Reduced Whole-Brain Network Segregation and Dorsal Anterior-Cingulate Cortex Neurochemical Alterations in Chronic Smokers

Background: Chronic tobacco use has been linked to alterations in brain structure, yet how these changes are organized across large-scale networks and relate to underlying neurochemistry remains unclear. This study combined structural magnetic resonance imaging (MRI) with proton magnetic resonance spectroscopy (¹H-MRS) to examine network organization and neurochemical alterations in smokers. Methods: Fifty-one smokers and 51 non-smokers underwent whole-brain structural MRI and single-voxel ¹H-MRS in the dorsal anterior cingulate cortex (dACC), a hub within executive-control and salience networks. Individualized structural covariance networks were constructed from cortical thickness values, and graph theory was applied to evaluate global and regional properties. Results: At the network level, smokers exhibited reduced modularity across multiple densities, indicating weaker segregation of brain systems with otherwise preserved global topology. Exploratory cortical thickness analyses suggested diffuse thinning in smokers, although these effects did not survive correction for multiple comparisons. At the neurochemical level, smokers demonstrated lower total N-acetylaspartate (tNAA) in the dACC (Cliff's δ = 0.35), consistent with reduced neuronal integrity. No group differences were observed for glutamine, glutathione, or GABA. Regional analyses revealed reduced centrality in executive-control areas and relatively increased centrality in sensory and reward-related regions. Exploratory correlations between smoking severity, network metrics, and tNAA were weak and did not survive multiple comparisons correction. Conclusion: Chronic smoking was associated with reduced network segregation and lower dACC tNAA values. By incorporating whole-brain network analyses with regionally specific spectroscopy in our study, we add a multiscale perspective on vulnerability in smokers and reinforce the importance of longitudinal, regionally specific studies.