Elsevier

Brain Research

Volume 1469, 21 August 2012, Pages 63-72
Brain Research

Research Report
Craving correlates with mesolimbic responses to heroin-related cues in short-term abstinence from heroin: An event-related fMRI study

https://doi.org/10.1016/j.brainres.2012.06.024Get rights and content

Abstract

Craving is an important factor in relapse to drug abuse, and cue-induced craving is an especially powerful form of this construct. Neuroimaging methods have been utilized to study drug cue-induced craving and neural correlates in the human brain. However, very few studies have focused on characterizing craving and the neural responses to heroin-related cues in short-term abstinent heroin-dependent patients. Twenty-four heroin-dependent subjects and 20 demographically matched drug-naïve subjects participated in this study. An event-related cue-reactivity paradigm was employed, while changes in blood oxygen level-dependent (BOLD) signals were acquired by functional magnetic resonance imaging (fMRI). The heroin-dependent group reported significantly increased craving following exposure to heroin-related cues. Direct comparison between the two groups showed that brain activation to heroin-related minus neutral cues was significantly greater for the heroin-dependent group in the bilateral nucleus accumbens (NAc), caudate, putamen, amygdala, hippocampus/parahippocampus, midcingulate cortex, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), medial frontal gyrus (MeFG), midbrain, thalamus, left anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and subcallosal gyrus. Changes in craving in the heroin-dependent group correlated positively with brain activation in the bilateral NAc, caudate, right putamen, and left ACC. The abstinence duration correlated positively with brain activation in the left caudate and right parahippocampal gyrus. In conclusion, the cue-reactivity paradigm significantly activated neural responses in the mesolimbic dopamine (DA) system and prefrontal cortex (PFC) and induced increased craving in short-term abstinent heroin-dependent patients. We suggest that these response patterns characterize the high vulnerability of relapse in short-term abstinent heroin-dependent subjects.

Highlights

►We studied the cue-induced brain reactivity in short-term abstinent heroin addicts. ► The heroin addicts reported significantly increased heroin-cue-induced craving. ► Craving increase is positively associated with activation of the mesolimbic system. ► The mesolimbic system's response patterns indicate a high vulnerability to relapse. ► The prefrontal cortex's response patterns indicate a high vulnerability to relapse.

Introduction

Drug addiction is a major health problem in modern society (Nordahl et al., 2005). Heroin addiction in particular has become an increasingly serious problem for China in recent years (Tang et al., 2006, Xiao et al., 2006). Such addiction is characterized by the failure to resist one's impulses to obtain and take drugs despite serious and negative consequences (Volkow and Li, 2004). It is assumed that the molecular and structural changes mainly within the mesolimbic dopamine (DA) system constitute the ‘switch’ from controlled drug intake to compulsive drug abuse (Spanagel and Heilig, 2005). Heroin craving is a trigger for relapse and dropping out of treatment (Fareed et al., 2010). It may be induced in addicted patients using drug-related cues known to prompt drug-seeking behavior (Zijlstra et al., 2009). As is shown, short-term abstinence is very difficult for heroin-dependent patients (Shi et al., 2007) and relapse was highly associated with shorter treatment duration for drug addicted individuals (Xie et al., 2011). The neural mechanism underlying high vulnerability to relapse during short-term abstinence is not very clear. Investigation of heroin cues-induced craving and brain response may be a key to solving the problem.

Neuroimaging studies on craving have mostly investigated cocaine (Kufahl et al., 2005, Sinha et al., 2005, Wexler et al., 2001, Wong et al., 2006). However, there are very few imaging studies focusing on heroin craving in short-term abstinent heroin-dependent individuals or which explore the role of drug-cue-induced craving in this regard. Some studies using cue-reactivity paradigms have been conducted on opioid-dependent but not heroin-dependent subjects. These studies have indicated that the mesolimbic DA system is mainly involved in the heroin-cues induced reactivity such as the nucleus accumbens (NAc), caudate, putamen (Wang et al., 2011a), anterior cingulate cortex (ACC) (Daglish et al., 2001, Langleben et al., 2008, Wang et al., 2011a), amygdala (Mei et al., 2010), hippocampus (Langleben et al., 2008, Mei et al., 2010), and ventral tegmental area (VTA) (Langleben et al., 2002, Mei et al., 2010, Zijlstra et al., 2009). Also, the prefrontal areas such as the medial prefrontal cortex (Daglish et al., 2001), orbitofrontal cortex (OFC) (Langleben et al., 2008, Mei et al., 2010), dorsolateral prefrontal cortex (DLPFC) (Wang et al., 2011a) and other brain regions including the thalamus (Langleben et al., 2002, Mei et al., 2010, Wang et al., 2011a), posterior cingulate cortex (PCC) (Langleben et al., 2002, Wang et al., 2011a), insula (Langleben et al., 2002, Langleben et al., 2008), subthalamic nucleus (Zijlstra et al., 2009) and midbrain (Sell et al., 1999) are involved in heroin-cues induced reactivity. However, few of the studies mentioned above showed a definite association between cue-elicited craving and brain activation in response to heroin-related cues in opioid-dependent patients. The results derived from studies with opioid-dependent patients cannot be directly linked to heroin addiction because of the potential impact of other opioids such as methadone (Langleben et al., 2008) and buprenorphine (Mei et al., 2010). Meanwhile, the potential relationship between craving and brain activation in response to heroin cues in short-term abstinent heroin-dependent patients is currently unknown.

Neuroimaging studies in drug addiction have demonstrated that the mesolimbic DA system is affected structurally (Wang et al., 2011b), metabolically (Schweitzer et al., 2011), functionally (Kufahl et al., 2005). The mesolimbic DA system has been suggested to be mainly involved in the mediation of cue-induced heroin craving (Wise, 2009). Two cocaine studies by Volkow and associates have demonstrated that cocaine cues significantly increase DA in the dorsal striatum mainly involved in the mesolimbic DA system, and the magnitude of this increase is correlated with subjective craving (Volkow et al., 2006, Wong et al., 2006). Based on the previous finding of studies on opioid-dependent patients, we hypothesized that heroin-related cues would significantly activate the brain regions mainly involved in the mesolimbic DA system and the prefrontal cortex (PFC) compared with neutral cues. We further predicted that the increase in drug-cue-induced craving would be positively correlated with an increase in the activation of the mesolimbic DA system.

Moreover, the cue stimuli in most previous functional imaging studies of heroin addiction were shown in a block design (Yang et al., 2009, Zijlstra et al., 2009). They analyzed brain activation during the block for a relatively long time (e.g. 18–30 s) under repeated heroin-related cue exposure. The paradigms could not indicate the ‘immediate response’ to drug cues (Ko et al., 2011). An event-related design may facilitate a characterization of the temporal response profiles that has a high effective temporal resolution relative to the repetition time (Friston et al., 1998). Even an event-related analysis can provide a more accurate model of the hemodynamic responses than an epoch-related analysis in a block design (Mechelli et al., 2003). Therefore, event-related fMRI studies are needed to determine the immediate reaction to heroin-related cues and to characterize the nature of the cue-induced craving response.

In the present study, we utilized an event-related fMRI cue-reactivity paradigm to test this hypothesis in short-term abstinent heroin-dependent patients.

Section snippets

Craving ratings

The subjective craving score before cue presentation was 2.5 ± 1.7 (mean ± SD) and after cue presentation was 3.4 ± 2.6 (mean ± SD). A paired sample t-test indicated that subjective craving scores after cue presentation were significantly higher than before cue presentation for the heroin-dependent patients (t = 2.82, P = 0.01).

The within-group differences

The activated brain regions relating to the “Heroin-Neutral” contrast in the heroin-dependent group included the bilateral NAc, caudate, putamen, ACC, DLPFC, OFC, superior frontal

Discussion

Our event-related study revealed that heroin-related cues elicited increased activation in the mesolimbic DA and PFC regions of the brain in short-term abstinent heroin-dependent patients. Furthermore, the activation in the mesolimbic DA regions was associated with the craving for heroin. These findings suggest that the mesolimbic DA and PFC regions were associated with the mechanism of heroin craving under cue exposure.

Our results support the model suggested by Volkow proposing a network of

Participants

Twenty-four short-term abstinent heroin-dependent patients were recruited from residential treatment programs in Tangdu Hospital. Twenty healthy control subjects were recruited through advertisements (Table 1). All of the subjects were male smokers. Subjects completed a clinical interview prior to inclusion in the study (Structured Clinical Interview for DSM-IV [SCID], a urine drug screening, naloxone test and an fMRI task). Inclusion criteria for the heroin-dependent group were (1) DSM-IV

Authors' contribution

Qiang Li undertook the MRI data analyses and wrote the manuscript; Yarong Wang wrote the protocol; Yi Zhang, Wei Li, Weichuan Yang, Jia Zhu, Ning Wu, Haifeng Chang Ying Zheng, Kai Yuan and Jixin Liu collected the clinical and MRI data and conducted the data analyses; and Jie Tian, Wei Wang, Wei Qin and Liyan Zhao contributed to the study design. All authors critically reviewed and have approved the final manuscript for publication.

Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 30870685, 81071142, 81071143 and 60901064) and the Development Project of Science and Technology of Shaanxi Province (Nos. 2008K12-02, 2009K01-65, 2010K16-03-01 and 2010K16-03-02). We thank Jiakuan Xu, Xinhai Wu and Xinsuo Wang for their contributions to the recruitment of heroin subjects. We thank Yunming Li for his help in statistical data processing. We also thank Karen M. von Deneen for her

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