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ARTICLE IN PRESS
Drug and Alcohol Dependence xxx (2015) xxxxxx
a r t i c l e
i n f o
Article history:
Received 13 July 2015
Received in revised form
14 September 2015
Accepted 15 September 2015
Available online xxx
Keywords:
Accumbens
Cingulate
Cigarette
Nicotine
rsFC
Glutamate
a b s t r a c t
Background: Chronic exposure to drugs of abuse disrupts frontostriatal glutamate transmission, which
in turn meditates drug seeking. In animal models, N-Acetylcysteine normalizes dysregulated frontostriatal glutamatergic neurotransmission and prevents reinstated drug seeking; however, the effects
of N-Acetylcysteine on human frontostriatal circuitry function and maintaining smoking abstinence is
unknown. Thus, the current study tested the hypothesis that N-Acetylcysteine would be associated with
stronger frontostriatal resting-state functional connectivity (rsFC), attenuated nicotine withdrawal and
would help smokers to maintain abstinence over the study period.
Methods: The present study examined the effects of N-Acetylcysteine on frontostriatal rsFC, nicotinewithdrawal symptoms and maintaining abstinence. Healthy adult, non-treatment seeking smokers
(N = 16; mean (SD) age 36.5 11.9; cigs/day 15.8 6.1; years/smoking 15.7 8.9) were randomized to
a double-blind course of 2400 mg N-Acetylcysteine (1200 mg b.i.d.) or placebo over the course of 3
days of monetary-incentivized smoking abstinence. On each abstinent day, measures of mood and craving were collected and participants attended a lab visit in order to assess smoking (i.e., expired-air carbon
monoxide [CO]). On day 4, participants underwent fMRI scanning.
Results: As compared to placebo (n = 8), smokers in the N-Acetylcysteine group (n = 8) maintained abstinence, reported less craving and higher positive affect (all ps < .01), and concomitantly exhibited stronger
rsFC between ventral striatal nodes, medial prefrontal cortex and precuneuskey default mode network
nodes, and the cerebellum [p < .025; FWE]).
Conclusions: Taken together, these ndings suggest that N-Acetylcysteine may positively affect dysregulated corticostriatal connectivity, help to restructure reward processing, and help to maintain abstinence
immediately following a quit attempt.
2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Nicotine addiction is the leading cause of preventable premature
death in the USA (CDC, 2002), costing nearly $200 billion each year
(AHA et al., 2010). Despite the relative effectiveness of current rstline medications for promoting smoking abstinence (Cahill et al.,
2013; Gonzales et al., 2006; Jorenby et al., 2006; Oncken et al.,
2006), most quit attempts result in relapse (Cahill et al., 2013).
Therefore, further research examining new medications for treating the neuropathophysiology of nicotine addiction is needed in
order to help initiate and maintain smoking abstinence and prevent
relapse.
Chronic drug abuse produces neuroplasticity in frontostriatal
(i.e., medial prefrontal cortex: mPFC, nucleus accumbens: NAcc)
glutamatergic circuitry, which subserves compulsive drug seeking and the loss of adaptive behavioral responding to changing
environmental contingencies (Kalivas, 2009). In animal models,
chronic nicotine exposurethe primary psychoactive component
of tobacco (Stolerman and Jarvis, 1995)is shown to impair functioning of the glial glutamate transporter (GLT-1) in the NAcc
(Gipson et al., 2013). Impaired GLT-1 function decreases the rate of
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
0376-8716/ 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
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glutamate elimination from the extracellular space, thereby augmenting the spillover of synaptically released glutamate during
reinstated drug seeking (Baker et al., 2003; Berglind et al., 2009;
Pierce et al., 1996). Increased release of synaptic glutamate, derived
from mPFC (e.g., anterior cingulate cortex; ACC) synapses in the
NAcc core, stimulates extrasynaptic glutamate receptors which
cause the rapid, transient synaptic potentiation required for reinstatement of nicotine seeking (Gipson et al., 2013). Consistent with
ndings from animal models, human positron emission tomography (PET) research using a glutamate receptor ligand reveals that,
as compared to both nonsmokers and former cigarette smokers,
current smokers have elevated glutamate receptor occupancy in
the mPFC (Akkus et al., 2013). This observation potentially resulted
from reduced glutamate receptor density or changes in afnity
of the glutamate binding site, either of which may be a result
of smoking or a predisposing factor in nicotine addiction (Akkus
et al., 2013). Further, cue-induced craving is associated with greater
functional magnetic resonance imaging (fMRI) blood-oxygenationlevel-dependent (BOLD) response in the ventral striatum/NAcc
(Bell et al., 2014; Jasinska et al., 2014) and mPFC (McClernon et al.,
2009; Wilson and Sayette, 2014); critically, the magnitude of smoking cue-reactivity in the mPFC predicts relapse (Janes et al., 2010).
Resting-state functional connectivity (rsFC) fMRI has emerged
as an effective method for examining systems-level functional
connectivity [Biswal et al., 1995; i.e., uctuating BOLD activation in distributed neural networks (Shmuel and Leopold,
2008)]. Recently, combined human rsFC and magnetic resonance
spectroscopy (MRS) evidence has been reported linking mPFC glutamate concentrations to rsFC in frontostriatal circuitry via positive
correlation (Duncan et al., 2013). Interestingly, elevated mPFC
glutamate concentrations have also been associated with mental imagery (Huang et al., 2015); when considering the role of
imagery in drug craving (Taylor et al., 2000), this nding offers
a plausible mechanism through which elevated mPFC glutamate
concentrations may contribute to frontostriatal desynchronization.
Indeed, other rsFC studies have revealed that frontostriatal rsFC
is weaker among drug-dependent populations, including nicotine
dependence (Hong et al., 2009), opiate addiction (Ma et al., 2010)
and polysubstance abuse (Motzkin et al., 2014). Therefore, a convergence of evidence from animal models and human research stresses
the need for a principled investigation of novel glutamatergic pharmacotherapies for treating frontostriatal circuitry in an effort to
prevent smoking relapse (Reissner and Kalivas, 2010).
N-Acetylcysteine, a cysteine prodrug that regulates intraand extra-cellular glutamate, holds promise as a medication
to normalize frontostriatal function and prevent relapse. NAcetylcysteine exerts antioxidant properties via activation of the
cystineglutamate exchanger (Dringen et al., 2001; Lewerenz et al.,
2013) and, in animal models, is shown to restore GLT-1 function
that has been down-regulated by chronic use of addictive drugs
(Baker et al., 2003). Preclinical models show that N-Acetylcysteine
blocks reinstated drug-seeking (Reichel et al., 2011) and restores
glutamatergic synapses in the NAcc (Kupchik et al., 2012; Moussawi
et al., 2009). Clinically, N-Acetylcysteine is shown to be safe and
well-tolerated (LaRowe et al., 2006; Mardikian et al., 2007; McClure
et al., 2014b) and some evidence suggests that N-Acetylcysteine
may treat frontostriatal glutamate-mediated behavior. In a MRS
study of cocaine-dependent individuals (Schmaal et al., 2012),
acute administration of N-Acetylcysteine normalized elevated glutamate levels in the mPFC (i.e., dACC). Further, N-Acetylcysteine
has been shown to signicantly attenuate withdrawal-induced
craving for cocaine (LaRowe et al., 2006), and in an open label
trial, reduced marijuana use and craving in adolescent marijuana
users (Gray et al., 2010). In spite of the nascent database on NAcetylcysteines potential role in treating substance-use disorders
(SUDs; McClure et al., 2014b) and compulsive behaviors (Berk
Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
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Table 1
Subject demographics/baseline self-report.
% Female
Mean age
Years of education
Race
African Americans (#)
Caucasians (#)
Baseline clinical measures
Nicotine dependence (FTND)
Years smoking
Average daily cigarettes
Carbon monoxide (CO) (screening)
Depressive symptoms (CESD)
Cognitive failures (CFQ)
Overall sample
N-Acetylcysteine group
Placebo group
Chi2 /t
p (two-tailed)
31
36.5 (11.9)
13.4 (1.9)
25
35.0 (14.4)
13.75 (2.1)
38
38 (9.6)
13.13 (1.9)
0.29
0.59
0.6
0.25
0.59
0.63
0.5
0.61
1.6
0.86
0.28
0.14
0.35
0.99
0.12
0.4
0.79
0.89
0.74
0.34
9
7
5.8 (1.4)
15.7 (8.9)
15.8 (6.1)
25.6 (16.8)
6.9 (4.9)
26.9 (16.3)
4
4
5
3
5.3 (1.6)
13.8 (9.9)
16.3 (5.3)
25.0 (18.4)
6.5 (5.9)
31.0 (12.1)
6.4 (1.1)
17.6 (8.0)
15.4 (7.2)
26.3 (16.3)
7.4 (4.1)
22.9 (19.6)
assessed using an 8-point Likert Scale querying the subject How much do you crave
a cigarette right now?; 1 indicating Not at all and 8 indicating Extremely.
2.3.3. Biochemically conrmed smoking. At the beginning of each of the 5 visits
(screening, abstinence days 13, and day 4fMRI visit), smoking was biochemically assessed via expired breath CO concentration (PPM; (Vitalograph BreathCO
Monitor, Lenexa, KS).
2.4. Behavioral analyses
Behavioral analyses were performed with = .05 using GreenhouseGeisser
corrected degrees of freedom. Between-subjects repeated-measures analyses of
variance/covariance (RM-ANOVA/ANCOVA) were performed in SPSS independently
for positive (PA) and negative (NA) affect, the SJWQ symptom subscale, and expiredair CO concentration. RM-ANOVA (2 4) for PA/NA and RM-ANCOVA (2 3) for
SJWQ, assessed mean variance across 4 time-points (abstinence days 1, 2, 3 and
4 (fMRI visit)) while controlling for years smoking in the SJWQ analysis. Baseline
SJWQ and PANAS data were missing for one Placebo subject so were excluded from
the analyses. RM-ANCOVA (2 3) for CO, reported in Table 3a, excluded day 3 from
analysis due to missing CO data from 4 subjects (2/group) and controlled for both
baseline CO and for years smoking. Simple main effects of group at each time point
were assessed post hoc using t-tests. Where signicant main effects of group or
group time interactions were observed, variables were further explored via correlational analysis with regard to their relationships with the different resting-state
pathways. To control for family-wise error across dependent measures in these correlational analyses, we adjusted the alpha levels for the number of total comparisons
for each pathway: 2 subjective (positive affect and craving; = 0.025) and 1 objective (CO; = 0.05). Lastly, to assess state craving on the experimental visit, ANCOVA
was used to assess group differences, controlling for years smoking.
2.5. Neuroimaging data acquisition, processing and analyses
2.5.1. Data acquisition. Data were collected on a Siemens Magnetom TrioTim 3T
MR scanner (Siemens, Erlangen, Germany) with a 32-channel head coil. A 3D,
T1-weighted, multi-planar rapid gradient-echo (MPRAGE) sequence was used to
acquire high-resolution (1 mm3 voxel) structural images. Next, a 6-min, eyesclosed rsFC scan was acquired using an echo-planar gradient-echo pulse sequence
(TR = 2000 ms, TE = 30 ms, ip angle = 90 ; 36 transverse slices, 3.0 mm thickness,
0.58 ms gap; voxel size was 3.3 mm 3.3 mm 3.0 mm).
Data processing. Structural images were pre-processed using the VBM8 toolbox (www.dbm.neuro.uni-jena.de/vbm8) for SPM12 (www.l.ion.ucl.ac.uk/spm).
Data were preprocessed according to default settings: bias correction; tissue classication/segmentation (Rajapakse et al., 1997); partial volume estimation (PVE;
Tohka et al., 2004); denoising/ltering (Manjn et al., 2010; Rajapakse et al.,
1997); warping to the DARTEL IXI-550 template in Montreal Neurologic Institute
(MNI) space; and resampling to a 1.5 mm3 voxel-size using afne and nonlinear
transforms (Ashburner, 2007). Forward-deformation elds were calculated from
each subjects skull-stripped and rigid-body registered T1 (PVE) image in order to
warp functional data into MNI space. Preprocessing of functional data included:
slice time correction and realignment (Friston et al., 1994); motion outlier detection (framewise displacement >1 mm; www.nitrc.org/projects/artifact detect) and
correction (via interpolation; www.cibsr.stanford.edu/tools/human-brain-project/
artrepair-software.html); coregistration of functional images to PVE image; warping to MNI space using forward deformations and resampling to 1.5 mm3 voxel
size; and smoothing with a 10 mm3 FWHM Gaussian lter. Motion was corrected
for ten subjects (N-Acetylcysteine: n = 3; Placebo: n = 7). Exclusion threshold for
rapid motion was 20% of run length but no subjects exceeded this threshold. Mean
volumes corrected did not differ signicantly between groups (t (14) = 1.4, p = .194).
2.5.2. Denoising of functional images. Modeled data were uploaded into the conn14
toolbox (www.nitrc.org/projects/conn) for denoising and connectivity analyses.
Unsmoothed segmented tissue images, along with region of interest (ROI) masks
(5 mm radius spheres around coordinates of interest, comprising 523.6 mm3 ) were
uploaded into the toolbox. Mean time-courses from the unsmoothed BOLD signal
from each ROI were characterized with no additional principal components. Confounds (mean white matter (WM) and cerebrospinal uid (CSF) signal, and motion)
were regressed out of the mean signal for each ROI. Analysis space was set to match
the functional images (i.e., 1.5 mm3 ) with an explicit mask generated by skullstripping the DARTEL IXI-550 template image. A band-pass lter of .008.09 Hz with
despiking performed after confound regression (no detrending) was used.
2.5.3. fMRI data analysis. All fMRI data analyses were performed with conn14 toolbox for SPM12. Hypothesis testing was conducted using seed-to-voxel bivariate
correlations with sources comprising L/R.NAcc (12, 8, 8) (Zink et al., 2003). At the
group level, effects of medication were examined with t-tests, correcting for multiple
comparisons using p < .025 FWE at the cluster level (p < .001 cluster-forming threshold). Among signicant clusters, weighted means from each ROI were extracted and
used for descriptive statistics (mean, SD, cohens d).
3. Results
3.1. Blind success and adverse events
The double-blind procedure used in the study was successful. Neither participants [X2 (2, N = 16) = 1.72, p = .19] or the
researcher [X2 (1, N = 16) = 2.28.1, p = .131] were able to identify the
condition. A total of 17 adverse events (AEs) (placebo: n = 12; NAcetylcysteine: n = 5) were reported for seven participants (44%).
All AEs were mild and consistent with symptoms that accompany
smoking withdrawal (Table 2).
3.2. Behavioral measures
3.2.1. Carbon monoxide. A signicant group time interaction
(F(1.83, 21.97) = 3.74, p = .043) was identied; whereas compared to
placebo group, the N-Acetylcysteine group exhibited signicantly
lower CO values beginning on abstinence day 2 and continuing to
the fMRI visit (Table 3a).
Table 2
Adverse events.
Group (total)
N-Acetylcysteine (5)
Placebo (12)
Event type
Reux
Bad aftertaste
Fatigue
Dry mouth
Light-headed
Nausea
Vomiting
Irritability
2
1
4
3
1
2
1
1
Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
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Table 3a
Carbon monoxide (CO): 2 (group) 3 (time) repeated measures ANCOVAa,b .
Group
Screening
Abst. Day 1
Abst. Day 2
Abst. Day 3c
Abst. Day 4 (fMRI visit)
Overall model
N-Acetylcysteine
Placebo
F (p)
25.0 (18.4)
10.0 (6.0)
4.4 (3.4)
3.5 (1.6)
26.3 (16.2)
11.75 (8.4)
13.3 (6.5)
15.4 (10.5)
0.1
0.5
3.4
3.12
ns
ns
0.004**
0.007**
3.74 (.043)*
p > .05.
Table 3b
Positive affect: 2 (group) 4 (time) repeated measures ANOVA.a
Group
Overall model
N-Acetylcysteine
Screening
Abst. Day 1
Abst. Day 2
Abst. Day 3
Abst. Day 4 (fMRI visit)
Placebo
32.8 (6.3)
33.5 (6.5)
33.9 (6.6)
33.3 (5.4)
37.0 (4.9)
34.7 (7.7)
29.8 (9.2)
28.6 (7.1)
26.9 (6.6)
25.1 (7.8)
t
0.5
0.9
1.5
2.1
3.6
F (p)
ns
ns
ns
0.050*
0.003**
3.66 (0.036)*
p > .05.
3.2.2. Daily self-report measures. A signicant group time interaction (F(2.10,29.35) = 3.66, p = .036) was identied for positive
affect. As compared to the placebo group, the N-Acetylcysteine
group reported a non-signicant trend for higher positive affect
beginning on Abst. Day 2 that was signicant on Abst. Days 3 and 4
(Table 3b). The group time interaction and main effects of group
and time for withdrawal symptoms (SJWQ) (see Table S1) and selfreported negative affect (see Table S2) failed to reach signicance
(all ps > .3).
State craving ratings. The groups exhibited a signicant difference in self-reported craving on the experimental visit (F
(1,13) = 9.54, p = .009); the N-Acetylcysteine group reported signicantly less craving (M = 4.3 1.2) than the placebo group
(M = 6.4 1.2) (Table 3c).
3.3. Effects of N-Acetylcysteine on bilateral nucleus accumbens
rsFC
Compared to placebo, smokers who received N-Acetylcysteine
exhibited stronger rsFC in four striatal pathways: between R.NAcc
and left medial prefrontal cortex (mPFC) and bilateral precuneus,
and between L.NAcc and ventromedial prefrontal cortex (vmPFC)
and bilateral cerebellum (see Table 4; Fig. 1). Years smoking was
Table 3c
State craving on fMRI visit.
Group
N-Acetylcysteine
Placebo
4.3 (1.2)
6.4 (1.2)
3.4
0.004*
Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
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Table 4
Main effect of medication condition on resting-state functional connectivity with the nucleus accumbens.
Pattern of group contrast
Seed
Cerebellum
10, 60, 22
3375
0.15 (.07)
0.09 (.07)
8.72
0.000
0.95
Precuneus
8, 51, 8
1563
0.13 (.10)
0.13 (.09)
6.53
0.010
0.87
mPFCc
9, 50, 9
1384
0.17 (.12)
0.11 (.12)
4.83
0.017
0.84
the fMRI visit. No association between rsFC and negative affect was
observed (Fig. 2).
4. Discussion
The current study sought to: (A) examine the effectiveness
of N-Acetylcysteine for treating dysregulated frontostriatal circuitry among nicotine-deprived smokers and (B) preliminarily
evaluate the potential value of using N-Acetylcysteine as a relapseprevention aid. Results from this study revealed that, as compared
to placebo, smokers assigned to a 3 day course of N-Acetylcysteine
exhibited stronger rsFC between NAcc and mPFC/vmPFC (frontostriatal), between NAcc and key nodes of the default mode
network (mPFC/Precuneus) and between NAcc and cerebellum.
Fig. 1. Resting-state functional connectivity (rsFC) in: (A) frontostriatal circuitry: between left Nucleus Accumbens (NAcc) seed and ventromedial PFC (vmPFC), and Cerebellum; and (B) corticostriatal circuitry: between right NAcc ROI seed and medial prefrontal cortex (mPFC) and Precuneus. As compared to the placebo group, smokers that
received N-Acetylcysteine exhibited stronger rsFC in pathways A and B (p < .025, FWE).
Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
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Fig. 2. Correlations between rsFC striatal pathways and: (A) recency of smoking; (B) craving; and (C) positive affect (all ps < .05).
Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
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Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
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Acknowledgements
The authors would like to thank the MUSC Center for Biomedical
Imaging (CBI), Taylor Salo at the University of California-Davis for
his assistance with computer programming and the Reviewers of
this manuscript for providing thoughtful critiques and insightful
comments.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.drugalcdep.2015.
09.021.
References
AHA, Lloyd-Jones, D., Adams, R.J., Brown, T.M., Carnethon, M., Dai, S., De Simone, G.,
Ferguson, T.B., Ford, E., Furie, K., Gillespie, C., Go, A., Greenlund, K., Haase, N.,
Hailpern, S., Ho, P.M., Howard, V., Kissela, B., Kittner, S., Lackland, D., Lisabeth,
L., Marelli, A., McDermott, M.M., Meigs, J., Mozaffarian, D., Mussolino, M.,
Nichol, G., Roger, V.L., Rosamond, W., Sacco, R., Sorlie, P., Stafford, R., Thom, T.,
Wasserthiel-Smoller, S., Wong, N.D., Wylie-Rosett, J., AHA Committee, Stroke
Statistics Subcommittee, 2010. Heart disease and stroke statistics2010
update: a report from the American Heart Association. Circulation 121,
e46e215.
Akkus, F., Ametamey, S.M., Treyer, V., Burger, C., Johayem, A., Umbricht, D., Gomez
Mancilla, B., Sovago, J., Buck, A., Hasler, G., 2013. Marked global reduction in
mGluR5 receptor binding in smokers and ex-smokers determined by
[11C]ABP688 positron emission tomography. Proc. Natl. Acad. Sci. U. S. A. 110,
737742.
Ashburner, J., 2007. A fast diffeomorphic image registration algorithm.
Neuroimage 38, 95113.
Augustus Diggs, H., Froeliger, B., Carlson, J.M., Gilbert, D.G., 2013.
Smoker-nonsmoker differences in neural response to smoking-related and
affective cues: an fMRI investigation. Psychiatry Res. 211, 8587.
Azizian, A., Nestor, L.J., Payer, D., Monterosso, J.R., Brody, A.L., London, E.D., 2010.
Smoking reduces conict-related anterior cingulate activity in abstinent
cigarette smokers performing a Stroop task. Neuropsychopharmacology 35,
775782.
Baker, D.A., McFarland, K., Lake, R.W., Shen, H., Toda, S., Kalivas, P.W., 2003.
N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann. N.
Y. Acad. Sci. 1003, 349351.
Bastian, A.J., 2006. Learning to predict the future: the cerebellum adapts
feedforward movement control. Curr. Opin. Neurobiol. 16, 645649.
Bell, R.P., Garavan, H., Foxe, J.J., 2014. Neural correlates of craving and impulsivity
in abstinent former cocaine users: towards biomarkers of relapse risk.
Neuropharmacology 85, 461470.
Berglind, W.J., Whiteld Jr., T.W., LaLumiere, R.T., Kalivas, P.W., McGinty, J.F., 2009.
A single intra-PFC infusion of BDNF prevents cocaine-induced alterations in
extracellular glutamate within the nucleus accumbens. J. Neurosci. 29,
37153719.
Berk, M., Malhi, G.S., Gray, L.J., Dean, O.M., 2013. The promise of N-acetylcysteine
in neuropsychiatry. Trends Pharmacol. Sci. 34, 167177.
Berridge, K.C., Robinson, T.E., Aldridge, J.W., 2009. Dissecting components of
reward: liking, wanting, and learning. Curr. Opin. Pharmacol. 9, 6573.
Biswal, B., Yetkin, F.Z., Haughton, V.M., Hyde, J.S., 1995. Functional connectivity in
the motor cortex of resting human brain using echo-planar MRI. Magn. Reson.
Med. 34, 537541.
Broadbent, D.E., Cooper, P.F., FitzGerald, P., Parkes, K.R., 1982. The Cognitive
Failures Questionnaire (CFQ) and its correlates. Br. J. Clin. Psychol. 21 (Pt 1),
116.
Brody, A.L., Mandelkern, M.A., London, E.D., Childress, A.R., Lee, G.S., Bota, R.G., Ho,
M.L., Saxena, S., Baxter Jr., L.R., Madsen, D., Jarvik, M.E., 2002. Brain metabolic
changes during cigarette craving. Arch. Gen. Psychiatry 59, 11621172.
Cahill, K., Stevens, S., Perera, R., Lancaster, T., 2013. Pharmacological interventions
for smoking cessation: an overview and network meta-analysis. Cochrane
Database Syst. Rev. 5, CD009329.
CDC, 2002. annual smoking-attributable mortality, years of potential life lost, and
productivity lossesUnited States, 19951999. MMWR 51, 300313.
Cook, J.W., Spring, B., McChargue, D., Hedeker, D., 2004. Hedonic capacity, cigarette
craving, and diminished positive mood. Nicotine Tob. Res. 6, 3947.
Doya, K., 2000. Complementary roles of basal ganglia and cerebellum in learning
and motor control. Curr. Opin. Neurobiol. 10, 732739.
Dringen, R., Gutterer, J.M., Gros, C., Hirrlinger, J., 2001. Aminopeptidase N mediates
the utilization of the GSH precursor CysGly by cultured neurons. J. Neurosci.
Res. 66, 10031008.
Duncan, N.W., Wiebking, C., Tiret, B., Marjanska, M., Hayes, D.J., Lyttleton, O.,
Doyon, J., Northoff, G., 2013. Glutamate concentration in the medial prefrontal
cortex predicts resting-state cortical-subcortical functional connectivity in
humans. PLOS ONE 8, e60312.
Friston, K.J., Jezzard, P., Turner, R., 1994. Analysis of functional MRI time-series.
Hum. Brain Mapp. 1, 153171.
Froeliger, B., Crowell Beckham, J., Feldman Dennis, M., Victoria Kozink, R., Joseph
McClernon, F., 2012a. Effects of nicotine on emotional reactivity in PTSD and
Non-PTSD smokers: results of a pilot fMRI Study. Adv. Pharmacol. Sci. 2012,
265724.
Froeliger, B., Modlin, L., Wang, L., Kozink, R.V., McClernon, F.J., 2012b. Nicotine
withdrawal modulates frontal brain function during an affective Stroop task.
Psychopharmacology (Berl.) 220, 707718.
Froeliger, B., Modlin, L.A., Kozink, R.V., Wang, L., Garland, E.L., Addicott, M.A.,
McClernon, F.J., 2013. Frontoparietal attentional network activation differs
between smokers and nonsmokers during affective cognition. Psychiatry Res.
211, 5763.
Froeliger, B., Modlin, L.A., Kozink, R.V., Wang, L., McClernon, F.J., 2012c. Smoking
abstinence and depressive symptoms modulate the executive control system
during emotional information processing. Addict. Biol. 17, 668679.
Garland, E.L., Froeliger, B., Howard, M.O., 2014. Mindfulness training targets
neurocognitive mechanisms of addiction at the attention-appraisal-emotion
interface. Front. Psychiatry 4, 173.
Gipson, C.D., Reissner, K.J., Kupchik, Y.M., Smith, A.C., Stankeviciute, N.,
Hensley-Simon, M.E., Kalivas, P.W., 2013. Reinstatement of nicotine seeking is
mediated by glutamatergic plasticity. Proc. Natl. Acad. Sci. U. S. A. 110,
91249129.
Goldman, M., Szucs-Reed, R.P., Jagannathan, K., Ehrman, R.N., Wang, Z., Li, Y., Suh,
J.J., Kampman, K., OBrien, C.P., Childress, A.R., Franklin, T.R., 2013.
Reward-related brain response and craving correlates of marijuana cue
exposure: a preliminary study in treatment-seeking marijuana-dependent
subjects. J. Addict. Med. 7, 816.
Goldstein, R.Z., Volkow, N.D., 2002. Drug addiction and its underlying
neurobiological basis: neuroimaging evidence for the involvement of the
frontal cortex. Am. J. Psychiatry 159, 16421652.
Gonzales, D., Rennard, S.I., Nides, M., Oncken, C., Azoulay, S., Billing, C.B., Watsky,
E.J., Gong, J., Williams, K.E., Reeves, K.R., Varenicline Phase 3 Study G., 2006.
Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs
sustained-release bupropion and placebo for smoking cessation: a randomized
controlled trial. JAMA 296, 4755.
Gray, K.M., Watson, N.L., Carpenter, M.J., Larowe, S.D., 2010. N-acetylcysteine
(NAC) in young marijuana users: an open-label pilot study. Am. J. Addict. 19,
187189.
Heatherton, T.F., Kozlowski, L.T., Frecker, R.C., Fagerstrom, K.O., 1991. The
Fagerstrom test for nicotine dependence: a revision of the Fagerstrom
Tolerance Questionnaire. Br. J. Addict. 86, 11191127.
Hong, L.E., Gu, H., Yang, Y., Ross, T.J., Salmeron, B.J., Buchholz, B., Thaker, G.K., Stein,
E.A., 2009. Association of nicotine addiction and nicotines actions with
separate cingulate cortex functional circuits. Arch. Gen. Psychiatry 66,
431441.
Huang, W., King, J.A., Ursprung, W., Zheng, S., Zhang, N., Kennedy, D.N., Ziedonis,
D., DiFranza, J.R., 2014. The development and expression of physical nicotine
dependence corresponds to structural and functional alterations in the
anterior cingulate-precuneus pathway. Brain Behav. 4, 408417.
Huang, Z., Davis Iv, H., Yue, Q., Wiebking, C., Duncan, N.W., Zhang, J., Wagner, N.F.,
Wolff, A., Northoff, G., 2015. Increase in glutamate/glutamine concentration in
the medial prefrontal cortex during mental imagery: a combined functional
mrs and fMRI study. Hum. Brain Mapp. 36, 32043212.
Janes, A.C., Pizzagalli, D.A., Richardt, S., de, B.F.B., Chuzi, S., Pachas, G., Culhane,
M.A., Holmes, A.J., Fava, M., Evins, A.E., Kaufman, M.J., 2010. Brain reactivity to
smoking cues prior to smoking cessation predicts ability to maintain tobacco
abstinence. Biol. Psychiatry 67, 722729.
Jasinska, A.J., Stein, E.A., Kaiser, J., Naumer, M.J., Yalachkov, Y., 2014. Factors
modulating neural reactivity to drug cues in addiction: a survey of human
neuroimaging studies. Neurosci. Biobehav. Rev. 38, 116.
Jorenby, D.E., Hays, J.T., Rigotti, N.A., Azoulay, S., Watsky, E.J., Williams, K.E., Billing,
C.B., Gong, J., Reeves, K.R., 2006. Efcacy of varenicline, an alpha4beta2
nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release
bupropion for smoking cessation: a randomized controlled trial. JAMA 296,
5663.
Kalivas, P.W., 2009. The glutamate homeostasis hypothesis of addiction. Nat. Rev.
Neurosci. 10, 561572.
Kilts, C.D., Gross, R.E., Ely, T.D., Drexler, K.P., 2004. The neural correlates of
cue-induced craving in cocaine-dependent women. Am. J. Psychiatry 161,
233241.
Knackstedt, L.A., LaRowe, S., Mardikian, P., Malcolm, R., Upadhyaya, H., Hedden, S.,
Markou, A., Kalivas, P.W., 2009. The role of cystine-glutamate exchange in
nicotine dependence in rats and humans. Biol. Psychiatry 65, 841845.
Knutson, B., Adams, C.M., Fong, G.W., Hommer, D., 2001. Anticipation of increasing
monetary reward selectively recruits nucleus accumbens. J. Neurosci. 21,
RC159.
Knutson, B., Gibbs, S.E., 2007. Linking nucleus accumbens dopamine and blood
oxygenation. Psychopharmacology (Berl.) 191, 813822.
Knutson, B., Westdorp, A., Kaiser, E., Hommer, D., 2000. FMRI Visualization of brain
activity during a monetary incentive delay task. Neuroimage 12, 2027.
Kober, H., Mende-Siedlecki, P., Kross, E.F., Weber, J., Mischel, W., Hart, C.L.,
Ochsner, K.N., 2010. Prefrontalstriatal pathway underlies cognitive regulation
of craving. Proc. Natl. Acad. Sci. 107, 1481114816.
Koob, G.F., Le Moal, M., 2001. Drug addiction, dysregulation of reward, and
allostasis. Neuropsychopharmacology 24, 97129.
Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021
G Model
DAD-5758; No. of Pages 9
ARTICLE IN PRESS
B. Froeliger et al. / Drug and Alcohol Dependence xxx (2015) xxxxxx
Pierce, R.C., Bell, K., Duffy, P., Kalivas, P.W., 1996. Repeated cocaine augments
excitatory amino acid transmission in the nucleus accumbens only in rats
having developed behavioral sensitization. J. Neurosci. 16, 15501560.
Prado, E., Maes, M., Piccoli, L.G., Baracat, M., Barbosa, D.S., Franco, O., Dodd, S., Berk,
M., Vargas Nunes, S.O., 2015. N-acetylcysteine for therapy-resistant tobacco
use disorder: a pilot study. Redox Rep. 20, 215222.
Radloff, L.S., 1977. The CES-D scale: a self report depression scale for research in
the general population. Appl. Psychol. Measure. 1, 385401.
Rajapakse, J.C., Giedd, J.N., Rapoport, J.L., 1997. Statistical approach to segmentation
of single-channel cerebral MR images. IEEE Trans. Med. Imaging 16, 176186.
Reichel, C.M., Moussawi, K., Do, P.H., Kalivas, P.W., See, R.E., 2011. Chronic
N-acetylcysteine during abstinence or extinction after cocaine
self-administration produces enduring reductions in drug seeking. J.
Pharmacol. Exp. Ther. 337, 487493.
Reissner, K.J., Kalivas, P.W., 2010. Using glutamate homeostasis as a target for
treating addictive disorders. Behav. Pharmacol. 21, 514522.
Risinger, R.C., Salmeron, B.J., Ross, T.J., Amen, S.L., Sanlipo, M., Hoffmann, R.G.,
Bloom, A.S., Garavan, H., Stein, E.A., 2005. Neural correlates of high and craving
during cocaine self-administration using BOLD fMRI. Neuroimage 26,
10971108.
Rogers, R.D., Ramnani, N., Mackay, C., Wilson, J.L., Jezzard, P., Carter, C.S., Smith,
S.M., 2004. Distinct portions of anterior cingulate cortex and medial prefrontal
cortex are activated by reward processing in separable phases of
decision-making cognition. Biol. Psychiatry 55, 594602.
Rushworth, M.F., Buckley, M.J., Behrens, T.E., Walton, M.E., Bannerman, D.M., 2007.
Functional organization of the medial frontal cortex. Curr. Opin. Neurobiol. 17,
220227.
Schmaal, L., Berk, L., Hulstijn, K.P., Cousijn, J., Wiers, R.W., van den Brink, W., 2011.
Efcacy of N-acetylcysteine in the treatment of nicotine dependence: a
double-blind placebo-controlled pilot study. Eur. Addict. Res. 17, 211216.
Schmaal, L., Veltman, D.J., Nederveen, A., van den Brink, W., Goudriaan, A.E., 2012.
N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a
randomized crossover magnetic resonance spectroscopy study.
Neuropsychopharmacology 37, 21432152.
Shiffman, S., Paty, J.A., Gnys, M., Kassel, J.A., Hickcox, M., 1996. First lapses to
smoking: within-subjects analysis of real-time reports. J. Consult. Clin. Psychol.
64, 366379.
Shiffman, S.M., Jarvik, M.E., 1976. Smoking withdrawal symptoms in two weeks of
abstinence. Psychopharmacology 50, 3539.
Shmuel, A., Leopold, D.A., 2008. Neuronal correlates of spontaneous uctuations in
fMRI signals in monkey visual cortex: implications for functional connectivity
at rest. Hum. Brain Mapp. 29, 751761.
Stolerman, I.P., Jarvis, M.J., 1995. The scientic case that nicotine is addictive.
Psychopharmacology (Berl.) 117, 210, discussion 1420.
Taylor, R.C., Harris, N.A., Singleton, E.G., Moolchan, E.T., Heishman, S.J., 2000.
Tobacco craving: intensity-related effects of imagery scripts in drug abusers.
Exp. Clin. Psychopharmacol. 8, 75.
Tohka, J., Zijdenbos, A., Evans, A., 2004. Fast and robust parameter estimation for
statistical partial volume models in brain MRI. Neuroimage 23, 8497.
Tzvi, E., Mnte, T.F., Krmer, U.M., 2014. Delineating the cortico-striatal-cerebellar
network in implicit motor sequence learning. Neuroimage 94, 222230.
Volkow, N.D., Wang, G.J., Fowler, J.S., Logan, J., Gatley, S.J., Hitzemann, R., Chen, A.D.,
Dewey, S.L., Pappas, N., 1997. Decreased striatal dopaminergic responsiveness
in detoxied cocaine-dependent subjects. Nature 386, 830833.
Wang, Z., Faith, M., Patterson, F., Tang, K., Kerrin, K., Wileyto, E.P., Detre, J.A.,
Lerman, C., 2007. Neural substrates of abstinence-induced cigarette cravings in
chronic smokers. J. Neurosci. 27, 1403514040.
Watson, D., Clark, L.A., Tellegen, A., 1988. Development and validation of brief
measures of positive and negative affect: the PANAS scales. J. Pers. Soc.
Psychol. 54, 10631070.
Westman, E.C., Behm, F.M., Simel, D.L., Rose, J.E., 1997. Smoking behavior on the
rst day of a quit attempt predicts long-term abstinence. Arch. Intern. Med.
157, 335340.
Wilson, S.J., Sayette, M.A., 2014. Neuroimaging craving: urge intensity matters.
Addiction 110, 195203.
Zink, C.F., Pagnoni, G., Martin, M.E., Dhamala, M., Berns, G.S., 2003. Human striatal
response to salient nonrewarding stimuli. J. Neurosci. 23, 80928097.
Please cite this article in press as: Froeliger, B., et al., The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity,
withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. (2015),
http://dx.doi.org/10.1016/j.drugalcdep.2015.09.021