Sex-Dependent Alterations of Regional Homogeneity in Cigarette Smokers

Abstract

Biological sex may play a large role in cigarette use and cessation outcomes and neuroimaging studies have demonstrated that cigarette smoking is associated with sex-related differences in brain structure and function. However, less is known about sex-specific alterations in spontaneous brain activity in cigarette smokers. In this study, we investigated the sex-related effects of cigarette smoking on local spontaneous brain activity using regional homogeneity (ReHo) based on resting-state fMRI. Fifty-six smokers (24 females) and sixty-three (25 females) healthy non-smoking controls were recruited. Whole-brain voxelwise 2-way analysis of covariance of ReHo was performed to detect brain regions with sex-dependent alterations on the spontaneous brain activity. Compared to non-smokers, smokers exhibited significant ReHo differences in several brain regions, including the right medial orbitofrontal cortex extended to the ventral striatum/amygdala/parahippocampus, left precuneus, and bilateral cerebellum crus. Smoking and sex interaction analysis revealed that male smokers showed significantly lower ReHo in the right ventral striatum, left cerebellum crus1, and left fusiform gyrus compared to male non-smokers, whereas there are no significant differences between female smokers and non-smokers. Furthermore, the ReHo within the left cerebellum crus1 was negatively correlated with craving scores in male smokers but not in female smokers. Such sex-dependent differences in spontaneous brain activity lays a foundation for further understanding the neural pathophysiology of sex-specific effects of nicotine addiction and promoting more effective health management of quitting smoking.

Keywords: craving; regional homogeneity; resting-state fMRI; sex; smokers.

Figure 1

Brain areas with significant main effect of smoking on regional homogeneity (ReHo) revealed by the 2-way analysis of covariance with age and education levels as covariates. Regions in red-yellow are brain areas where ReHo was significantly altered in smokers relative non-smokers. The areas include the right medial orbitofrontal cortex (OFC) extend to the ventral striatum/amygdala/parahippocampa gyrus, right cerebellum crus1/2, left precuneus, left cerebellum crus1 extended to the inferior temporal gyrus/fusiform gyrus, and right lateral OFC. The results were multiple compared at voxel-level p < 0.05 (FDR corrected). The left side of the image corresponds to the left hemisphere of the brain.

Figure 2

Brain areas with interaction between smoking and sex on regional homogeneity (ReHo) by the 2-way analysis of covariance (ANCOVA) with age and education levels as covariates. (A) Brain regions showing smoking-sex interaction on ReHo include the left fusiform gyrus, left cerebellum crus1 extended to the inferior temporal gyrus, and right ventral striatum [voxel-level p < 0.05 (FDR corrected]. (B) Post-hoc 1-way ANCOVA analyses revealed that male smokers had lower ReHo than male non-smokers in the right ventral striatum (p = 5.1 × e⁻⁹), left fusiform gyrus (p = 2.1 × e⁻⁷), left cerebellum crus1 extended to the inferior temporal gyrus (p = 1.2 × e⁻⁹), whereas female smokers showed no but no differences on ReHo values in these regions.

Figure 3

Sex-specific correlations between the regional homogeneity (ReHo) values and smoking-related measures in smokers. There were significant negative correlation of the mean ReHo values in the left cerebellum crus1 with the craving scores in male smokers (r = −0.402; p = 0.022) but not in female smokers (r = 0.110; p = 0.608). These correlations between ReHo values and craving scores were significantly different between male and female smokers (p = 0.03).