Fighting a giant: a translational neurofunctional hypothesis of tobacco dependence

Tobacco dependence is characterized by substantial interindividual variability in craving dynamics, relapse vulnerability, and treatment responsiveness. Although current neurobiological models describe core mechanisms of addiction, they less adequately explain why smokers with similar clinical severity differ in dominant craving triggers, relapse pathways, and responses to intervention. Converging evidence implicates dysfunction across large-scale neural systems, including executive-control, salience, and affective–self-referential networks, yet neuromodulation studies targeting these systems have yielded heterogeneous and sometimes polarity-dependent effects. Here, we propose a dual-profile neurofunctional hypothesis in which tobacco dependence reflects two dominant but dimensional configurations of network imbalance. The reactive–impulsive profile is characterized by reduced top-down executive control and salience dysregulation centered on dlPFC-related systems, favoring cue-driven craving and stimulus-bound responding. In contrast, the affective–reflexive profile is characterized by vmPFC–DMN dysfunction associated with maladaptive affect regulation, self-referential processing, and internally driven craving. These configurations are not mutually exclusive but represent dimensional poles that may co-occur, shift across stages of dependence, and be enriched by psychiatric comorbidity. This framework proposes that interindividual variability in addiction may arise from differential network weighting, with direct implications for relapse mechanisms and responsiveness to neuromodulation. By linking neurofunctional heterogeneity to differential treatment sensitivity, the model provides a testable, networkinformed basis for biomarker-guided stratification and personalized intervention development.