| Background Methadone maintenance treatment(MMT)is the mainstream treatment for heroin use disorder.Methadone is a type of synthetic opioid drug that works by acting on μ receptors.It plays an active role in reducing drug cravings,reducing drug use,and reducing complications in heroin use disorders.However,there are the following problems in the MMT process that need to be resolved urgently.First,as an opioid drug,the effect of long-term use of methadone on the structure and function of the gray matter of the patient’s brain is still unclear.Secondly,there is a high relapse rate during the MMT process,but the key targets of the brain structure related to relapse are not clear.Objective Previous studies have found that the use of methadone may cause different degrees of damage to the brain structure,function and metabolism,but there are disadvantages such as a small number of subjects and cross-sectional studies,which lead to problems such as inconsistent research conclusions and strong subjectivity;therefore,this study used Methadone-treated heroin use disorder as the research object,GE3.0T MRI was used as the research platform,and the longitudinal self-control method was used to conduct research around the above problems in the MMT process:Objective1.Using Voxel-based morphometry(VBM)and resting state functional connectivity technology to study the effects of long-term methadone use on the gray matter structure and functional connectivity of the brain.Objective 2.Using VBM technology to study the brain gray matter structure related to relapse during MMT,to obtain key brain areas related to relapse,to provide an imaging basis for exploring the potential neural mechanisms of relapse and to reduce the relapse rate of patients during MMT.MethodsPart Ⅰ Recruited heroin use disorders(N=50)who received MMT,surveyed demographic data,heroin use,and conducted psychological tests(using the Beck Depression Scale to assess the degree of depression of the patient,and the Hamilton Anxiety Scale to evaluate the patient’s anxiety state).After one year of follow-up,twelve of the subjects were missed.In addition,eight patients were excluded due to head movement or abnormal T2 WI signal.Therefore,thirty subjects were ultimately included in this study(average age 34.6 ± 8.1 years,age range 26-42 years,male/female 28/2).Before and after one year of MMT respectively,used Fast Spoiled gradient recalled echo(FSPGR)to perform Magnetic resonance(MR)inspection,and collected 3D structural data longitudinally;(1)Used the VBM method to calculate the brain gray matter volume of baseline state and after one year of MMT separately.Used paired t test to compare the difference of brain gray matter volume of baseline state and after one year of MMT(FDR correction,P<0.01);(2)Partial correlation analysis was used to analyze the correlation between brain gray matter volume and the dose of methadone in heroin use disorders(P<0.05).Age,gender,years of education,smoking volume and heroin dose were taken as covariates.Part Ⅱ Recruited heroin use disorders(N=50)receiving MMT treatment,investigated demographic data,heroin use,and conducted psychological tests.After one year of follow-up,twelve of the subjects were missing.In addition,eight patients were excluded due to head movement or abnormal T2 WI signal.Therefore,thirty subjects were ultimately included in this study(average age 34.6 ± 8.1 years,age range 26-42 years,male/female 28/2).Before and after one year of MMT,the MR examination was performed using Echo planar imaging(EPI)sequence to obtain the resting state functional data of the subjects respectively;(1)On the basis of experiment one,the brain areas which gray matter volume changed were used as the Regions of interest(ROI).The DPARSF software was used to do the whole brain functional connectivity analysis,and the paired t test was used to compare the difference of functional connectivity in the resting state of the brain between baseline state and after one year of MMT(FDR correction,P<0.01).(2)Partial correlation analysis was used to analyze the correlation between the resting state functional connectivity and the dose of methadone in heroin use disorders with long-term MMT(P<0.05).Part Ⅲ Recruited heroin use disorders(N=60)receiving MMT,investigated demographic data,heroin use and conducted behavioral psychology tests.FSPGR sequence was used for MRI examination and brain volume data was collected at baseline;After six months of follow-up,the heroin use situation in the past six months was assessed through self-report and the urine test results.The patients were divided into Relapse Group(RG)and No Relapse Group(NRG).(1)The VBM method was used to analyze the brain gray matter volume of patients,and the two-sample t test was used to compare the difference in brain gray matter volume between the two groups(P<0.01,Alphasim correction,cluster≥41).(2)In order to further observe the relationship between brain gray matter volume and relapse,in the RG,Spearman correlation was used to analyze the correlation between the brain gray matter volume and the number of relapses and the maintenance time(that is,the time from stopping heroin use to the first relapse).ResultsPart Ⅰ(1)After one year of MMT,compared with the baseline state(S2 vs S1),the volume of gray matter in the broad brain area of heroin use disorder decreased,mainly located in the bilateral insula,occipital lingual gyrus,right cingulate gyrus,and temporal Middle gyrus,left parietal inferior lobule,caudate nucleus,fusiform gyrus and middle occipital gyrus.There was no brain area of gray matter volume increase(FDR correction,P<0.01).(2)After one year of MMT,the patient’s Hamilton anxiety scale(HAMA)score increased(P<0.05).(3)The results of partial correlation analysis showed that the volumes of left middle occipital gyrus(r =-0.406,P = 0.040)and left caudate nucleus(r =-0.435,P = 0.026)were negatively correlated with the dose of MMT.PartⅡ(1)After one year of MMT,compared with the baseline state(S2 vs S1),the resting state neural network of the brain in heroin use disorder has changed,that is,functional connectivity was weakened in the right posterior cingulate gyrus/left superior frontal gyrus,left caudate nucleus/right superior temporal gyrus/right inferior parietal lobule,left fusiform gyrus/bilateral posterior cingulate gyrus/right central posterior gyrus,left middle occipital gyrus/bilateral superior occipital gyrus and left middle occipital gyrus/right cuneus.Functional connections were enhanced in left caudate nucleus/cerebellar vermi,left caudate nucleus/right caudate head,left fusiform gyrus/left superior temporal gyrus,left fusiform gyrus/left insula,left middle occipital gyrus/left parahippocampal gyrus(FDR correction,P<0.01).(2)There was no significant correlation between the resting state functional connectivity of the brain in heroin use disorders and the dosage of methadone(P>0.05).PartⅢ(1)Compared with NRG,the gray matter volume of extensive brain areas was significantly reduced in RG at baseline,including the left cerebellar hemisphere,left temporal pole,parahippocampal gyrus,left superior occipital gyrus,precuneus,and right insular lobe.There was no brain area of gray matter volume increase(P<0.01,Alphasim correction,cluster≥41).(2)There was no significant correlation between the volume of the gray matter in RG and the number of relapses and the maintenance time(P>0.05).Conclusions1.Long-term use of methadone can cause damage to the gray matter structure of the brain of heroin use disorders,mainly involving emotional perception,spatial positioning,working memory and other related brain regions.It is suggested that appropriate neuroprotective measures should be taken to reduce the negative effects of methadone while ensuring the effectiveness of methadone treatment.The volume of gray matter of caudate nucleus and left middle occipital gyrus was negatively correlated with the dose of methadone.It is suggested that the above brain regions may be used as potential targets to evaluate the negative effects of methadone and adjust the dose of methadone reasonably.2.Long-term use of methadone will cause adaptive changes in some circuits in the brain of heroin users with heroin use disorders,it mainly involves that the functional connection of control loop and visual attention related network are weakened,while the functional connection of working memory loop is enhanced.These secondary neuroadaptive changes provide neuroimaging experimental data for further understanding the mechanism of methadone on heroin use disorders.3.Compared with non-relapsed heroin use disorders,relapsed heroin user disorders have a smaller gray matter volume in extensive brain regions,which mainly involves brain areas such as motor control,visual attention,and inner perception.These brain regions may serve as potential evaluation targets for the prevention of relapse.It is helpful to deeply understand the neurobiological mechanism of relapse of heroin use disorders in the process of MMT,and provides an objective and semi quantitative neuroimaging experimental basis for preventing relapse or reducing the relapse rate.Summary: Long-term of MMT leads to extensive gray matter structure of brain damage and functional changes in heroin use disorders.Therefore,in the process of MMT,taking appropriate neuroprotective measures may reduce the toxic effects of methadone.Founded the brain regions related to relapse may expand the objective method of neuroimaging evaluation to prevent relapse and reduce relapse rate during MMT. |
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