The Rise of the Ego

Chapter 25

The Rise of the Ego: Social Cognition and Interaction in Cocaine Users Boris B. Quednow Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland; Neuroscience Centre Zurich, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland

Abbreviations ADHD  Attention deficit/hyperactivity disorder CATS-A  Comprehensive affect testing system CNS  Central nervous system DSM-IV  Diagnostic and Statistical Manual of Mental Disorders Version IV Text Revision fMRI  Functional magnetic resonance imaging MACH–IV  Machiavelli test MASC  Movie for the assessment of social cognition MDMA  3,4-Methylenedioxy-methamphetamine MET  Multifaceted empathy test MPFC  Medial prefrontal cortex MRI  magnetic resonance imaging OFC  Orbitofrontal cortex PET  Positron emission tomography PPI  Prepulse inhibition RMET  Reading the mind in the eyes test SCID-II  Structured Clinical Interview for Axis-II disorders, Diagnostic and Statistical Manual of Mental Disorders Version IV–Text Revision SEM  Standard error of means SNQ  Social Network Questionnaire SNSF  Swiss National Science Foundation TCI  Temperament and character inventory ToM  Theory-of-Mind ZuCo2St  Zurich Cocaine Cognition Study

INTRODUCTION In his famous poem Cocain, the German physician and writer Gottfried Benn attributed to the substance “Den Ich-Zerfall, den süssen, tiefersehnten, den gibst Du mir” (“The ego decay, sweet, deeply desired, that is what you give to me”, translated by Boris B. Quednow) without explaining to us whether he specifically alludes to the acute, postacute, or chronic effects of cocaine (Benn, 1917, p. 76). In fact, most users probably take cocaine in order to elevate their selfcontrol and self-confidence rather than to destroy their egos (Boys, Marsden, & Strang, 2001; Hartwell, Back, McRae-Clark, Shaftman, & Brady, 2012). Accordingly, Spotts and Shontz (1982) described

vividly that “cocaine produces exhilaration and euphoria, expands and enhances the distinctiveness of the ego, and produces feelings of supreme self-confidence and a remarkable sense of mastery over fate and the environment (p. 963).” Therefore, Benn possibly may have referred to the postacute and chronic emotional effects of the drug since its dark side does not surface until the acute effects slowly fade out. After the acute euphoria, many users experience a “crash”, in which “visual-motor functions become impaired, ego functions fail, emotionality careens out of control, and reality testing collapses” (Spotts & Shontz, 1984, p. 138). If cocaine is used chronically, affective symptoms, such as depression, anxiety, or even suicidality, occur frequently (Rounsaville, 2004; Rounsaville et al., 1991; Roy, 2001). Moreover, cocaine dependence is often accompanied by cluster B personality disorders, e.g., from the antisocial and borderline type (Fernandez-Montalvo & Lorea, 2007). After long-term chronic use, frequent consumption in a short time period, or after high doses, stimulant-induced psychotic symptoms can arise, indicating the maximal impairment of ego functions (Brady, Lydiard, Malcolm, & Ballenger, 1991). Such stimulant-induced psychoses are often associated with delusions of parasitosis (“cocaine bugs”), a symptom that only rarely appears in endogenous psychoses such as schizophrenia (Brewer, Meves, Bostwick, Hamacher, & Pittelkow, 2008; Mitchell & Vierkant, 1991). In contrast to schizophrenia, cocaine-induced psychotic symptoms usually fully recover after a period of abstinence (Elliott, Mahmood, & Smalligan, 2012; Elpern, 1988). Many psychiatrists and psychotherapists in practice observe that chronic cocaine users show changes of their personalities during the course of addiction. According to their clinical phenomenology, cocaine users become more and more egocentric and emotionally blunted as their drug use proceeds. Cocaine dependent patients show a 22-fold increase of risk for an antisocial personality disorder (Rounsaville, 2004), and the previously existing view was that a personality disorder, which is inherently characterized by nonadherence to social norms, may be a strong predisposition for drug use in general. However, whether chronic drug use itself might also cause sustained antisocial behavior, was scarcely investigated to date. Interestingly, several neuroimaging studies with chronic cocaine users revealed marked changes in brain regions, which have been shown to be crucially involved

Neuropathology of Drug Addictions and Substance Misuse, Volume 2. http://dx.doi.org/10.1016/B978-0-12-800212-4.00025-X Copyright © 2016 Elsevier Inc. All rights reserved.

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in social cognition and interaction (Adolphs, 2009; Lieberman, 2007): with positron emission tomography and magnetic resonance imaging it was shown that the medial prefrontal cortex (MPFC), the orbitofrontal cortex (OFC), the anterior cingulate cortex, as well as temporal cortical areas, such as the insula and the temporal pole, display either structural (decreased gray matter density) or metabolic (glucose utilization or cerebral blood flow) alterations in chronic cocaine users (Bolla et al., 2004; Ersche et al., 2011; Franklin et al., 2002; Makris et al., 2008; Volkow et al., 1992). Although social problems are well-known in drug users, systematic and experimental investigations broadly characterizing and quantifying social cognition and interaction in cocaine users were lacking before we started the Zurich Cocaine Cognition study (ZuCo2St) in 2010. Because sociocognitive abilities, such as empathy and Theory-of-Mind (ToM), have been demonstrated to be important factors in the development, progress, and treatment of schizophrenia (Couture, Penn, & Roberts, 2006), it was analogously proposed that social cognition and interaction may also play an essential role in the origin and course of drug addiction (Homer et al., 2008; Volkow, Baler, & Goldstein, 2011). Accordingly, deficits in social cognition and behavior may increase social isolation, aggression, and depression likely preserving the vicious circle of drug use (Homer et al., 2008). Moreover, it has been suggested that repeated stimulant intake impacts the reward system of the brain by enhancing the value of the drug of abuse, while simultaneously reducing the sensitivity for the rewarding nature of social contacts (Volkow et al., 2011). Thus, drug-induced impairment of social reward may contribute to the decay of social relationships in addicted patients which in turn has negative consequences for the treatment success as well (Volkow et al., 2011). Correspondingly, it has been shown that higher social support predicted longer abstinence durations of severe alcohol-dependent patients (Mutschler et al., 2013).

THE ZURICH COCAINE COGNITION STUDY In order to comprehensively characterize social cognition and basal social interaction in recreational and dependent cocaine users for the first time, we developed and implemented the ZuCo2St, which was funded by the Swiss National Science Foundation (grants PP00P1-123516/1 and PP00P1-146326/1). With this longitudinal study we pursued two main goals. First, we intended to characterize several facets of sociocognitive abilities and social interactions of cocaine users under experimental conditions and second, we aimed to investigate whether potential alterations in social cognition and behavior are predispositions or consequences of cocaine use. We not only focused on dependent cocaine users but also investigated the much more frequent group of recreational users who, while they are not (yet) addicted, administer the drug regularly for personal pleasure or other instrumentalizations (Muller & Schumann, 2011). Given that the transition to dependence is not dichotomous but instead gradual, advancing from habitual to a more and more compulsive use (Haber, 2008), recreational cocaine use can be seen as an intermediate step towards addiction. Examining recreational users holds several further important advantages: (1) they are, as a group, less burdened by psychiatric comorbidities (Smith, Thirthalli, Abdallah, Murray, & Cottler,

2009), (2) they are less likely medicated with psychotropic drugs, and (3) they commonly display a reduced amount of polytoxic drug use. These advantages are essential for a study examining the effects of cocaine on cognition, given that polytoxic drug abuse and psychiatric comorbidities are major confounding factors in addiction research especially with dependent cocaine users (Degenhardt & Hall, 2012; Prinzleve et al., 2004). For the same reason, we aimed to focus on relatively pure cocaine users with sparse cosubstance use. This was accomplished by analyzing 6 cm hair samples (when possible), allowing an objective estimation of drug use during the past 6 months (Society of Hair Testing, 2004), thus, excluding polydrug users. Intake of any prescription drugs affecting the central nervous system was a further exclusion criterion. Finally, participants with an axis-I psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder, and a current depressive episode were excluded as well, as these disorders have a strong impact on several cognitive functions (Etkin, Gyurak, & O’Hara, 2013). Importantly, cocaine users with previous depressive episodes or a diagnosis of an attention deficit/ hyperactivity disorder (ADHD) were not excluded due to the high prevalence of these disorders in cocaine users (Perez de Los Cobos et al., 2011; Rounsaville, 2004). At baseline, we were able to assess 250 individuals (142 cocaine users, 108 stimulant-naive healthy controls) of whom about 100 users (70 regular recreational users and 30 dependent users) and 70 controls strictly matched for age, education, sex, and smoking status, were included in the final analyses. We had to exclude 46 participants because of polytoxic drug use (primarily high concentrations of 3,4-methylenedioxy-methamphetamine [MDMA] and other amphetamines in the hair samples), lack of cocaine in the hair samples, or psychiatric comorbidities (e.g., schizophrenia or bipolar disorder) revealed by the psychiatric interview at the test day. At the 1-year follow-up, 132 individuals participated, however, only 105 subjects (57 cocaine users, 48 controls) were suitable for inclusion in the longitudinal analysis as some users had changed their preferred substance (mostly from cocaine to MDMA and in one case to methylphenidate) or due to other exclusion criteria (e.g., stroke during the study interval, medication with psychotropic drugs, etc.). Due to missing data in the different tasks and questionnaires, the actual number of subjects in the experimental groups slightly varies across publications. In the following paragraphs, the main results of the ZuCo2St will be discussed.

BASAL COGNITIVE FUNCTIONS First of all, in the cross-sectional analysis (Vonmoos, Hulka, Preller, Jenni, Baumgartner, et al., 2013), we were able to confirm previously described broad cognitive impairments in dependent cocaine users (Jovanovski, Erb, & Zakzanis, 2005). The impairments were not specific and affected all investigated cognitive domains: attention, working memory, declarative memory, and executive functions. Importantly, regular recreational users already showed highly similar but somewhat weaker deficits compared with dependent users. In dependent users the deficits were most pronounced in the domain of working memory, whereas recreational users showed the strongest impairment in the domain of attention. However, in both groups, the executive functions were comparatively less strong affected. Notably, age of onset of cocaine use

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was a critical factor; specifically, individuals, who started cocaine consumption before the age of 18 showed more pronounced cognitive impairments than users with a later onset—even when the data were adjusted for cumulative lifetime consumption or age (Vonmoos, Hulka, Preller, Jenni, Baumgartner, et al., 2013). In fact, 12% of the recreational users and 30% of the dependent users displayed clinically relevant cognitive decline (>2 standard deviations [SD] from the mean of the controls). Beyond a cumulative lifetime dose of 500 g cocaine, the risk for cognitive impairment was strongly increased—50% showed subclinical (>1 SD) and 20% clinically relevant cognitive deficits—and was largely independent from the diagnosis of cocaine dependence. After a lifetime dose of 1 kg of cocaine these numbers further increased; here, 75% showed subclinical and 50% clinically relevant cognitive deficits. These dose–response relationships were further confirmed by strong product–moment correlations showing linear relationships for example between cognitive performance and the cumulative lifetime dose (see Figure 1), duration of use, maximum dose, and concentrations of cocaine and its metabolites in hair, initially indicating that these cognitive deficits might be drug-induced (Vonmoos, Hulka, Preller, Jenni, Baumgartner, et al., 2013). Worth noting is that the cognitive abnormalities of cocaine users cannot be explained by the presence of depressive symptoms or a comorbid ADHD, as shown by detailed analyses of subgroups. However, the combination of ADHD and cocaine consumption was considerably worse in terms of cognitive functions. A further extension of the ZuCo2St, in which we included patients with ADHD without cocaine consumption, confirmed that the detrimental effects of cocaine and ADHD on cognition might be summed up. Consequently, cocaine users with ADHD are much stronger cognitively impaired than cocaine users without

ADHD or ADHD patients without cocaine use (Wunderli et al., submitted). In our subsequent longitudinal data analysis (Vonmoos et al., 2014), we first observed that the change of hair cocaine concentrations during the 1-year study interval showed a lot of variation: one-third of the users (n = 19) displayed strongly increased cocaine levels (mean +297%), while a second third (n = 19) showed substantially decreased concentrations (−72%). Of these 19 decreasing users, eight did not show significant traces of cocaine in the hair at the follow-up and, thus, had been abstinent for at least 3 months. The last third (n = 19) had not changed their consumption pattern, as hair concentrations were largely similar both at baseline and follow-up. However, as hair analyses revealed, this group included rather moderate users showing much lower cocaine contamination in the hair compared with the users who had changed their consumption pattern after 1 year (Vonmoos et al., 2014). Remarkably, users who had substantially increased their cocaine consumption within the 1-year interval showed a further reduction of cognitive performance primarily in working memory. Contrarily, decreased cocaine use was associated with small but consistent cognitive improvements in all four domains. Remarkably, users who ceased taking cocaine seemed to recover completely, attaining cognitive performance comparable to that of the control group. Importantly, recovery of working memory was correlated with age of onset of cocaine use, as early-onset users showed only limited improvements (Vonmoos et al., 2014). We concluded that these longitudinal data suggest that cognitive impairment of cocaine users might partially be drug-induced but also reversible within 1 year, at least after moderate exposure and late onset of use. Consequently, the shown reversibility exposes that neurochemoplastic adaptations likely underlie cognitive alterations in stimulant users. These acquired neuroadaptations are considered as potentially modifiable in psychotherapeutical or pharmacological interventions, which is encouraging for the individuals affected.

COLOR VISION AND EARLY INFORMATION PROCESSING

FIGURE 1  Correlation of cocaine lifetime consumption with cognitive performance. The strong positive correlation (r = 0.50; p < 0.0001, n = 98) between the log-transformed cumulative lifetime consumption (ranging from 9g–40 kg) of cocaine and the cognitive performance as reflected by the z-scored Global Cognitive Index (GCI), indicates that cognition declines with more cocaine used. The GCI was calculated from 15 neuropsychological parameters standardized to the mean and standard deviation of an age, verbal intelligence quotient, and gender-matched control group (for details please see Vonmoos, Hulka, Preller, Jenni, Baumgartner, et al., 2013).

In addition to the changes in higher cognitive functions, our cocaine users also revealed alterations in sensory and early information processing. Recreational as well as dependent cocaine users suffered from strong alterations in color vision (Hulka, Wagner, Preller, Jenni, & Quednow, 2013) and displayed a characteristic increase of the prepulse inhibition (PPI) of the acoustic startle response (Preller et al., 2013), which is an established electrophysiological measure of sensorimotor gating (Quednow, 2008). Interestingly, both findings point towards chronic alterations in catecholaminergic neurotransmitter systems, which seem to constitute already in recreational users (Hulka, Wagner, et al., 2013; Preller et al., 2013). Specifically, 40–50% of all investigated cocaine users display a blue-yellow color vision impairment called tritanopia (Hulka, Wagner, et al., 2013), which is usually very rare in the normal population given the prevalence of about 0.002% (Simunovic, 2010). As dopamine is involved in the function of the blue cones in the retina, cocaine might not only alter dopamine neurotransmission in the brain but also retinal dopamine levels with respective consequences for color vision (Witkovsky, 2004). Alternatively, blue-yellow color vision deficits potentially mirror changes of the

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mesolimbic dopamine system that have been previously demonstrated in cocaine users, including downregulation of dopamine D2 receptors, dopamine synthesis, and storage, as well as blunted dopamine release and upregulated dopamine transporter densities, resulting in a chronic dopamine depletion syndrome (Trifilieff & Martinez, 2013). Given that color vision performance was strongly correlated with cognitive functions such as memory, color vision problems might indeed indicate drug-induced neuroplasticity within the brain (Hulka, Wagner, et al., 2013). We will now further investigate if such color vision deficits of cocaine users are in fact druginduced and maybe reversible and whether these impairments arise from retinal or central neuroadaptations. Furthermore, the alterations found in sensorimotor gating functions likely reflect changes of dopamine or noradrenaline neurotransmission in the brain of cocaine users (Preller et al., 2013). As PPI levels were positively correlated with the intensity of craving for cocaine, we proposed that the intensification of sensorimotor gating might be cocaine-induced as well. This assumption was recently confirmed by the analysis of our longitudinal data clearly showing that elevated PPI levels normalize when cocaine users strongly decrease their consumption, while a further increase in cocaine use does not further elevate PPI levels (publication in preparation).

SOCIAL COGNITION AND INTERACTION In the investigation of social functions of cocaine users we focused on three crucial aspects: (1) social cognition, i.e., the capability to recognize, understand, and feel the emotions and intentions of others; (2) social interaction, that we assessed by interactive money distribution tasks, by social gaze behavior as measured in an interactive eye-tracking paradigm, and by a marker of real-life social functioning, i.e., the number of all social contacts during the previous month; and (3) social attitudes that were explored by personality questionnaires.

Social Cognition In order to assess emotion perception and recognition we used several tasks in which visual and acoustic stimuli with emotional content were presented. In these tasks, the participants were requested to label the correct emotion shown in facial expressions (comprehensive affect testing system, CATS-A; Schaffer, Wisniewski, Dahdah, & Froming, 2009), in eye pairs (reading the mind in the eyes test; Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001), and in complex scenes of everyday life situations with emotional significance (multifaceted empathy test, MET; Dziobek et al., 2008), or featured in emotionally toned voices (CATS-A). Unexpectedly, our recreational and dependent cocaine users were completely able to recognize and name the right emotion when visual stimuli were presented involving eye pairs, faces, and complex scenes (Hulka, Preller, Vonmoos, B ­ roicher, & Quednow, 2013; Preller, Hulka, et al., 2014). This finding was in contrast to previous smaller studies suggesting deficits in emotional intelligence and fear recognition from faces in cocaine users (Fox, Bergquist, Casey, Hong, & Sinha, 2011; Kemmis, Hall, Kingston, & Morgan, 2007). However, the cocaine users in our study indeed had problems recognizing the correct emotion from



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FIGURE 2  Composite scores of the comprehensive affect testing system for controls and cocaine users. This diagram shows that cocaine users display problems in affect recognition from prosody (Hulka, Preller, et al., 2013). The bars represent correct responses in percent (means and standard error of means [SEM], t-tests: ***p < 0.001, (*)p < 0.06).

voices (prosody) and detecting matches and mismatches between emotional faces and voices when both were presented together (Hulka, Preller, et al., 2013) (see Figure 2). Specifically, the latter finding indicates that the integration of different pathways of emotional processing might be disturbed in cocaine users, thus possibly reflecting alterations in higher-level top-down mechanisms. As multisensory integration is essential for real-world social situations, insufficient processing of complex information from the environment likely impedes socially-adapted behavioral responses (Hulka, Preller, et al., 2013). Notably, longer duration and higher cumulative doses of cocaine use correlated with worse integration of visual an facial emotions, indicating that not only cognitive but also social problems of cocaine users might be partially drug-induced (Hulka, Preller, et al., 2013). In contrast to simple emotion recognition from picture material, both recreational and dependent users clearly displayed insufficient emotional empathy, i.e., they showed less emotional responsiveness to the photorealistic stimuli of the MET (Preller, Hulka, et al., 2014). This was true for both the explicit condition (“How much do you feel with this person?”) and the implicit condition (“How excited are you when looking at this picture?”). Importantly, the implicit emotional empathy score was correlated with cumulative lifetime cocaine dose (r = 0.23, p < 0.05) and with gram of cocaine used per week (r = 0.33, p < 0.01). Parallel to the basal cognitive functions (see above), comorbid ADHD had an additional impact on emotional empathy but did not explain the empathy impairment in general. Furthermore, emotional empathy deficits were most pronounced in early age-of-onset users (Preller, Hulka, et al., 2014). Current analyses of longitudinal data and preliminary results surprisingly suggest that emotional empathy covaries with changing cocaine use within 1 year. Increasing cocaine use results in a further decrease of emotional empathy, whereas decreased use leads to considerable improvements of emotional empathy (paper in preparation). This finding might be a sign of hope for affected persons as a prospect of improved emotional exchange with others might motivate some dependent users to remain in therapy and support treatment success.

Social Cognition in Cocaine Users Chapter | 25  261

Social Interaction Although maladaptive decision-making was proposed to be a core feature of cocaine addiction (Lucantonio, Stalnaker, Shaham, Niv, & Schoenbaum, 2012), decision-making in social contexts had not been examined in cocaine users prior to the ZuCo2St. Therefore, we investigated whether recreational and dependent cocaine users show alterations in two social interaction paradigms that were derived from the game theory of economics: the Distribution Game and the Dictator Game (Charness & Rabin, 2002; Engelmann & Strobel, 2004). The tasks were carried out consecutively and, thus, allowed the measurement of fairness preferences and altruism in the presence (Distribution Game) and the absence of potential efficiency preferences (Dictator Game). In both tasks, the participants chose one of different point distributions for another player and themselves, which were predefined in the Distribution Game (10 possible distributions) or freely selectable in the Dictator Game (a range of 0–40 points). In order to warrant anonymity of the drug users, which was necessary for ethical reasons and for professional secrecy, a cover story was used where participants were told that they would interact with another subject via an internet connection. Prior to the start of the test, participants were informed that the points won were afterward converted into real money. As assumed, the task-related decisions of recreational and dependent cocaine users were less prosocial compared with controls because cocaine users preferred higher monetary payoffs for themselves (Hulka et al., 2014) (see Figure 3). We observed that control subjects, who chose distributions classified as “unfair but efficient” in the Distribution Game often chose “fair” point allocations in the Dictator Game, whereas dependent cocaine users, who also chose distributions classified as “unfair but efficient” in the Distribution Game were more likely to distribute points in a “unfair” manner in the Dictator Game, respectively. Thus, controls preferred efficient distributions at the cost of fairness towards the other player but if efficiency did not matter (as in the Dictator Game) the same subjects still cared for fairness. This phenomenon was not observed in

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As we aimed to test mental and emotional perspective taking (ToM) in an ecologically valid way, we used the movie for the assessment of social cognition (MASC), a video-based multimodal (visual and auditory input) test of social cognition (Dziobek et al., 2006). In this paradigm, participants were asked to watch a 15-minute movie about an everyday-life situation (dinner with friends) and to answer questions regarding the video characters’ mental states. This required the understanding of emotions, thoughts and intentions, and concepts such as false belief, faux pas, metaphor, and sarcasm. Dependent but not recreational cocaine users committed more errors in this test indicating that worse mental perspective taking is primarily associated with more severe cocaine consumption (Preller, Hulka, et al., 2014). This was further supported by correlations between performance in the MASC and the duration of cocaine use (r = 0.25, p < 0.05), the cumulative lifetime cocaine dose used (r = 0.24, p < 0.05), and cocaine concentration in the hair (r = 0.20, p < 0.05). When we explored the type of errors committed by the cocaine users, it became visible that they often recognized the right emotion or intention, however, exaggerated the emotional significance of the scene. This might point to a cognitive compensation mechanism and further supports our hypothesis that chronic cocaine users develop disturbed integration of complex emotional information.

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FIGURE 3  Social decision-making in cocaine users and controls. Recreational and dependent cocaine users are less prosocial compared with controls in social money distribution games (Hulka et al., 2014) as shown by negative z-transformed composite payoff scores (mean and SEM) calculated from the Distribution Game and the Dictator Game (multiple regression analysis corrected for age, sex, years of education: *p < 0.05).

dependent cocaine users, as they seem to care primarily about efficiency and less about fairness. Furthermore, among recreational and dependent cocaine users the number of subjects choosing one of the “unfair but inefficient” distributions in the Distribution Game was substantially higher compared with controls, and, among these, almost everyone allocated points in an “unfair” manner in the Dictator Game (Hulka et al., 2014). Consequently, these findings suggest that cocaine users are less concerned about fairness in dyadic interactions when compared with controls. As we did not find correlations between fairness preferences and cocaine use parameters, we initially proposed that self-serving behavior per se might represent a predisposition of stimulant use (Hulka et al., 2014). However, our analyses of longitudinal data indicated that not only emotional empathy but also social preferences might be partially drug-induced as users who strongly decreased their cocaine intake also showed improved prosocial decisions in the money distribution games (paper in preparation). Again, this is an encouraging signal for cocaine-dependent patients that some of their social problems might be ameliorated when they significantly reduce or stop their consumption. We used the Social Network Questionnaire (SNQ) in order to assess the number of individual social contacts during the last month. The SNQ is based on the structured social contact circle interview designed to evaluate the size of an individual’s social network and its emotional support and strain (Linden, Lischka, Popien, & Golombek, 2007). In this interview, participants were required to write down the initials or nicknames of personal contacts in different spheres of life (e.g., household, family, work or apprenticeship, friends, neighbors, and other areas) so that a total number of social contacts (the social network size) could be calculated. We saw that cocaine users exhibited a smaller social network irrespective if they were recreational or dependent users (Preller, Hulka, et al., 2014). Moreover, cocaine users reported less emotional support from their social network and this tendency was more pronounced in dependent cocaine users. Remarkably, the network size decreased with an increase of the amount (r = 0.25, p < 0.01) and duration (r = 0.30, p < 0.01) of lifetime cocaine use, well reflecting the social destructivity of increasing cocaine use.

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Even so, the interrelations were relatively weak. A smaller social network size was also correlated with lower explicit emotional empathy in the MET (r = 0.18, p < 0.05), less mental perspective taking in the MASC (r = 0.16, p < 0.05), higher scores on the narcissistic personality disorder scale (r = −0.17, p < 0.05) of the Structured Clinical Interview for Axis-II Diagnostic and Statistical Manual of Mental Disorders Version IV TR disorders (SCID-II) questionnaire, and more depressive symptoms measured with the Beck Depression Inventory (r = −0.20, p < 0.05) (Preller, Hulka, et al., 2014). These correlations depict the ecologic validity of the social network size as assessed by the SNQ. Another central part of social interaction is social gaze contact, which, on the one hand, can be used by the gazing individual as a deictic cue to influence the attention of others. On the other hand, the gaze can be perceived by an observer as a hint to the attentional focus of the gazing person (Calder et al., 2002). Both aspects of social gaze can converge in a phenomenon called “joint attention,” representing an essential element of social interaction. It is established when a person follows the direction of another person’s gaze resulting in both having the same object in their attentional focus (Nummenmaa & Calder, 2009). Joint attention is considered to reflect our understanding of another

person’s point of view (Shepherd, 2010). It develops between 8–12 months of age (Corkum & Moore, 1998), and is predictive for later language learning and mental perspective taking (Brooks & Meltzoff, 2005; Charman et al., 2000). ­Moreover, impaired joint attention is one of the social symptoms of autism spectrum disorders (Charman, 2003). It has been shown that specifically self-initiated joint attention is perceived as pleasurable and associated with activation of reward-related brain areas in healthy volunteers (Schilbach et al., 2010). As it was proposed that changes in social reward processing might underlie alterations in social behavior in cocaine users (Volkow et al., 2011), we considered joint attention as a mechanism that might be potentially disturbed in a cocaine using population. In order to test joint attention in cocaine users and controls, we applied an interactive eye-tracking paradigm designed to capture the reciprocal and exchanging nature of social gaze contact in an online interaction with an anthropomorphic virtual character in real time (Preller, Herdener, et al., 2014). In the frame of the ZuCo2St, we initially tested the interactive joint attention task of Schilbach et al. (2010) in which valence and arousal ratings, error scores, reaction time, and pupil size during interaction with a virtual character were obtained. As shown before (Schilbach et al., 2010), controls perceived trial, in

FIGURE 4  Emotional responses to joint attention of cocaine users and controls. Cocaine users show blunted emotional reactions to social gaze contact as shown by the mean difference (error bars refer to SEM, *p < 0.05) in (A) valence ratings and (B) arousal ratings for joint versus nonjoint attention trials for controls (n = 60) and cocaine users (n = 3), and (C) mean pupil size difference between joint attention and nonjoint attention trials for controls (n = 60) and cocaine users (n = 72) (Preller, Herdener, et al., 2014).

Social Cognition in Cocaine Users Chapter | 25  263

which joint attention between the participant and the virtual avatar were established as more pleasurable and less arousing than trials in which no joint attention occurred (see Figure 4), pointing to the rewarding nature of joint attention. By contrast, cocaine users did not differentiate between joint and nonjoint attention conditions regarding valence, arousal, and also pupil response (Preller, Herdener, et al., 2014). We interpreted this pattern as a blunted emotional response to social gaze contact by cocaine users. In a subsequent imaging study, we investigated the neural responses to joint attention in a subsample of 16 cocaine users and 16 healthy controls. Initially, we were able to largely replicate the previous findings of Schilbach et al. (2010) in our control group showing that joint attention activates parts of the reward circuit, specifically the MPFC extending to the medial OFC and parts of the basal ganglia (Preller, Herdener, et al., 2014). In fact, cocaine users showed less activation of the medial OFC (mOFC) during joint attention supporting our assumption that social gaze contact might be less rewarding for them (see Figure 5). Importantly, we found that the social network size and the activation of the mOFC during joint attention were correlated indicating that a blunted ability to perceive social reward goes along with diminished social functioning. These results suggest that basal social interaction impairments may arise from blunted social reward processing pointing to the importance of reinstatement of social

reward in the treatment of probably all kinds of stimulant addiction (Preller, Herdener, et al., 2014). In the same sample, we also investigated social reward in the context of social feedback and compared social with nonsocial reward processing (Tobler et al., in revision). Robustly, cocaine users showed a diminished response to social reward in the medial OFC also in the context of social feedback. The activation in the mOFC partly overlapped with a reduced response to nonsocial reward. Thus, reward processing is disturbed in cocaine users, irrespective of reward type, suggesting a final common path. As the medial OFC has been proposed to be critically involved in the encoding and maintenance of reward value of reinforcers (Peters & Buchel, 2010; Sescousse, Redoute, & Dreher, 2010), and as it seems to be essential for all forms of emotional learning (Nashiro, Sakaki, Nga, & Mather, 2012), we propose that cocaine users suffer from a generalized impairment in value processing, also affecting their social life (Tobler et al., in revision).

Social Attitudes Socially relevant attitudes are critical components of each individual’s personality and might be either a predisposition for drug use or a potential subject of change in the course of drug addiction, or both.

FIGURE 5  Diminished neural responses to joint attention in cocaine users. The figure shows (A) between-group activation (controls > cocaine users for the self-initiated joint attention > self-initiated nonjoint attention contrast (yellow shades represent significant activations displayed at uncorrected p < 0.01)) and (B) corresponding contrast estimates in the medial OFC (mOFC), indicating that cocaine users activate this part of the reward system less than controls. Error bars refer to standard error of contrast estimates. The positive association (C) between social network size and mOFC activation for the self-initiated joint attention > self-initiated nonjoint attention contrast in controls (r = 0.49, p < 0.05, first eigenvariate), reflects that people with large social networks show more activation in the mOFC during joint attention (Preller, Herdener, et al., 2014).

264  PART | I Stimulants

Thus, we applied the Machiavelli test (MACH–IV) of Christie and Geis (1970), and the temperament and character inventory (TCI) of Cloninger, Pryzbeck, Svrakic, and Wetzel (1994) in order to assess different facets of social attitudes and socially relevant personality traits. As its name implies, the MACH–IV measures the personal level of Machiavellianism. We observed that both recreational and dependent cocaine users show significantly higher scores of Machiavellianism than controls, reflecting a stronger tendency towards interpersonal manipulation and pragmatic moral beliefs in cocaineaffine individuals (Quednow et al., submitted). In line with this, particularly dependent cocaine user achieved lower scores in the “cooperativeness” scale of the TCI (see Figure 6), which was mainly driven by the subscores “social acceptance versus intolerance” (C1) and “principles versus self-advantage” (C5). Correspondingly, the MACH–IV was strongly correlated with the TCI the “cooperativeness” scale (r = −0.55, p < 0.001, n = 161) and all of its subscales (r = −0.33 to −0.44, p < 0.001). Cocaine users also displayed reduced levels in the subscale “dependence on approval by others” (RD4) and higher values of subscale “disorderliness” (NS4) of the TCI (Vonmoos, Hulka, Preller, Jenni, Schulz, et al., 2013) suggesting that they are less interested in social feedback and less compliant to social norms (Cloninger et al., 1994). Not surprisingly, the MACH– IV scores were well correlated with both of these TCI subscales too (RD4: r = −0.26, p < 0.001; NS4: r = 0.30, p < 0.001). We were also able to replicate previous findings of elevated scores for antisocial and narcissistic personality disorders measured with the SCID–II questionnaire (Kranzler, Satel, & Apter, 1994; Preller, Hulka, et al., 2014; Rounsaville et al., 1991), which both correlated with the MACH–IV values as well (antisocial: r = 0.26, p < 0.001; narcissistic: r = 0.44, p < 0.001). Finally, the MACH–IV scores correlated with the payoff of player B in the distribution game (r = −0.29, p < 0.001, n = 161) and also - even though weakly - with payoff B in the Dictator Game (r = −0.15, p = 0.07), well reflecting the ecological

APPLICATIONS TO OTHER SUBSTANCE ADDICTIONS AND MISUSES Although the importance of social cognition and interaction for drug addiction is self-evident (Yacubian & Buchel, 2009), little is known about sociocognitive dysfunctions in substance addictions other than cocaine dependence. However, there is some evidence that alcohol dependent patients show robust impairments in social cognitive functions including problems in emotion recognition from faces and prosody, ToM deficits, and difficulties in humor processing (for review see: Donadon & Osorio, 2014; Uekermann & Daum, 2008). Moreover, we have recently demonstrated that individuals who take methylphenidate regularly for nonmedical neuroenhancement purposes show higher levels of novelty-­seeking (again, mainly explained by the TCI subscore “disorderliness”, which means less compliance with social norms) and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Additionally, the methylphenidate users also reported smaller social networks and exhibited less prosocial behavior in our social interaction tasks (Maier et al., 2015). However, the lack of correlations between drug intake and social cognition parameters suggests that these alterations might not be drug-induced, which stands in contrast to the findings in cocaine users (see above). Nevertheless, these findings point to the fact

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validity of the MACH–IV with regard to prosocial behavior. On the contrary, in the ZuCo2St the MACH–IV was not correlated with measures of empathy or mental perspective-taking, suggesting that such social attitudes are independent of social cognitive functions. In the ongoing longitudinal analysis of the ZuCo2St data, we will now evaluate if the Machiavellianistic tendencies of cocaine users change with decreased or increased cocaine consumption.

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FIGURE 6  Cooperativeness scale and according subscales of the Temperament and character inventory (TCI) in cocaine users and controls. Dependent users show lower social cooperativeness including less social tolerance and more pursuit of self-advantage in the TCI Cooperativeness scales of Cloninger et al. (1994). Data of 67 recreational and 28 dependent cocaine users as well as of 67 healthy controls are shown (means and SEM, Sidak post hoc tests versus controls: *p < 0.05, ***p < 0.001).

Social Cognition in Cocaine Users Chapter | 25  265

that stimulant users in general might display dysfunctional social cognition and interaction.

CONCLUSION As demonstrated above, cocaine users show specific impairments in social cognitive functions that are related to real-life social functioning. They have fewer social contacts, and deficits in emotional empathy and emotion recognition from voices, while particularly dependent users show difficulties in mental and emotional perspective-taking. Furthermore, cocaine users show less prosocial behavior in social interaction tasks and reveal more pronounced antisocial attitudes such as increased levels of Machiavellianism. Finally, cocaine users seem to be less rewarded by social interactions, which might explain why social consequences of drug use (e.g., imprisonment or familial problems) do not discourage cocaine-addicted individuals to quit using the drug (Preller, Herdener, et al., 2014). Although not investigated yet, it is likely that these disturbances of social perception and behavior also affect the therapeutic relationship between chronic stimulant user and psychiatrist or psychologist, and, thus, hamper the success of the addiction treatment. These interpersonal problems might partially explain the high relapse rates among cocaine dependent subjects shown in any kind of psychological or psychopharmacological treatment developed so far (Dutra et al., 2008; Mendelson & Mello, 1996). As social cognition and prosocial behavior changes with alterations in cocaine use across time, we assume that these impairments are at least partially drug-induced but, at the same time, potentially reversible due to neurochemoplastic adaptations of the brain. Therefore, new treatments of cocaine addiction might address these social problems more distinctively in order to improve the therapeutic relationship and hence the treatment success. The following approaches might be promising: 1. The training of empathy, mental perspective taking, and other social competences might be initiated before starting a psychotherapy (or applied in parallel), which focuses on behavioral changes with the ultimate goal of abstinence. However, such specialized trainings have yet to be developed. 2. As social and nonsocial dysfunctions were strongly correlated with the cumulative lifetime dose of cocaine, and seem to be, at least partially, reversible after prolonged abstinence, it is questionable if strategies favoring controlled use over drug abstinence are advantageous for patients in the long-term. However, controlled use is certainly a useful treatment goal to motivate addicted users starting treatment anyway. It is probable that the quality of social relationships worsens even with controlled but sustained cocaine use, bearing the risk for aggravated social problems while simultaneously decreasing the chance for abstinence in the long-term. 3.  The substitution approach, i.e., the treatment of cocaine addiction or thereof consequential cognitive dysfunctions with other stimulants such as amphetamine or methylphenidate should be reassessed. These stimulants have similar mechanisms of action as cocaine because they all bind to monoamine transporters resulting in an elevated monaminergic neurotransmission (Svetlov, Kobeissy, & Gold, 2007).

Therefore, these compounds potentially preserve and prolong the neurochemoplastic adaptations induced by cocaine and, thus, impede the rebalancing of the natural neurotransmitter homeostasis. Consequently, the best approach to improve cognition in stimulant users seems to be abstinence, whereas the medication with prescription stimulants might improve concentration and memory acutely but not continuously (Quednow, 2010). Another trivial yet important finding is that the developing brain should be averted from cocaine as long as possible because the emergence of social and non-social cognitive deficits was most pronounced in individuals who had begun consuming cocaine before the age of 18. Therefore, drug prevention should have an intensified focus on the delay of the onset of any kind of stimulant use. An early and undogmatic informing of the youth about the consequences of stimulant use (including cognitive and social sequela) should be initiated at the beginning of puberty the latest. It should be emphasized that cognitive and social deficits only develop after intense regular use but that they are not reserved to dependent individuals. We also observed that, across one year, onethird of the cocaine users decreased or even quit (13%) cocaine consumption without systematic therapeutic intervention, while the major part of the users, who were primarily moderate users, did not show significant changes in cocaine intake (39%). However, about one-third (29%) of the cocaine users strongly increased their cocaine consumption or change their preferred drug (14%) within one year. We now aim to find out whether the risk for escalating cocaine use is predictable by cognitive, behavioral, social, and/or genetic or biologic parameters. As a final point, in agreement with Gottfried Benn, who literarily attested that cocaine causes a form of “ego decay”, the social self seems to disintegrate continuously during chronic cocaine use. The good news is that it can be rebuilt if the substance use decays.

DEFINITION OF TERMS Cognitive empathy Together with ToM, emotion recognition from complex stimulus material is sometimes subsumed under the term cognitive empathy reflecting the ability of the individual to represent the internal mental state of another individual (Blair, 2005; Dziobek et al., 2008). Delusions of parasitosis  It is tactile and visceral hallucinations of insects or worms crawling underneath the skin or in the muscles. Emotional empathy  It is the ability to feel and share the emotions of others. Joint attention  Joint attention is the shared focus of two individuals on an object. It is achieved when one individual alerts another to an object by means of eye-gazing, speech, or gestures. Money distribution tasks  This is also called “neuroeconomic games”, which are derived from the game theory of economics (Sanfey, Loewenstein, McClure, & Cohen, 2006). Social cognition  Like executive functions, social cognition is a somewhat problematic umbrella term subsuming different perceptive and cognitive abilities vital for social interactions between humans. These include all forms of emotion perception and recognition from faces, voices, gestures, mental and emotional perspective-taking

266  PART | I Stimulants

(ToM), social gaze contact (e.g., the phenomenon of joint attention), emotional empathy, morale, fairness, altruism, and trust. Theory-of-Mind (ToM)  It is the attribution of emotions, intentions, and goals to others, also known as emotional and mental perspective-taking.

KEY FACTS OF COCAINE USE l Cocaine

addiction is a debilitating, chronically relapsing disorder that is characterized by persistent and compulsive drugseeking despite of harmful consequences (APA, 1994). l  After cannabis, cocaine is the second most common illegal drug used in Europe, the United States, and also worldwide (EMCDDA, 2014; UNODC, 2014). l Current lifetime prevalence rates of cocaine use are estimated at 4.2% in Europe and 14.3% in the United States (EMCDDA, 2014; NSDUH, 2014). l Notwithstanding the high addictive potential of cocaine, only a relatively small fraction of users (5–6%) transit from controlled drug use to drug dependence within the first year but 15–16% develop dependency during their lifetime (Nutt, King, Saulsbury, & Blakemore, 2007; Wagner & Anthony, 2007).

SUMMARY POINTS l Recreational

and dependent cocaine users display broad cognitive impairments. l Cognitive dysfunctions are correlated with several subjective and objective drug intake parameters. l Emotional empathy, ToM, joint attention, prosocial behavior, and social network size are altered in cocaine users. l Cocaine users show blunted reward from social interactions. l  Basal cognitive functions, emotional empathy, and prosocial behavior covary with changing cocaine use. l Impairment of basal cognitive functions, empathy, and social decision-making are partially drug-induced and potentially caused by neuroplastic adaptations following chronic cocaine use. l Age of onset is an important factor for cognitive impairment and recovery.

ACKNOWLEDGMENTS The author is highly grateful to Daniela Jenni, Lea M. Hulka, Katrin H. Preller, and Matthias Vonmoos who all contributed so much for the success of the ZuCo2St. Moreover, the author thanks Hallie Batschelet, Sarah Hirsiger, and Matthias Vonmoos for critical comments and suggestions to the first draft of the manuscript.

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268  PART | I Stimulants

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