Increased Mesostriatal Intrinsic Connectivity Associated With Cue Exposure in Adult Cannabis Users: Preliminary Findings

Abstract

Cue-induced craving-the desire to use a drug triggered by exposure to cues associated with prior use-is a central mechanism in the development and maintenance of problematic substance use behaviours. Drug cues have the power to induce craving even in long-term abstinent individuals, which has led clinicians to advise patients to avoid the people, places and objects that are associated with their use. This preliminary study builds on prior behavioural research that demonstrates that exposure to multimodal drug cues can increase craving even after the drug cues are removed from the environment. We used a novel fMRI paradigm that combined multimodal cannabis cue-exposure with resting-state functional connectivity to examine positive and negative functional connectivity (i.e., correlations and anticorrelations) between the ventral tegmental area (VTA) and the striatum, a circuit critically involved in reward processing and addiction. Intrinsic VTA-striatal connectivity was measured in 28 individuals who use cannabis regularly (CU group) and 26 age- and sex-matched controls who had never used cannabis before and after multimodal (visual and olfactory) cannabis cue exposure. Craving was assessed at baseline using the Marijuana Craving Questionnaire-Short Form to test whether VTA-striatal connectivity was correlated with self-reported craving measured prior to the fMRI scan. There were no significant group differences in VTA-striatal connectivity during the baseline resting-state scan. However, following cue exposure, CU participants showed significantly greater VTA-caudate connectivity compared to controls. Further, within the CU group, baseline craving was positively correlated with VTA-striatal connectivity at both time points. Our preliminary findings support prior investigations demonstrating that alterations of mesostriatal connectivity are associated with cannabis use and craving in individuals with problematic cannabis use. In addition, the observation of altered connectivity during the post-cue resting-state scan-after multimodal cannabis cues were removed-suggests a potential neural mechanism by which cue exposure may contribute to relapse vulnerability in individuals with problematic cannabis use.

Keywords: VTA; anticorrelation; craving; marijuana; nucleus accumbens; resting‐state fMRI; ventral tegmental area.

FIGURE 1

(A) Experimental design consisting of two resting state fMRI scans separated by a 12‐min event related fMRI cue‐reactivity task. The VAS rating scale was administered prior to each fMRI scan. During each cue‐exposure fMRI trial, participants were instructed to prepare to breathe when they saw the yellow cross, and to inhale when the green cross appeared. This figure depicts an example of a bimodal‐congruent trial. (B) Example cannabis and control cue stimuli presented in the fMRI cue‐reactivity task, grouped by type: unimodal, bimodal‐congruent (picture and odour match), bimodal‐incongruent (picture and odour differ). Pink roses = phenylethyl alcohol odorant; green cannabis leaves = cannabis odorant.

FIGURE 2

All study (N = 49) group intrinsic connectivity maps (preCue + postCue). The ventral tegmental area is significantly correlated with the putamen and body of the caudate (red‐yellow clusters) and anticorrelated with the nucleus accumbens and head of the caudate (blue to light blue clusters). Images are presented in radiological convention (R = L).

FIGURE 3

Group × time interaction in ventral tegmental area (VTA)‐striatal resting‐state connectivity. (A) Sagittal image cluster shows the significant interaction effect in VTA connectivity with the head of the caudate nucleus. (B) Bar chart illustrates the mean z‐score of the all the voxels in the caudate cluster at each time point for each group separately (controls = blue, CU = green). CU participants showed increased connectivity following cue expose between the VTA and caudate, while the control participants showed reduced connectivity in VTA connectivity between the two resting‐state scans.

FIGURE 4

Correlations with ventral tegmental area‐striatal connectivity (preCue + postCue) and craving in the CU group. (A) Significant clusters of activation were observed in the nucleus accumbens (left), the head of the caudate (middle) and the right putamen (right). (B) Scatter plots reflect the mean z‐score within the significant cluster for each individual and are included for illustrative purposes only. Images are presented in radiological convention (R = L).