A Multimodal MR Imaging Study Of Tobacco Addiction And Smoking Cessation Treatment

BackgroundTobacco epidemic has become a public health problem.Long-term smoking cause high risks of disability and death,resulting in heavy disease burden and economic loss in family and society.Although the understanding of smoking-related harm effects has been improved in recent years,smokers are still facing the difficulty that they want to quit but fail.On one hand,it is tobacco addiction that causes the situation.Once addicted to tobacco,smokers present with compulsive seeking and taking of cigarette smoking despite its harmful health effects,which increases the difficulty of quitting.On the other hand,the selections of smoking cessation strategy are short of the consideration of individual differences and the understanding of intervention mechanisms,which reduces its effects and makes smokers trapped on their road to quitting.Therefore,to figure out the underlying mechanism of tobacco addiction and select proper strategy for every smoker remains an important question in the field of quitting smoking.For these reasons,this study aims to use multimodal MRI to conduct a series of neuroimaging studies about tobacco addiction and smoking cessation treatment.(1)To further investigate the neural mechanism of tobacco addiction and identify the role of reward circuit and cerebellum in tobacco addiction;(2)To analyze the underlying mechanism of individual differences,especially the neural basis of gene-related smoking phenotype;(3)To explore the target and mechanism of smoking cessation treatment.Taking all these factors into consideration will help to realize individualized intervention,solve the problem of smoking quitting.MethodsExperiment 1:A total of 65 smokers(aged 22-54 years)and 37 non-smokers(aged 25-56 years)underwent resting-state functional magnetic resonance imaging(fMR1).The smokers were divided into low-dependent(FTND<5,n = 26)and high-dependent smoker groups(FTND>5,n = 39)based on their nicotine-dependence severity(as measured by the Fagerstrom test for nicotine dependence[FTND]).The region of interest(ROI)-wise functional connectivity(FC)within the reward circuit was compared between smokers and nonsmokers as well as between low-dependent and high-dependent smokers and then correlated with smokers’ FTND scores.Experiment 2:High-resolution structural MRI data were acquired from 85 smokers(aged 22-54 years)and 41 nonsmokers(aged 25-56 years).We applied voxel-based morphometry(VBM)and the SUIT cerebellar atlas to compare the cerebellar gray matter volume(GMV)between smokers and nonsmokers.Using resting-state functional MRI data,we also performed seed-based FC analysis to examine the functional correlates of the GMV changes.Experiment 3:A total of 81 smokers(aged 22-54 years)and 42 nonsmokers(aged 25-56 years)were enrolled in the study.High-resolution structural MRI and resting-state fMRI data were acquired from every participant.According the genotype of MAOA rs1137070,the subjects were divided into ones with C allele and ones with T allele.A full factorial design was used to analyze the interactions between rs1137070 and smoking on GMV and functional connectivity strength(FCS).We further assess the relationship between gene related brain alterations and smoking behavior.Experiment 4:Using structural MRI and resting-state fMRI,we acquired images from 43 smokers(aged 22-54 years)before and after treatment.After 12-week treatment with varenicline,smokers were divided into relapsers(n = 18)and quitters(n = 25)(quitter:continuously abstinent for weeks 9-12).Paired-t tests were used to investigate the structural and functional brain alterations before and after treatment.A Logistic regression model was used to identify imaging measures associated with smoking cessation outcomes.ResultsExperiment 1:Widespread rsFC attenuation was observed in the reward circuit of smokers compared with non-smokers.Compared with low-dependent smokers,high-dependent smokers showed greater rsFC between the right amygdale and the left nucleus accumbens(NAcc)as well as between the bilateral hippocampus.Furthermore,a positive correlation between the inter-hippocampus rsFC and the severity of nicotine dependence(FTND)was detected among all smokers(r=0.416,p=0.001).Experiment 2:Both VBM and lobular analyses revealed smaller GMV in the bilateral Crus I in smokers.The GMV of the left Crus I was inversely correlated with the severity of nicotine dependence as assessed by FTND(r-0.268,p=0.013).We also found reduced FC between the bilateral Crus I and brain regions involved in the default mode network and motor system,as well as the frontal and temporal cortex in smokers.Experiment 3:VBM analysis showed a significant rs1137070 genotype x smoking effect on the GMV of the left orbitofrontal cortex(OFC)that individuals with risk allele had greater GMV among nonsmokers but not smokers.Meanwhile,rs1137070 variant and nicotine dependence interactively altered the FCS of the right hippocampus,the left inferior parietal lobule(IPL),the left dorsolateral prefrontal cortex and bilateral OFC.In addition,the FCS in the left IPL was correlated with smoking initiation(r=0.556,p=0.001)and smoking years(r=-0.425,p=0.014)in smokers with risk allele.Experiment 4:VBM analysis showed decreased gray matter density in the right ventral striatum,thalamus,inferior frontal gyrus,but increased gray matter density in the right middle frontal gyrus.Seed-based functional connectivity analysis showed decreased functional connectivity with cerebellum posterior lobe,insula,inferior parietal lobule,middle temporal gyrus and inferior frontal gyrus.Logistic regression models showed that the connectivity between right middle frontal gyrus and right insula,and the functional connectivity between the right ventral striatum and right middle temporal gyrus were associated with smoking cessation outcomes.ConclusionsOur findings suggest that(1)there is a dysfunction of the reward circuit in smokers,and the hippocampus related learning and memory play a role in the progression of tobacco addiction;(2)structural and functional alterations in cerebellum are implicated in tobacco addiction,and these may underlie the core ND phenotypes,including automatized smoking behavior,cognitive,and emotional deficits;(3)MAO Ars1137070 contributes to the susceptibility to nicotine dependence through its influence on brain structure and function,and interacts with smoking in the progression;(4)structural and functional alterations induced by varenicline treatment,which reveal that the possible mechanism of varenicline including reducing the response to smoking related stimuli and craving for smoking.This preliminary study explored the neural mechanisms of tobacco addiction and smoking cessation treatment,revealing the possibility of individualized interventions.