practice of this sport. RESULTS: The launch of the study was authorized on October 26, 2021, under the trial number 21-0166 after a favorable opinion from the Comité de Protection des Personnes Ouest III (21.09.61/SIRIPH 2G 21.01586.000009). Of the 55 runners enrolled, 41 (75%) completed the race and 14 (25%) dropped out for various reasons, including gastric problems, hypothermia, fatigue, and musculoskeletal injuries. All the measurements for each team were completed in full. The race times (ie, excluding the measurements) ranged from 17.8206 hours for the first runner to 35.9225 hours for the last runner. The average time to complete all measurements for each lap was 64 (SD 3) minutes. CONCLUSIONS: The Trail Scientifique de Clécy, by its protocol, allowed for a multidisciplinary approach to the discipline. This approach will allow for the explanation of the studied parameters in relation to each other and observation of the systems of dependence and independence. The initial results are expected in June 2022. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/38027.

Dopaminergic modulation of the exploration/exploitation trade-off in human decision-making.

Involvement of dopamine in regulating exploration during decision-making has long been hypothesized, but direct causal evidence in humans is still lacking. Here, we use a combination of computational modeling, pharmacological intervention and functional magnetic resonance imaging to address this issue. Thirty-one healthy male participants performed a restless four-armed bandit task in a within-subjects design under three drug conditions: 150 mg of the dopamine precursor L-dopa, 2 mg of the D2 receptor antagonist haloperidol, and placebo. Choices were best explained by an extension of an established Bayesian learning model accounting for perseveration, directed exploration and random exploration. Modeling revealed attenuated directed exploration under L-dopa, while neural signatures of exploration, exploitation and prediction error were unaffected. Instead, L-dopa attenuated neural representations of overall uncertainty in insula and dorsal anterior cingulate cortex. Our results highlight the computational role of these regions in exploration and suggest that dopamine modulates how this circuit tracks accumulating uncertainty during decision-making.

A potential link between gambling addiction severity and central dopamine levels: Evidence from spontaneous eye blink rates.

Accumulating evidence points at similarities between substance use disorders (SUD) and gambling disorder on the behavioral and neural level. In SUD, attenuation of striatal D2/3-receptor availability is a consistent finding, at least for stimulating substances. For gambling disorder, no clear association with striatal D2/3-receptor availability has been unveiled so far. With its presumably negligible dopaminergic toxicity, possible differences in receptor availability in gambling disorder might constitute a vulnerability marker. Spontaneous eye blink rate (sEBR) is discussed as a potential proxy measure for striatal dopamine D2/3-receptor availability. Here we examined sEBR in 21 male problem gamblers and 20 healthy control participants. In addition, participants completed a screening questionnaire for overall psychopathology and self-reported measures of alcohol and nicotine consumption. We found no significant difference in sEBR between gamblers and controls. However, in gamblers, sEBR was negatively associated with gambling severity and positively associated with psychopathology. A final exploratory analysis revealed that healthy controls with low sEBR displayed higher alcohol and nicotine consumption than healthy participants with high sEBR. Although the exact association between dopamine transmission and sEBR is still debated, our findings reveal that sEBR is sensitive to inter-individual differences in gambling disorder severity in problem gamblers.

Episodic Tags Enhance Striatal Valuation Signals during Temporal Discounting in pathological Gamblers.

Similar to many addiction disorders, pathological gambling is associated with an increased preference for immediate rewards (steep temporal discounting). In healthy participants, episodic future thinking has been shown to reduce impulsivity during intertemporal choice. Here, we examine for the first time a modulation of temporal discounting via episodic future thinking in a group of pathological gamblers. We investigated a sample of 24 pathological gamblers and 24 matched healthy controls with functional magnetic resonance imaging (fMRI). Participants made intertemporal choices in two experimental conditions. In the control condition, delayed monetary rewards were offered with the respective amount and delay. In the episodic condition, rewards were additionally associated with participant-specific personal future events. We replicated previous findings of increased temporal discounting in pathological gambling. On a trend level, episodic future thinking attenuated discounting across all participants. We found that pathological gamblers could successfully recruit a prospection related network during decision-making in the presence of episodic information. The episodic condition modulated the functional connection between ventromedial prefrontal cortex (vmPFC) and ventral striatum, a mechanism that might support the increase in striatal value coding observed in the episodic condition in gamblers. However, in controls, but not in gamblers, valuation signal changes in the hippocampus were associated with less impulsive behavior. We provide first evidence that by episodic cues during intertemporal decision-making striatal valuation signals can be enhanced in pathological gamblers. Further research is needed to explore interventions that reliably reduce impulsive choice behavior in pathological gambling.

Reward-based decision making in pathological gambling: the roles of risk and delay.

Pathological gambling (PG) is a non-substance based addiction that shares many behavioral and neural features with substance based addictions. However, in PG behavioral and neural changes are unlikely to be confounded by effects of acute or chronic drug exposure. Changes in reward based decision-making in particular increases in impulsivity are hallmark features of addictions. Here we review studies in PG that applied three reward-related decision tasks: the Iowa Gambling Task, probability discounting and delay discounting. We discuss the findings and focus on the impact of addiction severity and the relation of effects to impulsivity measures. While there is evidence that PGs differ from healthy controls on all three tasks, there is only little support for a further modulation of impairments by addiction severity. Conceptually, delay discounting is related to impulsivity measures and findings in this task show a considerable correlation with e.g. questionnaire-based measures of impulsivity. Taken together, impairments in PG on these three tasks are relatively well replicated, although impairments appear to be largely uncorrelated between tasks. An important next step will be to conceptualize a process-based account of behavioral impairments in PG.

The Role of Prospection in Steep Temporal Reward Discounting in Gambling Addiction.

Addiction and pathological gambling (PG) have been consistently associated with high impulsivity and a steep devaluation of delayed rewards, a process that is known as temporal discounting (TD). Recent studies indicated that enhanced episodic future thinking (EFT) results in less impulsive TD in healthy controls (HCs). In a separate line of research, it has been suggested that non-linearities in time perception might contribute to reward devaluation during inter-temporal choice. Therefore, in addition to deficits in valuation processes and executive control, impairments in EFT and non-linearities in time perception have been hypothesized to contribute to steep TD in addiction. In this study, we explore such a potential association of impairments in EFT and time perception with steep TD in PG. We investigated 20 PGs and 20 matched HCs. TD was assessed via a standard computerized binary choice task. EFT was measured using a variation of the Autobiographical Memory Interview by Levine et al. (1). Time perception was assessed with a novel task, utilizing a non-linear rating procedure via circle-size adjustments. Groups did not differ in baseline EFT. In both groups, a power law accounted time perception best, and the degree of non-linearity in time perception correlated with discounting across groups. A multiple regression analysis across all predictors and covariates revealed that only group status (PG/HC) and depression were significantly associated with discounting behavior such that PG increased TD and depression attenuated TD. Our findings speak against the idea that steep TD in PG is due to a skewed perception of time or impairments in EFT, at least under the present task conditions. The lack of overall group differences in EFT does not rule out the possibility of more complex interactions of EFT and decision-making. These interactions might be diminished in pathological gambling or addiction more generally, when other task configurations are used.

Nicotine deprivation, temporal discounting and choice consistency in heavy smokers.

The subjective value of rewards declines the longer rewards are delayed into the future ("delay discounting"). Discounting behavior varies both as a function of an individual's trait and current state. The degree of discounting has repeatedly been associated with relapse following treatment of addiction. Therefore, the effects of acute drug deprivation on discounting processes are potentially of high clinical relevance. In two testing sessions (24 hr of nicotine deprivation vs. normal smoking) 37 heavy smoking participants made choices between immediate and delayed rewards as well as between shorter and longer delayed rewards. We found no evidence for an effect of nicotine deprivation on delay discounting of potentially real monetary rewards in both types of decision tasks. Although choice stochasticity was numerically increased after deprivation, this effect was not significant (p>.1). Participants responded significantly slower after nicotine deprivation. Our study supports previous findings that choice impulsivity as measured using discounting tasks is not affected by nicotine deprivation, at least not if real monetary rewards of lower amounts are at stake.

Nocebo context modulates long-term habituation to heat pain and influences functional connectivity of the operculum.

In the past, nocebo manipulations have been found to modulate pain perception and influence long-term habituation to pain. Recently, neural correlates accompanying this finding have been identified: habituation over days is mirrored by decreased activity in pain-processing brain areas, whereas nocebo-specific modulation specifically involves the opercular cortex. Focusing on duration and central network characteristics of nocebo information in a longitudinal heat pain paradigm, we investigated 40 healthy participants over a period of 21 consecutive days, whereof sessions on days 1, 8, 14, and 21 were performed during functional magnetic resonance imaging scanning. Negative context information was given to half of the participants, inducing a nocebo manipulation through verbal suggestions. The analysis was focused on brain areas associated with habituation and nocebo effects and identified coupled brain regions using functional connectivity analysis. Decreased pain perception over days was reflected in reduced blood oxygenation level dependent signal in pain-processing areas, such as the insula and somatosensory cortices, whereas increased rostral anterior cingulate cortex activation reflected the central correlate for habituation over time. Habituation was significantly less pronounced in the nocebo group. Consistent with previous results, the nocebo manipulation not only modulated pain perception but also was accompanied by the activation of the operculum over an extended period of time. Importantly, the operculum exhibited changes in coupling during nociceptive input over time, as demonstrated by decreased connectivity with the basal ganglia and pinpoints differences, depending on whether a nocebo context was given. These data suggest that negative verbal suggestions prognosticating increasing pain may prevail by modulating basal ganglia-thalamocortical loops.