Neuroimaging Impaired Response Inhibition and Salience Attribution in Human Drug Addiction: A Systematic Review

Abstract

The impaired response inhibition and salience attribution (iRISA) model proposes that impaired response inhibition and salience attribution underlie drug seeking and taking. To update this model, we systematically reviewed 105 task-related neuroimaging studies (n > 15/group) published since 2010. Results demonstrate specific impairments within six large-scale brain networks (reward, habit, salience, executive, memory, and self-directed networks) during drug cue exposure, decision making, inhibitory control, and social-emotional processing. Addicted individuals demonstrated increased recruitment of these networks during drug-related processing but a blunted response during non-drug-related processing, with the same networks also being implicated during resting state. Associations with real-life drug use, relapse, therapeutic interventions, and the relevance to initiation of drug use during adolescence support the clinical relevance of the results. Whereas the salience and executive networks showed impairments throughout the addiction cycle, the reward network was dysregulated at later stages of abuse. Effects were similar in alcohol, cannabis, and stimulant addiction.

Keywords: cocaine; craving; dependence; fMRI; heroin; marijuana; nicotine; opioid; smoking; youth.

Figure 1. Aberrant brain networks in addiction

Results were integrated for six large-scale brain networks that showed aberrant activation levels in individuals with addiction (color coding is the same for all figures and tables). Here, we also indicate which task aspect each brain network supports based on our current understanding of the basic neuroscience literature on animals and healthy humans (as described in the introduction).

Figure 2. PRISMA Flow Diagram

The search in Pubmed/Medline identified 869 studies. We included 105 large studies (n>15 per group) that used a task paradigm comparing an addicted population to a control group through corrected whole-brain analyses.

Figure 3. Investigated Populations and Task Paradigms

The majority of studies investigated stimulant addiction and the most frequently used task paradigm was inhibitory control. Only 7% of the reviewed studies conducted gender comparisons, with only three studies well powered for conducting such comparisons (N> 20 females).

Figure 4. Aberrant brain activation patterns during task performance

We found consistent impairments in brain function in six large-scale brain networks during four different tasks, suggesting broad multi-faceted impairments of multiple domains across tasks. While the involvement of specific brain networks was task-specific, we generally observed increased engagement of relevant brain networks during exposure to drug cues, but a blunted brain response during non-drug related tasks, as predicted by the iRISA model. These aberrant brain activation patterns were observed across addictions, independent of use status.

Figure 5. Clinical relevance of impaired brain function

The reviewed results suggest a crucial role of the habit network in phases of marked behavioral change, such as during the initiation of drug use and relapse. In contrast, impairments in the salience and executive networks were not only linked to the prediction of early abuse in adolescence and relapse; they also correlated with current drug use and were modulated by therapeutic interventions. The association between salience network activation and drug use was only observed in individuals with cannabis and stimulant addiction (non-filled arrow). The reward network showed a strong upregulation with frequent and long term drug use, which was also predictive of relapse and reversed during therapeutic interventions. The memory network was specifically involved during therapeutic cognitive interventions.

Figure 6. Aberrant functional connectivity during resting-state

In chronic stimulant users, the reward, salience, habit and memory networks demonstrated enhanced coupling with each other, as well as with the executive network, while a decreased coupling was observed within the executive control network. Five of the six networks implicated in aberrant task performance (excluding the self-directed network) showed altered resting-state connectivity.