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Rationale: Task-state and resting-state functional magnetic resonance imaging (fMRI) studies have revealed different brain responses in chronic cigarette smokers compared with healthy controls. However, little is known about the differences between chronic cigarette smokers and healthy subjects regarding the local synchronization of spontaneous brain activity in the resting state. Objectives: In this study, we used regional homogeneity (ReHo) analysis based on resting-state fMRI to investigate intrinsic brain activity in heavy smokers. Methods: Thirty-one heavy smokers and 33 healthy non-smokers were included in this study. ReHo was used to measure spontaneous brain activity, and whole-brain voxel-wise comparisons of ReHo were performed to detect brain regions with altered spontaneous brain activity between groups. Results: Compared with non-smokers, heavy smokers showed decreased ReHo primarily in brain regions associated with the default-mode, frontoparietal attention, and inhibitory control networks; heavy smokers showed increased ReHo predominately in regions related to motor planning. Conclusions: Our results suggest that heavy smokers may have altered spontaneous brain activity in some brain regions that are associated with higher cognitive networks. Moreover, our study improves the understanding of the effects of chronic cigarette smoking on spontaneous brain activity and the pathophysiological mechanisms of nicotine dependence. [ABSTRACT FROM AUTHOR]