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1.  Effect of d-amphetamine on post-error slowing in healthy volunteers 
Psychopharmacology  2011;220(1):109-115.
Post-error slowing has long been considered a sign of healthy error detection and an important component of cognitive function. However, the neuropharmacological processes underlying post-error slowing are poorly understood.
This study investigated the effect of the dopamine agonist d-amphetamine on post-error slowing and secondarily, the potential mediator of drug-induced euphoria and potential moderators of personality and baseline task performance.
Healthy male and female participants (N=110) completed four study sessions, at which d-amphetamine (placebo 5, 10, 20 mg) was administered under double-blind, counter-balanced conditions. At each session, participants completed subjective drug effect assessments and a working memory task (N-back) to measure post-error slowing. They completed the Multidimensional Personality Questionnaire (MPQ) during screening.
Amphetamine (20 mg) reduced post-error slowing, consistent with a dampened behavioral reactivity to errors. This was not related to drug-induced euphoria. Although higher scores on MPQ constraint were related to less post-error slowing under placebo conditions, neither personality nor baseline cognitive performance moderated the effects of amphetamine on post-error slowing.
The finding that amphetamine reduced post-error slowing supports the idea that dopamine plays a role in error stimulus processing. The finding is discussed in relation to an existing literature on the mechanisms and function of behavioral and electrophysiological indices of error sensitivity.
PMCID: PMC4241763  PMID: 21894485
Amphetamine; Dopamine; Post-error slowing; Error monitoring; Error-related negativity
2.  Does COMT genotype influence the effects of d-amphetamine on executive functioning? 
Genes, brain, and behavior  2012;12(1):13-20.
In a widely cited study, Mattay et al. (2003) reported that amphetamine (0.25 mg/kg oral, or 17mg for a 68kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N-Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d-amphetamine 5mg, 10mg, and 20mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double-blind conditions, and completed WCST and N-back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. (Mattay et al., 2003). We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research.
PMCID: PMC3553317  PMID: 23231539
COMT genotype; executive functioning; working memory; d-amphetamine; genetics; stimulant response
3.  Caffeine increases psychomotor performance on the effort expenditure for rewards task 
Preclinical studies suggest that cost/benefit decision-making involves interactions between adenosine and dopamine (DA). In rats, DA depletion decreases willingness to incur effort costs, while adenosine antagonism reverses these effects, likely by increasing DA transmission. Caffeine is a non-selective adenosine antagonist commonly used to facilitate effortful tasks, and thus may affect decisions involving effort costs in humans. The current study examined acute effects of 200 mg of caffeine on willingness to exert effort for monetary rewards at varying levels of reward value and reward probability, in young adult light caffeine users. Based on previous findings with amphetamine, we predicted that caffeine would increase willingness to exert effort. At separate sessions, 23 healthy normal adults received placebo or 200 mg caffeine under counterbalanced double-blind conditions, then completed the effort expenditure for rewards task (EEfRT). Measures of subjective and cardiovascular effects were obtained at regular intervals. Caffeine produced small but significant subjective and cardiovascular effects, and sped psychomotor performance on the EEfRT. Caffeine did not alter willingness to exert effort, except in high cardiovascular responders to caffeine, in whom it decreased willingness to exert effort. These results were contrary to our predictions, but consistent with rodent studies suggesting that moderate doses of caffeine alone do not affect effort, but rather only influence effort in the context of DA antagonism. Our results demonstrate that psychomotor speeding and decisional effects on the EEfRT are dissociable, providing additional evidence for the EEfRT as a specific measure of effort-based decision-making. This study provides a starting point for exploring contributions of the adenosine system to motivation in humans.
PMCID: PMC3578395  PMID: 22750066
Caffeine; Adenosine; Dopamine; Effort-based decision-making
4.  Amphetamine as a social drug: Effects of d-amphetamine on social processing and behavior 
Psychopharmacology  2012;223(2):199-210.
Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others.
We examined effects of d-amphetamine on processing of emotional facial expressions, and on the social behavior of talking. We predicted amphetamine would enhance attention, identification and responsivity to positive expressions, and that this in turn would predict increased talkativeness.
Over three sessions, 36 healthy normal adults received placebo, 10mg, and 20mg d-amphetamine under counterbalanced double-blind conditions. At each session we measured processing of happy, fearful, sad and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking.
Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine.
The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine.
PMCID: PMC3422595  PMID: 22526538
amphetamine; emotional faces; attentional bias; social interaction; psychophysiology
5.  The Caudate Signals Bad Reputation during Trust Decisions 
PLoS ONE  2013;8(6):e68884.
The ability to initiate and sustain trust is critical to health and well-being. Willingness to trust is in part determined by the reputation of the putative trustee, gained via direct interactions or indirectly through word of mouth. Few studies have examined how the reputation of others is instantiated in the brain during trust decisions. Here we use an event-related functional MRI (fMRI) design to examine what neural signals correspond to experimentally manipulated reputations acquired in direct interactions during trust decisions. We hypothesized that the caudate (dorsal striatum) and putamen (ventral striatum) and amygdala would signal differential reputations during decision-making. Twenty-nine healthy adults underwent fMRI scanning while completing an iterated Trust Game as trusters with three fictive trustee partners who had different tendencies to reciprocate (i.e., likelihood of rewarding the truster), which were learned over multiple exchanges with real-time feedback. We show that the caudate (both left and right) signals reputation during trust decisions, such that caudate is more active to partners with two types of “bad” reputations, either indifferent partners (who reciprocate 50% of the time) or unfair partners (who reciprocate 25% of the time), than to those with “good” reputations (who reciprocate 75% of the time). Further, individual differences in caudate activity related to biases in trusting behavior in the most uncertain situation, i.e. when facing an indifferent partner. We also report on other areas that were activated by reputation at p < 0.05 whole brain corrected. Our findings suggest that the caudate is involved in signaling and integrating reputations gained through experience into trust decisions, demonstrating a neural basis for this key social process.
PMCID: PMC3688684  PMID: 23922638
6.  Lack of Association Between COMT and Working Memory in a Population-Based Cohort of Healthy Young Adults 
Neuropsychopharmacology  2013;38(7):1253-1263.
The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is an important regulator of dopamine in the prefrontal cortex, an area critical to working memory. Working memory deficits are present in several psychiatric disorders, and there is wide variation in working memory capacity in the normal population. Association studies of COMT and working memory in healthy volunteers have yielded inconsistent results, possibly because of small sample sizes. Here we examine COMT in relation to N-Back working memory task performance in a large population-based cohort of young adults. We predicted individuals with one or two copies of the Met allele would perform better, and that this relationship would be more evident in males than females. Participants (N=1857–2659) tested at 18 years of age, were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). We used multiple regression to examine effects of sex and COMT genotype on N-Back hits, false positives, discriminability (d'), and reaction time while controlling for important covariates. COMT genotype did not predict hits or d'. There was a nominally significant interaction between COMT and sex on false positives, but this was not in the predicted direction, and was not significant after controlling for covariates. COMT genotype was not related to working memory in this large population-based cohort. It is possible COMT is not meaningfully associated with working memory in healthy young adults, or that COMT effects are detectable only in assessments reflecting neural processes underlying cognition, such as fMRI, rather than in behavioral performance.
PMCID: PMC3656369  PMID: 23337869
dopamine; cognition; learning & memory; neurogenetics; COMT genotype; executive functioning; ALSPAC; COMT genotype; executive functioning; working memory; genetics; ALSPAC
7.  Effects of amphetamine on reactivity to emotional stimuli 
Psychopharmacology  2011;220(1):143-153.
Most studies of the reinforcing effects of stimulants have focused on the drugs’ capacity to induce positive mood (i.e., euphoria). However, recent findings suggest drugs may also alter emotional reactivity to external stimuli, and that this may occur independently of direct effects on mood.
We aimed to examine effects of d-amphetamine, a prototypic stimulant, on self-reported and psychophysiological reactivity to emotional stimuli as well as overall subjective mood. We predicted that amphetamine would enhance reactivity to pleasant stimuli, particularly, stimuli with social content and that these effects would be independent of the drug’s direct effects on mood.
Over three sessions, 36 healthy normal adults received placebo, d-amphetamine 10 and 20 mg under counterbalanced double-blind conditions. At each session, emotional reactivity to standardized positive, neutral, and negative pictures with and without social content was measured in self-reports and facial muscles sensitive to emotional state. Drug effects on cardiovascular variables and subjective mood were also measured.
Amphetamine produced euphoria, feelings of drug effect, and increased blood pressure. Most notably, amphetamine enhanced self-reported positive reactions to all pictures and psychophysiological reactions to positive pictures. These effects were not significantly related to drug-induced mood changes. Contrary to our hypothesis, effects of amphetamine on emotional reactivity were not moderated by social content.
This study demonstrates a previously unexamined and potentially reinforcing effect of stimulant drugs in humans, distinct from more typically measured euphorigenic effects, and suggests new areas of research in stimulant abuse risk and adaptations occurring during drug dependence.
PMCID: PMC3277682  PMID: 21947316
Amphetamine; Emotion; Reward; Electromyography; Psychophysiology
8.  Effect of social stress during acute nicotine abstinence 
Psychopharmacology  2011;218(1):39-48.
Relapse to smoking is often precipitated by stress, yet little is known about the effects of nicotine withdrawal on responses to acute stress, or whether nicotine replacement reverses withdrawal-induced changes in stress response.
The aim of the present study is to use an effective social stressor, the Trier Social Stress Test (TSST), to study subjective, cardiovascular and hormonal responses to stress during withdrawal, and examine whether nicotine replacement moderates responses to stress during withdrawal.
Forty-nine current regular smokers were randomly assigned to smoke as normal (SM), 12-h abstention with placebo patch (PL), or 12-h abstention with nicotine patch (NIC). They participated in a single session using the TSST, during which subjective affect, heart rate (HR), mean arterial blood pressure (MAP) and salivary cortisol were measured.
The TSST produced expected increases in subjective negative affect, HR, MAP, and cortisol. Groups did not differ in subjective or cardiovascular responses, but the PL group exhibited larger stress-induced increase in cortisol than the other groups.
The increased cortisol response might indicate a greater hormonal stress response during nicotine withdrawal. Alternatively, considering that cortisol also provides negative feedback to the stress system, and blunted cortisol responses are predictive of smoking relapse, the lower cortisol responses in the NIC and SM groups might indicate chronic dysregulation of the stress system. In this case, restoration of cortisol response by nicotine treatment to the lower levels seen during regular smoking may actually represent an undesired side effect of nicotine replacement.
PMCID: PMC3094594  PMID: 21234550
Nicotine withdrawal; Stress; Nicotine replacement; Cortisol
9.  Genome-Wide Association Study of d-Amphetamine Response in Healthy Volunteers Identifies Putative Associations, Including Cadherin 13 (CDH13) 
PLoS ONE  2012;7(8):e42646.
Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8th intron of cadherin 13 (CDH13; P = 4.58×10−8), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1st intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10−7), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses.
PMCID: PMC3429486  PMID: 22952603
10.  Amping Up Effort: Effects of d-Amphetamine on Human Effort-Based Decision-Making 
Animal studies suggest the neurotransmitter dopamine (DA) plays an important role in decision-making. In rats, DA depletion decreases tolerance for effort and probability costs, while drugs enhancing DA increase tolerance for these costs. However, data regarding the effect of DA manipulations on effort and probability costs in humans remains scarce. The current study examined acute effects of d-amphetamine, an indirect DA agonist, on willingness of healthy human volunteers to exert effort for monetary rewards at varying levels of reward value and reward probability. Based on preclinical research, we predicted amphetamine would increase exertion of effort, particularly when reward probability was low. Over three sessions, 17 healthy normal adults received placebo, d-amphetamine 10 mg, and 20 mg under counterbalanced double-blind conditions and completed the Effort Expenditure for Rewards Task. Consistent with predictions, amphetamine enhanced willingness to exert effort, particularly when reward probability was lower. Amphetamine did not alter effects of reward magnitude on willingness to exert effort. Amphetamine sped task performance, but its psychomotor effects were not strongly related to its effects on decision-making. This is the first demonstration in humans that dopaminergic manipulations alter willingness to exert effort for rewards. These findings help elucidate neurochemical substrates of choice, with implications for neuropsychiatric diseases characterized by dopaminergic dysfunction and motivational deficits.
PMCID: PMC3234999  PMID: 22090487
11.  Quantifying talk: developing reliable measures of verbal productivity 
Behavior research methods  2011;43(1):168-178.
Measuring talkativeness is of interest to several areas of research. However, there are few brief, validated measures available. We examined test-retest reliability, inter-relationships and convergent/divergent validity for five brief measures of verbal productivity. Nineteen men and 32 women participated in four sessions, completing five speech tasks that varied in demand, purpose of speech and sociability. Several potential metrics (word count, duration and rate) were examined. All tasks except a novel Unprompted Speech task demonstrated good word count test-retest reliability (interclass correlation coefficients from .71 to .85). Factor analysis revealed low-demand, non-functional tasks formed one factor (“Voluntary Talkativeness”), while higher demand tasks formed a second factor (“Speech Ability”). This finding and examination of relationships with IQ, personality and gender indicate “Voluntary Talkativeness” is not wholly accounted for by verbal ability, and is only weakly related to self-reported personality. Recommendations for the measurement of “Voluntary Talkativeness” are made.
PMCID: PMC3049967  PMID: 21287128
Talkativeness; Speech; Task validation; Factor analysis
12.  Predictors and Sequelae of Smoking Topography Over the Course of a Single Cigarette in Adolescent Light Smokers 
The objective of this study was to determine whether adolescent smokers, who varied in their smoking histories and symptoms of nicotine dependence, exhibit any decrease in puff volume and duration similar to that typically seen in dependent adolescent and adult smokers. Moreover, we examined whether puffing trajectories were moderated by individual difference factors, as well as whether puffing topography over the course of smoking a single cigarette was predictive of an escalation in dependence symptoms.
We assessed smoking topography (puff number, duration, volume, maximum flow rate [velocity], and inter-puff interval) over the course of smoking a single cigarette in a sample of 78 adolescent light smokers, using hierarchical linear modeling. We examined moderators (anxiety, depression, nicotine dependence) of the topographic trajectories, as well as whether smoking topography predicted any change in dependence over a 2-year period.
Puff volume and puff duration decreased over the course of smoking the cigarette, whereas puff velocity and inter-puff interval increased. Slopes for puff volume and duration were moderated by anxiety and depressive symptoms. Moreover, individuals with a less “typical” topography pattern (exhibited stable or increasing volume and duration over the course of smoking the cigarette) demonstrated a heightened dependence escalation in the subsequent 2 years.
Our findings suggest that adolescent light smokers self-regulate nicotine during the course of smoking a single cigarette, similar to that reported in dependent adolescent and adult smokers. However, single cigarette self-regulation was influenced by certain affective factors. Implications of these findings and future directions for adolescent smoking research are discussed.
PMCID: PMC3044318  PMID: 21257117
Adolescence; Smoking; Dependence; Topography
13.  Influence of Procedural Learning on Iowa Gambling Task Performance Among HIV+ Individuals with History of Substance Dependence 
HIV+ individuals have been shown to demonstrate deficits on the Iowa Gambling Task (IGT), a complex measure of “decision-making.” Little remains known about what other neurocognitive processes may account for variability in IGT performance among HIV+ samples or the role of procedural learning (PL) in IGT performance. A sample of 49 HIV+ individuals with a history of substance use disorders was examined to explore the relationship between IGT performance and three measures of PL: The Rotary Pursuit, Mirror Star Tracing, and Weather Prediction tasks. We found no statistically significant relationships between IGT performance and any of the PL tasks, despite finding significant correlations among the PL tasks. This pattern of results persisted when analyzing IGT performance in various ways (e.g., performance on earlier trial blocks or impairment classifications). Although other nondeclarative processes (e.g., somatic markers) may be important for IGT performance, these findings do not support PL as an important component neurocognitive process for the IGT. Similarly, these results suggest that differences in PL performance does not account for the decision-making deficits or variability in performances observed on the IGT among HIV+ individuals with a history of substance dependence.
PMCID: PMC2809553  PMID: 19939850
HIV; Substance use disorders; Nondeclarative memory; Implicit memory; Decision-making; Basal ganglia; Orbitofrontal cortex; Executive functions

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