| Background:Heroin related disorder is a chronic and complex brain disease that is caused by complex genetic,environmental and neurobiological factors.Methadone maintenance treatment(MMT)is the mainstream alternative therapy for heroin addiction,but this treatment still has a significant relapse,which seriously affects the efficacy of MMT.Dopamine D2 receptor TaqIA polymorphism regulates dopamine efficiency in the brain DA system by affecting the expression of dopamine D2 receptor,and affects the activity of the neural circuits in addicts with heroin related disorders finally,which is differences in susceptibility and therapeutic efficacy betwween the genotypes from epidemiology and genetics.Studies haveshown that the insular is the important brain area of the addictive neural circuit,which is the hub of interoception.At the same time,the insular is also one of the brain regions with the largest density of DRD2 receptors in the brain,However,during the regulation of MMT efficacy by DRD2 TaqIA gene polymorphism,the changes in the neural activity of the insula and its contribution to the efficacy are still unclear.Based on the complexity of brain neural activity and the progress of new technologies,the study of addiction has expanded from the neural circuit to the overall brain network level.In particular,the related research on the characteristics of brain networks at the voxel level,and from the genotype perspective analysis of the heroic brain network characteristics of heroin addicts and its impact on the efficacy of MMT,can provide a broad and new perspective for further understanding the neural mechanism of MMT high relapse rate,and then optimize the treatment strategy.Therefore,from the perspective of DRD2 TaqIA gene,targeted research on heroin addicts' neural circuits and brain networks,analyzing the neural mechanisms in the treatment of addicts,and optimizing MMT treatment strategies have become important scientific issues.Purpose:To explore the differences in the insula functional connections with whole brain and voxel-wise brain networks of heroin addicts who is in the methadone maintenance treatment with different DRD2 TaqIA genotypes,and the relationship between the brain functional differences and the curative effect of the MMT were analyzed.These analysises will provide potential neurobiological targets and scientific basis for the diagnosis and treatment according to different DRD2 TaqIA genotypes of heroin addiction in future.Methods:Experiment 1: Recruiting 47 male heroin HA during methadone maintenancetreatments;PCR-RFLP gene assay was used to classify the DRD2 TaqIA gene polymorphismof the subjects into DRD2TaqIA+type(A+group,27 cases),and DRD2TaqIA-type(A-group,20 cases),matching A+,A-group demographics and medication situation.The GE Signa Excite HD 3.0T MRI instrument was used to collect the resting function and structural MRI data of the brain.The Dpabi software was used to analyze the MRI data.After the experiment,the HA was followed for one year,and the relapse status was statistically analyzed.The length of the first relapse time after the completion of the experiment is defined as the maintenance time of the MMT.Based on the Anatomical automatic labeling(AAL)template,the bilateral insula as ROI was fabricated for functional connectivity(FC)analysis.Comparison of FC intensity differences between A+ and A-groups by two-sample t-test.Influencing factors such as age,education,smoking,heroin and MMT were analyzed by Pearson correlation with relapse rate in one year,and significant variables were selected as follow-up analysis factors for partial correlation analysis.SPSS19.0 was used to analyze the partial correlation between the differential insula FC brain area of A+ and A-group and the MMT maintains time within one year.Experiment 2: 37 male MMT male heroin addicts(HA)were recruited,and 33 male health controls(HC)with matching demographic characteristics participated in the experiment.Heroin addicts were further divided into DRD2TaqIA+(A+ group,23 cases)and DRD2TaqIA-(A-group,14 cases)by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).matching A+,A-group demographics and medication history.The GE Signa Excite HD 3.0T MRI system was used to collect the resting function and structural MRI data for all the subjects.After the end of the experiment,the HA was followed for one year.The situation of relapse was statistically analyzed.The MRI data were analyzed by dpabi software to calculate the Degree centrality(DC)of the brain..The differences between the groups in the HA and HC groups,the A+ group and the A-group werecompared by using the two-sample t-test between groups.Influencing factors such as age,education,smoking,heroin and MMT were analyzed by Pearson correlation with relapse rate in one year,and significant variables were selected as follow-up analysis factors for partial correlation analysis..SPSS19.0 was used to analyze the partial correlation between the DC values of A+ and A-group brain regions and the relapse frequency during MMT in one year.Results:Experiment 1: Compared with A-group,A+ group showed reduced FC between the right insula and the bilateral dorsolateral prefrontal cortex,and the bilateral caudate nucleus(voxel P < 0.001,cluster size >23,Alphasim correction).In addition,FC intensity between the right insula and the right dorsolateral prefrontal cortex had a positive correlation with the MMT maintains time(r=0.378,P=0.011;Bonferroni correction P<0.05/4).Experiment 2: Compared with HC,HA had a significant reduced activities on the right caudate,the right putamen,the bilateral thalamus,the left insula and middle temporal gyrus(voxel P < 0.001,cluster size > 21,Alphasim correction).In relation to A-group,A+ group had increased DC value in the right obitofrontal cortex,left parahippocampus right posterior cingulate cortex(PCC),and brain area with reduced DC value is right caudate nucleus,right frontal gyrus,bilateral dorsolateral prefrontal cortex,bilateral caudate nucleus,left insula.In addition,the positive correlation between DC values of the right PCC and relapse rate were found in HA(r=0.541,P=0.002,Bonferroni correction P<0.05/11)Conclusion:Experiment 1: There are differences in interoception between different DRD2 TaqIA genotype of heroin addicts.The regulation of DRD2 TaqIA gene polymorphism in heroin addicts may be directly or indirectly regulated by the inhibitory control function of the Dorsal lateral prefrontal cotex(dlPFC).At thesame time,the state of interoception may affect the maintenance of drug abuse habits of different DRD2 TaqIA genotype addicts.Compared with A-type,the inhibitory control function of A+ type addicts is more vulnerable,which may be one of the important reasons for the high risk of A+ MMT relapse.Experiment 2: In resting state,the decline of heroin addiction DRD2 TaqIA A+type patient's important brain area Involved in interoception function,habitual behavior formation and inhibition,and the increase of motivation-driven,learning memory,default function network(DMN)neural activity in important brain regions may be the neurobiological basis of DRD2 TaqIA polymorphism affecting heroin addiction and MMT efficacy.DC value of PCC can be used as a potential predictor of relapse behavior in MMT patients. |
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