Smoking Cue Reactivity in Relation to Uncertain-Threat and Reward-Anticipation Networks: A Coordinate-Based...

Smoking is a concerning medical and social problem; however, how the brain links stress to continued smoking is still not well understood. Our coordinate-based meta-analysis identifies convergent activations for smoking cues, uncertain threat, and reward anticipation, and examines coactivation patterns to clarify whether smoking-cue activity in smokers relates to threat and reward activity in nonaddicted control participants.

We conducted a coordinate-based activation likelihood estimation meta-analysis of 102 functional magnetic resonance imaging studies (N = 3979), including 30 studies on smoking cue reactivity (n = 945), 48 on reward anticipation (n = 1413), and 24 on uncertain threat processing (n = 1621). We performed single, conjunction, and contrast analyses, followed by meta-analytic connectivity modeling (MACM) of key regions.

A single analysis revealed that smoking engaged bilateral anterior cingulate cortex (ACC) (-1.1, 46.2, -1.1), uncertain threat engaged bilateral insula (left = -33.6, 22, 4.3; right = 41.3, 22, 1), and reward anticipation activated the thalamus (0.9, 1.3, -3.1) and medial frontal gyrus (2.7, 6.6, 52.1). Conjunction and contrast analyses showed shared or unique activation for each task in its respective regions. MACM showed that ACC coactivated with the thalamus and medial frontal gyrus, whereas the insula coactivated with the ACC and inferior frontal gyrus.

Each process converged in a separate region, with no overlap between the smoking-cue map and either the threat or the reward map. The ACC nonetheless coactivated with reward-related regions and shared network membership with the threat-related insula. On this basis, we hypothesize a shift in motivation from stress-driven reward toward cue-driven craving, to be tested within individuals, and identify candidate neuromodulation targets for preventing stress-precipitated relapse.