Neural responses to subliminally presented cannabis and other emotionally evocative cues in cannabis-dependent individuals

Abstract

Rationale: Addiction theories posit that drug-related cues maintain and contribute to drug use and relapse. Indeed, our recent study in cocaine-dependent patients demonstrated that subliminally presented cocaine-related stimuli activate reward neurocircuitry without being consciously perceived. Activation of reward neurocircuitry may provoke craving and perhaps prime an individual for subsequent drug-seeking behaviors.

Objectives: Using an equivalent paradigm, we tested whether cannabis cues activate reward neurocircuitry in treatment-seeking, cannabis-dependent individuals and whether activation was associated with relevant behavioral anchors: baseline cannabis craving (drug-seeking behavior) and duration of use (degree of conditioning).

Methods: Twenty treatment-seeking, cannabis-dependent individuals (12 males) underwent event-related blood oxygen level-dependent functional magnetic resonance imaging during exposure to 33-ms cannabis, sexual, and aversive cues presented in a backward-masking paradigm. Drug use history and cannabis craving were assessed prior to imaging.

Results: Participants showed increased activity to backward-masked cannabis cues in regions supporting reward detection and interoception, including the left anterior insula, left ventral striatum/amygdala, and right ventral striatum. Cannabis cue-related activity in the bilateral insula and perigenual anterior cingulate cortex was positively associated with baseline cannabis craving, and cannabis cue-related activity in the medial orbitofrontal cortex was positively correlated with years of cannabis use. Neural responses to backward-masked sexual cues were similar to those observed during cannabis cue exposure, while activation to aversive cues was observed only in the left anterior insula and perigenual anterior cingulate cortex.

Conclusions: These data highlight the sensitivity of the brain to subliminal reward signals and support hypotheses promoting a common pathway of appetitive motivation.

Fig. 1

Backward-masking cue paradigm. Twenty-four targets from four categories (i.e., cannabis, aversive, sexual, neutral) and neutral masks were paired randomly, and each target–mask pair was presented quasi-randomly (no more than two targets of the same category in succession) without replacement. Targets were presented for 33 ms followed by a 467-ms neutral mask. As requested by the International Affective Picture System (IAPS), sexual and aversive images are not depicted. All task images are presented in color, but are shown here in grayscale

Fig. 2

Neural activation during exposure to backward-masked cannabis, sexual, and aversive cues in cannabis-dependent treatment seekers. Cannabis cues (versus neutral) elicited greater activation in the left anterior and bilateral ventral striatum. Sexual cues (versus neutral) elicited greater activation in the left ventral striatum, bilateral anterior insula, right hippocampus/amygdala, and left perigenual anterior cingulate cortex. Aversive cues (versus neutral) elicited greater activation in the left insula and perigenual anterior cingulate cortex. Data are displayed neurologically (left is left). The color bar represents T values. MNI coordinate of all images displayed at −42, 8, and −4. An interactive visual display of unmasked brain data in all three planes at p =0.01 can be found at http://franklinbrainimaging.com

Fig. 3

Correlations between brain responses during backward-masked cannabis cues and cannabis craving or years of cannabis use. Scatterplots showing significant correlations between MCQ-SF craving scores and β coefficients extracted from the cluster and averaged. Illustrated are statistical maps in the axial view: a Cannabis craving versus left insula, x = −40; b cannabis craving versus perigenual anterior cingulate cortex (pgACC), x = −4; and c years of cannabis use versus medial orbitofrontal cortex (mOFC), x = 8. Data are displayed neurologically (left is left). The color scale represents the T values. An interactive visual display of unmasked brain data in all three planes at p =0.01 can be found at http://franklinbrainimaging.com