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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 taskrelated 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.blood-oxygen-level-dependent fMRI ͉ salience ͉ brain-behavior dissociation ͉ craving ͉ cocaine use I n the impaired response inhibition and salience attribution (I-RISA) model we have emphasized the role of the anterior cingulate (ACC) and orbitofrontal cortices (OFC) in core clinical symptoms of drug addiction that encompass attribution of enhanced salience to drug cues at the expense of the salience attributed to nondrug-related stimuli (1). Supporting this core I-RISA hypothesis, neuroimaging studies in drug addicted individuals demonstrate ACC and OFC hyperactivations during drug-related cue reactivity (2), including craving (3, 4) and hypoactivations during performance of neutrally valenced cognitive tasks (5-9). Because these hypoactivations in addicted individuals could reflect impaired performance (5-8) or decreased engagement (9), in the current study we set out to determine whether ACC hypoactivations in addiction can still be observed in groups matched for overt performance on an emotionally salient task. This is a crucial question because the clinical implications for such hypoactivations even in the absence of overt behavioral group differences may be pronounced. For example, t...

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 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.

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 enhanced following cocainerelated compared to neutral stimuli in individuals with cocaine use disorders (CUD). However, previous studies have not directly compared cocaine-related to 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 timecourse of attention to these stimuli, we analyzed 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. KeywordsCocaine addiction; motivated attention; emotional processing; late positive potential Drug-related compared to neutral stimuli elicit increases in physiological reactivity in drug addicted individuals (Carter & Tiffany, 1999). Similar research demonstrates unique reactions to emotional compared to neutral stimuli in healthy individuals (Lang et al., 1997;Vuilleumier, 2005;Schupp et al., 2007). Termed 'motivated attention', it is hypothesized that motivational systems automatically allocate attention to, and enhance the salience of, emotional stimuli (Lang et al., 1997). Two event-related potentials (ERP), the early posterior negativity (EPN) and the late positive potential (LPP), are larger for both pleasant and unpleasant compared to neutral visual stimuli, interpreted as reflecting increased * Corresponding Author: Rita Z. Goldstein, Medical Research, Brookhaven National Laboratory, 30 Bell Ave., Bldg. 490, Upton, NY, 11973-5000; tel. (631) 344-2657; fax (631) Schupp et al., 2000;Schupp et al., 2003a;2004b;Hajcak et al., 2007;Hajcak & Olvet, 2008;Foti et al., 2009). These ERPs capture different stages within emotional processing; specifically, the EPN reflects early selective attentional processing, while the LPP reflects continued processing of motivationally significant stimuli. Also, evidence suggests that the LPP is...

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.D rug addiction is a chronically relapsing disorder associated with dysregulated dopaminergic neurotransmission as well as functional impairments in the brain regions innervated by dopamine [e.g., the prefrontal cortex (PFC)] (1, 2). Psychostimulants such as cocaine have high abuse and dependence potential because of their ability to increase dopamine in limbic brain regions. Similarly to cocaine, methylphenidate (MPH; e.g., Ritalin) blocks the dopamine transporter increasing extracellular dopamine. However, although speed of uptake of both drugs is similar, rate of clearance of MPH from the brain is substantially slower than that for cocaine (90-vs. 20-min half-life), and these slower pharmacokinetic properties may contribute to the lower abuse potential for MPH (1). Both these neuropharmacological mechanisms, interference with the binding of the drug to its target and different (i.e., slower) pharmacokinetics, proved valuable in the management of heroin (e.g., with methadone and buprenorphine) and nicotine addiction (e.g., with nicotine patch and nicotine gum) (3). In contrast, adapting a similar pharmacological strategy (use of stimulant medications such as MPH) in individuals with cocaine-use disorders (CUD) did not decrease cocaine use or prevent relapse (1).Nevertheless, oral MPH decreases abnormal risk taking in patients with frontotemporal dementia (4) and children with attention deficit hyperactivity disorder (ADHD) (5). Furthermore, when on stimulant medication (including MPH), youth with ADHD showed a trend to improved inhibitor...

Background-Individuals with cocaine use disorder (CUD) chose cocaine over non-drug rewards. In two newly designed laboratory tasks with pictures, we document this modified choice outside of a cocaine administration paradigm.

BackgroundChronic 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 FindingsWe 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/SignificanceThese findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

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.