In the Impaired Response Inhibition and Salience Attribution (iRISA) model, our research emphasizes 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, suggesting that inhibitory control would be especially impaired under conditions of high drug salience (Goldstein and Volkow, 2002; Goldstein and Volkow, 2011).
Using combinations of neuroimaging techniques targeting blood flow, glucose metabolism, and neurochemistry, we have been able to document abnormal functioning of the striato-thalamo-orbitofrontal circuit during acute drug intoxication, short-term and protracted withdrawal, and drug craving. This same circuit has been repeatedly implicated in salience attribution and reward processing, and inhibitory control in both animal and human neurophysiology, lesion, and neuroimaging studies.
In this study, we focus on 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 clinical symptoms of addiction encompass intoxication, craving, drug bingeing, and relapse.
Reward Processing in Cocaine Addiction
We have reported differences between cocaine-addicted individuals and healthy control subjects in the processing of monetary reward in several brain regions encompassing the lateral orbitofrontal cortex, ventromedial prefrontal cortex, and dorsal striatum (Goldstein et al., 2007; Konova et al., 2012). These brain abnormalities in reward processing were associated with measures of impaired self-control and greater severity of drug use; correlations with dopamine receptor availability were also reported (Asensio et al., 2010). Some of these results have been validated with electroencephalographies and vis-à-vis anatomical brain scans.
Pharmacological Functional Magnetic Resonance Imaging with Methylphenidate
Methylphenidate is a dopamine agonist traditionally used to treat attention deficit/hyperactivity disorder. We reasoned that low-dose oral methylphenidate could help ameliorate deficits in prefrontal and other dopamine-modulated brain regions commonly observed in stimulant dependent individuals.
Results have supported our hypotheses. For example, functional hypoactivations in the anterior cingulate cortex to an emotionally salient task in cocaine-addicted individuals (Goldstein et al., 2009) were normalized with single-dose methylphenidate (Goldstein et al., 2010); methylphenidate similarly normalized activity in the dorsolateral prefrontal cortex when subjects performed a classical task of executive function (i.e., the Stroop task) (Moeller et al., 2012a). In another study, healthy non-addicted individuals (but not cocaine users) showed increased activity in the dopaminergic midbrain during mental fatigue, presumably boosting motivation to complete the task; oral methylphenidate rescued this midbrain response in the cocaine users (Moeller et al., 2012b). More recently, we have examined the effects of methylphenidate on the brain at rest (resting-state functional connectivity). Methylphenidate reduced an abnormally strong connectivity, or cross-talk, of the ventral striatum with the dorsal striatum (putamen/globus pallidus), regions crucial for habit formation that may underlie core addiction symptomatology (Konova et al., 2013). When looking across these imaging modalities (task and resting-state), methylphenidate exerted a consistent effect on the dorsolateral prefrontal cortex in cocaine addiction (Moeller et al., 2016).
Recovery of Brain Structure and Function with Abstinence
Many addiction treatment centers promote abstinence or reduction of use as their recovery model. NARC embarked on a longitudinal study to examine whether protracted abstinence (for approximately six months) results in functional and structural changes in the brain. Using fMRI, we showed that the activity in the midbrain regions recovered with abstinence, and these changes in brain function were accompanied by reduced drug seeking (Moeller et al., 2012). Using structural MRI, we showed that prefrontal brain regions involved in cognitive control (i.e., inferior frontal and medial frontal gyri), with typically reduced gray matter volume in cocaine-addicted individuals compared to healthy controls, showed an increase in gray matter volume from baseline to six months of abstinence. This recovery in the prefrontal brain structures was also accompanied by improved cognitive flexibility and decision making in addicted individuals (Parvaz et al., 2016a). Finally, the ERP data revealed an enhancement in the sensitivity to generally pleasant stimuli with abstinence, however, the anticipated reduction in the sensitivity to drug-related stimuli did not appear (Parvaz et al., 2016b). Counterintuitively, reactivity to drug-cues shows a non-linear change with increasing abstinence duration. While the cocaine addicted individuals reported decreasing craving with increasing abstinence, the objective ERP markers showed that cue-induced craving increased during the early periods of abstinence, reaching its maximum at one to six months of abstinence before declining at one year of abstinence (Parvaz et al., 2016d). Longitudinal studies are currently being carried out in the lab to further study this phenomenon.