Clinical correlates of attentional bias to drug cues associated with cocaine dependence.

BACKGROUND AND OBJECTIVE: Preoccupation (attentional bias) related to drug-related stimuli has been consistently observed for drug-dependent persons with several studies reporting an association of the magnitude of measured attentional bias with treatment outcomes. The major goal of the present study was to determine if pre-treatment attentional bias to personal drug use reminders in an addiction Stroop task predicts relapse in treatment-seeking, cocaine-dependent subjects. METHODS: We sought to maximize the potential of attentional bias as a marker of risk for relapse by incorporating individualized rather than generalized drug use cues to reflect the personal conditioned associations that form the incentive motivation properties of drug cues in a sample of cocaine-dependent subjects (N = 35). RESULTS: Although a significant group Stroop interference effect was present for drug versus neutral stimuli (ie, attentional bias), the level of attentional bias for cocaine-use words was not predictive of eventual relapse in this sample (d = .56). A similar lack of prediction power was observed for a non-drug counting word Stroop task as a significant interference effect was detected but did not predict relapse outcomes (d = .40). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results of the present study do not provide clear support for the predictive value of individual variation in drug-related attentional bias to forecast probability of relapse in cocaine-dependent men.

Neural network activation during a stop-signal task discriminates cocaine-dependent from non-drug-abusing men.

Cocaine dependence is defined by a loss of inhibitory control over drug-use behaviors, mirrored by measurable impairments in laboratory tasks of inhibitory control. The current study tested the hypothesis that deficits in multiple subprocesses of behavioral control are associated with reliable neural-processing alterations that define cocaine addiction. While undergoing functional magnetic resonance imaging (fMRI), 38 cocaine-dependent men and 27 healthy control men performed a stop-signal task of motor inhibition. An independent component analysis on fMRI time courses identified task-related neural networks attributed to motor, visual, cognitive and affective processes. The statistical associations of these components with five different stop-signal task conditions were selected for use in a linear discriminant analysis to define a classifier for cocaine addiction from a subsample of 26 cocaine-dependent men and 18 controls. Leave-one-out cross-validation accurately classified 89.5% (39/44; chance accuracy = 26/44 = 59.1%) of subjects with 84.6% (22/26) sensitivity and 94.4% (17/18) specificity. The remaining 12 cocaine-dependent and 9 control men formed an independent test sample, for which accuracy of the classifier was 81.9% (17/21; chance accuracy = 12/21 = 57.1%) with 75% (9/12) sensitivity and 88.9% (8/9) specificity. The cocaine addiction classification score was significantly correlated with a measure of impulsiveness as well as the duration of cocaine use for cocaine-dependent men. The results of this study support the ability of a pattern of multiple neural network alterations associated with inhibitory motor control to define a binary classifier for cocaine addiction.

A controlled trial of the adjunct use of D-cycloserine to facilitate cognitive behavioral therapy outcomes in a cocaine-dependent population.

Cocaine dependence is a chronically relapsing disorder for which its predominant behavioral therapies are associated with only partial efficacy. The goal of this study was to determine if the N-methyl-d-aspartate (NMDA) glutamate receptor partial agonist and cognitive enhancer, d-cycloserine (DCS), could boost the cocaine abstinence and treatment retention goals of cognitive behavioral therapy (CBT). This study employed a placebo-controlled, randomized double-blind trial design of 44 cocaine-dependent men enrolled in a 4-week outpatient Substance Abuse Treatment Program (SATP) at the Atlanta Veteran's Administration Medical Center. Subjects received 50mg of DCS or placebo prior to four weekly sessions of a condensed version of a manual-based CBT for cocaine dependence. Cocaine abstinence and treatment retention measures represented primary outcome variables. Relative to a 12-step based treatment-as-usual, an under-dosed CBT was associated with significant improvements in drug abstinence and treatment retention at 4-weeks and for maintenance of drug abstinence after four more weeks of follow-up. The robust response to the under-dosed CBT was not enhanced by the adjunct administration of DCS at either the 4- or 8-week endpoints. This controlled clinical trial failed to demonstrate an ability of DCS to boost the relapse prevention or treatment retention goals of CBT.

The neural correlates of social anxiety disorder and response to pharmacotherapy.

This study attempted to define further the neural processing events underlying social anxiety in patients with social anxiety disorder (SAD) and their response to pharmacotherapy. Social anxiety-related changes in regional cerebral blood flow were defined by [15O]H2 positron emission tomography (PET) in medication-free individuals with generalized SAD (gSAD), and age- and sex-matched comparison subjects, and analyzed using a linear mixed effects model. PET studies were again acquired in the gSAD individuals following an 8-week, flexible dose treatment trial of nefazodone. Both script-guided mental imagery of an anxiogenic social situation and a confrontational mental arithmetic task were associated with marked increases in self-rated anxiety in both subject groups. For gSAD subjects, social anxiety induced by guided mental imagery was associated with increased activity in the left postcentral gyrus and lenticulate, and the right inferior frontal and middle temporal gyri. Social anxiety induced by the mental arithmetic task was associated with activation of the medial and left dorsolateral prefrontal cortex, cerebellum, thalamus, insula, and ventral striatum. Both tasks were associated with relative decreases in activity in the right amygdala and the hippocampus. A direct group comparison indicated that comparison subjects exhibited a differing pattern of social anxiety-related neural activations. Nefazodone treatment was associated with marked clinical improvement. Comparison of social anxiety-related neural activations prior to and after nefazodone administration indicated greater activity in the precentral gyrus, insula, midbrain/hypothalamus, and middle frontal and anterior cingulate gyrus prior to treatment, and greater activity in the left middle occipital and bilateral lingual gyri, postcentral gyrus, gyrus rectus, and hippocampus after treatment. The results of an analysis relating neural activity and treatment-related changes in symptom severity indicated differential neural responses associated with states of symptom remission vs partial response. The observed social anxiety-related changes in distributed neural activity are consistent with cognitive models of SAD and adaptive decreases in amygdala activity in response to social anxiogenics, and support the association of altered frontal cortical responses with treatment response.

The neural correlates of cue-induced craving in cocaine-dependent women.

OBJECTIVE: Drug use reminders are associated with localized changes in brain activity related to intense drug wanting or craving in cocaine-dependent men. While cocaine dependence is prevalent and disabling in women, and certain clinically relevant sex differences exist, there is an absence of knowledge related to the neural correlates of cocaine craving in cocaine-dependent women. METHOD: The differential neural response to imagery depicting cocaine use and neutral imagery was defined by using [15O]H2O positron emission tomography (PET) imaging in eight cocaine-dependent women. Results were compared with a matched group of eight cocaine-dependent men. RESULTS: Cocaine-related imagery was associated with relative increases in cocaine craving and increases in regional cerebral blood flow in the superior temporal gyrus, dorsal anterior and posterior cingulate cortex, nucleus accumbens area, and the central sulcus. Compared with the results of an identical PET study in matched cocaine-dependent men, conditioned cocaine craving in women was associated with less activation of the amygdala, insula, orbitofrontal cortex, and ventral cingulate cortex and greater activation of the central sulcus and widely distributed frontal cortical areas. CONCLUSIONS: These findings suggest the presence of sex differences in the functional anatomy of cue-induced cocaine craving associated with drug dependence. Such differences may reflect sex differences in conditioned associations to cocaine use, in affective and other corollaries of cocaine craving, or in their volitional regulation and may underlie apparent sex differences in the effects of cocaine abstinence and the expectations of treatment outcome. Some support for the need for sex-specific strategies for treatment of cocaine dependence is also furnished by the findings of this study.

Effects of neurotensin receptor antagonism on latent inhibition in Sprague-Dawley rats.

RATIONALE: It has been postulated that the tridecapeptide neurotensin (NT) functions as an endogenous antipsychotic peptide. A critical test of this hypothesis would be to determine if NT is involved in the expression of latent inhibition (LI), a psychophysiological and pharmacological model of schizophrenia. OBJECTIVE: This report describes the effects of disrupting NT neurotransmission by systemic administration of the NT receptor antagonists SR48692 and SR142948A on the acquisition of LI in rats. METHODS: The effects of 30-300 microg/kg SR48692 or 0.1-100 microg/kg SR142948A on the expression of LI following 0, 20 or 30 pre-exposures were first investigated. This was followed by the assessment of the effects of 10 microg/kg SR142948 A on the LI effect of increasing stimulus pre-exposures (10-40). Finally, the role of dopamine transmission in the effects of SR142948A on the acquisition of LI (30 pre-exposures) was tested by coadministering 10 microg/kg SR142948A and 100 mg/kg of the dopamine D(2) antagonist sulpiride. RESULTS: The higher tested doses of SR48692 (100-300 microg/kg) and SR142948A (10-100 microg/kg) decreased acquisition of LI following 20, 30 and even 40 pre-exposures to the to-be-conditioned stimulus. Cotreatment with the dopamine D(2) antagonist sulpiride prevented the LI-disrupting effects of SR142948A. CONCLUSIONS: NT neurotransmission appears to be necessary for the acquisition of LI. The main effect of NT receptor antagonism is a disruption of LI, most likely via enhancement of dopamine transmission. This effect is opposite that of antipsychotic drugs, which have been shown to enhance NT release, supporting the hypothesis of NT as an endogenous antipsychotic peptide.