Kimberly Goodyear

Neural signatures of trust in reciprocity: A coordinate-based meta-analysis

Trust in reciprocity (TR) is defined as the risky decision to invest valued resources in another party with the hope of mutual benefit. Several fMRI studies have investigated the neural correlates of TR in one‐shot and multiround versions of the investment game (IG). However, an overall characterization of the underlying neural networks remains elusive. Here, a coordinate‐based meta‐analysis was employed (activation likelihood estimation method, 30 articles) to investigate consistent brain activations in each of the IG stages (i.e., the trust, reciprocity and feedback stage). Results showed consistent activations in the anterior insula (AI) during trust decisions in the one‐shot IG and decisions to reciprocate in the multiround IG, likely related to representations of aversive feelings. Moreover, decisions to reciprocate also consistently engaged the intraparietal sulcus, probably involved in evaluations of the reciprocity options. On the contrary, trust decisions in the multiround IG consistently activated the ventral striatum, likely associated with reward prediction error signals. Finally, the dorsal striatum was found consistently recruited during the feedback stage of the multiround IG, likely related to reinforcement learning. In conclusion, our results indicate different neural networks underlying trust, reciprocity, and feedback learning. These findings suggest that although decisions to trust and reciprocate may elicit aversive feelings likely evoked by the uncertainty about the decision outcomes and the pressing requirements of social standards, multiple interactions allow people to build interpersonal trust for cooperation via a learning mechanism by which they arguably learn to distinguish trustworthy from untrustworthy partners. Hum Brain Mapp 38:1233–1248, 2017.

Higher pretreatment blood pressure is associated with greater alcohol drinking reduction in alcohol-dependent individuals treated with doxazosin

BACKGROUND Preclinical and clinical research suggest that the α1 receptor antagonist prazosin reduces alcohol consumption. Furthermore, clinical studies indicate a role for prazosin in treating Post-Traumatic Stress Disorder (PTSD) symptoms and a recent trial suggested that pre-treatment blood pressure (BP) predicts therapeutic response for prazosin in PTSD patients. Whether pre-treatment BP may predict response to α1 blockers in alcohol-dependent (AD) patients is unknown. We previously reported a randomized controlled trial (RCT) where doxazosin, an α1 receptor antagonist with a more favorable pharmacokinetic profile than prazosin, reduced drinks per week (DPW) and heavy drinking days (HDD) in AD patients with a high family history density of alcoholism. In this study, we tested pre-treatment BP as another potentially valuable clinical moderator of doxazosins response on alcohol consumption. METHODS This was a double-blind placebo-controlled RCT testing doxazosin up to 16mg/day in AD treatment-seeking patients (N=41). The hypothesized moderator effect of baseline standing systolic and diastolic BP on DPW and HDD was tested. RESULTS With pre-treatment standing diastolic BP as a moderator, there were significant BP x medication interactions for both DPW [**p=0.009, d=0.80] and HDD [*p=0.018, d=1.11]. Post-hoc analyses indicated significant doxazosin effects in patients with higher standing BP in reducing both DPW and HDD. CONCLUSION These findings suggest that higher standing diastolic BP at baseline (pre-treatment) may represent a predictor of doxazosins response on alcohol consumption in AD patients. These results further elucidate the possible efficacy and mechanisms of action of α1 receptor antagonism in AD individuals.

An fMRI and effective connectivity study investigating miss errors during advice utilization from human and machine agents

ABSTRACT As society becomes more reliant on machines and automation, understanding how people utilize advice is a necessary endeavor. Our objective was to reveal the underlying neural associations during advice utilization from expert human and machine agents with fMRI and multivariate Granger causality analysis. During an X-ray luggage-screening task, participants accepted or rejected good or bad advice from either the human or machine agent framed as experts with manipulated reliability (high miss rate). We showed that the machine-agent group decreased their advice utilization compared to the human-agent group and these differences in behaviors during advice utilization could be accounted for by high expectations of reliable advice and changes in attention allocation due to miss errors. Brain areas involved with the salience and mentalizing networks, as well as sensory processing involved with attention, were recruited during the task and the advice utilization network consisted of attentional modulation of sensory information with the lingual gyrus as the driver during the decision phase and the fusiform gyrus as the driver during the feedback phase. Our findings expand on the existing literature by showing that misses degrade advice utilization, which is represented in a neural network involving salience detection and self-processing with perceptual integration.

Advice Taking from Humans and Machines: An fMRI and Effective Connectivity Study.

With new technological advances, advice can come from different sources such as machines or humans, but how individuals respond to such advice and the neural correlates involved need to be better understood. We combined functional MRI and multivariate Granger causality analysis with an X-ray luggage-screening task to investigate the neural basis and corresponding effective connectivity involved with advice utilization from agents framed as experts. Participants were asked to accept or reject good or bad advice from a human or machine agent with low reliability (high false alarm rate). We showed that unreliable advice decreased performance overall and participants interacting with the human agent had a greater depreciation of advice utilization during bad advice compared to the machine agent. These differences in advice utilization can be perceivably due to reevaluation of expectations arising from association of dispositional credibility for each agent. We demonstrated that differences in advice utilization engaged brain regions that may be associated with evaluation of personal characteristics and traits (precuneus, posterior cingulate cortex, temporoparietal junction) and interoception (posterior insula). We found that the right posterior insula and left precuneus were the drivers of the advice utilization network that were reciprocally connected to each other and also projected to all other regions. Our behavioral and neuroimaging results have significant implications for society because of progressions in technology and increased interactions with machines.

A Phase I randomized clinical trial testing the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy volunteers

&NA; Preclinical work suggests that the metabotropic glutamate receptor subtype 5 (mGlu5) may represent a novel target to treat neuropsychiatric disorders, including alcohol use disorder and obesity. The goal of this first‐in‐man study was to evaluate the safety, tolerability and pharmacokinetics (PK) of GET 73 (PubChem SID: 329974174), a novel mGluR5 negative allosteric modulator. This was a double‐blind, placebo‐controlled, ascending dose, Phase I study conducted in healthy male volunteers in two experiments. GET 73 was administered as single ascending doses (N = 48; Experiment 1; 10, 30, 100, 300, 450, 600‐mg) or multiple ascending doses (N = 32; Experiment 2; 100, 300, 450, 450‐mg twice a day). Primary endpoints were the incidence of adverse events (AEs) among drug conditions and drug tolerability. The secondary endpoints were the PK parameters of GET 73 and its metabolite MET 2. Single GET 73 doses of up to 600‐mg and repeated ascending doses of up to 450‐mg twice/day were safe and well‐tolerated. There were no serious or severe AEs. All AEs were mild or moderate in severity. Total GET 73 exposure increased with each increased GET 73 dose. A dose‐related increase in mean maximum plasma drug concentration was observed after repeated dosing. Maximum plasma drug concentrations occurred between 0.5 and 2.05 h after administration in all groups for both single and repeated doses. This first‐in‐human study indicates that GET 73, as single or multiple ascending doses, is safe and well‐tolerated when administered to healthy male volunteers. Graphical abstract Figure. No caption available.

Comparing and Combining Topiramate and Aripiprazole on Alcohol-Related Outcomes in a Human Laboratory Study

Aims The goal of this study was to evaluate the efficacy of topiramate up to 200 mg/day and of aripiprazole up to 15 mg/day, alone and combined, in reducing alcohol-related outcomes in a human laboratory study. Method This was a 5 week, between-subject, double-blind, placebo-controlled human laboratory study with topiramate [0 mg/day (placebo), 100 mg/day, 200 mg/day] and aripiprazole [0 mg/day (placebo), 7.5 mg/day, 15 mg/day] in 90 non-treatment seeking, heavy drinking, alcohol-dependent individuals. Main outcomes were the efficacy of 200 mg/day topiramate and 15 mg/day aripiprazole, alone and combined, in reducing drinks consumed during an alcohol self-administration procedure (human laboratory phase) and while receiving the study medications prior to the laboratory session (naturalistic drinking phase). Other outcomes in the laboratory phase included alcohol craving, and alcohol biphasic effects. Results In the human laboratory phase, topiramate 200 mg/day reduced alcohol craving [**P < 0.01] and amplified alcohol-induced stimulation [*P < 0.05], but did not reduce the number of drinks consumed. Topiramate 200 mg/day was also effective in reducing drinking days [*P < 0.05], and alcohol craving [*P < 0.05], in the naturalistic drinking phase. No significant findings were found for aripiprazole for any of the outcomes analyzed. Conclusion Participants receiving 200 mg/day topiramate reported reduced alcohol drinking and craving, and increased alcohol-related stimulation. These findings provide further support for the role of topiramate as a pharmacological treatment for AUD. ClinicalTrial.gov Identifier NCT00884884. Short Summary This study tested topiramate and aripiprazole alone and in combination. The results replicate past findings and suggest that topiramate may be an effective treatment for alcohol use disorder. The present results suggest that the combination of topiramate and aripiprazole do not warrant further evaluation.

Dataset for Phase I randomized clinical trial for safety and tolerability of GET 73 in single and repeated ascending doses including preliminary pharmacokinetic parameters

The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled “Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers” (Haass-Koffler et al., 2017) [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted. The next series of tables provided includes Pharmacokinetic (PK) parameters for GET 73 and its main metabolite MET 2. This set of data is comprised by two experiments: Experiment 1 references a single ascending dose administration of GET 73 and Experiment 2 references a repeated ascending dose administration of GET 73.

A Little Anthropomorphism Goes a Long Way.

Objective: We investigated the effects of exogenous oxytocin on trust, compliance, and team decision making with agents varying in anthropomorphism (computer, avatar, human) and reliability (100%, 50%). Background: Authors of recent work have explored psychological similarities in how people trust humanlike automation compared with how they trust other humans. Exogenous administration of oxytocin, a neuropeptide associated with trust among humans, offers a unique opportunity to probe the anthropomorphism continuum of automation to infer when agents are trusted like another human or merely a machine. Method: Eighty-four healthy male participants collaborated with automated agents varying in anthropomorphism that provided recommendations in a pattern recognition task. Results: Under placebo, participants exhibited less trust and compliance with automated aids as the anthropomorphism of those aids increased. Under oxytocin, participants interacted with aids on the extremes of the anthropomorphism continuum similarly to placebos but increased their trust, compliance, and performance with the avatar, an agent on the midpoint of the anthropomorphism continuum. Conclusion: This study provides the first evidence that administration of exogenous oxytocin affected trust, compliance, and team decision making with automated agents. These effects provide support for the premise that oxytocin increases affinity for social stimuli in automated aids. Application: Designing automation to mimic basic human characteristics is sufficient to elicit behavioral trust outcomes that are driven by neurological processes typically observed in human–human interactions. Designers of automated systems should consider the task, the individual, and the level of anthropomorphism to achieve the desired outcome.

Oxytocin influences intuitions about the relationship between belief in free will and moral responsibility

Philosophers have proposed that laypeople can have deterministic or indeterministic intuitions about the relationship between free will and moral responsibility. However, the psychophysiological mechanisms that generate these extreme intuitions are still underexplored. Exogenous oxytocin offers a unique opportunity to gain a deeper understanding of these underlying mechanisms, since this neuropeptide influences a wide range of outcomes related to social cognition and prosociality. This study investigated the effects of intranasal oxytocin on intuitions about the relationship between free will and moral responsibility by applying a randomized, double-blind, placebo-controlled, between-subject design. Healthy male participants rated the moral responsibility of a hypothetical offender, who committed crimes in either a primed deterministic or an indeterministic universe. Under placebo, participants held the offender more morally responsible when acting in an indeterministic compared to a deterministic universe, which could be accredited to recognition of the offender’s freely chosen action to commit the crimes. Under oxytocin, participants rated the offender’s actions with greater leniency and similarly assigned lower moral responsibility in both universes. These findings strengthen the assumption that a person can have different intuitions about the relationship between free will and moral responsibility, which can be presumably dependent on motivational states associated with affiliation.

Administration of the metabotropic glutamate receptor subtype 5 allosteric modulator GET 73 with alcohol: A translational study in rats and humans:

Preclinical work suggests that GET 73 (N-[4-(trifluoromethyl)benzyl]-4-methoxybutyramide), a novel metabotropic glutamate receptor subtype 5 negative allosteric modulator, may represent a novel pharmacological treatment for alcohol use disorder. Two independent experiments evaluated the effect of acutely administered GET 73 (0, 30, and 100 mg/kg, intragastrically) on alcohol-induced hypolocomotion (n=72) and sedation/hypnosis (n=36) in rats. In healthy male volunteers (n=14), an open-label, randomised, crossover study was conducted to compare adverse events and pharmacokinetic parameters, in two experiments in which 300 mg GET 73 was administered, with and without alcohol, once and thrice. In rats, when administered with alcohol-vehicle, 100 mg/kg, but not 30 mg/kg, GET 73 reduced spontaneous locomotor activity. When administered with alcohol, no dose of GET 73 altered either alcohol-induced hypolocomotion or sedation/hypnosis. In humans, both single and thrice 300 mg GET 73 administration were well tolerated, in the presence and absence of alcohol, with no differences in adverse events. There were no significant differences in relative bioavailability between administering 300 mg GET 73 in the presence or absence of alcohol.