Lea M. Hulka

Cognitive dysfunctions in recreational and dependent cocaine users: role of attention-deficit hyperactivity disorder, craving and early age at onset

BACKGROUND Dependent cocaine users consistently display cognitive deficits but cognitive performance of recreational cocaine users has rarely been investigated. AIMS To examine whether cognitive performance is impaired in relatively pure recreational and dependent cocaine users. METHOD The cognitive performance of recreational (n = 68) and dependent cocaine users (n = 30) was compared with the performance of stimulant-naive controls (n = 68) employing an extensive neuropsychological test battery. Moreover, the impact of attention-deficit hyperactivity disorder (ADHD) symptoms, craving and early age at onset was analysed. RESULTS Dependent cocaine users display broad cognitive impairments in the domains of attention, working memory, declarative memory and executive functions. The performance of recreational cocaine users in all four domains was intermediate between that of controls and dependent users and they displayed significant deficits foremost in the domains of attention and working memory. In addition, ADHD symptoms, craving and age at onset were important modulators of cognitive function in cocaine users. CONCLUSIONS Cognitive deficits occur at a recreational and non-dependent level of cocaine use. Cocaine use and ADHD seem to have mutually aggravating effects on cognitive impairment.

Impaired emotional empathy and related social network deficits in cocaine users

Chronic cocaine users consistently display neurochemical and functional alterations in brain areas involved in social cognition (e.g. medial and orbitofrontal cortex). Although social functioning plays a crucial role in the development and treatment of drug dependence, studies investigating social cognition in cocaine users are lacking. Therefore, we investigated mental perspective taking (‘theory of mind’) and emotional and cognitive empathy in recreational (RCU) and dependent (DCU) cocaine users. Furthermore, we related these measures to real‐life indicators of social functioning. One‐hundred cocaine users (69 RCU, 31 DCU) and 68 stimulant‐naïve healthy controls were tested with the Multifaceted Empathy Test (MET), Movie for the Assessment of Social Cognition (MASC) and Reading the Mind in the Eyes Test (RMET). The Social Network Questionnaire was conducted to assess social network size. Furthermore, participants provided information on committed criminal offenses. RCU and DCU showed less emotional empathy compared to controls (MET), whereas cognitive empathy was not impaired (MET, RMET). Additionally, DCU made more errors in mental perspective taking (MASC). Notably, cocaine users committed more criminal offenses and displayed a smaller social network and higher cocaine use was correlated with less social contacts. Diminished mental perspective taking was tentatively correlated with more intense cocaine use as well. Finally, younger age of onset of cocaine use was associated with more pronounced empathy impairment. In conclusion, social cognition impairments in cocaine users were related to real‐life social functioning and should therefore be considered in therapy and prevention strategies.

Altered social and non-social decision-making in recreational and dependent cocaine users.

BACKGROUND Maladaptive decision-making is assumed to be a core feature of cocaine addiction. Indeed, numerous studies have reported deficits in non-social decision-making tasks and reward-related impulsivity in dependent cocaine users. However, social decision-making has not been examined in cocaine users yet. Moreover, it is unknown if even recreational and non-dependent cocaine use is linked to decision-making deficits. Therefore, we investigated whether recreational and dependent cocaine users exhibit alterations in social and non-social decision-making. METHOD The performance of healthy controls (n = 68), recreational cocaine users (n = 68) and dependent cocaine users (n = 30) in classical decision-making paradigms (Iowa Gambling Task, Delay Discounting) and in social interaction paradigms (Distribution Game, Dictator Game) was assessed. RESULTS Decisions in the social interaction tasks of both cocaine user groups were more self-serving compared with controls as cocaine users preferred higher monetary payoffs for themselves. In the Iowa Gambling Task, only dependent cocaine users were more likely to choose disadvantageous card decks, reflecting worse decision-making. They were also more likely to choose immediate smaller rewards over larger delayed rewards in the Delay Discounting task. CONCLUSIONS Our results imply that both recreational and dependent cocaine users are more concerned with their own monetary gain when interacting with another person. Furthermore, primarily dependent cocaine users are less foresighted and more impulsive regarding immediate reward. Overall, social interaction deficits are already present in recreational users, while non-social decision-making deficits occur predominantly in dependent cocaine users. Thus, social interaction training and cognitive remediation strategies may improve treatment success and quality of life in cocaine dependence.

Cognitive impairment in cocaine users is drug-induced but partially reversible: evidence from a longitudinal study.

Cocaine users consistently display cognitive impairments. However, it is still unknown whether these impairments are cocaine-induced and if they are reversible. Therefore, we examined the relation between changing intensity of cocaine use and the development of cognitive functioning within 1 year. The present data were collected as part of the longitudinal Zurich Cocaine Cognition Study (ZuCo2St). Forty-eight psychostimulant-naive controls and 57 cocaine users (19 with increased, 19 with decreased, and 19 with unchanged cocaine use) were eligible for analysis. At baseline and after a 1-year follow-up, cognitive performance was measured by a global cognitive index and four neuropsychological domains (attention, working memory, declarative memory, and executive functions), calculated from 13 parameters of a broad neuropsychological test battery. Intensity of cocaine use was objectively determined by quantitative 6-month hair toxicology at both test sessions. Substantially increased cocaine use within 1 year (mean +297%) was associated with reduced cognitive performance primarily in working memory. By contrast, decreased cocaine use (−72%) was linked to small cognitive improvements in all four domains. Importantly, users who ceased taking cocaine seemed to recover completely, attaining a cognitive performance level similar to that of the control group. However, recovery of working memory was correlated with age of onset of cocaine use—early-onset users showed hampered recovery. These longitudinal data suggest that cognitive impairment might be partially cocaine-induced but also reversible within 1 year, at least after moderate exposure. The reversibility indicates that neuroplastic adaptations underlie cognitive changes in cocaine users, which are potentially modifiable in psychotherapeutical or pharmacological interventions.

Functional changes of the reward system underlie blunted response to social gaze in cocaine users

Significance Social interaction deficits in drug users likely impede treatment, increase the burden of the affected families, and consequently contribute to the high costs for society associated with addiction. However, the neural origin contributing to altered social interaction in drug users is unknown thus far. The present study illuminates the nature of basic social interaction deficits as exemplified by social gaze behavior in cocaine users by applying behavioral, psychophysiological, and functional brain-imaging methods. The results suggest that basal social interaction impairments probably arise from blunted social reward processing that was again related to impaired real-life social behavior in cocaine users. These results point to the importance of reinstatement of social reward in the treatment of stimulant addiction. Social interaction deficits in drug users likely impede treatment, increase the burden of the affected families, and consequently contribute to the high costs for society associated with addiction. Despite its significance, the neural basis of altered social interaction in drug users is currently unknown. Therefore, we investigated basal social gaze behavior in cocaine users by applying behavioral, psychophysiological, and functional brain-imaging methods. In study I, 80 regular cocaine users and 63 healthy controls completed an interactive paradigm in which the participants’ gaze was recorded by an eye-tracking device that controlled the gaze of an anthropomorphic virtual character. Valence ratings of different eye-contact conditions revealed that cocaine users show diminished emotional engagement in social interaction, which was also supported by reduced pupil responses. Study II investigated the neural underpinnings of changes in social reward processing observed in study I. Sixteen cocaine users and 16 controls completed a similar interaction paradigm as used in study I while undergoing functional magnetic resonance imaging. In response to social interaction, cocaine users displayed decreased activation of the medial orbitofrontal cortex, a key region of reward processing. Moreover, blunted activation of the medial orbitofrontal cortex was significantly correlated with a decreased social network size, reflecting problems in real-life social behavior because of reduced social reward. In conclusion, basic social interaction deficits in cocaine users as observed here may arise from altered social reward processing. Consequently, these results point to the importance of reinstatement of social reward in the treatment of stimulant addiction.

Differences in self-reported and behavioral measures of impulsivity in recreational and dependent cocaine users.

BACKGROUND Dependent cocaine users consistently display increased trait impulsivity on self-report questionnaires and less consistently exhibit elevated motor impulsivity in some behavioral tasks. However, trait and behavioral impulsivity measures have rarely been investigated in recreational users. Therefore, we examined self-reported trait and motor impulsivities in recreational and dependent cocaine users to clarify the role of impulse control in cocaine addiction and non-dependent cocaine use. METHODS We investigated relatively pure recreational (n=68) and dependent (n=30) cocaine users, as well as psychostimulant-naïve controls (n=68), with self-report questionnaires (Barratt Impulsiveness Scale 11; Temperament and Character Inventory) and behavioral tasks (Rapid Visual Information Processing Task; Stop-Signal Task). RESULTS Compared with controls, recreational and dependent cocaine users displayed higher trait impulsivity and novelty seeking scores on self-report questionnaires. Trait impulsivity scores were strongly associated with an increased number of symptoms of depression and attention deficit hyperactivity disorder and correlated significantly with long-term cocaine intake parameters. By contrast, none of the behavioral motor impulsivity measures showed significant group effects or correlated with cocaine use parameters. The correlations among the self-report measures were high, but self-reports were scarcely correlated with behavioral task measures. CONCLUSIONS These findings suggest that relatively pure cocaine users already display increased trait impulsivity at a recreational level of use. However, the results do not indicate any cocaine-related elevation of behavioral impulsivity in terms of motor or response inhibition. In summary, our data imply that elevated trait impulsivity is not a specific feature of dependent cocaine use.

Increased Sensorimotor Gating in Recreational and Dependent Cocaine Users Is Modulated by Craving and Attention-Deficit/Hyperactivity Disorder Symptoms

BACKGROUND Cocaine dependence has been associated with blunted dopamine and norepinephrine signaling, but it is unknown if recreational cocaine use is also associated with alterations of catecholamine systems. Prepulse inhibition (PPI) of the acoustic startle response-a measure of sensorimotor gating-is highly sensitive for manipulations of the catecholamine system. Therefore, we investigated whether relatively pure recreational users (RCU) and dependent cocaine users (DCU) display alterations of PPI, startle reactivity, and habituation. Moreover, the influences of methylenedioxymethamphetamine and cannabis co-use, craving, and attention-deficit/hyperactivity disorder (ADHD) symptoms on startle measures were examined. METHODS In 64 RCU, 29 DCU, and 66 stimulant-naïve control subjects, PPI of acoustic startle response, startle reactivity, habituation, ADHD symptoms, and cocaine craving were assessed. Drug use of all participants was controlled by hair and urine toxicologies. RESULTS Both RCU and DCU showed increased PPI in comparison with control participants (Cohens d=.38 and d=.67, respectively), while RCU and DCU did not differ in PPI measures (d=.12). No significant group differences were found in startle reactivity or habituation measures. In cocaine users, PPI was positively correlated with cumulative cocaine dose used, craving for cocaine, and ADHD symptoms. Users with a diagnosis of ADHD and strong craving symptoms displayed the highest PPI levels compared with control subjects (d=.78). CONCLUSIONS The augmented PPI in RCU and DCU suggests that recreational use of cocaine is associated with altered catecholamine signaling, in particular if ADHD or craving symptoms are present. Finally, ADHD might be a critical risk factor for cocaine-induced changes of the catecholamine system.

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation.

Cocaine Users Manifest Impaired Prosodic and Cross-Modal Emotion Processing

Background: A small number of previous studies have provided evidence that cocaine users (CU) exhibit impairments in complex social cognition tasks, while the more basic facial emotion recognition is widely unaffected. However, prosody and cross-modal emotion processing has not been systematically investigated in CU so far. Therefore, the aim of the present study was to assess complex multisensory emotion processing in CU in comparison to controls and to examine a potential association with drug use patterns. Method: The abbreviated version of the comprehensive affect testing system (CATS-A) was used to measure emotion perception across the three channels of facial affect, prosody, and semantic content in 58 CU and 48 healthy control (HC) subjects who were matched for age, sex, verbal intelligence, and years of education. Results: CU had significantly lower scores than controls in the quotient scales of “emotion recognition” and “prosody recognition” and the subtests “conflicting prosody/meaning – attend to prosody” and “match emotional prosody to emotional face” either requiring to attend to prosody or to integrate cross-modal information. In contrast, no group difference emerged for the “affect recognition quotient.” Cumulative cocaine doses and duration of cocaine use correlated negatively with emotion processing. Conclusion: CU show impaired cross-modal integration of different emotion processing channels particularly with regard to prosody, whereas more basic aspects of emotion processing such as facial affect perception are comparable to the performance of HC.

Cognitive and emotional impairments in adults with attention-deficit/hyperactivity disorder and cocaine use

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is an important modulator of cognitive and social functioning in cocaine addiction but it is unclear whether ADHD symptoms and cocaine use display mutually aggravating interaction effects on cognition, social functioning, and depressive symptoms. Therefore, we investigated the interaction of cocaine use and adult ADHD on social and non-social cognition and depressive symptoms. METHODS Twenty-four cocaine users with (CU+ADHD) and 30 without ADHD (CU-ADHD), 29 cocaine-naïve ADHD patients, and 40 cocaine-naïve healthy controls underwent comprehensive neuropsychological testing including assessment of social cognition (cognitive/emotional empathy and Theory-of-Mind). Additionally, depressive symptoms were measured with the Beck Depression Inventory. RESULTS The effect size of global cognitive impairment was largest in CU+ADHD (d=1.22 vs. controls) followed by CU-ADHD (d=0.74), and cocaine-naïve ADHD patients (d=0.33). A similar pattern appeared regarding depressive symptoms (CU+ADHD: d=1.47; CU-ADHD: d=0.49, ADHD: d=0.34). In the measures of Theory-of-Mind (CU+ADHD: d=0.76; CU-ADHD: d=0.06, ADHD: d=0.01) and cognitive empathy (CU+ADHD: d=0.80; CU-ADHD: d=0.39, ADHD: d=-0.11) only CU+ADHD showed moderate to large impairments. Moreover, two-way analyses of covariance revealed a significant interaction effect of the factors ADHD and cocaine use on depressive symptoms (p<0.05) and Theory-of-Mind (p<0.05) but not on global cognitive performance (p=0.64). CONCLUSIONS When occurring together, cognitive impairments associated with both ADHD and cocaine use are largely additive, whereas both factors seem to mutually potentiate one another with respect to mood and mental perspective-taking disturbances. Given the high comorbidity between ADHD and cocaine use, longitudinal studies are needed to investigate the origin of these potentiated impairments.