IntroductionCognitive dysfunction is a key component of addictive disorders. With heroin addiction, specific deficits in salience attribution and inhibitory control emerge during long-term drug abuse and promote heroin relapse during withdrawal.1 Although most heroin-dependent individuals are willing to quit, available interventions for heroin addiction have shown only limited efficacy so far. Methadone maintenance treatment programs (MMTPs) are a common treatment approach thought to be effective for heroin addiction; however, the heroin-dependent patients in MMTPs are at high risk for relapse, with about 70% of individuals relapsing once they leave such a program.2 Despite the high relapse rate, few neuroimaging studies so far have addressed the neural predictors of risk for heroin relapse. Studies using task-related functional MRI (fMRI) have shown some usefulness in identifying relapse predictors 3-5 or quitting predictors. 6,7 For example, a previous study by our group showed that drugrelated cues induced activity of the nucleus accumbens/ subcallosal cortex and that the cerebellum was associated with subsequent relapse in heroin-dependent individuals. 3Brain activity associated with error processing was shown to predict relapse in cocaine-dependent patients.4 Disrupted ventromedial prefrontal function was shown to be associated with relapse in alcohol-dependent patients.5 Greater response of the medial prefrontal cortex and precuneus to self-related tailored smoking-cessation messages was shown to be associated with quitting. 6 And pretreatment medial prefrontal cortical response to heroin-related cues was shown to be associated with greater adherence to injectable extended-release naltrexone.7 However, more effective imaging markers that We conducted a prospective resting-state functional MRI study comparing the functional connectivity strength among healthy controls and heroin-dependent men who had either relapsed or were in early remission. Men were considered to be either relapsed or in early remission based on urine drug screens during a 3-month follow-up period. We also examined how the coupling of large-scale networks correlated with relapse behaviour among heroin-dependent men. Results: We included 20 controls and 50 heroin-dependent men (26 relapsed and 24 early remission) in our analyses. The relapsed men showed greater connectivity than the early remission and control groups between the dorsal anterior cingulate cortex (key node of the SN) and the dorsomedial prefrontal cortex (included in the DMN). The relapsed men and controls showed lower connectivity than the early remission group between the left dorsolateral prefrontal cortex (key node of the left ECN) and the dorsomedial prefrontal cortex. The percentage of positive urine drug screens positively correlated with the coupling between the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex, but negatively correlated with the coupling between the left dorsolateral prefrontal cortex and dorsomedial prefrontal cortex. Limitations:...

Calcitonin gene-related peptide (CGRP) is known to induce osteoblastic differentiation and alkaline phosphatase activity in bone marrow stromal stem cells (BMSCs). However, it has remained elusive whether this effect is mediated by CGRP receptors directly or whether other signaling pathways are involved. The present study assessed the possible involvement of the Wnt/β-catenin signaling pathway in the activation of CGRP signaling during the differentiation of BMSCs. First, the differentiation of BMSCs was induced in vitro and the expression of CGRP receptors was examined by western blot analysis. The effects of exogenous CGRP and LiCl, a stimulator of the Wnt/β-catenin signaling pathway, on the osteoblastic differentiation of BMSCs were assessed; furthermore, the expression of mRNA and proteins involved in the Wnt/β-catenin signaling pathway was assessed using quantitative PCR and western blot analyses. The results revealed that CGRP receptors were expressed throughout the differentiation of BMSCs, at days 7 and 14. Incubation with CGRP and LiCl led to the upregulation of the expression of osteoblastic genes associated with the Wnt/β-catenin pathway, including the mRNA of c-myc, cyclin D1, Lef1, Tcf7 and β-catenin as well as β-catenin protein. However, the upregulation of these genes and β-catenin protein was inhibited by CGRP receptor antagonist or secreted frizzled-related protein, an antagonist of the Wnt/β-catenin pathway. The results of the present study therefore suggested that the Wnt/β-catenin signaling pathway may be involved in CGRP- and LiCl-promoted osteoblastic differentiation of BMSCs.

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