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The Addiction Process

In the “Impaired Response Inhibition and Salience Attribution” (I-RISA) model, we have emphasized the interaction between inhibitory control (e.g., willed-control over automatic processes, interruption of ongoing behavior) and reward processing (e.g., the experience of pleasure, attribution of relative reward value) in drug addiction, implying that inhibitory control would be especially disturbed under conditions of high drug salience (Goldstein & Volkow, 2002).

Using neuroimaging techniques, and targeting blood oxygenation, blood flow, glucose metabolism, or D2 receptors, we have previously documented abnormalities in the functioning of the striato-thalamo-orbitofrontal circuit during acute drug intoxication, short-term and protracted withdrawal and during drug craving. This same circuit has been repeatedly implicated in salience attribution/reward processing and inhibitory control in animal and human (neurophysiology, lesion, neuroimaging) studies.

The brain circuits we target are the mesolimbic and mesocortical dopamine pathways encompassing the dorsal and ventral striatum (caudate, putamen, nucleus accumbens), thalamus, amygdala and hippocampus, anterior cingulate, insula, and the orbitofrontal cortex. The core behaviors encompass intoxication, craving, drug bingeing, and relapse, as presented in the figure above.

Reward Processing in Cocaine Addiction

We examined the prefrontal cortical (PFC) sensitivity to a secondary (monetary) reward and its association with motivation and self-control in 16 cocaine addicted individuals and 13 matched healthy comparison subjects. 

Results of this fMRI study revealed that whereas control subjects valued high money more than low money, more than half of the cocaine addicted subjects valued all monetary amounts equally ($10=$1000) (Goldstein et al., 2007a).

In parallel, the cocaine addicted individuals demonstrated reduced PFC responsivity to differences between the monetary amounts received for accurate performance on the fMRI task. These altered neural responses to money were associated with the blunted subjective sensitivity to reward gradients and with poorer self-control in the cocaine addicted subjects (Goldstein et al., 2007b).

We have since validated these results using ERPs (see ERP link). Concomitant with a reduced response to monetary reward, neural responses to drug-related cues are enhanced in addicted individuals (Goldstein et al., 2009).

Development of Sensitive Behavioral Assays 

Drug Fluency: We tailored semantic fluency, a classical neuropsychological measure of executive/PFC brain function, to increase its sensitivity and ecological validity in the study of drug use disorders.

Cocaine addicted individuals and matched healthy control subjects were asked to "call to mind and name as many drug-related words as possible for one minute". The cocaine subjects who tested positive for cocaine at study day named more drug-related words than controls. The number of words provided on the classical semantic fluency tasks did not differ between the groups. A qualitative analysis also indicated that all cocaine addicted subjects (including those who tested negative for cocaine at study day) provided significantly more words pertaining to the experience of using drugs (paraphernalia, administration) than the matched control subjects (Goldstein et al., 2007c).

Drug Stroop This task was developed for fMRI. Instead of color words (classical Color-Word Stroop task), this task uses drug-related words and matched neutral (e.g., household) words. The individual is required to press a button for an unrelated dimension of the task (word color), allowing us to explicitly combine salience processing with inhibitory control.

Initial observations indicate engagement of the anterior cingulate cortex in processing these drug-related words in cocaine addicted individuals (Goldstein et al., 2007d). Compared to healthy controls, cocaine addicted individuals demonstrated hypoactivation in both major subdivisions of the anterior cingulate cortex (the caudal dorsal and rostroventromedial regions, the former implicated in error monitoring and the latter in emotion suppression), even when there were no differences between the groups in task engagement and performance (Goldstein et al., 2009). Oral methylphenidate, a dopamine agonist, normalized these hypoactivations as associated with decreased impulsivity (Goldstein et al., 2010).

These novel neuropsychological tasks highlight the importance of developing cue-sensitive tasks for probing the neurobiology underlying the particular functional (cognitive-emotional) changes in addicted individuals.