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Altered economic decision-making in abstinent heroin addicts: Evidence from the ultimatum game
Neuroscience Letters 627 (2016) 148–154
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
Altered economic decision-making in abstinent heroin addicts: Evidence from the ultimatum game夽 Yu Hou a , Liyan Zhao b,∗ , Qi Yao a , Lixiang Ding a a b
Beijing Shijitan Hospital, the 9th Clinical Medical College of Peking University, Beijing 100038, China Peking University Health Science Center, Beijing 100191, China
h i g h l i g h t s • This is the first investigation of how heroin addiction modulates responder behavior in the UG. • Responder behavior in the UG was differentially modulated by heroin addiction under different stake-level conditions. • Heroin addicts had higher scores on BIS attention /cognitive impulsivity and non-planning impulsivity, but not in motor impulsivity.
a r t i c l e
i n f o
Article history: Received 13 January 2016 Received in revised form 18 May 2016 Accepted 1 June 2016 Available online 2 June 2016 Keywords: Economic decision-making Ultimatum game Heroin addiction Emotion Self-interest Impulsivity
a b s t r a c t Background: The development and persistence of drug addiction has been suggested to involve decisionmaking deficits. The Ultimatum Game is a widely used economic decision-making paradigm that illustrates the tension between financial self-interest and fairness motives. The behavior of responders in the Ultimatum Game has been associated with emotional reactions and cognitive control abilities, both of which are dysregulated in drug addicts. In this study, we investigated whether this economic decision-making process that involves considerations of social norms is affected by heroin addiction. Methods: Heroin addicts (n = 17) and demographically matched healthy control subjects (n = 18) were recruited to play the part of responders in the Ultimatum Game, during which they decided to accept or reject the monetary offers proposed by strangers. The offers were manipulated by varying the stake sizes and fairness scales. The rejection rates of all of the offer categories, response times, fairness judgments, and impulsivity were compared between heroin addicts and healthy controls. Results: Compared with healthy subjects, the rejection rates of most unfair offers in the Ultimatum Game were significantly higher under low-offer-size conditions among heroin addicts. In contrast, the most unfair offers were more likely to be accepted by heroin addicts in the high-offer-size condition than by healthy subjects. The ratings of unfairness were equal in both conditions although the rejection rates were different. Heroin addicts had higher scores on BIS attentional/cognitive impulsivity and non-planning impulsivity, but not in motor impulsivity. Rejection rates to most unfair offers under lowoffer-size conditions significantly correlated with score on BIS non-planning impulsivity and total score of impulsivity. Conclusions: Heroin addicts differentially responded under different stake-level conditions in the Ultimatum Game, with emotional impulses in low-offer-size conditions and selfish motives in the face of high monetary reward. These findings indicate that Ultimatum Game may be associated with heroin addiction and provide a productive new target for enhancing treatment for heroin addiction. © 2016 Published by Elsevier Ireland Ltd.
1. Introduction 夽 This work was supported in part by the Qingmiao Program (no. QML20150702) and the Natural Science Foundation of China (no. 31100809 and 81202123). The authors declare that they do not have any conflicts of interest related to the data presented in this manuscript. ∗ Corresponding author at: Peking University, 38, Xue Yuan Road, Beijing 100191, China. E-mail address: [email protected] (L. Zhao). http://dx.doi.org/10.1016/j.neulet.2016.06.002 0304-3940/© 2016 Published by Elsevier Ireland Ltd.
Decision-making deficits are thought to play an important role in the development and persistence of drug addiction [1–3]. Individual differences in decision-making abilities, therefore, may constitute an important predictor of the course of drug addiction [4]. Decision-making is a complex, multifaceted process. During decision making, our preference is often based on differences in
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Table 1 Characteristics of participants. Characteristic
Heroin addicts
Healthy controls
t
p
Age (years) Education (years) Number of cigarettes per day Years of smoking Income per month (Yuan, RMB) Gender (male/female) Average years of heroin abuse Average amount of heroin use per day (g) Average months of heroin abstinence
34.57 ± 4.76 8.39 ± 2.76 38.26 ± 13.37 17.78 ± 4.21 1996.67 ± 604.88 10/7 10.26 ± 3.52 0.75 ± 0.40 6.41 ± 3.98
35.82 ± 7.53 8.14 ± 1.96 35.91 ± 17.19 17.18 ± 5.69 2147.06 ± 798.53 9/9
−0.67 0.36 0.66 0.4 0.76
0.51 0.72 0.51 0.16 0.46 0.67
expected losses or gains, the capacity to retrieve this information from memory, and the capacity to maintain and manipulate the information “online” (working memory) [5,6]. However, the decision-making process is not simply a cost-benefit analysis. Because we live in complex social environments, decision-making often takes place in the form of social interaction and is influenced by their social cognitive abilities. To date Social decision-making has not been investigated in an experimental setting in heroin users. Socio-cognitive abilities are known to affect the course of dependence and treatment success in addicts [7,8], and thus understanding how heroin addiction may be associated with maladaptive social interaction is fundamentally important. The Ultimatum Game is a widely used laboratory model of economic decisionmaking that is the conflict between accepting unfair treatment and foregoing financial gain. Economic decision-making has been applied to the study of addiction, and it may have the potential to generate breakthrough research in addiction science [4]. Evidence showed that both recreational cocaine users and dependent cocaine users distributed money in a more self-serving manner than control in Distribution Game [8]. Any of the irrationalities that are prominent in economic decision-making are plausible candidates for playing a role in the development and maintenance of addiction. The Ultimatum Game is often played in economic experiments to illustrate the tension between economic self-interest and reciprocity and equity motives [9]. The Ultimatum Game may represent a source of systematic irrationality that can be linked to addiction. Social interaction often involves emotional reactions and selfish motives. However, for evolutionary benefits, humans across many cultures have established and enforced social norms that constitute human sociality with the unique capacity to stably maintain large-scale cooperation [10–14]. Social norms are expected to exert a restraining force over self-interest impulses when conflicts occur. Fairness norms play a crucial role in social life and have been studied using the Ultimatum Game [15], in which one player (the proposer) makes a proposition about how to split a given amount of money with another player (the responder). If the responder decides to accept the offer, then both players are paid accordingly. If the responder rejects the offer, then neither player gets paid. Frequently, most responders tend to reject offers less than 20–30% of the total stake [16,17], suggesting that people are willing to forgo self-interest and maintain fairness. The rejection of unfair offers in the Ultimatum Game has been related to negative emotional reactions [18] and the appropriate cognitive control of implementing fairness motives [9,19]. Increasing evidence has shown that drug addiction is associated with a variety of psychopathological disturbances, including emotional dysregulation and cognitive dysfunction [20–22]. Specifically, heroin addicts have a tendency to rate unpleasant affective stimuli more negatively [23–26], but this has not been consistent across studies [27]. Additionally, personality traits of heroin addicts may impact their social behavior [28,29], such as impulsivity (poor self-control), hostility, and irritability. Their behaviors tend to be easily influenced by subjective feelings, and they make
little consideration of social rules [30,31]. Moreover, neuroimaging studies have implicated some overlapping neural structures between responder behavior in the Ultimatum Game and heroin addiction, including the amygdala, insula, anterior cingulate cortex, medial prefrontal cortex, and dorsal lateral prefrontal cortex [3,9,32–35]. Abnormalities in these brain regions may lead heroinaddicted subjects to respond differently in the Ultimatum Game. Altogether, heroin addiction may have some modulatory effects on Ultimatum Game responder behavior. To investigate this possibility, we conducted a study in which heroin addicts acted as responders in the Ultimatum Game. We independently manipulated social reward (fairness) and basic monetary reward by varying both the stake size and offer amount across trials. 2. Materials and methods 2.1. Participants Prior to enrollment, participants underwent thorough physical and psychiatric evaluations, including a medical history interview. Participants met DSM-IV criteria for heroin dependence. Exclusion criteria included current use of any medications, current DSM-IV diagnosis of any affective, or psychotic disorder, and dependence on any substance other than heroin and nicotine (assessed by urine test and DSM-IV diagnosis). Seventeen heroin-dependent subjects (10 males, 7 females) were recruited from the Addiction Treatment Center, Shenzhen, China. These subjects were abstinent from heroin for at least 1 month, documented by negative weekly supervised urine tests. In addition, 18 sex-, age-, education-, smoking- and economic status-matched healthy control participants (9 males, 9 females) with no DSM-IV Axis I disorders were recruited by advertisement from the local communities. Exclusion criteria for the controls were psychiatric or neurological disorders, history of substance abuse, and current use of any medications. BDI was used to assess anxiety and depression. The demographics are summarized in Table 1. The study was conducted according to human research guidelines and was approved by the Peking University Research Ethics Board. After a full description of the study procedure was provided to the participants, written informed consent was obtained before testing. The subjects were monetarily compensated for participating in the study. 2.2. Task The subjects acted as responders in a series of 24 trials in the Ultimatum Game. In each trial, the offer condition was indicated by a 4 s presentation of the picture of a person making an ultimatum offer along with the person’s name. The participant then saw the offer for 4 s. The subjects could then accept or reject the offer by pressing a corresponding button, indefinite. If the subject rejected the offer, then both players received no payoff in this trial. If the subject accepted the offer, then the payoffs implied by the offer
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Fig. 1. (A) Schematic of the trial design. In each trial, the offer condition included 4 s presentation of a picture of a person making an ultimatum with the person’s name. The participant then saw the offer for 4 s. The subjects then made a decision, indefinite. The subjects could accept or reject the offer by pressing the appropriate button. The outcome was then presented for 3 s. In this example, the offer was rejected. (B) Offer categories. The offers fell into one of six “fairness” categories: 45% stake from high offer size (fair + high), 45% stake from low offer size (fair + low), 30% stake from high offer size (unfair + high), 30% stake from low offer size (unfair + low), 15% stake from high offer size (most unfair + high), and 15% stake from low offer size (most unfair + low).
were implemented. Finally, the participant saw the outcome based on his/her response for 3 s (see Fig. 1Afor a schematic of the trial design). The intertrial interval included the presentation of a fixation cross for 4–6 s. All of the subjects received the same 24 offers in a fixed random order from 24 different proposers. The subjects were required to answer a series of test questions successfully after reading the instructions to verify comprehension. Before beginning the test, the subjects were instructed that the offers were real, and the subjects’ responses would not affect subsequent offers.
study were instructed about the rules of the Ultimatum Game and asked to make a subjective judgment of each offer amount as fair or unfair. The 50% and 40% offers were judged to be fair in 20 of 20 cases and 19 of 20 cases, respectively. The 30%, 20%, and 10% offers were judged to be fair in 7 of 20 cases, 3 of 20 cases, and 0 of 20 cases, respectively. We independently manipulated social reward (fairness) and basic monetary reward by varying both the stake size and offer amount across trials (Fig. 1B). 2.4. Measurement of response time
2.3. Offers Offers fell into one of six “fairness” categories: 45% stake from high offer size (fair + high, four offers), 45% stake from low offer size (fair + low, four offers), 30% stake from high offer size (unfair + high, four offers), 30% stake from low offer size (unfair + low, four offers), 15% stake from high offer size (most unfair + high, four offers), and 15% stake from low offer size (most unfair + low, four offers). The justification for this was based on our pilot study. Twenty neurologically normal adults who did not participate in the present
Response time was measured as the time interval that began with the presentation of the offer and ended when the subject pressed the response button. 2.5. Fairness judgments The fairness assessments occurred after the Ultimatum Game ended. Responders were shown a list of all of the offers and asked
Control
A 100
*
Heroin
B 100 80 Rejection rates (%)
Rejection rates (%)
80 60 40
*
60 40 20
20
0
0 45% 30% 15% % of stake offered, low offers
45% 30% 15% % of stake offered, high offers
Fig. 2. Behavioral responses in the different offer conditions. (A) Rejection rates in the low-offer-size condition trials. Heroin addicts exhibited a much higher rejection rate of most unfair offers than the control group. (B) Rejection rates in high-offer-size condition trials. Heroin addicts exhibited a significantly lower rejection rate of most unfair offers than the control group. *p < 0.05. The data are expressed as mean ± SEM.
Y. Hou et al. / Neuroscience Letters 627 (2016) 148–154
Control
Heroin
4000
4000
Response time (ms)
B 5000
Response time (ms)
A 5000
3000 2000 1000
151
3000 2000 1000
0
0 45% 30% 15% % of stake off ered, low off ers
45% 30% 15% % of stake off ered, high off ers
Fairness (1 = very unfair; 7 = very fair)
Fig. 3. Response times for fair and unfair offers in different offer conditions. (A) Response times in the low-offer-size condition trials. (B) Response times in the high-offer-size condition trials. When the subjects faced a fair offer or most unfair offer, they quickly accepted or rejected it, and no response-time difference was found between groups (all p > 0.05). In contrast, the subjects needed a much longer time to accept or reject an unfair offer. The data are expressed as mean ± SEM.
8
45% 30% 15%
7
rejection rates, response times, and fairness judgments. Significance levels were set at p < 0.05.
6
3. Results
5
3.1. Rejection rates in the different offer conditions
4
Repeated-measure ANOVAS, with group as the between-subject factor and fairness and offer size as the within-subject factors, revealed significant main effects of fairness (F2,66 = 322.2, p < 0.001) and offer size (F1,33 = 36.13, p < 0.001) and significant group × fairness × offer size (F2,66 = 12.34, p < 0.001), group × offer size (F1,33 = 17.6, p < 0.001), and fairness × offer size (F2,66 = 18.91, p < 0.001) interactions. Follow-up t-tests showed that heroin addicts had significantly increased rejection rates to most unfair offers under low-offer-size conditions (t33 = 3.39, p = 0.002; Fig. 2A) but not to fair and unfair offers compared with healthy control subjects. In contrast, heroin addicts had significantly decreased rejection rates to most unfair offers under high-offer-size conditions (t33 = −2.31, p = 0.03; Fig. 2B). There was no significant correlation between time of abstinence/time of heroin abuse and reject rate. These results indicate that resistance to selfish temptations depends on the offer size in heroin addicts. They appear to be less able to resist selfish temptations to accept higher offers, although they still view them as very unfair.
3 2 1 0 Low High Heroin addicts
Low High Healthy control
Fig. 4. Perceived unfairness for different offers in the low- and high-offer-size conditions. Subjects in the two groups judged the offer of 45%, 30% and 15% as rather fair, unfair and most unfair respectively when partner made these offers. However, there was no significant main effect of group and offer size in different offer stakes (all p > 0.05). The data are expressed as mean ± SEM.
to report the extent to which they perceived an offer as fair or unfair on a 7-point scale (1 = very unfair, 7 = very fair). 2.6. Measurement of impulsivity The subjects were administered the Chinese version of the Barratt Impulsivity Scale-11 (BIS-11) [36]: a validated 30-item questionnaire that measures different dimensions of impulsivity: (1) attentional/cognitive impulsivity, measuring tolerance for cognitive complexity and persistence; (2) motor impulsivity were used as a trait measure of motor impulsivity (“acting without thinking”) measuring the tendency to act on the spur of the moment; and (3) non-planning impulsivity, measuring the lack of sense of the future. A higher total score indicated a higher level of impulsivity. 2.7. Data analysis Demographic characteristics and impulsivity in the two groups were compared using t-tests. Rejection rates (% offers rejected) were calculated for each subject at each level of fairness. Repeatedmeasures analyses of variance (ANOVAs) were used to analyze
3.2. Response times for fair and unfair offers in different offer conditions To investigate whether long-term heroin use influences the impulse to reject offers that are perceived as unfair, we measured response times for different offers. Repeated-measure ANOVAs, with a group as the between-subject factor and fairness and offer size as the within-subject factors, revealed a significant main effect of fairness (F2,66 = 14.14, p < 0.001; Fig. 3) but not group (F1,33 = 0.11, p = 0.75; Fig. 3) or offer size (F1,33 = 1, p = 0.32; Fig. 3). The post hoc tests indicated that both heroin addicts and healthy control accepted or rejected it more quickly, if they faced a fair offer or most unfair offer, In contrast, the subjects needed a longer time to accept or reject an unfair offer, suggesting that a conflict existed between self-interest and fairness motives with unfair offers that caused an increase in response times (fair offer vs most unfair offer, t68 = −0.67, p = 0.51; fair offer vs unfair offer, t68 = −0.27, p = 0.04; most unfair offer vs unfair offer, t68 = −1.39, p = 0.17; Fig. 3). There
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Healthy control
80
Heroin addicts *
70 Scores of BIS
60 50 40 *
30 *
20 10 0
Attentional / cognitive
Motor
Non-planning
Total
Fig. 5. Impulsivity scores. Heroin addicts had higher scores on BIS attentional/cognitive impulsivity, non-planning impulsivity and total score. No significant difference in motor impulsivity was found between groups. *p < 0.05. The data are expressed as mean ± SEM.
was no significant correlation between time of abstinence/time of heroin abuse and reject rate. 3.3. Perceived unfairness for different offers Subjects in the two groups judged the offer of 45%, 30% and the lowest offer of 15% as rather fair, unfair and most unfair when partner made these offers respectively (Fig. 4). Repeated-measures ANOVAs, with group as the between-subject factor and offer size as the within-subject factor, revealed no significant main effects of group (F1,33 = 1.81, p = 0.19 for 45% offer; F1,33 = 1.1, p = 0.3 for 30% offer; F1,33 = 0.29, p = 0.59 for 15% offer; Fig. 4) or offer size (F1,33 = 3.44, p = 0.07 for 45% offer; F1,33 = 0.4, p = 0.53 for 30% offer; F1,33 = 0.2, p = 0.66 for 15% offer; Fig. 4). Thus, although the rejection rates for the most unfair offers were significantly different between groups, the subjects’ fairness judgments were not influenced by heroin addiction. 3.4. Impulsivity scores Impulsivity was also assessed using a personality questionnaire. Heroin addicts had higher scores on BIS attentional/cognitive impulsivity (t33 = 2.98, p = 0.005; Fig. 5) and BIS non-planning impulsivity (t33 = 5.06, p < 0.001; Fig. 5). No significant difference in motor impulsivity was found between groups (t33 = 1.83, p = 0.08; Fig. 5). Rejection rates to most unfair offers under low-offer-size conditions significantly correlated with a score on BIS non-planning impulsivity (r = 0.36, p = 0.03) and total score of impulsivity (r = 0.46, p = 0.01). There was no other significant correlation. 4. Discussion Compared with healthy control subjects, the rejection rates of most unfair offers among heroin addicts in the Ultimatum Game significantly increased under low-offer-size conditions but decreased as the offer size became higher. Heroin addicts had higher scores on BIS attentional/cognitive impulsivity and nonplanning impulsivity, but not in motor impulsivity. Rejection rates to most unfair offers under low-offer-size conditions significantly correlated with a score on BIS non-planning impulsivity and total score of impulsivity indicating that the differing choices of the two
groups may associated with the differences in attentional/cognitive impulsivity and non-planning impulsivity. Social norms, emotional reactions, and a lack of control (impulsivity) have been attributed to the rejection of unfair offers in the Ultimatum Game. Increasing evidence indicates that unfair offers can trigger a strong negative emotional reaction in the responders that motivates them toward a rejection response [18]. The rejection of unfair offers has been associated with physiological responses that represent emotional arousal, such as higher skin conductance [37] and decelerated heart rate [38]. Moreover, previous studies have indicated that the expression of negative emotions significantly impacts responders’ decisions in the Ultimatum Game [39]. Attempts to regulate the subjectively evoked negative emotions may also affect Ultimatum Game responder behavior [40,41]. Monetary offers in the Ultimatum Game have a certain degree of intrinsic subjective value that derives from financial self-interest and the appreciation of social norms. A human imaging study showed that fair offers could lead to higher ratings of happiness and increased activity in reward-related neural circuits compared with unfair offers [42,43]. In responders in the Ultimatum Game, accepting these unfair offers would only benefit them financially, whereas rejecting them could convey their aversive feelings and maintain the social norm of fairness by punishing inequity, although at the cost of sacrificing self-interest. People with well-established cognitive control abilities are expected to settle conflicts in the decision-making process and as a result consistently behave in a normatively appropriate way. In the present study, heroin addicts appeared to be unable to commit to their responses to unfairness under different conditions. First, the results showed that when subjects with heroin addiction faced most unfair offers under low-offer-size conditions, they were more prone to reject the offer compared with healthy subjects. This could indicate that the available economic gains were too small for them to create strong conflicts with the intention to restore the social norm of fairness and allowed subjective emotions to drive the response more intensely. Compared with healthy subjects, heroin users have been shown to exhibit heightened negative emotional responses in the face of unpleasant stimuli [23–25]. Heroin addicts have been frequently characterized by strong aggressiveness, high irritability and anger, fewer abasement needs, and poor self-control. In addition, their actions are more easily influenced by subjective feelings, with minor concerns about group rules [28–31,44,45]. From this perspective, negative emotions might play a dominant role in the response to unfair offers in heroin addicts under low-offer-size conditions. Being offered too little money from a low total stake might be perceived as more insulting and evoke stronger negative emotions, thus motivating heroin addicts to behave in a more aggressive manner. As a result, the rejection rate of most unfair offers in the heroin addiction group was significantly higher than in the healthy control group. However, because the current study was not designed to obtain a direct measure of subjects’ subjectively experienced anger during performance of the Ultimatum Game and standards of reciprocity and altruism, our conclusions about the specific role of emotion in Ultimatum Game responding are inferred based on the convergent psychological and neurophysiological data regarding the Ultimatum Game. Collection of direct, systematic measurements of emotional responses is an important next step in this line of work. In contrast, the higher offer size markedly switched heroin addicts’ responses to a higher acceptance rate when faced with the most unfair offers. Notably, in both groups, fairness judgments about the most unfair offers were not different under either offer size condition, indicating that concerns about social norms are less likely to have competitive value in the higher offer condition. However, as the monetary value increased, social rules were even less able to restrain self-interested impulses. Meanwhile, self-
Y. Hou et al. / Neuroscience Letters 627 (2016) 148–154
interested impulses elicited more tension with aversive emotional reactions. In heroin addicts, a larger monetary gain was particularly more important because of its more favorable association with drug seeking, which became a most salient motivation for their behavior. Consequently, subjects with heroin addiction were more resistant to expending the cost of economic interest and became more tolerant of inequity. Impairments in executive control in heroinaddicted patients may override of self-interested impulses upon social norms and emotional reactions. A higher degree of impulsivity on the BIS-11 in heroin addicts is consistent with other studies, showing that heroin addicts are more impulsive than healthy controls [46]. We found that increased non-planning impulsivity and total score of impulsivity positively correlated with rejection rates to most unfair offers under lowoffer-size conditions. This suggests that the form of impulsivity assayed by Ultimatum Game is a general feature of addiction, representing an important risk factor, a long-term consequence, or both. To our knowledge, this is the first investigation of how heroin addiction modulates responder behavior in the Ultimatum Game, extending our understanding of the relative importance and concerns that drug addicts attach to self-interest, emotion, and social norms in their social behavior. Future efforts should clarify the underlying mechanisms of the distinct social decision-making process associated with heroin addiction. Such studies should help restore normative and appropriate social interaction in heroin addicts, aid their re-adaption into normal social life, and reduce drug addiction-related antisocial behavior and crime. One limitation of the present study was the lack of objective measurements of the subjects’ emotional reactions during the experiment. However, such extra pressure or interference caused by these measurements may affect the subjects’ performance in an unexpected way. Personality traits regarding affective temperament in heroin addicts were also not assessed in the present study. Thus, the role of personality in this particular social decisionmaking process cannot be determined. Depression score should have been measured, because it may influence their responses in UG. In summary, we have found that abstinent heroin addicts had significantly different rejection rates of most unfair offers in the Ultimatum Game under the different offer-size conditions. Our data showed that economic decision-making related to attentional/cognitive and non-planning impulsivity under the lower offer-size conditions as an important feature in subjects with heroin dependence. Future investigations of the underlying neural mechanisms of this choice behavior may prove illuminating for the development of therapeutic interventions for heroin addiction. References [1] J. Cousijn, R.W. Wiers, K.R. Ridderinkhof, W. van den Brink, D.J. Veltman, L.J. Porrino, A.E. Goudriaan, Individual differences in decision making and reward processing predict changes in cannabis use: a prospective functional magnetic resonance imaging study, Addict. Biol. 18 (2012) 1013–1023. [2] M.P. Paulus, S.F. Tapert, M.A. Schuckit, Neural activation patterns of methamphetamine-dependent subjects during decision making predict relapse, Arch. Gen. Psychiatry 62 (2005) 761–768. [3] G.F. Koob, N.D. Volkow, Neurocircuitry of addiction, Neuropsychopharmacology 35 (2010) 217–238. [4] J. Monterosso, P. Piray, S. Luo, Neuroeconomics and the study of addiction, Biol. Psychiatry 72 (2012) 107–112. [5] M. Ernst, M.P. Paulus, Neurobiology of decision making: a selective review from a neurocognitive and clinical perspective, Biol. Psychiatry 58 (2005) 597–604. [6] M.P. Paulus, Neurobiology of decision-making: quo vadis? Brain Res. Cogn. Brain Res. 23 (2005) 2–10. [7] L.J. Maier, M.D. Wunderli, M. Vonmoos, A.T. Rommelt, M.R. Baumgartner, E. Seifritz, M.P. Schaub, B.B. Quednow, Pharmacological cognitive enhancement in healthy individuals: a compensation for cognitive deficits or a question of personality? PLoS One 10 (2015) e0129805.
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Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
Altered economic decision-making in abstinent heroin addicts: Evidence from the ultimatum game夽 Yu Hou a , Liyan Zhao b,∗ , Qi Yao a , Lixiang Ding a a b
Beijing Shijitan Hospital, the 9th Clinical Medical College of Peking University, Beijing 100038, China Peking University Health Science Center, Beijing 100191, China
h i g h l i g h t s • This is the first investigation of how heroin addiction modulates responder behavior in the UG. • Responder behavior in the UG was differentially modulated by heroin addiction under different stake-level conditions. • Heroin addicts had higher scores on BIS attention /cognitive impulsivity and non-planning impulsivity, but not in motor impulsivity.
a r t i c l e
i n f o
Article history: Received 13 January 2016 Received in revised form 18 May 2016 Accepted 1 June 2016 Available online 2 June 2016 Keywords: Economic decision-making Ultimatum game Heroin addiction Emotion Self-interest Impulsivity
a b s t r a c t Background: The development and persistence of drug addiction has been suggested to involve decisionmaking deficits. The Ultimatum Game is a widely used economic decision-making paradigm that illustrates the tension between financial self-interest and fairness motives. The behavior of responders in the Ultimatum Game has been associated with emotional reactions and cognitive control abilities, both of which are dysregulated in drug addicts. In this study, we investigated whether this economic decision-making process that involves considerations of social norms is affected by heroin addiction. Methods: Heroin addicts (n = 17) and demographically matched healthy control subjects (n = 18) were recruited to play the part of responders in the Ultimatum Game, during which they decided to accept or reject the monetary offers proposed by strangers. The offers were manipulated by varying the stake sizes and fairness scales. The rejection rates of all of the offer categories, response times, fairness judgments, and impulsivity were compared between heroin addicts and healthy controls. Results: Compared with healthy subjects, the rejection rates of most unfair offers in the Ultimatum Game were significantly higher under low-offer-size conditions among heroin addicts. In contrast, the most unfair offers were more likely to be accepted by heroin addicts in the high-offer-size condition than by healthy subjects. The ratings of unfairness were equal in both conditions although the rejection rates were different. Heroin addicts had higher scores on BIS attentional/cognitive impulsivity and non-planning impulsivity, but not in motor impulsivity. Rejection rates to most unfair offers under lowoffer-size conditions significantly correlated with score on BIS non-planning impulsivity and total score of impulsivity. Conclusions: Heroin addicts differentially responded under different stake-level conditions in the Ultimatum Game, with emotional impulses in low-offer-size conditions and selfish motives in the face of high monetary reward. These findings indicate that Ultimatum Game may be associated with heroin addiction and provide a productive new target for enhancing treatment for heroin addiction. © 2016 Published by Elsevier Ireland Ltd.
1. Introduction 夽 This work was supported in part by the Qingmiao Program (no. QML20150702) and the Natural Science Foundation of China (no. 31100809 and 81202123). The authors declare that they do not have any conflicts of interest related to the data presented in this manuscript. ∗ Corresponding author at: Peking University, 38, Xue Yuan Road, Beijing 100191, China. E-mail address: [email protected] (L. Zhao). http://dx.doi.org/10.1016/j.neulet.2016.06.002 0304-3940/© 2016 Published by Elsevier Ireland Ltd.
Decision-making deficits are thought to play an important role in the development and persistence of drug addiction [1–3]. Individual differences in decision-making abilities, therefore, may constitute an important predictor of the course of drug addiction [4]. Decision-making is a complex, multifaceted process. During decision making, our preference is often based on differences in
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Table 1 Characteristics of participants. Characteristic
Heroin addicts
Healthy controls
t
p
Age (years) Education (years) Number of cigarettes per day Years of smoking Income per month (Yuan, RMB) Gender (male/female) Average years of heroin abuse Average amount of heroin use per day (g) Average months of heroin abstinence
34.57 ± 4.76 8.39 ± 2.76 38.26 ± 13.37 17.78 ± 4.21 1996.67 ± 604.88 10/7 10.26 ± 3.52 0.75 ± 0.40 6.41 ± 3.98
35.82 ± 7.53 8.14 ± 1.96 35.91 ± 17.19 17.18 ± 5.69 2147.06 ± 798.53 9/9
−0.67 0.36 0.66 0.4 0.76
0.51 0.72 0.51 0.16 0.46 0.67
expected losses or gains, the capacity to retrieve this information from memory, and the capacity to maintain and manipulate the information “online” (working memory) [5,6]. However, the decision-making process is not simply a cost-benefit analysis. Because we live in complex social environments, decision-making often takes place in the form of social interaction and is influenced by their social cognitive abilities. To date Social decision-making has not been investigated in an experimental setting in heroin users. Socio-cognitive abilities are known to affect the course of dependence and treatment success in addicts [7,8], and thus understanding how heroin addiction may be associated with maladaptive social interaction is fundamentally important. The Ultimatum Game is a widely used laboratory model of economic decisionmaking that is the conflict between accepting unfair treatment and foregoing financial gain. Economic decision-making has been applied to the study of addiction, and it may have the potential to generate breakthrough research in addiction science [4]. Evidence showed that both recreational cocaine users and dependent cocaine users distributed money in a more self-serving manner than control in Distribution Game [8]. Any of the irrationalities that are prominent in economic decision-making are plausible candidates for playing a role in the development and maintenance of addiction. The Ultimatum Game is often played in economic experiments to illustrate the tension between economic self-interest and reciprocity and equity motives [9]. The Ultimatum Game may represent a source of systematic irrationality that can be linked to addiction. Social interaction often involves emotional reactions and selfish motives. However, for evolutionary benefits, humans across many cultures have established and enforced social norms that constitute human sociality with the unique capacity to stably maintain large-scale cooperation [10–14]. Social norms are expected to exert a restraining force over self-interest impulses when conflicts occur. Fairness norms play a crucial role in social life and have been studied using the Ultimatum Game [15], in which one player (the proposer) makes a proposition about how to split a given amount of money with another player (the responder). If the responder decides to accept the offer, then both players are paid accordingly. If the responder rejects the offer, then neither player gets paid. Frequently, most responders tend to reject offers less than 20–30% of the total stake [16,17], suggesting that people are willing to forgo self-interest and maintain fairness. The rejection of unfair offers in the Ultimatum Game has been related to negative emotional reactions [18] and the appropriate cognitive control of implementing fairness motives [9,19]. Increasing evidence has shown that drug addiction is associated with a variety of psychopathological disturbances, including emotional dysregulation and cognitive dysfunction [20–22]. Specifically, heroin addicts have a tendency to rate unpleasant affective stimuli more negatively [23–26], but this has not been consistent across studies [27]. Additionally, personality traits of heroin addicts may impact their social behavior [28,29], such as impulsivity (poor self-control), hostility, and irritability. Their behaviors tend to be easily influenced by subjective feelings, and they make
little consideration of social rules [30,31]. Moreover, neuroimaging studies have implicated some overlapping neural structures between responder behavior in the Ultimatum Game and heroin addiction, including the amygdala, insula, anterior cingulate cortex, medial prefrontal cortex, and dorsal lateral prefrontal cortex [3,9,32–35]. Abnormalities in these brain regions may lead heroinaddicted subjects to respond differently in the Ultimatum Game. Altogether, heroin addiction may have some modulatory effects on Ultimatum Game responder behavior. To investigate this possibility, we conducted a study in which heroin addicts acted as responders in the Ultimatum Game. We independently manipulated social reward (fairness) and basic monetary reward by varying both the stake size and offer amount across trials. 2. Materials and methods 2.1. Participants Prior to enrollment, participants underwent thorough physical and psychiatric evaluations, including a medical history interview. Participants met DSM-IV criteria for heroin dependence. Exclusion criteria included current use of any medications, current DSM-IV diagnosis of any affective, or psychotic disorder, and dependence on any substance other than heroin and nicotine (assessed by urine test and DSM-IV diagnosis). Seventeen heroin-dependent subjects (10 males, 7 females) were recruited from the Addiction Treatment Center, Shenzhen, China. These subjects were abstinent from heroin for at least 1 month, documented by negative weekly supervised urine tests. In addition, 18 sex-, age-, education-, smoking- and economic status-matched healthy control participants (9 males, 9 females) with no DSM-IV Axis I disorders were recruited by advertisement from the local communities. Exclusion criteria for the controls were psychiatric or neurological disorders, history of substance abuse, and current use of any medications. BDI was used to assess anxiety and depression. The demographics are summarized in Table 1. The study was conducted according to human research guidelines and was approved by the Peking University Research Ethics Board. After a full description of the study procedure was provided to the participants, written informed consent was obtained before testing. The subjects were monetarily compensated for participating in the study. 2.2. Task The subjects acted as responders in a series of 24 trials in the Ultimatum Game. In each trial, the offer condition was indicated by a 4 s presentation of the picture of a person making an ultimatum offer along with the person’s name. The participant then saw the offer for 4 s. The subjects could then accept or reject the offer by pressing a corresponding button, indefinite. If the subject rejected the offer, then both players received no payoff in this trial. If the subject accepted the offer, then the payoffs implied by the offer
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Fig. 1. (A) Schematic of the trial design. In each trial, the offer condition included 4 s presentation of a picture of a person making an ultimatum with the person’s name. The participant then saw the offer for 4 s. The subjects then made a decision, indefinite. The subjects could accept or reject the offer by pressing the appropriate button. The outcome was then presented for 3 s. In this example, the offer was rejected. (B) Offer categories. The offers fell into one of six “fairness” categories: 45% stake from high offer size (fair + high), 45% stake from low offer size (fair + low), 30% stake from high offer size (unfair + high), 30% stake from low offer size (unfair + low), 15% stake from high offer size (most unfair + high), and 15% stake from low offer size (most unfair + low).
were implemented. Finally, the participant saw the outcome based on his/her response for 3 s (see Fig. 1Afor a schematic of the trial design). The intertrial interval included the presentation of a fixation cross for 4–6 s. All of the subjects received the same 24 offers in a fixed random order from 24 different proposers. The subjects were required to answer a series of test questions successfully after reading the instructions to verify comprehension. Before beginning the test, the subjects were instructed that the offers were real, and the subjects’ responses would not affect subsequent offers.
study were instructed about the rules of the Ultimatum Game and asked to make a subjective judgment of each offer amount as fair or unfair. The 50% and 40% offers were judged to be fair in 20 of 20 cases and 19 of 20 cases, respectively. The 30%, 20%, and 10% offers were judged to be fair in 7 of 20 cases, 3 of 20 cases, and 0 of 20 cases, respectively. We independently manipulated social reward (fairness) and basic monetary reward by varying both the stake size and offer amount across trials (Fig. 1B). 2.4. Measurement of response time
2.3. Offers Offers fell into one of six “fairness” categories: 45% stake from high offer size (fair + high, four offers), 45% stake from low offer size (fair + low, four offers), 30% stake from high offer size (unfair + high, four offers), 30% stake from low offer size (unfair + low, four offers), 15% stake from high offer size (most unfair + high, four offers), and 15% stake from low offer size (most unfair + low, four offers). The justification for this was based on our pilot study. Twenty neurologically normal adults who did not participate in the present
Response time was measured as the time interval that began with the presentation of the offer and ended when the subject pressed the response button. 2.5. Fairness judgments The fairness assessments occurred after the Ultimatum Game ended. Responders were shown a list of all of the offers and asked
Control
A 100
*
Heroin
B 100 80 Rejection rates (%)
Rejection rates (%)
80 60 40
*
60 40 20
20
0
0 45% 30% 15% % of stake offered, low offers
45% 30% 15% % of stake offered, high offers
Fig. 2. Behavioral responses in the different offer conditions. (A) Rejection rates in the low-offer-size condition trials. Heroin addicts exhibited a much higher rejection rate of most unfair offers than the control group. (B) Rejection rates in high-offer-size condition trials. Heroin addicts exhibited a significantly lower rejection rate of most unfair offers than the control group. *p < 0.05. The data are expressed as mean ± SEM.
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Control
Heroin
4000
4000
Response time (ms)
B 5000
Response time (ms)
A 5000
3000 2000 1000
151
3000 2000 1000
0
0 45% 30% 15% % of stake off ered, low off ers
45% 30% 15% % of stake off ered, high off ers
Fairness (1 = very unfair; 7 = very fair)
Fig. 3. Response times for fair and unfair offers in different offer conditions. (A) Response times in the low-offer-size condition trials. (B) Response times in the high-offer-size condition trials. When the subjects faced a fair offer or most unfair offer, they quickly accepted or rejected it, and no response-time difference was found between groups (all p > 0.05). In contrast, the subjects needed a much longer time to accept or reject an unfair offer. The data are expressed as mean ± SEM.
8
45% 30% 15%
7
rejection rates, response times, and fairness judgments. Significance levels were set at p < 0.05.
6
3. Results
5
3.1. Rejection rates in the different offer conditions
4
Repeated-measure ANOVAS, with group as the between-subject factor and fairness and offer size as the within-subject factors, revealed significant main effects of fairness (F2,66 = 322.2, p < 0.001) and offer size (F1,33 = 36.13, p < 0.001) and significant group × fairness × offer size (F2,66 = 12.34, p < 0.001), group × offer size (F1,33 = 17.6, p < 0.001), and fairness × offer size (F2,66 = 18.91, p < 0.001) interactions. Follow-up t-tests showed that heroin addicts had significantly increased rejection rates to most unfair offers under low-offer-size conditions (t33 = 3.39, p = 0.002; Fig. 2A) but not to fair and unfair offers compared with healthy control subjects. In contrast, heroin addicts had significantly decreased rejection rates to most unfair offers under high-offer-size conditions (t33 = −2.31, p = 0.03; Fig. 2B). There was no significant correlation between time of abstinence/time of heroin abuse and reject rate. These results indicate that resistance to selfish temptations depends on the offer size in heroin addicts. They appear to be less able to resist selfish temptations to accept higher offers, although they still view them as very unfair.
3 2 1 0 Low High Heroin addicts
Low High Healthy control
Fig. 4. Perceived unfairness for different offers in the low- and high-offer-size conditions. Subjects in the two groups judged the offer of 45%, 30% and 15% as rather fair, unfair and most unfair respectively when partner made these offers. However, there was no significant main effect of group and offer size in different offer stakes (all p > 0.05). The data are expressed as mean ± SEM.
to report the extent to which they perceived an offer as fair or unfair on a 7-point scale (1 = very unfair, 7 = very fair). 2.6. Measurement of impulsivity The subjects were administered the Chinese version of the Barratt Impulsivity Scale-11 (BIS-11) [36]: a validated 30-item questionnaire that measures different dimensions of impulsivity: (1) attentional/cognitive impulsivity, measuring tolerance for cognitive complexity and persistence; (2) motor impulsivity were used as a trait measure of motor impulsivity (“acting without thinking”) measuring the tendency to act on the spur of the moment; and (3) non-planning impulsivity, measuring the lack of sense of the future. A higher total score indicated a higher level of impulsivity. 2.7. Data analysis Demographic characteristics and impulsivity in the two groups were compared using t-tests. Rejection rates (% offers rejected) were calculated for each subject at each level of fairness. Repeatedmeasures analyses of variance (ANOVAs) were used to analyze
3.2. Response times for fair and unfair offers in different offer conditions To investigate whether long-term heroin use influences the impulse to reject offers that are perceived as unfair, we measured response times for different offers. Repeated-measure ANOVAs, with a group as the between-subject factor and fairness and offer size as the within-subject factors, revealed a significant main effect of fairness (F2,66 = 14.14, p < 0.001; Fig. 3) but not group (F1,33 = 0.11, p = 0.75; Fig. 3) or offer size (F1,33 = 1, p = 0.32; Fig. 3). The post hoc tests indicated that both heroin addicts and healthy control accepted or rejected it more quickly, if they faced a fair offer or most unfair offer, In contrast, the subjects needed a longer time to accept or reject an unfair offer, suggesting that a conflict existed between self-interest and fairness motives with unfair offers that caused an increase in response times (fair offer vs most unfair offer, t68 = −0.67, p = 0.51; fair offer vs unfair offer, t68 = −0.27, p = 0.04; most unfair offer vs unfair offer, t68 = −1.39, p = 0.17; Fig. 3). There
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Healthy control
80
Heroin addicts *
70 Scores of BIS
60 50 40 *
30 *
20 10 0
Attentional / cognitive
Motor
Non-planning
Total
Fig. 5. Impulsivity scores. Heroin addicts had higher scores on BIS attentional/cognitive impulsivity, non-planning impulsivity and total score. No significant difference in motor impulsivity was found between groups. *p < 0.05. The data are expressed as mean ± SEM.
was no significant correlation between time of abstinence/time of heroin abuse and reject rate. 3.3. Perceived unfairness for different offers Subjects in the two groups judged the offer of 45%, 30% and the lowest offer of 15% as rather fair, unfair and most unfair when partner made these offers respectively (Fig. 4). Repeated-measures ANOVAs, with group as the between-subject factor and offer size as the within-subject factor, revealed no significant main effects of group (F1,33 = 1.81, p = 0.19 for 45% offer; F1,33 = 1.1, p = 0.3 for 30% offer; F1,33 = 0.29, p = 0.59 for 15% offer; Fig. 4) or offer size (F1,33 = 3.44, p = 0.07 for 45% offer; F1,33 = 0.4, p = 0.53 for 30% offer; F1,33 = 0.2, p = 0.66 for 15% offer; Fig. 4). Thus, although the rejection rates for the most unfair offers were significantly different between groups, the subjects’ fairness judgments were not influenced by heroin addiction. 3.4. Impulsivity scores Impulsivity was also assessed using a personality questionnaire. Heroin addicts had higher scores on BIS attentional/cognitive impulsivity (t33 = 2.98, p = 0.005; Fig. 5) and BIS non-planning impulsivity (t33 = 5.06, p < 0.001; Fig. 5). No significant difference in motor impulsivity was found between groups (t33 = 1.83, p = 0.08; Fig. 5). Rejection rates to most unfair offers under low-offer-size conditions significantly correlated with a score on BIS non-planning impulsivity (r = 0.36, p = 0.03) and total score of impulsivity (r = 0.46, p = 0.01). There was no other significant correlation. 4. Discussion Compared with healthy control subjects, the rejection rates of most unfair offers among heroin addicts in the Ultimatum Game significantly increased under low-offer-size conditions but decreased as the offer size became higher. Heroin addicts had higher scores on BIS attentional/cognitive impulsivity and nonplanning impulsivity, but not in motor impulsivity. Rejection rates to most unfair offers under low-offer-size conditions significantly correlated with a score on BIS non-planning impulsivity and total score of impulsivity indicating that the differing choices of the two
groups may associated with the differences in attentional/cognitive impulsivity and non-planning impulsivity. Social norms, emotional reactions, and a lack of control (impulsivity) have been attributed to the rejection of unfair offers in the Ultimatum Game. Increasing evidence indicates that unfair offers can trigger a strong negative emotional reaction in the responders that motivates them toward a rejection response [18]. The rejection of unfair offers has been associated with physiological responses that represent emotional arousal, such as higher skin conductance [37] and decelerated heart rate [38]. Moreover, previous studies have indicated that the expression of negative emotions significantly impacts responders’ decisions in the Ultimatum Game [39]. Attempts to regulate the subjectively evoked negative emotions may also affect Ultimatum Game responder behavior [40,41]. Monetary offers in the Ultimatum Game have a certain degree of intrinsic subjective value that derives from financial self-interest and the appreciation of social norms. A human imaging study showed that fair offers could lead to higher ratings of happiness and increased activity in reward-related neural circuits compared with unfair offers [42,43]. In responders in the Ultimatum Game, accepting these unfair offers would only benefit them financially, whereas rejecting them could convey their aversive feelings and maintain the social norm of fairness by punishing inequity, although at the cost of sacrificing self-interest. People with well-established cognitive control abilities are expected to settle conflicts in the decision-making process and as a result consistently behave in a normatively appropriate way. In the present study, heroin addicts appeared to be unable to commit to their responses to unfairness under different conditions. First, the results showed that when subjects with heroin addiction faced most unfair offers under low-offer-size conditions, they were more prone to reject the offer compared with healthy subjects. This could indicate that the available economic gains were too small for them to create strong conflicts with the intention to restore the social norm of fairness and allowed subjective emotions to drive the response more intensely. Compared with healthy subjects, heroin users have been shown to exhibit heightened negative emotional responses in the face of unpleasant stimuli [23–25]. Heroin addicts have been frequently characterized by strong aggressiveness, high irritability and anger, fewer abasement needs, and poor self-control. In addition, their actions are more easily influenced by subjective feelings, with minor concerns about group rules [28–31,44,45]. From this perspective, negative emotions might play a dominant role in the response to unfair offers in heroin addicts under low-offer-size conditions. Being offered too little money from a low total stake might be perceived as more insulting and evoke stronger negative emotions, thus motivating heroin addicts to behave in a more aggressive manner. As a result, the rejection rate of most unfair offers in the heroin addiction group was significantly higher than in the healthy control group. However, because the current study was not designed to obtain a direct measure of subjects’ subjectively experienced anger during performance of the Ultimatum Game and standards of reciprocity and altruism, our conclusions about the specific role of emotion in Ultimatum Game responding are inferred based on the convergent psychological and neurophysiological data regarding the Ultimatum Game. Collection of direct, systematic measurements of emotional responses is an important next step in this line of work. In contrast, the higher offer size markedly switched heroin addicts’ responses to a higher acceptance rate when faced with the most unfair offers. Notably, in both groups, fairness judgments about the most unfair offers were not different under either offer size condition, indicating that concerns about social norms are less likely to have competitive value in the higher offer condition. However, as the monetary value increased, social rules were even less able to restrain self-interested impulses. Meanwhile, self-
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interested impulses elicited more tension with aversive emotional reactions. In heroin addicts, a larger monetary gain was particularly more important because of its more favorable association with drug seeking, which became a most salient motivation for their behavior. Consequently, subjects with heroin addiction were more resistant to expending the cost of economic interest and became more tolerant of inequity. Impairments in executive control in heroinaddicted patients may override of self-interested impulses upon social norms and emotional reactions. A higher degree of impulsivity on the BIS-11 in heroin addicts is consistent with other studies, showing that heroin addicts are more impulsive than healthy controls [46]. We found that increased non-planning impulsivity and total score of impulsivity positively correlated with rejection rates to most unfair offers under lowoffer-size conditions. This suggests that the form of impulsivity assayed by Ultimatum Game is a general feature of addiction, representing an important risk factor, a long-term consequence, or both. To our knowledge, this is the first investigation of how heroin addiction modulates responder behavior in the Ultimatum Game, extending our understanding of the relative importance and concerns that drug addicts attach to self-interest, emotion, and social norms in their social behavior. Future efforts should clarify the underlying mechanisms of the distinct social decision-making process associated with heroin addiction. Such studies should help restore normative and appropriate social interaction in heroin addicts, aid their re-adaption into normal social life, and reduce drug addiction-related antisocial behavior and crime. One limitation of the present study was the lack of objective measurements of the subjects’ emotional reactions during the experiment. However, such extra pressure or interference caused by these measurements may affect the subjects’ performance in an unexpected way. Personality traits regarding affective temperament in heroin addicts were also not assessed in the present study. Thus, the role of personality in this particular social decisionmaking process cannot be determined. Depression score should have been measured, because it may influence their responses in UG. In summary, we have found that abstinent heroin addicts had significantly different rejection rates of most unfair offers in the Ultimatum Game under the different offer-size conditions. Our data showed that economic decision-making related to attentional/cognitive and non-planning impulsivity under the lower offer-size conditions as an important feature in subjects with heroin dependence. Future investigations of the underlying neural mechanisms of this choice behavior may prove illuminating for the development of therapeutic interventions for heroin addiction. References [1] J. Cousijn, R.W. Wiers, K.R. Ridderinkhof, W. van den Brink, D.J. Veltman, L.J. Porrino, A.E. Goudriaan, Individual differences in decision making and reward processing predict changes in cannabis use: a prospective functional magnetic resonance imaging study, Addict. Biol. 18 (2012) 1013–1023. [2] M.P. Paulus, S.F. Tapert, M.A. Schuckit, Neural activation patterns of methamphetamine-dependent subjects during decision making predict relapse, Arch. Gen. Psychiatry 62 (2005) 761–768. [3] G.F. Koob, N.D. Volkow, Neurocircuitry of addiction, Neuropsychopharmacology 35 (2010) 217–238. [4] J. Monterosso, P. Piray, S. Luo, Neuroeconomics and the study of addiction, Biol. Psychiatry 72 (2012) 107–112. [5] M. Ernst, M.P. Paulus, Neurobiology of decision making: a selective review from a neurocognitive and clinical perspective, Biol. Psychiatry 58 (2005) 597–604. [6] M.P. Paulus, Neurobiology of decision-making: quo vadis? Brain Res. Cogn. Brain Res. 23 (2005) 2–10. [7] L.J. Maier, M.D. Wunderli, M. Vonmoos, A.T. Rommelt, M.R. Baumgartner, E. Seifritz, M.P. Schaub, B.B. Quednow, Pharmacological cognitive enhancement in healthy individuals: a compensation for cognitive deficits or a question of personality? PLoS One 10 (2015) e0129805.
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