0712
DRD2 TaqIA Polymorphism related Functional Connectivity Between Anterior Insula and Dorsolateral Prefrontal Cortex in Heroin-dependent Individuals under Methadone Maintenance Treatment Predicts Retention Time1The First Affilicated Hospital of Xi'An JiaoTong University, Xi'an, China, 2Department of Radiology, The Hospital of Shannxi provincial geology and mineral resources bureau, Xi'an, China, 3Department of Radiology, The First Affilicated Hospital of Xi'An JiaoTong University, Xi'an, China
Synopsis
The present study adopted functional parcellation method to get functional-different subdivisions atlas of insula from healthy controls, and performed whole brain functional connectivty(FC) based on these subdivisions with resting-state fMRI data aquired from heroin-dependent participants under methadone maintantreatment (HDM). These HDM were grouped by DRD2 Taq1A polymorphism, and compared the FC differences of each insula subdivisions group-wise. Results showed the way DRD2 gene influence the FC between the left anterior insula and right dorsolateral prefrontal cortex. This gene-influenced FC further demonstrated its positive association with retention time, in a survival analysis.
Introduction
Although methadone maintenance treatment (MMT) is the most efficacy treatment for opioid dependency, improving retention time (RT) is still a big challenge for heroin dependents undergoing MMT (HDM) program in China1. Previous studies demonstrated that the efficacy of brain dopamine (DA) system is crucial for reinforcing value of addictive drugs in the process of addiction2. Dopamine receptor D2 (DRD2) Taq1A polymorphism(A1,A2 allele) mediates brain DA system efficacy in a way through which DRD2 density is influenced3. Recently, lesion studies of insula addressed its role in maintaining addiction behavioral4. Furthermore, studies revealed that insula participates into the decision-making procedure with negative consequences present.This study aimed to explore whether variation in the DRD2 Taq1A gene modifies the functional connectivity(FC) of the insula subdivisions in HDM, and the association between the genotype-related FC of the insula subdivision and the RT of HDM.Methods
The present study was approved by Institutional Board of the Fourth Military Medical University, China. 57 right-handed HDM participated in this study. They were genotyped for the DRD2Taq1A site by the method of restriction fragment length polymorphism, grouped as carriers of the A1 allele (Group A1+, 37 males) or homozygous for the A2 allele (Group A1-, 20 males). The two groups were matched at demographic information, smoking and heroin use history, MMT information, BDI score, HAMA score and baseline drug craving score(measured by visual analogy scales before MRI scan). 49 male healthy controls (HC) matched on demographic information and smoking history with HDM were recruited too. All participants undertook regular MRI scans and resting-state fMRI with a 3.0T GE scanner. The monthly follow-up interviews and urine heroin tests(to record relapse behavior) program lasted 2 years for all HDM. MRI data was preprocessed with DPABI software, and insula was subdivided by FC-based parcellation method5 in HC. Individual whole brain FC maps of each insula subdivision were calculated and two sample t-test was performed to study the inter-group FC differences (corrected p<0.05, permutation test with TFCE). FC strength (FCS) were extracted from ROIs(3mm radius spheres, peak voxel from significant group FC differences as sphere centers) and put into Cox regression model to do survival analysis, together with age, craving score, gene type of DRD2, cumulative drug and methadone dosage as predictor variables. Survival time was defined as the HDM's RT.Results
The optimized subdivisions number of bilateral insula was found to be 2 (Fig.1), and the insula was thus parcellated into anterior part (AI) and posterior part (PI) (Fig.2). Compared to Group A1-, Group A1+ showed significant decreased FC between the left AI and the right dorsolateral prefrontal cortex (dlPFC) (Fig.3), and no significant increased FC was found. There were no significant differences existed in the FC of PI between geno-Group. Survival analysis for left AI and right dlPFC (AI model) results showed significant positive relationship between changed FCS and RT (p=0.048, exp(-coef)=4.34). Age was also significantly positive related with RT in AI model (p=0.0001, exp(-coef)=1.09). The craving score, not significant, but has a strong trend of negative relationship with RT in AI model (p=0.077, exp(-coef)=0.77). The retention probability curve predicted by this multi-variate retention model is shown in Fig.4.Discussion
Our study successfully parcellates the billateral insula into anterior and posterior parts, which is consistent with previous studies. AI is necessary for the retieval and reconsolidation of drug-context assiciations, and requires the interaction with working-memory and attentional functions6 modulated by dlPFC. Executive-inhibition function is mainly controlled by dlPFC, which judges the need for drug-taking and risky consequences to make decisions. Heroin abusement disrupts both AI and dlPFC's function, in the mean time, lower D2 receptor density in AI and dlPFC further reduces their function of risky decision-making in A1+ HDM, compared to A1- HDM. Our results showed reduced FC between left AI and right dlPFC in A1+ vesus A1- HDM , demonstrates the DRD2 Taq1A polymorphism effect alters AI's integration of awareness, salience detection and interoceptive functions to interfere decision-making process with dlPFC7. Furthermore, this reduced FC between AI and dlPFC corrupts decision-making procedure to distinguish risky from safe choices, and thus higher probability to drug-taking and relapse, and finally results in a shorter RT among HDM. Our survival analysis showed significant positive association between RT and FC-strength between left AI and right dlPFC well confirmed this inference.
Conclusion
Our findings revealed the way the D2 TaqA polymorphism influence the insula’s function, and the connection strength between dlPFC and particular anterior insula could serve as an import bio-marker for the relapse prediction for heroin abusers.Acknowledgements
This work was supported by the grants from National Natural Science Foundation of China (No.81471648)References
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