Neural substrates of cue reactivity and craving in gambling disorder

Abstract

Cue reactivity is an established procedure in addictions research for examining the subjective experience and neural basis of craving. This experiment sought to quantify cue-related brain responses in gambling disorder using personally tailored cues in conjunction with subjective craving, as well as a comparison with appetitive non-gambling stimuli. Participants with gambling disorder (n=19) attending treatment and 19 controls viewed personally tailored blocks of gambling-related cues, as well as neutral cues and highly appetitive (food) images during a functional magnetic resonance imaging (fMRI) scan performed ~2-3 h after a usual meal. fMRI analysis examined cue-related brain activity, cue-related changes in connectivity and associations with block-by-block craving ratings. Craving ratings in the participants with gambling disorder increased following gambling cues compared with non-gambling cues. fMRI analysis revealed group differences in left insula and anterior cingulate cortex, with the gambling disorder group showing greater reactivity to the gambling cues, but no differences to the food cues. In participants with gambling disorder, craving to gamble correlated positively with gambling cue-related activity in the bilateral insula and ventral striatum, and negatively with functional connectivity between the ventral striatum and the medial prefrontal cortex. Gambling cues, but not food cues, elicit increased brain responses in reward-related circuitry in individuals with gambling disorder (compared with controls), providing support for the incentive sensitization theory of addiction. Activity in the insula co-varied with craving intensity, and may be a target for interventions.

Figure 1

Examples of the cues used in the task.

Figure 2

Craving to gamble ratings during the functional magnetic resonance imaging task. Ratings were provided after each block using a nine point Likert scale. The median and inter-quartile range (IQR) are represented by the boxplot. The whiskers extend to the minimum/maximum scores within 1.5 times the IQR, and the dots are individual scores that fall outside of this range.

Figure 3

Cue-related activity to gambling>gambling-matched neutral contrast in the gambling disorder group. We observed three clusters of activity that showed a relative activity increase for gambling cues compared with gambling-matched neutral cues. An extensive cluster (covering 57 425 voxels in 2 mm standard space) extended to multiple brain regions, and so we report local maxima (Z>6.5). Peaks were localized to the left (−2, −42, 28, Z=7.14) and right (−4, −32, 32, Z=6.75) posterior cingulate gyrus, the left superior frontal gyrus (−2, 46, 50, Z=7.08), the left frontal pole ((−4, 50, 46, Z=7.01) and (−4, 58, 4, Z=6.81)) and the left paracingulate gyrus (−12, 50, 12, Z=6.54). Two smaller clusters showed peaks within the left angular gyrus (−52, −52, 40, Z=6.33) and the right lateral occipital cortex (62, −58, 34, Z=4.09). All images cluster corrected, Z>2.3, P<0.05 and presented using radiological convention.

Figure 4

Group differences in gambling cue reactivity. Top panel: (a) Activity differences. The gambling disorder group showed increased activity relative to controls, in the gambling>gambling-matched-neutral contrast, in four clusters. One peaked within the anterior cingulate cortex (−2, 22, 28, Z=3.85), extending to the superior frontal gyrus. One peaked in the left frontal operculum (−48, 16, −4, Z=3.56) extending to the left insula, one peaked in the right inferior frontal gyrus (52, −52, −26, Z=4.33). An additional cluster was observed in the cerebellum (−16, −48, −42, Z=4.45), (b) extracted signal from the operculum/insula cluster, (c) extracted signal from the anterior cingulate cluster. Bottom panel: (d) Functional connectivity differences. The gambling disorder group showed increased connectivity changes, in the gambling>gambling-matched neutral contrast, between the nucleus accumbens and two clusters; one peaked within the left insula (−34, 6, 0, Z=4.07) (e), and the second within the superior frontal gyrus (−18, 18, 60, Z=4.35) (f).

Figure 5

Correlations between craving ratings and gambling cue reactivity (gambling>neutral contrast) within the gambling disorder group. The whole-brain activity analysis (a) revealed three clusters showing a positive correlation, one peaked within the right insula (38, 4, 8, Z=5.84), a second within left central operculum (−44, −4, 10, Z=5.32) extending to the left insula and a third in the cerebellum (−10, −40, −10, Z=3.82). A region-of-interest analysis of activity within the bilateral nucleus accumbens (b) revealed a positive correlation between craving ratings and the percent signal change within this mask (r(19)=0.491,=P<0.05). The bilateral nucleus accumbens shown here in green, as defined by the Harvard–Oxford subcortical structural atlas. The functional connectivity analysis (c) revealed a single cluster showing a negative correlation with a peak within the paracingulate gyrus (2, 24, 36, Z=3.72).