[PREPRINT] The cue-reactivity paradigm: An ensemble of networks driving attention and cognition when viewing drug-related and natural-reward stimuli


Background The cue-reactivity paradigm is a widely adopted neuroimaging probe assessing brain activity linked to attention, memory, emotion, and reward processing associated with the presentation of appetitive stimuli. Lacking, is the apperception of more precise brain regions, neurocircuits, and mental operations comprising cue-reactivity’s multi-elemental nature. To resolve such complexities, we employed emergent meta-analytic techniques to enhance insight into drug and natural cue-reactivity in the brain.

Methods Operating from this perspective, we first conducted multiple coordinate-based meta-analyses to define common and distinct brain regions showing convergent activation across studies involving drug-related and natural-reward cue-reactivity paradigms. In addition, we examined the activation profiles of each convergent brain region linked to cue-reactivity as seeds in task-dependent and task-independent functional connectivity analyses. Using methods to cluster regions of interest, we categorized cue-reactivity into cliques, or sub-networks, based on the functional similarities between regions. Cliques were further classified with psychological constructs.

Results We identified a total of 164 peer-reviewed articles: 108 drug-related, and 56 natural-reward. When considering cue-reactivity collectively, across both drug and natural studies, activity convergence was observed in the dorsal striatum, limbic, insula, parietal, occipital, and temporal regions. Common convergent neural activity between drug and natural cue-reactivity was observed in the caudate, amygdala, thalamus, cingulate, and temporal regions. Drug distinct convergence was observed in the putamen, cingulate, and temporal regions, while natural distinct convergence was observed in the caudate, parietal, occipital, and frontal regions. We seeded identified cue-reactivity regions in meta-analytic connectivity modeling and resting-state functional connectivity analyses. Consensus hierarchical clustering of both connectivity analyses identified six distinct cliques that were further functionally characterized using the BrainMap and Neurosynth databases.

Conclusions We examined the multifaceted nature of cue-reactivity and decomposed this construct into six elements of visual, executive function, sensorimotor, salience, emotion, and self-referential processing. Further, we demonstrated that these elements are supported by perceptual, sensorimotor, tripartite, and affective networks, which are essential to understanding the neural mechanisms involved in the development and or maintenance of addictive disorders.