Disentangling craving- and valence-driven brain responses to smoking cues in individuals with nicotine use disorder

Tobacco smoking is one of the leading causes of preventable death and disease worldwide. Most smokers want to quit, but relapse rates are high. To improve current smoking cessation treatments, a better understanding of the underlying mechanisms of nicotine dependence and related craving behavior is needed. Studies on cue-driven cigarette craving have been a particularly useful tool for investigating the neural mechanisms of drug craving. Here, functional neuroimaging studies in humans have identified a core network of craving-related brain responses to smoking cues that comprises of amygdala, anterior cingulate cortex, orbitofrontal cortex, posterior cingulate cortex, and ventral striatum. However, most functional Magnetic Resonance Imaging (fMRI) cue-reactivity studies do not adjust their stimuli for emotional valence, a factor assumed to confound craving-driven brain responses to smoking cues. Here, we investigated the influence of emotional valence on key addiction brain areas by disentangling craving- and valence-related brain responses with parametric modulators in 32 smokers. For one of the suggested key regions for addiction, the amygdala, we observed significantly stronger brain responses to the valence aspect of the presented images than to the craving aspect. Our results emphasize the need for carefully selecting stimulus material for cue-reactivity paradigms, in particular with respect to emotional valence. Further, they can help designing future research on teasing apart the diverse psychological dimensions that comprise nicotine dependence, and, therefore, can lead to a more precise mapping of craving-associated brain areas, an important step towards more tailored smoking cessation treatments. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement A. H. was supported by the Forschungskredit of the University of Zurich (FK-18-030). F. S. was supported by the Swiss National Science Foundation (BSSG10\_155915, 100014\_178841, 32003B\_166566), the Foundation for Research in Science and the Humanities at the University of Zurich (STWF-17-012), and the Baugarten Stiftung. A. M. was supported by the Swiss National Science Foundation (P2SKP3\_178107). M. K. was supported by the National Bank Fellowship Award (Montreal Neurological Institute, McGill University, Canada). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee (University of Zurich). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The used smoking stimuli, a more detailed overview of stimuli ratings, and the exact scripts used for performing stimulus ratings are all available on the Open Science Framework (OSF) platform (). Further, we have made all scripts used for fMRI analyses and image presentation publicly available in another repository on the OSF platform (). This repository also includes group-level neuroimaging data, while individual data were not allowed to be shared publicly by our local ethics regulations.