12 h abstinence-induced right anterior insula network pattern changes in young smokers

Drug and Alcohol Dependence 176 (2017) 162–168

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12 h abstinence-induced right anterior insula network pattern changes in young smokers ⁎

Yanzhi Bia,b, Yajuan Zhanga,b, Yangding Lic, Dahua Yud, Kai Yuana,b,d, , Jie Tiana,b,e,

MARK

⁎

a

School of Life Science and Technology, Xidian University, Xi’an, PR China Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, PR China c Guangxi Key Laboratory of Multi-source Information Mining and Security, Guangxi Normal University, Guilin, PR China d Information Processing Laboratory, School of Information Engineering, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, PR China e Institute of Automation, Chinese Academy of Sciences, Beijing, PR China b

A R T I C L E I N F O

A B S T R A C T

Keywords: Abstinence-induced craving Insula Orbitofrontal cortex Resting state functional connectivity Young smoker

Background: The strong craving to smoke is a core factor of smoking abstinence that precipitates relapse. Insula plays critical roles in maintaining nicotine dependence, especially in the interoceptive awareness of craving. Despite evidence indicating a link between insula and abstinence-induced craving, less is known about the neural basis of abstinence-induced craving from the circuit level of insula. Methods: The present study examined the effects of 12 h of abstinence from smoking on the resting state functional connectivity (RSFC) of anterior (AI) and posterior insula in young smokers using a within-subject design. Thirty-three young male smokers underwent functional magnetic resonance imaging scanning on two separate sessions: (1) smoking satiety and (2) abstinence (after ≥12 h of smoking deprivation), in counterbalanced order. Multiple regression analysis was applied to investigate the possible relationships between the RSFC changes of insula (abstinence minus satiety) and the abstinence-induced craving changes. Results: Smoking abstinence state (versus satiety) was associated with increased RSFC between right AI and right medial orbitofrontal cortex (OFC), ventromedial prefrontal cortex as well as anterior cingulate cortex. The abstinence-induced RSFC changes between right AI and right lateral OFC was significantly correlated with the craving changes. Conclusions: These findings improve the understanding of the effects of short-term smoking abstinence on insula circuit connectivity and may contribute new insights into the neural basis of abstinence-induced craving to smoke.

1. Introduction Cigarette smoking is associated with negative health consequences including lung cancer, cardiovascular, and respiratory diseases (Services, 2004). Although most smokers realized the negative outcomes of smoking and expressed a strong desire to stop smoking, the vast majority of these quit attempts ended in relapse. During abstinence from smoking, craving develops rapidly (Tiffany and Drobes, 1991) and the severity of abstinence-induced craving is theorized to be a key predictor of relapse to smoking (Killen and Fortmann, 1997; Shiffman et al., 1997). Studies indicated that the abstinence-induced craving appears to be sensitive to the effects of nicotine delivery (Tiffany et al., 2000). Within the human cerebral cortex, the insula has the high density of nicotinic acetylcholine receptors (nAChRs) (Picard et al., 2013). Nicotine binds to α4β2 nAChRs and can alter neural activity by

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activating this nicotine receptor (Changeux, 2010). During abstinence, the availability of unbound α4β2 nAChRs was correlated with the smoking urges (Staley et al., 2006). Thus, the rich environment of nicotinic receptor in insula may be more vulnerable to the addictive effects of nicotine as well as the abstinence-induced craving. Currently, converging lines of neuroimaging findings have emphasized the critical roles of insula in maintaining nicotine dependence (Addicott et al., 2015; Naqvi et al., 2007), especially its role in the interoceptive awareness of smoking craving (Bi et al., 2016; Maria et al., 2015). Lesion studies found that smokers with brain damage to the insula would undergo a disruption of smoking addiction and reported feeling no craving to smoke since quitting (Contreras et al., 2007; Gaznick et al., 2014; Naqvi et al., 2007). The increased cerebral blood flow in the right insula following abstinence could predict the abstinence-induced craving (Wang et al., 2007). Smoking cue-elicited

Corresponding authors at: School of Life Science and Technology, Xidian University, Xi’an, Shaanxi 710071, PR China. E-mail addresses: [email protected] (K. Yuan), [email protected] (J. Tian).

http://dx.doi.org/10.1016/j.drugalcdep.2017.02.019 Received 5 November 2016; Received in revised form 14 February 2017; Accepted 19 February 2017 Available online 15 May 2017 0376-8716/ © 2017 Published by Elsevier Ireland Ltd.

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Edinburgh Handedness Inventory (Oldfield, 1971), reported smoking ≥ 10 cigarettes per day for at least the past 6 months, and moderately to heavily nicotine dependent as indicated by the Fagerstrom test for nicotine dependence (FTND) (Heatherton et al., 1991). Participants were assessed by the structured clinical interview for DSMIV and no current or past disorders were detected. All participants met criteria for current nicotine dependence. Smoking behaviors were characterized by recording the average number of cigarettes per day and years of smoking regularly. Lifetime cigarette use was assessed by pack-years (cigarettes smoked per day/20 × years as a smoker). Potential participants were excluded if they had any physical illness, any contraindications (e.g., non-removable metallic implants, claustrophobia, etc.) for MRI scanning, or a lifetime diagnosis of the following conditions: neurological or psychiatric disorders (e.g., organic mental disorder, bipolar depression, schizophrenia spectrum disorder) and substance use disorder other than nicotine dependence.

craving was positively correlated with the increased insula activation in smokers (Engelmann et al., 2012). Despite all these evidence supported that cigarette craving, including the abstinence-induced craving, depends (at least partially) on the functional integrity of the insula, few studies have examined the interactions between insula and brain areas in the context of abstinence-induced craving in young smokers. Circuit level interactions between brain regions may inform specific neurobiological substrates underlying psychological dysfunctions associated with craving, reward and cognitive processing that were often observed in smokers (Sutherland et al., 2012). Resting state functional connectivity (RSFC) assessment has been increasingly employed to investigate the temporal correlation across brain regions implicated in cigarette smoking in vivo. With respect to cigarette craving, by applying a whole brain RSFC analysis using the anterior cingulate cortex (ACC) as a seed, Huang et al. found that abstinence induced increased RSFC between ACC and insula in smokers, and this connectivity strength was correlated with the intensity of withdrawal-induced craving (Huang et al., 2014). Our previous study revealed that the RSFC between anterior insula (AI) and ventromedial prefrontal cortex (VMPFC) was correlated with the craving to smoke in young smokers (Bi et al., 2016). Craving to smoke could be regulated through cognitive strategies (Kober et al., 2010a, 2010b) and the insula, particularly the AI, has been implicated in cognitive control processing (Menon and Uddin, 2010; Naqvi and Bechara, 2010). In smokers, correlation between the activity of insula and the abstinence-induced cognitive declines (Krishnan-Sarin et al., 2013; Nestor et al., 2011) as well as the association of resting state AI-ACC circuit connectivity with the cognitive impairments in young smokers were detected (Bi et al., 2016). Moreover, prior research revealed that greater RSFC between insula and regions linked to motor control could predict improved smoking cessation outcomes (Addicott et al., 2015). Thus, investigating how smoking abstinence affects the RSFC of insula might provide new insights into the neural basis of abstinence-induced craving to smoke in young smokers. In the present study, by employing a within-subject design, the RSFC changes of anterior and posterior insula (PI) across two separate occasions: during a resting abstinent state (at least 12 h of smoking deprivation) versus a resting state of smoking satiety were investigated in young smokers. Given the critical roles of abstinence-induced craving in precipitating smoking relapse during abstinence (Campos et al., 2016; Jacobsen et al., 2005), craving scores were collected. Multiple regression analysis was applied to investigate the possible relationships between the abstinence-induced RSFC changes of insula and the subjective craving changes. Based on our prior research (Bi et al., 2016) and the fact of the critical roles of AI in craving to smoke (Gu et al., 2013), we were particularly interested in functional connectivity of AI. We hypothesized that, after 12 h of abstinence from smoking, AI would exhibit stronger RSFC with brain regions linked to craving and cognitive control functions. We hope this work could facilitate our understanding of the roles of insula in abstinence-induced craving in young smokers.

2.3. Procedure The experiment used a within-subject design with two imaging sessions occurring 1–3 weeks apart: (1) smoking as usual and (2) overnight (≥12 h) abstinence. The order of sessions was counterbalanced across participants. Prior to the MRI scanning, for both sessions, subjects were instructed to refrain from alcohol and other drugs (including caffeine) consumption for 24 h, confirmed by results of a urine drug screen and a breath test for alcohol. During the satiety session, participants were asked to smoke one of their own brand cigarette about 20 min before the scan. Just prior to scanning, subjective craving was assessed using the brief 10-item form of the questionnaire for smoking urges (QSU-Brief) (Cox et al., 2001). The questionnaire used ten ‘agree–disagree' Likert items. Five items were characterized by both desire and intention to smoke with an anticipation of pleasure from smoking. For example, “I have a desire for a cigarette right now”. The other five items were related to relief from nicotine withdrawal or negative affect with an urgent and overwhelming desire to smoke. For example, “I could control things better right now if I could smoke”. The QSU-Brief asked participants to indicate how strongly they agree or disagree with each item on the questionnaire using a scale from 1 (strongly disagree) to 7 (strongly agree). Additionally, smoking was measured by expired carbon monoxide (CO) using the Smokerlyzer system (Bedfont Scientific Ltd., Rochester, UK). CO level in the expired air was verified as ≤8 parts per million (p.p.m) in abstinence state, which showed a distinct reduction for each participant compared to that measured in satiety state ( > 10 p.p.m) (Table 1). 2.4. Data acquisition The experiment was carried out on a 3-Telsa MRI system (EXCITE; General Electric; Milwaukee; Wisc.) with an eight-channel phase-array head coil at the First Affiliated Hospital of the Medical College, Xi’an Jiaotong University in China. Earplugs and a head coil with foam pads were used to minimize machine noise and head motion. High-resolution structural MR images for each subject were acquired using a threedimensional MRI sequence with a voxel size of 1 mm3 employing an axial fast spoiled gradient recalled sequence (TR = 1900 ms; TE = 2.26 ms; data matrix = 256 × 256; field of view = 256 × 256 mm2). The structural images were examined to exclude the possibility of clinically silent lesions for all of the participants by two expert radiologists. The resting-state functional images were obtained in both sessions with echo-planar imaging (30 contiguous slices with a slice thickness of 5 mm; TR = 2000 ms; TE = 30 ms; flip angle = 90°; field of view = 240 × 240 mm2; data matrix = 64 × 64; total volumes = 180). During the 6 mins functional scan, participants were instructed to keep their head still and eyes closed, not to think about anything and to stay awake during the entire

2. Material and methods 2.1. Ethics statement This study was approved by the Medical Ethical Committee of the First Affiliated Hospital of the Medical College, Xi’an Jiaotong University and was in accordance with the latest version of the Declaration of Helsinki. All participants provided written informed consent and were financially compensated for their time. 2.2. Participants Thirty-three male smokers (19–24 years of age) participated in this study. Inclusion criteria included: right-handed as measured by the 163

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of insula. Four seed regions of interest (ROIs) including the left and right AI as well as the left and right PI were defined on the basis of our previous study (Bi et al., 2016) using the analytic scripts download via http://fcon_1000.projects.nitrc.org as seeds (Kelly et al., 2012). For each individual dataset of both sessions, RSFC analysis was implemented using 3dfim+ (AFNI) to produce individual-level correlation maps of all voxels that were positively or negatively correlated with the averaged time series across all voxels in each seed ROI. Finally, the resultant correlation maps were converted to Z-value maps using Fisher’s r-to-z transformation.

Table 1 Craving scores and CO levels in both sessions as well as the duration of smoking abstinence for each subject. Subject ID

Items Duration of Abstinence (h)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

16 15 17.5 19 15 12 23.5 13.5 16.5 19 20 20 16 23 15 21 18 17 15 13 20 12 22 13 19 19.5 13.5 23.5 18 13 16 14 21

QSU-Brief

CO (p.p.m)

Satiety

Abstinence

satiety

Abstinence

12 25 24 31 53 49 10 32 42 28 44 45 37 10 14 20 16 20 27 32 18 13 34 26 34 41 25 27 16 35 36 11 50

13 64 54 55 37 52 40 25 45 45 10 48 45 29 18 48 41 37 12 38 39 17 52 21 34 43 20 43 25 27 19 12 26

10 11 13 22 11 11 11 19 13 16 11 11 14 18 11 16 14 10 10 13 12 12 16 18 11 10 10 13 13 13 12 14 11

5 7 4 5 4 6 5 6 7 5 5 3 6 6 4 6 4 4 3 6 3 8 4 8 3 3 3 5 4 5 5 5 2

2.7. Statistical analysis Two-sample paired t-tests were employed to assess the differences between two resting sessions (satiety and abstinence) across the sample of subjects for each seed using Permutation-based non-parametric testing with 5000 random permutations. The resulting statistical maps were thresholded at p = 0.05, with correction for multiple comparisons (family-wise error, FWE) at the cluster level by using the threshold-free cluster enhancement method in the randomise permutation-testing tool in FSL (Smith and Nichols, 2009). Bonferroni correction was conducted for four seeds at the whole brain level (p < 0.0125). For each seed, individual abstinence-induced RSFC map was generated by applying the individual RSFC map (standardized Z-value map) for each subject in abstinence state minus the RSFC map in satiety state. Then, to evaluate the possible relationship between the abstinence-induced RSFC changes of insula and subjective craving changes, voxelwise whole-brain multiple regression analysis with the craving changes (abstinence minus satiety) included as covariates was applied. Significance threshold was set to p < 0.001 uncorrected (t > 3.5). Besides, a series of Pearson’s correlation analysis were performed to evaluate the possible relationships between abstinence-induced craving changes and FTND, CO levels as well as the duration of smoking abstinence (Bonferroni corrected, p < 0.0125). 3. Results

QSU-Brief, the brief 10-item form of the questionnaire for smoking urges.

3.1. Demographics session. After the scan, the subjects were asked whether or not they remained awake during the whole procedure.

All thirty-three male smokers were local college students and had a mean of 13.9 (standard deviation, SD = 0.6) years of education. The average age was 21.2 (SD = 1.3) and participants smoked, on average, 15.1 (SD = 5.2) cigarettes per day for 4.7 (SD = 2.5) years. The average FTND score was 4. 7 (SD = 1.7). During abstinence, young smokers were deprived from smoking with an average of 17.26 (SD = 3.42) h. The smoking abstinence elicited significantly increased craving to smoke in young smokers than the satiety session [average score of 34.36 (SD = 14.65) in abstinence state versus 28.39 (SD = 12.41) in satiety state, p = 0.049, Table 2]. No significant correlations were detected between abstinence-induce craving changes and FTND (r = 0.22; p = 0.21), CO changes elicited by abstinence (r = 0.20; p = 0.26) as well as the duration of smoking abstinence (r = 0.32; p = 0.07), Bonferroni corrected, p < 0.0125.

2.5. Resting state functional data preprocessing For both sessions, Analysis of Functional NeuroImages (AFNI, http://afni.nimh.nih.gov/) and FMRIB Software Library (FSL,www. fmrib.ox.ac.uk) were used for data analysis. As described in our previous study (Bi et al., 2016; Yuan et al., 2016a, 2016b), functional data were slice timing corrected and rigid-body head motion corrected with exclusion criteria of movement parameters exceeding 3.0 mm in translation or 3° in rotation. Registration was performed by the following steps: obliquity transform to the structural image, affine coregistration to the skull-stripped structural image and standard spatial transform to the MNI152 template. Then, the data were spatially smoothed using a 6-mm kernel and intensity normalized to a wholebrain median of 1000. Previous studies detected that wavelet despiking could control head motion-induced noise better than nuisance regression and bandpass filtering alone (Patel et al., 2014). Therefore, denoising was performed in the present study: (1) wavelet despiking; (2) nuisance signal regression including the 6 motion parameters, their first order temporal derivatives and ventricular cerebrospinal fluid signal (14-parameter regression); and (3) a temporal Fourier filter.

3.2. RSFC results As shown in Fig. 1, right AI exhibited stronger RSFC with bilateral ACC, bilateral VMPFC and right medial orbitofrontal cortex (OFC) after12 h of abstinence from smoking (FWE corrected, p < 0.05). Left AI and bilateral PI showed no significant RSFC differences across the two sessions (FWE corrected, p < 0.05). After Bonferroni correction, only left ACC and left VMPFC showed increased RSFC with right AI during abstinence (Bonferroni corrected, p < 0.0125; Table 3). Multiple regression analysis detected that abstinence-induced craving (abstinence minus satiety) was significantly correlated with the RSFC changes between right AI and right lateral OFC (uncorrected,

2.6. Resting state functional connectivity of insula Seed-based correlation analysis was performed to examine the RSFC 164

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Table 2 Demographic information of young smokers. Behaviors

Smoker (n = 33, male) Satiety

Duration of Abstinence (hour) QSU-Brief CO (p.p.m)

Abstinence

P Value

Mean ± SD

Range

Mean ± SD

Range

– 28.39 ± 12.41 13.03 ± 2.96

– 10–53 11–22

17.26 ± 3.42 34.36 ± 14.65 4.82 ± 1.49

12–23.5 10–64 2–8

– .049 < 0.0001

SD, standard deviations. QSU-Brief, the brief 10-item form of the questionnaire for smoking urges.

p < 0.001; Fig. 2b), although it did not survive multiple comparison correction at p < 0.05. Pearson’s correlation analysis also detected this positive correlation (r = 0.50; p = 0.003, Bonferroni corrected, p < 0.0125; Fig. 2c).

Table 3 Regions exhibiting significantly increased RSFC with right AI in abstinence state relative to satiety state. Region

Brodmann area

Peak voxel

Volume (mm3)

Peak p value

X

Y

Z

32

−2

50

10

640

0.01

32

2

50

10

120

0.02

10

−2

68

0

1856

0.009

10/11

0

54

6

576

0.02

4. Discussion Left Anterior Cingulate Gyrus Right Anterior Cingulate Gyrus Left Medial Frontal Gyrus Right Medial Frontal Gyrus

Data from China indicate that the age period spanning late adolescence to emerging adulthood is associated with the high prevalence of cigarette smoking (http://www.chinacdc.cn/). Smokers who start smoking at an early age are more likely to become life-long smokers and are more susceptible to nicotine addiction than adults (White et al., 2009). During late adolescence to emerging adulthood, maturational brain processes are continuing (Sowell et al., 2003). It has been hypothesized that cigarette smoking during this critical period produces neurobiological changes that promote tobacco dependence later in life (Tiffany, 2008). Therefore, studying the neural correlates of smoking behaviors in this age period is of great importance, which may contribute to clarifying the neural mechanism that causes addiction in late adolescence to emerging adulthood. The present study examined the effects of 12 h of abstinence from smoking on the RSFC of insula in young smokers, as well as the correlations between abstinence-induced RSFC changes in insula and the changes of abstinence-induced craving to smoke. We found that, after 12 h of abstinence from smoking, right AI exhibited stronger RSFC with ACC, VMPFC and right medial OFC, regions commonly implicated in craving and cognitive control (Goldstein and Volkow, 2011; Hayashi et al., 2013; MacDonald et al., 2000; Volkow and Fowler, 2000). The abstinence-induced right AI-right lateral OFC circuit connectivity

All the coordinates are located in the MNI space. RSFC: resting state functional connectivity; AI: anterior insula.

changes was significantly correlated with the craving changes in young smokers. The present findings from the circuit level of insula may provide new insights into the neurobiological mechanisms underlying the abstinence-induced craving.

4.1. The AI-OFC circuit in abstinence-induced craving Abstinence from smoking gives rise to a conscious feeling of urges to smoke. Current study found that abstinence from smoking for ≥12 h induced significantly increased craving to smoke in young smokers (Fig. 2a). Particularly, this abstinence-induced craving to smoke was positively correlated with the changes of RSFC between right AI and

Fig. 1. Resting state functional connectivity (RSFC) changes of insula following 12 h of abstinence (abstinence minus satiety). Right anterior insula showed enhanced RSFC with bilateral anterior cingulate cortex (ACC), bilateral ventromedial prefrontal cortex (VMPFC) and right medial orbitofrontal cortex (OFC) following abstinence from smoking versus the satiety state. Family wise error (FWE) corrected, p < 0.05.

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Fig. 2. Increased craving to smoke elicited by smoking abstinence (versus satiety state) and its correlation with the resting state functional connectivity (RSFC) changes of insula (abstinence minus satiety). (a) 12 h of abstinence from smoking significantly increased the craving to smoke in young smokers. (b) Multiple regression analysis revealed correlation between abstinence-induced right anterior insula (AI)-right lateral orbitofrontal cortex (OFC) circuit connectivity changes and craving changes. Uncorrected, p < 0.001. (c) The RSFC changes between right AI and right lateral OFC was positively correlated with abstinence-induced craving changes. Bonferroni corrected, p < 0.0125. QSU, the brief 10-item form of the questionnaire for smoking urges.

2012). The AI has reciprocal connections to VMPFC (Chang et al., 2012). The interactions between the insula and VMPFC have been suggested to underlie affective processes at multiple stages of the addiction cycle, particularly during abstinence from smoking (Naqvi and Bechara, 2010). One pharmacotherapy study indicated that abstinence-induced craving was mediated by the RSFC of AI-VMPFC and elevated AI-VMPFC circuit connectivity was associated with increased withdrawal severity (Sutherland et al., 2013). Collectively, we suggest that the interactions between right AI and VMPFC may be crucial during abstinence.

right lateral OFC (Fig. 2c). The insula and OFC are regarded as critical neural substrates perpetuating cigarette smoking (Goldstein and Volkow, 2011; Naqvi and Bechara, 2009; Naqvi et al., 2007). A broad literature has addressed the critical role of the AI, in particular the right anterior insula, in monitoring and regulating conscious feelings of craving to smoke (Naqvi and Bechara, 2010) as well as the role of OFC in encoding the subjective value of craving to guide motivated smoking behaviors (Hayashi et al., 2013; Volkow and Fowler, 2000). Smokers who acquired brain damage in insula reported no craving to smoke and smokers with brain damage in OFC experienced a reduction in conscious craving (Naqvi et al., 2007). Elevated insula and OFC responses to smoking-related cues were associated with increased craving (Chase et al., 2011; Engelmann et al., 2012) and greater relapse susceptibility (Janes et al., 2010). During smoking withdrawal, abstinence-induced craving to smoke could be predicted by cerebral blood flow increases in the right OFC and right insula, which might be important in smoking relapse (Wang et al., 2007). Additionally, the AI is structurally and functionally connected to the OFC (Mesulam and Mufson, 1982). In the present study, except for the findings of the positive correlation between abstinence-induced craving and right AIright lateral OFC circuit connectivity changes, significantly increased RSFC between right AI and right medial OFC after 12 h of abstinence from smoking was also detected. Thus, we suggest that a strengthen AIOFC circuit appears to render smokers with ≥12 h of smoking abstinence particularly vulnerable to cigarette craving. Furthermore, evidence demonstrated that abnormal OFC structural connectivity was correlated with the severity of nicotine addiction (Huang et al., 2013), therefore, investigating the structural connectivity between AI and OFC and its relationship with the abstinence-induced craving changes might further our understanding the neural basis of abstinence-induced craving in future study.

4.3. The potential functions of AI-ACC circuit during abstinence In the present study, smoking abstinence produced elevated RSFC between right AI and ACC in young smokers (Fig. 1), which supports the previous findings of 11 h of abstinence-induced increased RSFC between the insula and ACC (Huang et al., 2014). From the circuit level perspective, the AI together with the ACC form a salience network (SN) that is responsible for maintaining a variety of foundational capacities fundamental to cognitive function. Our previous study has pointed the AI-ACC circuit connectivity changes and its correlation with the cognitive impairments in young smokers (Bi et al., 2016; Li et al., 2016). Smoking abstinence was associated with deficiencies in cognitive functions in smokers (Jacobsen et al., 2005; Mendrek et al., 2006; Xu et al., 2005). Lerman and colleagues proposed that, in the nicotinedeprived state, the SN increases the allocation of attentional resources to attend to the abstinence-induced craving to smoke, leading to a bias toward enhanced default mode network activity (including VMPFC) (Lerman et al., 2014). The failure to suppress default mode network activity may increase the probability of error on cognitive tasks during smoking abstinence (Eichele et al., 2008). Collectively, all these evidence may provide insights into the potential functions of the right AI-ACC circuit during abstinence in young smokers.

4.2. The possible role of AI-VMPFC circuit during abstinence

4.4. Theoretical implications of the current findings

Enhanced resting state right AI-VMPFC circuit connectivity following 12 h of smoking abstinence was detected in the present study (Fig. 1). Although no correlations were found between the changes of this circuit connectivity and the abstinence-induced craving (Fig. 2b), the altered circuit level interactions between AI and VMPFC should also receive attention for the important functions of these areas in perpetuating cigarette smoking. The VMPFC has been implicated in processing and regulation of emotion and motivation to smoke (Goldstein and Volkow, 2011). Smoking cue-induced craving was associated with increased VMPFC activation (Chase et al., 2011; Engelmann et al.,

Craving is an important symptom of nicotine dependence that could be triggered by abstinence and relieved by the cigarette smoking. The sensitization-homeostasis theory indicates that smoking abstinence stimulate neural system (including OFC, PFC and ACC) that generate craving, the increased spontaneous activity in craving generation system is correlated with the intensity of craving (DiFranza et al., 2012; DiFranza and Wellman, 2005). The current finding confirms the sensitization-homeostasis model’s prediction. Besides, researchers de166

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Large-scale brain network coupling predicts acute nicotine abstinence effects on craving and cognitive function. JAMA Psychiatry 71, 523–530. Li, Y., Yuan, K., Guan, Y., Cheng, J., Bi, Y., Shi, S., Xue, T., Lu, X., Qin, W., Yu, D., 2016. The implication of salience network abnormalities in young male adult smokers. Brain Imag. Beahv. 1–11. http://dx.doi.org/10.1007/s11682-11016-19568-11688. MacDonald, A.W., Cohen, J.D., Stenger, V.A., Carter, C.S., 2000. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science 288, 1835–1838. Maria, M.S., Megan, M., Hartwell, K.J., Hanlon, C.A., Canterberry, M., Lematty, T., Owens, M., Brady, K.T., George, M.S., 2015. Right anterior insula connectivity is

tected that the activity within default mode network (Cole et al., 2010; Tanabe et al., 2011), circuit connectivity in ACC (Huang et al., 2014) and cerebral blood flow in ACC (Domino et al., 2004; Zubieta et al., 2005), OFC (Wang et al., 2007) were increased during abstinence in smokers. These increased spontaneous activity were also correlated with the intensity of abstinence-induced craving. All of these findings may provide insight into the location of the “Craving Generation System” postulated by the theory and the neural mechanism of abstinence-induced craving. 4.5. Limitations Except for the strengths presented in the current study, such as the within-subject design and the abstinence manipulation, several limitations should be considered. First, only male smokers were included in this study. Previous studies pointed that abstinence-induced craving to smoke (Saladin et al., 2012) and the neural mechanism of craving (e.g. smoking cue-induced craving) differed by sex (McClernon et al., 2008). In China, although males are particularly at risk for smoking (http:// www.chinacdc.cn/), future studies should verify that our findings could be generalized to female smokers or were only specific to young male smokers. Another limitation is that functional connectivity can only measure the degree of correlated activity, the direction of the dynamic interactions between brain regions cannot be described only using RSFC approach. Therefore, future studies should consider to apply the effective connectivity analysis, which may provide new insights into the precise role of the insula in abstinence-induced craving. Conflict of interest None. Role of the funding source The funding sources have no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the article; or in the decision to submit the paper for publication. Contributors YB, DY, KY and JT were responsible for the study concept and design. YB, YZ, YL and DY contributed to the acquisition of MRI data. YB, YZ and YL performed the data analysis and interpretation of findings. YB drafted the manuscript. All authors critically reviewed content and approved final version for publication. Acknowledgements This work is supported by the National Natural Science Foundation of China under Grant nos. 81571751, 81571753, 61502376, 81401478, 81401488, 81470816, 81471737, 81301281, 81271546, 81271549, the Natural Science Basic Research Plan in Shaanxi Province of China under Grant no. 2014JQ4118, the Fundamental Research Funds for the Central Universities under Grant nos. JB151204, JB121405, the Natural Science Foundation of Inner Mongolia under Grant no. 2014BS0610, the Innovation Fund Project of Inner Mongolia University of Science and Technology Nos. 2015QNGG03, 2014QDL002, and General Financial Grant the China Post- doctoral Science Foundation under Grant no. 2014M552416. References Addicott, M.A., Sweitzer, M.M., Froeliger, B., Rose, J.E., McClernon, F.J., 2015. Increased functional connectivity in an insula-based network is associated with improved smoking cessation outcomes. Neuropsychopharmacology 40, 2648–2656. Bi, Y., Yuan, K., Guan, Y., Cheng, J., Zhang, Y., Li, Y., Yu, D., Qin, W., Tian, J., 2016.

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