Tobacco smoking, the leading cause of preventable death worldwide, is associated with many serious health problems including cardiovascular disease and lung cancer (1). Despite the growing number of evidence-based treatments for smoking addiction, the efficacy remains moderate, with high relapse rate (2). Biological sex may play a large role in patterns of nicotine use and cessation. outcomes For instance, higher smoking rates, greater reinforcement of nicotine and better nicotine replacement therapies has been reported among men than women (3). Women are inclined to smoke for stress relief and mood regulation, and difficult to maintain abstinence (4). Therefore, sex differences may be crucial to target the neural pathophysiology of nicotine addiction and develop more effective relapse prevention therapies (5).

Neuroimaging studies showed that cigarette smoking is associated with sex-specific alterations in brain structure and function. Compared to sex-matched non-smokers, male rather than female nicotine-dependent subjects had a larger volume in the left putamen and a smaller volume in the left caudate, whereas female but not male smokers showed a smaller volume in the right amygdala (6). Exposure to smoking cues, direct comparisons between male and female smokers revealed that male smokers showed greater reactivity in reward-related brain regions (7) and greater coupling between the interhemispheric regions within the executive control network (8) than female smokers. In contrast, female smokers had greater connectivity within the limbic and default mode network than male smokers (9, 10). Earlier work of our team analyzed middle-aged chronic heavy smokers and found that the regional homogeneity (ReHo) of the right paracentral lobule of male smokers was significantly different from that of female smokers (11). Another study of our team reported that young male but not young female smokers had decreased resting-state functional connectivity (rsFC) between the right amygdala and right orbitofrontal cortex (OFC) (12). RsFC of the amygdala-OFC circuity was negatively correlated with the craving score in male but not female smokers (12). Despite increasing knowledge of the sex-specific effects of tobacco use on brain structure and connectivity between spatially distinct brain regions, it remains unclear whether cigarette smoking has differential influence on the local spontaneous brain activity between men and women, particularly young adults.

Resting-state fMRI (rs-fMRI) provides a non-invasive method of assessing changes in resting-state brain activity and functional connectivity across the whole-brain (13). ReHo measures the synchronization of intra-regional spontaneous low-frequency BOLD signal fluctuations by calculating Kendall's coefficient of concordance (14), which have high test-retest reliability (15). The ReHo metric has been widely used to investigate abnormal local spontaneous brain activity in psychiatric and neurologic conditions (16). Recent literature review demonstrated differences in adolescent vulnerability to neurotoxicity of drugs of abuse from adult (17). Brain imaging studies showed humans might achieve full adulthood after the ages of 25 and 30 (18, 19). Hence, it is important to study the abnormal changes of brain function in smokers at younger age group. In view of the gender influence of smoking on neural structure and functional networks, we assume that young male and female smokers would show constant change patterns in the reward-related areas [as in our previous article (11)], and display different change patterns in local synchronization of the brain.

To test our hypothesis, we employed ReHo method to depict spontaneous brain activity and then performed a voxel-wise analysis to examine the intrinsic brain activity differences between smokers and non-smokers, and to further explore the sex interaction on smoking dependency. Such sex-dependent differences in spontaneous brain activity lays a foundation for further understanding the neural pathophysiology nicotine addiction and promoting more effective health management of quitting smoking.

In this study, we investigated sex-specific differences in local spontaneous brain activity between smokers and healthy non-smoking subjects using rs-fMRI and ReHo analysis. Our findings demonstrated that both male and female smokers showed higher ReHo in the left precuneus compared to sex-matched non-smokers while only male smokers had greater ReHo value in the cerebellum crus 1/2. However, male smokers had lower ReHo in the right medial OFC extending to the ventral staiatum/amygdala/parahippocampal gyrus, right lateral OFC, left cerebellum crus 1 extending to the inferior temporal gyrus, and left fusiform gyrus. Moreover, the ReHo in the left cerebellum crus1 was negatively correlated with craving scores in male smokers but not in female smokers. Taken together, these findings suggest that cigarette smoking may have differential effects on the spontaneous brain activity between men and women, especially in regions that are associated with reward and motivation functions, which are known to be affected by nicotine dependence.

One of the main results of this study using smoking by sex interaction, was found to reduce ReHo in several regions, such as the right ventral striatum/putamen, left fusiform gyrus, and left cerebellum crus 1 extending to the inferior temporal gyrus (Table 3; Figure 2). The ventral striatum is functionally implicated in reward anticipation, reward-related behaviors, and reward outcome of individuals with substance use disorders (26) and it is a reinforcement site (27). Men who smoke for the reinforcing effects of nicotine have significant responses in the ventral striatum. Using the same dataset and functional connectivity analysis, Lin et al. found that smoking has differential effects on the amygdala-OFC circuits between men and women, which is characterized by greater functional connectivity in the male circuits than that in women (12). Therefore, the change of ventral striatum activity may indicate that the reward learning defects of nicotine-addicted male individuals will eventually lead to the impairment of decision-making ability.

There is increasing evidence that cerebellum is involved in substance use disorders (28). Cerebellum was considered as a critical component of the addiction circuit, which is related to coordination of the smoking movement, motivation driving, and inhibition control (28). Male smokers, but not female smokers, have great cerebellar β2-nicotinic acetylcholine receptors (nAChRs) availability (29) and low putamen D2/D3 receptor availability (30), which may affect the up- and down-regulation. A PET studies showed that cigarette smoking increased density of nicotine binding and increased CBF in the cerebellum, which was correlated with plasma nicotine levels (31). Unlike the consensus that the GMV of cerebellum crus 1 in nicotine dependents is less than that in the controls (32–35), the activation of cerebellum varied with the expected degree of drug during exposure to drug-related cues rather than neutral cues (28, 36). In this study, we found decreased ReHo in the cerebellum crus 1/2 in male smokers (Table 3; Figure 2), while our previous studies on middle-aged heavy smokers reported that the ReHo of cerebellum increased (11). Lower ReHo in the left cerebellum crus 1 was correlated with the higher craving scores (r = −0.402; p = 0.022) in male smokers. This may be explained by the significant differences in smoking duration (SM 5.78 ± 2.84 years, SW 4.50 ± 2.50 years vs. 25.42 ± 9.10 years), and the complex mechanisms of chronic smoking, such as early dysfunction and late compensation Interestingly, female smokers did not show the same pattern of brain activity as male smokers. This finding may be partially explained by circulations in the menstrual cycle phase that modulates the reward-related regions in females (37, 38). An arterial spin labeling study examined the neural activity in response to video clip of smoking clues in females, differences emerged in the medial OFC in the follicular phase of the cycle (when progesterone levels are low), but no significant differences were observed in the luteal phase (39). Together, one may speculate that altered activity in the ventral striatum and cerebellum may indicate the selective effects of smoking on dopamine receptors and nicotinic receptors in men and women. The effect might be hampered in male smokers because of their greater reliance on nicotine. Female smokers may be exempted from smoking addiction because of their menstrual cycle.

Our team has been focusing on structural and functional MRI to study the neural mechanism underlying substance addictions. For example, Wu et al. (11) revealed that ReHo was significantly reduced in default-mode, frontoparietal attention and inhibition control networks, and regions related to motor planning increased in among the middle-aged chronic smokers (11). Lin et al. (40) and Cai et al. (35) reported the decreased nodal efficiency in default-mode and cerebellum-striatum networks, respectively, among the middle-aged chronic smokers. Qiu et al. comparing the differences of whole-brain ALFF between young adult smokers and controls, it was found that the ALFF of smoking group in the right MPFC/ventral striatum and left temporal gyrus was significantly higher than that of healthy group (41). Similarly, compared to non-smokers, our study observed that significant spontaneous brain activity changes in the right medial OFC extending to the ventral striatum, amygdala and parahippocampal gyrus of young adult smokers (Table 2; Figure 1), which is consistent with our previous results.

It is well-accepted that addiction produce the long-lasting functional and structural plasticity alterations in the corticostriatal-limbic circuitry (42). The medial OFC, ventral striatum, and amygdala, are core components of the corticostriatal-limbic circuitry related to addiction. The medial OFC is involved in integrating endogenous and exogenous information to make decision, playing an important role in the development and maintenance of addictive behaviors (43). The parahippocampal gyrus and amygdala are brain areas associated with emotional and memory processing (44), which may mediate the relief from negative emotions by smoking (45). The mesocorticolimbic dopamine systems including the amygdala, nucleus accumbens, and prefrontal cortex, are thought to be involved in burst release of dopamine and production of pleasure feelings (46). The finding of dysfunction within the prefrontal-striatal circuits is analogous to previous task-related fMRI studies showing greater activity in the reward regions in response to SCs relative to non-SCs (47–49). Similarly, rs-fMRI studies showed disrupted activity in the medial frontal cortex and precuneus/posterior cingulate cortex (11, 50, 51). Moreover, structural MRI studies exhibited that smokers had lower gray matter volumes or densities in the medial frontal cortex, precuneus, parahippocampal gyrus and temporal lobe (52–55) and reduced cortical thickness in the medial OFC (56). Taken together, our study backed up the idea that the imbalance between cognitive and reward functions in the brain may lead to smoking addiction.

Several limitations in this study must be considered before interpreting the findings. First, the number of participants in each group is relatively small, which may bias the sex-specific effects of cigarette smoking on spontaneous brain activity. Second, age or education level was not well-matched among groups. Although these factors were used as covariates in the statistical analysis, potential effects from these factors cannot be absolutely ruled out. Future studies with matched larger samples should be needed to verify the results. Third, this study is staged, longitudinal study is needed to draw conclusions about whether sex differences are a cause or a consequence of nicotine addiction. Therefore, our findings should be considered as preliminary and further longitudinal studies with larger sample size should be investigated to formulate final conclusions.

In summary, the harm of cigarette smoking is recessive, and to a certain extent it is lagging. It is crucial to investigate the different neural mechanisms underlying male and female in smoking behaviors and nicotine dependence. Our findings indicate that cigarette smoking has differential effects on reward-related activity between men and women. Our study may provide a methodological framework for education of quitting smoke, intervention treatment, and health management.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Research Ethics Committee of Renji Hospital, School of Medicine of Shanghai Jiaotong University. The patients/participants provided their written informed consent to participate in this study.

FL and HL designed and conceptualized the study. XH, YW, WD, YS, and YZ collected the clinical and MRI data. YK organized the data. ZW and FL analyzed the MRI data and wrote the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81571757, 82171885) and the Frontier Scientific Significant Breakthrough Project of CAS (Grant No. QYZDB-SSW-SLH046), the Shanghai Science and Technology Committee Project (Natural Science Funding; grant number. 20ZR1433200), and the Explorer Project in Shanghai (Grant No. 21TS1400700).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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