Methylphenidate enhances executive function and optimizes prefrontal function in both health and cocaine addiction.

Previous studies have suggested dopamine to be involved in error monitoring/processing, possibly through impact on reinforcement learning. The current study tested whether methylphenidate (MPH), an indirect dopamine agonist, modulates brain and behavioral responses to error, and whether such modulation is more pronounced in cocaine-addicted individuals, in whom dopamine neurotransmission is disrupted. After receiving oral MPH (20 mg) or placebo (counterbalanced), 15 healthy human volunteers and 16 cocaine-addicted individuals completed a task of executive function (the Stroop color word) during functional magnetic resonance imaging (fMRI). During MPH, despite not showing differences on percent accuracy and reaction time, all subjects committed fewer total errors and slowed down more after committing errors, suggestive of more careful responding. In parallel, during MPH all subjects showed reduced dorsal anterior cingulate cortex response to the fMRI contrast error>correct. In the cocaine subjects only, MPH also reduced error>correct activity in the dorsolateral prefrontal cortex (controls instead showed lower error>correct response in this region during placebo). Taken together, MPH modulated dopaminergically innervated prefrontal cortical areas involved in error-related processing, and such modulation was accentuated in the cocaine subjects. These results are consistent with a dopaminergic contribution to error-related processing during a cognitive control task.

Choice to view cocaine images predicts concurrent and prospective drug use in cocaine addiction.

BACKGROUND: Identifying variables that predict drug use in treatment-seeking drug addicted individuals is a crucial research and therapeutic goal. This study tested the hypothesis that choice to view cocaine images is associated with concurrent and prospective drug use in cocaine addiction. METHODS: To establish choice-concurrent drug use associations, 71 cocaine addicted subjects (43 current users and 28 treatment seekers) provided data on (A) choice to view cocaine images and affectively pleasant, unpleasant, and neutral images [collected under explicit contingencies (when choice was made between two fully visible side-by-side images) and under more probabilistic contingencies (when choice was made between pictures hidden under flipped-over cards)]; and (B) past-month cocaine and other drug use. To establish choice-prospective drug use associations, 20 of these treatment-seeking subjects were followed over the next 6 months. RESULTS: Baseline cocaine-related picture choice as measured by both tasks positively correlated with subjects' concurrent cocaine and other drug use as driven by the actively-using subjects. In a subsequent multiple regression analysis, choice to view cocaine images as compared with affectively pleasant images (under probabilistic contingencies) was the only predictor that continued to be significantly associated with drug use. Importantly, this same baseline cocaine>pleasant probabilistic choice also predicted the number of days drugs were used (cocaine, alcohol, and marijuana) over the next 6 months. CONCLUSIONS: Simulated cocaine choice - especially when probabilistic and when compared with other positive reinforcers - may provide a valid laboratory marker of current and future drug use in cocaine addiction.

Sensitivity to monetary reward is most severely compromised in recently abstaining cocaine addicted individuals: a cross-sectional ERP study.

Recent studies suggest that drug-addicted individuals have a dampened cortical response to non-drug rewards. However, it remains unclear whether recency of drug use impacts this impairment. Therefore, in this event-related potential study, recency of cocaine use was objectively determined by measuring cocaine in urine on study day. Thirty-five individuals with current cocaine use disorder [CUD: 21 testing positive (CUD+) and 14 testing negative (CUD-) for cocaine in urine] and 23 healthy controls completed a sustained attention task with graded monetary incentives (0¢, 1¢ and 45¢). Unlike in controls, in both CUD subgroups P300 amplitude was not modulated by the varying amounts of money and the CUD- showed the most severe impairment as documented by the lowest P300 amplitudes and task accuracy. Moreover, while recency of drug use was associated with better accuracy and higher P300 amplitudes, chronic drug use was associated with lower sensitivity to money. These results extend our previous findings of decreased sustained sensitivity to monetary reward in CUD+ to recently abstaining individuals, where level of impairment was most severe. Taken together, these results support the self-medication hypothesis, where CUD may be self-administering cocaine to avoid or compensate for underlying cognitive and emotional difficulties albeit with a long-term detrimental effect on sensitivity to non-drug reward.

Enhanced midbrain response at 6-month follow-up in cocaine addiction, association with reduced drug-related choice.

Drug addiction is characterized by dysregulated dopamine neurotransmission. Although dopamine functioning appears to partially recover with abstinence, the specific regions that recover and potential impact on drug seeking remain to be determined. Here we used functional magnetic resonance imaging (fMRI) to study an ecologically valid sample of 15 treatment-seeking cocaine addicted individuals at baseline and 6-month follow-up. At both study sessions, we collected fMRI scans during performance of a drug Stroop task, clinical self-report measures of addiction severity and behavioral measures of cocaine seeking (simulated cocaine choice); actual drug use in between the two study sessions was also monitored. At 6-month follow-up (compared with baseline), we predicted functional enhancement of dopaminergically innervated brain regions, relevant to the behavioral responsiveness toward salient stimuli. Consistent with predictions, whole-brain analyses revealed responses in the midbrain (encompassing the ventral tegmental area/substantia nigra complex) and thalamus (encompassing the mediodorsal nucleus) that were higher (and more positively correlated) at follow-up than baseline. Increased midbrain activity from baseline to follow-up correlated with reduced simulated cocaine choice, indicating that heightened midbrain activations in this context may be marking lower approach motivation for cocaine. Normalization of midbrain function at follow-up was also suggested by exploratory comparisons with active cocaine users and healthy controls (who were assessed only at baseline). Enhanced self-control at follow-up was suggested by a trend for the commonly hypoactive dorsal anterior cingulate cortex to increase response during a drug-related context. Together, these results suggest that fMRI could be useful in sensitively tracking follow-up outcomes in drug addiction.

Neuroimaging for drug addiction and related behaviors.

In this review, we highlight the role of neuroimaging techniques in studying the emotional and cognitive-behavioral components of the addiction syndrome by focusing on the neural substrates subserving them. The phenomenology of drug addiction can be characterized by a recurrent pattern of subjective experiences that includes drug intoxication, craving, bingeing, and withdrawal with the cycle culminating in a persistent preoccupation with obtaining, consuming, and recovering from the drug. In the past two decades, imaging studies of drug addiction have demonstrated deficits in brain circuits related to reward and impulsivity. The current review focuses on studies employing positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and electroencephalography (EEG) to investigate these behaviors in drug-addicted human populations. We begin with a brief account of drug addiction followed by a technical account of each of these imaging modalities. We then discuss how these techniques have uniquely contributed to a deeper understanding of addictive behaviors.

Motivated attention to cocaine and emotional cues in abstinent and current cocaine users--an ERP study.

Event-related potentials (ERPs) are a direct measure of neural activity and are ideally suited to study the time-course of attentional engagement with emotional and drug-related stimuli in addiction. In particular, the late positive potential (LPP) appears to be enhanced following cocaine-related compared with neutral stimuli in human participants with cocaine use disorders (CUD). However, previous studies have not directly compared cocaine-related with emotional stimuli while examining potential differences between abstinent and current cocaine users. The present study examined ERPs in 55 CUD (27 abstinent and 28 current users) and 29 matched healthy controls while they passively viewed pleasant, unpleasant, neutral and cocaine-related pictures. To examine the time-course of attention to these stimuli, we analysed both an early and later window in the LPP as well as the early posterior negativity (EPN), established in assessing motivated attention. Cocaine pictures elicited increased electrocortical measures of motivated attention in ways similar to affectively pleasant and unpleasant pictures in all CUD, an effect that was no longer discernible during the late LPP window for the current users. This group also exhibited deficient processing of the other emotional stimuli (early LPP window - pleasant pictures; late LPP window - pleasant and unpleasant pictures). Results were unique to the LPP and not EPN. Taken together, results support a relatively early attention bias to cocaine stimuli in cocaine-addicted individuals, further suggesting that recent cocaine use decreases such attention bias during later stages of processing but at the expense of deficient processing of other emotional stimuli.

A pattern of perseveration in cocaine addiction may reveal neurocognitive processes implicit in the Wisconsin Card Sorting Test.

The ability to adapt behavior in a changing environment is necessary for humans to achieve their goals and can be measured in the lab with tests of rule-based switching. Disease models, such as cocaine addiction, have revealed that alterations in dopamine interfere with adaptive set switching, culminating in perseveration. We explore perseverative behavior in individuals with cocaine use disorders (CUD) and healthy controls (CON) during performance of the Wisconsin Card Sorting Test (WCST) (N=107 in each group). By examining perseverative errors within each of the 6 blocks of the WCST, we uniquely test two forms of set switching that are differentiated by either the presence (extradimensional set shifting (EDS) - first 3 blocks) or absence (task-set switching - last 3 blocks) of new contingency learning. We also explore relationships between perseveration and select cognitive and drug use factors including verbal learning and memory, trait inhibitory control, motivational state, and urine status for cocaine (in CUD). Results indicate greater impairment for CUD than CON on the WCST, even in higher performing CUD who completed all 6 blocks of the WCST. Block by block analysis conducted on completers' scores indicate a tendency for greater perseveration in CUD than CON but only during the first task-set switch; no such deficits were observed during EDS. This task-set switching impairment was modestly associated with two indices of immediate recall (r=-.32, -.29) and urine status for cocaine [t (134)=2.3, p<.03]. By distinguishing these two forms of switching on the WCST, the current study reveals a neurocognitive context (i.e. initial stage of task-set switching) implicit in the WCST that possibly relies upon intact dopaminergic function, but that is impaired in CUD, as associated with worse recall and possibly withdrawal from cocaine. Future studies should investigate whether dopaminergically innervated pathways alone, or in combination with other monoamines, underlie this implicit neurocognitive processes in the WCST.

Gene x disease interaction on orbitofrontal gray matter in cocaine addiction.

CONTEXT: Long-term cocaine use has been associated with structural deficits in brain regions having dopamine-receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. OBJECTIVE: To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA, in men with cocaine use disorders (CUD) and healthy male controls. DESIGN: Cross-sectional comparison. SETTING: Clinical Research Center at Brookhaven National Laboratory. PATIENTS: Forty individuals with CUD and 42 controls who underwent magnetic resonance imaging to assess GMV and were genotyped for the MAOA polymorphism (categorized as high- and low-repeat alleles). MAIN OUTCOME MEASURES: The impact of cocaine addiction on GMV, tested by (1) comparing the CUD group with controls, (2) testing diagnosis × MAOA interactions, and (3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GMV beyond other factors. RESULTS: (1) Individuals with CUD had reductions in GMV in the orbitofrontal, dorsolateral prefrontal, and temporal cortex and the hippocampus compared with controls. (2) The orbitofrontal cortex reductions were uniquely driven by CUD with low- MAOA genotype and by lifetime cocaine use. (3) The GMV in the dorsolateral prefrontal cortex and hippocampus was driven by lifetime alcohol use beyond the genotype and other pertinent variables. CONCLUSIONS: Long-term cocaine users with the low-repeat MAOA allele have enhanced sensitivity to gray matter loss, specifically in the orbitofrontal cortex, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, long-term alcohol use is a major contributor to gray matter loss in the dorsolateral prefrontal cortex and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task.

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers.

BACKGROUND: Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task. METHODOLOGY/PRINCIPAL FINDINGS: We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. CONCLUSIONS/SIGNIFICANCE: These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour.

Neuropsychiatric disorders are often characterized by impaired insight into behaviour. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Here we tested for the first time this impaired insight hypothesis in drug addiction, and examined its potential association with drug-seeking behaviour. We also tested potential modulation of these effects by cocaine urine status, an individual difference known to impact underlying cognitive functions and prognosis. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessed objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). This choice task concluded by asking subjects to report their most selected picture type; correspondence between subjects' self-reports with their objective choice behaviour provided our index of behavioural insight. Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behaviour compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behaviour was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behaviour, especially in urine negative cocaine subjects, potentially to improve their longer-term clinical outcomes.

The Substance Use Risk Profile Scale: a scale measuring traits linked to reinforcement-specific substance use profiles.

The Substance Use Risk Profile Scale (SURPS) is based on a model of personality risk for substance abuse in which four personality dimensions (hopelessness, anxiety sensitivity, impulsivity, and sensation seeking) are hypothesized to differentially relate to specific patterns of substance use. The current series of studies is a preliminary exploration of the psychometric properties of the SURPS in two populations (undergraduate and high school students). In study 1, an analysis of the internal structure of two versions of the SURPS shows that the abbreviated version best reflects the 4-factor structure. Concurrent, discriminant, and incremental validity of the SURPS is supported by convergent/divergent relationships between the SURPS subscales and other theoretically relevant personality and drug use criterion measures. In Study 2, the factorial structure of the SURPS is confirmed and evidence is provided for its test-retest reliability and validity with respect to measuring personality vulnerability to reinforcement-specific substance use patterns. In Study 3, the SURPS was administered in a more youthful population to test its sensitivity in identifying younger problematic drinkers. The results from the current series of studies demonstrate support for the reliability and construct validity of the SURPS, and suggest that four personality dimensions may be linked to substance-related behavior through different reinforcement processes. This brief assessment tool may have important implications for clinicians and future research.

Neural mechanisms of anger regulation as a function of genetic risk for violence.

Genetic risk may predispose individuals to compromised anger regulation, potentially through modulation of brain responses to emotionally evocative stimuli. Emphatically expressed, the emotional word No can prohibit behavior through conditioning. In a recent functional magnetic resonance imaging study, the authors showed that healthy males attribute negative valence to No while showing a lateral orbitofrontal response that correlated with their self-reported anger control. Here, the authors examined the influence of the monoamine oxidase A (MAOA) gene (low vs. high transcription variants) on brain response to No and in relationship to trait anger reactivity and control. The orbitofrontal response did not differ as a function of the genotype. Instead, carriers of the low-MAOA genotype had reduced left middle frontal gyrus activation to No compared with the high variant. Furthermore, only for carriers of the up low-MAOA genotype, left amygdala and posterior thalamic activation to No increased with anger reactivity. Thus, vulnerability to aggression in carriers of the low-MAOA genotype is supported by decreased middle frontal response to No and the unique amygdala/thalamus association pattern in this group with anger reactivity but not anger control.

Dopaminergic response to drug words in cocaine addiction.

When exposed to drug conditioned cues (stimuli associated with the drug), addicted individuals experience an intense desire for the drug, which is associated with increased dopamine cell firing. We hypothesized that drug-related words can trigger activation in the mesencephalon, where dopaminergic cells are located. During functional magnetic resonance imaging (fMRI), 15 individuals with cocaine use disorders and 15 demographically matched healthy control subjects pressed buttons for color of drug-related versus neutral words. Results showed that the drug words, but not neutral words, activated the mesencephalon in the cocaine users only. Further, in the cocaine users only, these increased drug-related mesencephalic responses were associated with enhanced verbal fluency specifically for drug words. Our results for the first time demonstrate fMRI response to drug words in cocaine-addicted individuals in mesencephalic regions as possibly associated with dopaminergic mechanisms and with conditioning to language (in this case drug words). The correlation between the brief verbal fluency test, which can be easily administered (crucial for clinical studies), and fMRI cue reactivity could be used as a biomarker of neurobiological changes in addiction.

Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction.

Anterior cingulate cortex (ACC) hypoactivations during cognitive processing characterize drug addicted individuals as compared with healthy controls. However, impaired behavioral performance or task disengagement may be crucial factors. We hypothesized that ACC hypoactivations would be documented in groups matched for performance on an emotionally salient task. Seventeen individuals with current cocaine use disorders (CUD) and 17 demographically matched healthy controls underwent functional magnetic resonance imaging during performance of a rewarded drug cue-reactivity task previously shown to engage the ACC. Despite lack of group differences in objective or subjective task-related performance, CUD showed more ACC hypoactivations throughout this emotionally salient task. Nevertheless, intensity of emotional salience contributed to results: (i) CUD with the largest rostroventral ACC [Brodmann Area (BA) 10, 11, implicated in default brain function] hypoactivations to the most salient task condition (drug words during the highest available monetary reward), had the least task-induced cocaine craving; (ii) CUD with the largest caudal-dorsal ACC (BA 32) hypoactivations especially to the least salient task condition (neutral words with no reward) had the most frequent current cocaine use; and (iii) responses to the most salient task condition in both these ACC major subdivisions were positively intercorrelated in the controls only. In conclusion, ACC hypoactivations in drug users cannot be attributed to task difficulty or disengagement. Nevertheless, emotional salience modulates ACC responses in proportion to drug use severity. Interventions to strengthen ACC reactivity or interconnectivity may be beneficial in enhancing top-down monitoring and emotion regulation as a strategy to reduce impulsive and compulsive behavior in addiction.

Enhanced choice for viewing cocaine pictures in cocaine addiction.

BACKGROUND: Individuals with cocaine use disorder (CUD) chose cocaine over nondrug rewards. In two newly designed laboratory tasks with pictures, we document this modified choice outside of a cocaine administration paradigm. METHODS: Choice for viewing cocaine, pleasant, unpleasant, or neutral pictures--under explicit contingencies (choice made between two fully visible side-by-side images) and under more implicit contingencies (selections made between pictures hidden under flipped-over cards)--was examined in 20 CUD and 20 matched healthy control subjects. Subjects also provided self-reported ratings of each picture's pleasantness and arousal. RESULTS: Under both contingencies, CUD subjects chose to view more cocaine pictures than control subjects, group differences that were not fully explained by the self-reported picture ratings. Furthermore, whereas CUD subjects' choice for viewing cocaine pictures exceeded choice for viewing unpleasant pictures (but did not exceed choice for viewing pleasant pictures, in contrast to their self-reported ratings), healthy control subjects avoided viewing cocaine pictures as frequently as, or even more than, unpleasant pictures. Finally, CUD subjects with the most cocaine viewing selections, even when directly compared with selections of the pleasant pictures, also reported the most frequent recent cocaine use. CONCLUSIONS: Enhanced drug-related choice in cocaine addiction can be demonstrated even for nonpharmacologic (pictorial) stimuli. This choice, which is modulated by alternative stimuli, partly transcends self-reports (possibly indicative of a disconnect in cocaine addiction between self-reports and objective behavior) to provide an objective marker of addiction severity. Neuroimaging studies are needed to establish the neural underpinnings of such enhanced cocaine-related choice.

The neuropsychology of cocaine addiction: recent cocaine use masks impairment.

Individuals with current cocaine use disorders (CUD) form a heterogeneous group, making sensitive neuropsychological (NP) comparisons with healthy individuals difficult. The current study examined the effects on NP functioning of four factors that commonly vary among CUD: urine status for cocaine (positive vs negative on study day), cigarette smoking, alcohol consumption, and dysphoria. Sixty-four cocaine abusers were matched to healthy comparison subjects on gender and race; the groups also did not differ in measures of general intellectual functioning. All subjects were administered an extensive NP battery measuring attention, executive function, memory, facial and emotion recognition, and motor function. Compared with healthy control subjects, CUD exhibited performance deficits on tasks of attention, executive function, and verbal memory (within one standard deviation of controls). Although CUD with positive urine status, who had higher frequency and more recent cocaine use, reported greater symptoms of dysphoria, these cognitive deficits were most pronounced in the CUD with negative urine status. Cigarette smoking, frequency of alcohol consumption, and dysphoria did not alter these results. The current findings replicate a previously reported statistically significant, but relatively mild NP impairment in CUD as compared with matched healthy control individuals and further suggest that frequent/recent cocaine use [corrected] may mask underlying cognitive (but not mood) disturbances. These results call for development of pharmacological agents targeted to enhance cognition, without negatively impacting mood in individuals addicted to cocaine.

Compromised sensitivity to monetary reward in current cocaine users: an ERP study.

We studied modulation of the P300 by monetary reward expected to be received on a sustained attention task in 18 individuals with current cocaine use disorders (CUD) and 18 control subjects. Results in the controls revealed sensitivity to money as measured with P300 amplitude and speed of behavioral response and their intercorrelations. In contrast, despite generally faster P300 waveforms and higher self-reported interest in the task, individuals with CUD did not display these responses to money versus nonreward; at the behavioral level, this impairment correlated with frequency of recent cocaine use. These preliminary results suggest a compromised sensitivity to a secondary reinforcer in CUD. This deficit, which needs to be replicated in larger samples of people with currently active versus abstaining CUD, may underlie the compromised ability to advantageously modify behavior in response to changing inner motivations and environmental contingencies.