| Objective:Heroin addiction is the most prevalent type of drug addiction in China, methadone maintenance treatmentis regarded as the most commonly and effective treatment mode for heroin addiction. However, despite of its effectiveness in reducing heroin craving, reducing the crime rate and improving the life status, there still some problems which should be considered in the program of the methadone maintenance treatment. Firstly, as a long-acting synthetic opioid drug, some studies demonstrated that chronic MMT can induce impairments in neuropsychology, neurotransmitter function, brain function and structures. However, the impact of chronic methadone use on brain white matter is not fully revealed. Secondly, heroin relapse rate is still high, while the neurobiological base of the heroin relapse is unclear. Therefore, the aim of this study is to explore these two problems using the functional magnetic resonance imaging methods, the whole studyinclude three experiments, Part I:The effects of chronic methadone use on white matterin methadone maintaince patients: a self-control DTI study, Part II:Heroin relapse related brain white matter integrity alteration in methadone maintenance treatment patients and Part III:Heroin relapse related organization modeof resting-sate default mode network in methadone treated patients. Methods:Part I:Thirty-three stable methadone maintenance patients executed diffusion tensor imaging twice, at the entrance of the study(S1) and one year interval(S2). Voxel-wise comparisons(S2 vs. S1) of fractional anisotropy(FA) were performed by paired t test. The inter-group differences of radial diffusivity(RD) and axial diffusivity(AD) in identified regions which showed significant FA difference were analyzed, along with the investigation of the correlation between methadone consumption and neuropsychological status within one year and the DTI indices. Part II:Forty-eight heroin addicts underwent methadone maintenance treatment completed the baseline DTI scanning and six months’ longitudinal follow-up subsequently, and divided into heroin relapers(HR) and heroin abstainers(HA) according to results of urine test. Voxel-wise comparisons on FA and region of interestwised analyses of RD and AD as well as the correlation between the degree of the heroin relapse and DTI indices were analyzed. Part III:Twenty-three heroin addiction patients under methadone maintenance treatment were included in this study. Resting-state functional magnetic resonance imaging data were collected. All participators were divided into HR and HA according to results of urine test.Independent component analysis was used to identify the organization mode of the default mode network. Group comparison were performed between the two groups. Additionally, correlation between the degree of the relapseand connectivitywere analyzed in regions of interests. Results:Part I:We found significantly reduced FA in S2 in bilateral external capsule, right posterior thalamic radiation, superior longitudinal fasciculus, anterior corona radiata, left posterior limb of internal capsule, superior and posterior corona radiata, corticospinal tract and corpus callosum(P < 0.01, corrected by TFCE and FWE). All regions shown significantly reduced FA had increased RD, reduced AD were found in right external capsule, posterior thalamic radiation, anterior corona radiata,superior longitudinal fasciculus and corpus callosum. The percentage of RD change in left corticospinal tract positively correlated with the accumulated methadone consumption within one year(r = 0.47, P = 0.008). The RD values in S2 were positively correlated with the score of non-planning impulsiveness measured after one-year follow-up(Cluster 3, r = 0.47, P = 0.003;Cluster 2, r = 0.46, P = 0.004;Cluster1, r = 0.44, P = 0.005). Part II:Compared with HA, HR had lower FA in right retrolenticular part, left anterior and posterior limb of the internal capsule, bilateral anterior corona radiata and right external capsule(P< 0.05, corrected by TFCE and FWE). Among these, right retrolenticular part,left posterior limb of the internal capsuleand right external capsule showed significantly increased RD, and no significant difference in AD was found. The FA and AD values in left posterior limb of the internal capsule correlated negatively with the heroin positive urinalysis rate within follow-up(r=-0.89, P < 0.001; r=-0.88, P < 0.001). Part III:Our study found that left inferior temporal gyrus and right superior occipital gyrus associated with DMN showed decreased functional connectivity in HR comparing with HA, while left precuneus and right middle cingulum have increased functional connectivity(P < 0.05, corrected by FDR). Intensity signals, extracted from left inferior temporal gyrus of HR patients, showed a significant negative correlation with corresponding degree of the heroin relapse(r=-0.578, P=0.038). Conclusions:The results suggested methadone have scathing effects on white matter integrity,in spite of its positive therapeutic effectiveness. The dose-dependence pattern of the impairment and the dominating pathological characteristics of demyelination may suggest a new approach to protect white matter integrity and to enhance the clinical effectiveness of methadone maintenance treatment. In addition, significantly reduced white matter integrity and altered functional connectivity of default mode networkwere identified among methadone treated heroin addicts who subsequently relapse, and these abnormalities in brain white matter and resting functional connectivity were associated with higher relapse frequency. Therefore, we conjecture that these altered white matter integrity and functional connectivity of default mode network may contributed to the potential neurobiology mechanism of heroin relapse, may have the predictive value of heroin relapse in methadone treated patients and provide new strategy for heroin addiction treatment and reducing the relapse rate. |
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