Differential reward network functional connectivity in cannabis dependent and non-dependent users

Abstract

Background: Emergent studies show that similar to other substances of abuse, cue-reactivity to cannabis is also associated with neural response in the brain's reward pathway (Filbey et al., 2009). However, the inter-relatedness of brain regions during cue-reactivity in cannabis users remains unknown.

Methods: In this study, we conducted a series of investigations to determine functional connectivity during cue-reactivity in 71 cannabis users. First, we used psychophysiological interaction (PPI) analysis to examine coherent neural response to cannabis cues. Second, we evaluated whether these patterns of network functional connectivity differentiated dependent and non-dependent users. Finally, as an exploratory analysis, we determined the directionality of these connections via Granger connectivity analyses.

Results: PPI analyses showed reward network functional connectivity with the nucleus accumbens (NAc) seed region during cue exposure. Between-group contrasts found differential effects of dependence status. Dependent users (N=31) had greater functional connectivity with amygdala and anterior cingulate gyrus (ACG) seeds while the non-dependent users (N=24) had greater functional connectivity with the NAc, orbitofrontal cortex (OFC) and hippocampus seeds. Granger analyses showed that hippocampal and ACG activation preceded neural response in reward areas.

Conclusions: Both PPI and Granger analyses demonstrated strong functional coherence in reward regions during exposure to cannabis cues in current cannabis users. Functional connectivity (but not regional activation) in the reward network differentiated dependent from non-dependent cannabis users. Our findings suggest that repeated cannabis exposure causes observable changes in functional connectivity in the reward network and should be considered in intervention strategies.

Keywords: Craving; Cue-reactivity; Granger; Marijuana; PPI; Ventral striatum.

Fig. 1

Whole brain functional connectivity between the nucleus accumbens (NAc) and other brain areas in response to cannabis cues (vs. neutral cues) in all participants (cluster-corrected z = 2.3, p < 007).

Fig. 2

Connectivity differences between participants who did and did not meet SCID IV cannabis dependence criteria for the cannabis cue ON > neutral cue ON contrast psychophysiological interaction (PPI) analysis for the a) amygdala and b) anterior cingulate gyrus (ACG) seeds (cluster-corrected, z = 1.96, p < 0.007).

Fig. 3

Connectivity differences between participants who did and did not meet SCID IV cannabis dependence criteria for the cannabis cue ON > neutral cue ON contrast psychophysiological interaction (PPI) analysis for the (a) nucleus accumbens (NAc), (b) orbitofrontal cortex (OFC), and (c) hippocampus seeds (cluster-corrected, z = 1.96, p < 0.007).

Fig. 4

Correlation between subjective craving scores (MCQ) and cannabis cue ON > neutral cue ON contrast PPI for the (a) nucleus accumbens (NAc) seed and (b) amygdala seed (cluster-corrected, z = 2.3, p < 0.007). ROIs = regions of interest, fcMRI = functional connectivity MRI.

Fig. 5

Granger error reduction (log ratio of residual improvement) for: (a) all cannabis users, (b) dependent users, and, (c) non-dependent users. Only connections whose bootstrap confidence intervals exceeded threshold at p < 0.01 are included. Color and arrow indicate the temporal precedence of the connection and the size is proportional to the magnitude of error reduction (strength of connection).