Elsevier

Drug and Alcohol Dependence

Volume 182, 1 January 2018, Pages 78-85
Drug and Alcohol Dependence

Full length article
Brain substrates of early (4 h) cigarette abstinence: Identification of treatment targets

https://doi.org/10.1016/j.drugalcdep.2017.10.010Get rights and content

Highlights

  • Regional Cerebral Blood Flow (rCBF) is reduced in corticolimbic regions during early abstinence vs recent smoking.

  • Abstinence-induced changes may negatively impact neural processing.

  • Across conditions, the change in rCBF correlated with the change in craving.

  • Identifying early abstinence treatment targets has far-reaching implications.

Abstract

Introduction

Research indicates that overnight nicotine abstinence disrupts neural activity in the mesocorticolimbic reward network; however, less is known about the time course of abstinence-induced brain changes. To examine the potential neural effects of early abstinence, we used arterial spin labeling perfusion fMRI, to measure regional cerebral blood flow (rCBF) changes in the resting brain induced by 4 h of nicotine abstinence.

Methods

In a repeated measures design, 5 min of resting perfusion fMRI data were acquired in awake nicotine-dependent individuals (eyes open) during ‘smoking as usual’ (SMK) and following 4 h of monitored nicotine abstinence (ABS) conditions (N = 20). Conditions were compared using a paired t test in SPM8. Craving was assessed prior to each condition.

Results

Compared to SMK, ABS significantly increased craving and reduced rCBF in select regions, including the hippocampus and ventral striatum (cluster corr, α = 0.01, 943 contiguous voxels). The magnitude of the abstinence-induced change in rCBF correlated with the magnitude of the change in craving across conditions in select regions, including the medial and lateral orbitofrontal cortices and the anterior ventral insula (r values ranging from 0.59–0.74).

Conclusions

Results show that as few as 4 h of abstinence can reduce resting rCBF in multiple nodes of the brain’s mesocorticolimbic network, disrupting neural processing. Identifying early withdrawal treatment targets has far-reaching implications, which include thwarting relapse proclivities. Results parallel those of the extant human literature and are in agreement with an extensive preclinical literature showing compromised mesolimbic dopaminergic function and impairments in reward function during nicotine withdrawal.

Introduction

Cigarette smoking is the leading cause of preventable disease and premature death, yet one in five adults in the United States continue to smoke (World Health Organization, 2015). Many of these individuals have a strong desire to quit smoking; however, their quit attempts are often unsuccessful, and relapse after a short cessation period is typical (Baillie et al., 1995, Hughes et al., 2008). A host of factors may be involved in the motivation to smoke and the risk of relapse, including exposure to smoking reminders (cues), stress, peer pressure, availability, hormonal status and weight management (Baker et al., 1986, Caggiula et al., 2001, Dagher et al., 2009, Franklin et al., 2008, Janes et al., 2010, Killen and Fortmann, 1997, Perkins, 2001, Perkins et al., 2001, Rose, 1996, Sinha and Li, 2007). Of note, withdrawal-induced craving is cited as a major motivator for continued smoking and relapse, particularly in the early phases of smoking cessation (Baker et al., 2004, Doherty et al., 1995, Piper et al., 2011). Withdrawal is an intense phase of smoking cessation, roused by the absence of the pharmacological effects of nicotine on its brain targets (Rada et al., 2001). Nicotine’s terminal half-life is approximately two hours; thus, conservative estimates might place the onset of withdrawal within two hours after last smoking (Benowitz et al., 1982); however, withdrawal symptoms can emerge as early as 30 min after smoking (Hendricks et al., 2006). Withdrawal is characterized by a constellation of symptoms including anger, irritability and restlessness, anxiety, dysphoria, difficulty with focus and attention, and sleep problems including insomnia (Hatsukami et al., 1985, Hendricks et al., 2006, Hughes, 2007). Generally, to our knowledge, symptoms are the most severe within the first 24–72 h and continue for 2–4 weeks (Hendricks et al., 2006, Hughes, 2007). Notably, most individuals who attempt to abstain from smoking lapse within the first several hours after quitting, prompting Hendricks et al. (2006) to conduct a comprehensive multi-modal assessment of early withdrawal to provide a scientific basis for the observed phenomenon. As little as 1 h of monitored abstinence produced deficits in sustained attention, and reductions in heart rate and increased self-reported withdrawal symptoms (i.e., anger, anxiety, craving) that dramatically intensified over the course of 4 h (Hendricks et al., 2006).

The neural mechanisms underlying the abstinence-induced syndrome and how smoking relieves such symptoms are only partially understood. As suggested by the available literature and the sensitization-homeostasis theory of drug addiction (Robinson and Berridge, 2008) nicotine’s indirect effects on the dopaminergic system may underlie the motivation to seek and use nicotine. When nicotine is present in the brain, it enhances dopamine release in the ventral striatum and attenuates motivation to seek drug (Corrigall et al., 1992, Di Chiara and Imperato, 1988, Natividad et al., 2010, Rada et al., 2001). In contrast, when nicotine levels decline, as during abstinence, striatal dopamine levels decrease and motivation to seek and use drugs is enhanced (Corrigall et al., 1992, Di Chiara and Imperato, 1988, Epping-Jordan et al., 1998, Natividad et al., 2010, Rada et al., 2001, Zhang et al., 2012). Although not always the case, some studies have shown that mesolimbic activation correlates with dopamine release in humans (Schott et al., 2008), suggesting that activation of the mesolimbic pathway may be considered a surrogate marker of dopaminergic activity. In line with the preclinical data, in human work, positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies show that cigarette smoking and/or nicotine administration increases resting brain response in striatal areas and other regions of the mesolimbic system, including the amygdala, anterior cingulate cortex, frontal lobe, and thalamus (Domino et al., 2013, Stein et al., 1998, Tanabe et al., 2008, Zubieta et al., 2005).

Despite the physiological (Cruickshank et al., 1989, Domino et al., 2013, Hendricks et al., 2006) and behavioral (Hendricks et al., 2006) evidence for early withdrawal, all of the neuroimaging studies examining the effects of nicotine abstinence on regional resting brain response have been conducted in overnight abstinent smokers (Domino et al., 2013, Stein et al., 1998, Tanabe et al., 2008, Zubieta et al., 2005); however, studies examining other brain end points at earlier time points have been conducted. Hong et al. (2009) examined resting-state cingulate functional connectivity in individuals who had abstained from smoking for 4.5 h and then were administered either nicotine or placebo patch to determine the effects of acute nicotine administration on cingulate connectivity. Acute nicotine was found to enhance cingulate-neocortical functional connectivity patterns (Hong et al., 2009). Brain responses during a monetary incentive reward task have also been shown to differ in participants 2.5 h after smoking (a period chosen to minimize early withdrawal effects) when imaged under placebo versus nicotine patch conditions, with acute nicotine increasing activity in the dorsal striatum for anticipated magnitude of reward (Rose et al., 2013). Neither of these studies examined rCBF. Given the available data, we hypothesized that shorter periods of abstinence may also alter resting rCBF. Specifically, we hypothesized that 4 h of nicotine deprivation versus ‘smoking as usual’ would disrupt resting rCBF in key nodes within mesocorticolimbic circuitry.

Testing the hypothesis that 4 h of abstinence can perturb the brain is important for at least two reasons. Primarily, it will characterize the functional substrates of early withdrawal, which has not been shown previously and which may have meaningful implications for the treatment of cigarette dependence. Given that most lapses occur within hours after attempting to abstain and are motivated by the absence of nicotine in the brain, which promotes the abstinence syndrome, knowledge of the brain substrates of early withdrawal would offer a rational target for medications development. This knowledge would also be useful for the development of short-term relief medications for smokers who are not quite ready to make a quit attempt and yet who may be forbidden to smoke in the work place and in most hotels, airports, etc. For example, in the U.S., smoking is banned in most internal work environments and given that even 1 h of abstinence produced deficits in sustained attention, reductions in heart rate, and increased self-reported withdrawal symptoms (Hendricks et al., 2006), current moderate to heavy smokers are likely experiencing withdrawal symptoms during work hours, reducing their ability to attend, focus and respond appropriately to stress. Identifying the brain substrates of early abstinence is a first step in the development of effective treatments that may relieve withdrawal symptoms throughout the day, which may improve work productivity and aid smokers in their goal of quitting. Secondarily, on a practical level, if effects of abstinence can be observed in compressed time frames, many of the caveats associated with the measurement of overnight abstinence for research purposes can be minimized. For example, unequivocal overnight smoking abstinence cannot be established in an outpatient laboratory experiment. The current methods used to gauge overnight abstinence are through carbon monoxide (CO) measurements from exhaled breath or self-report. Both methods are unreliable as CO levels rapidly decrease after smoking and can fall below 10 ppm in as little as 3 h (Hendricks et al., 2006) and treatment-seeking smokers are known to misrepresent their smoking status (Gariti et al., 2002). Another caveat introduced by relying on CO levels in experimental research is a lack of standardization of time since last smoked, which could be as little as 3 h or as great as 18 h prior to obtaining a CO measurement. Failure to standardize time since last smoked can introduce noise, resulting in inaccurate reporting. Therefore, restricting the window for studying the effects of withdrawal on brain and behavioral endpoints to occur within the time constraints of a laboratory session would reduce costs and improve scientific rigor.

To test the hypothesis that brief periods of abstinence may affect brain blood flow selectively in mesocorticolimbic circuits, we used arterial spin labeling (ASL) perfusion fMRI to measure absolute resting rCBF in smokers when smoking as usual and following 4 h of monitored abstinence. Perfusion refers to the delivery of oxygen and nutrients to tissue by means of blood flow and is regionally coupled to brain metabolism and, therefore, neural activity (Aguirre et al., 2005). Similar to PET, perfusion fMRI is quantitative (ml of blood/100 g of tissue/minute) (Aguirre et al., 2005, Franklin et al., 2011a), and is therefore preferable for longitudinal studies examining the effects of state versus the more widely used blood oxygen level dependent (BOLD) fMRI technique. We have successfully used the quantitative perfusion fMRI technique over the last 10 years to elucidate the brain substrates of smoking cue reactivity, the effects of medications on resting brain blood flow and to identify individual differences in smoking cue reactivity and resting brain blood flow (Franklin et al., 2011a, Franklin et al., 2011b, Franklin et al., 2015a, Franklin et al., 2015b, Franklin et al., 2012, Franklin et al., 2007, Wetherill et al., 2014, Wetherill et al., 2013).

Section snippets

Participants

The study was conducted at the University of Pennsylvania Perelman School of Medicine. All procedures were approved and monitored by the Institutional Review Board, and adhered to the Declaration of Helsinki. Participants received compensation ranging from $235 to $250 for participating in the study. Eligible participants were non-treatment-seeking smokers (18–60 years of age) who reported smoking at least 10 cigarettes per day for the past 3 years and had baseline carbon monoxide (CO) levels

Pre-scanning session craving

Table 1 depicts the summed responses to the CWQ. Compared to the SMK condition, 4-h abstinent participants were significantly less content (t19 = 2.10; p = 0.05), and had increased general craving for a cigarette (t19 = −7.10; p < 0.001), craving a cigarette for pleasure (t19 = 2.10; p < 0.001) and craving a cigarette for relief (t19 = 9.30; p < 0.001).

rCBF comparisons

Compared to the SMK condition, a paired t-test showed that 4-h abstinent participants had significantly reduced rCBF in several regions. The strongest finding

Overview

The knowledge that behavioral indices of withdrawal emerge rapidly and dramatically increase over the course of 4 h (Hendricks et al., 2006) and that acute nicotine can alter brain endpoints (Hong et al., 2009, Rose et al., 2013) prompted us to explore the neurobiological effects of 4 h of abstinence on resting baseline brain blood flow, which has not been previously studied. Four hours of abstinence decreased rCBF in multiple mesocorticolimbic regions including the hippocampus, the ventral

Contributors

TRF, ARC and RRW were responsible for the study concept and design. Supervised by TRF, NH conducted the study and acquired the data, assisted by JW. KJ, ZF and RRW performed the analyses. TRF, HR and RRW assisted in the interpretation of the findings. TRF and RRW drafted the manuscript. HR and JAD optimized the ASL technique. All authors provided critical revision of the manuscript for important intellectual content. All authors critically reviewed content and approved final version for

Role of funding source

This work was supported by the National Institutes of Health, National Institute for Drug Abuse (P60DA005186; K01DA015426; R21DA025882; R21DA032022; R01DA029845 and R01DA030394). The funding organizations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

Nothing declared.

Acknowledgments

The authors would like to thank the MRI technical staff at the Hospital of the University of Pennsylvania and the clinical staff (MDs, nurses, psychologists) and support staff (reception, clerical, administration) at the Center for the Studies of Addiction, with special thanks to M. Maron (Lab Manager). The authors would also like to thank D. Harper, R. Holczer, and J. Shin, who assisted in data acquisition. The authors wish to acknowledge Sarah Sivilich, the webmaster for //franklinbrainimaging.com

References (66)

  • A.C. Janes et al.

    Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence

    Biol. Psychiatry

    (2010)
  • M.L. Kringelbach et al.

    The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology

    Prog. Neurobiol.

    (2004)
  • E.J. Rose et al.

    Acute nicotine differentially impacts anticipatory valence- and magnitude-related striatal activity

    Biol. Psychiatry

    (2013)
  • R.C. Smith et al.

    Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia

    Neuropsychopharmacology

    (2002)
  • R.R. Wetherill et al.

    Sex differences in resting state neural networks of nicotine-dependent cigarette smokers

    Addict. Behav.

    (2014)
  • L. Zhang et al.

    Withdrawal from chronic nicotine exposure alters dopamine signaling dynamics in the nucleus accumbens

    Biol. Psychiatry

    (2012)
  • T.B. Baker et al.

    The motivation to use drugs: a psychobiological analysis of urges

    Nebr. Symp. Motiv.

    (1986)
  • T.B. Baker et al.

    Addiction motivation reformulated: an affective processing model of negative reinforcement

    Psychol. Rev.

    (2004)
  • N.L. Benowitz et al.

    Interindividual variability in the metabolism and cardiovascular effects of nicotine in man

    J. Pharmacol. Exp. Ther.

    (1982)
  • D. Borsook et al.

    Use of functional imaging across clinical phases in CNS drug development

    Transl. Psychiatry

    (2013)
  • E.D. Claus et al.

    Association between nicotine dependence severity, BOLD response to smoking cues, and functional connectivity

    Neuropsychopharmacology

    (2013)
  • W.A. Corrigall et al.

    The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine

    Psychopharmacology (Berl.)

    (1992)
  • K.P. Cosgrove et al.

    Sex Differences in the brain's dopamine signature of cigarette smoking

    J. Neurosci.

    (2014)
  • J.M. Cruickshank et al.

    Acute effects of smoking on blood pressure and cerebral blood flow

    J. Hum. Hypertens

    (1989)
  • E.E. DeVito et al.

    Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase

    Neuropsychopharmacology

    (2014)
  • G. Di Chiara et al.

    Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

    Proc. Nat. Acad. Sci. U. S. A.

    (1988)
  • T. Dill

    Contraindications to magnetic resonance imaging: non-invasive imaging

    Heart

    (2008)
  • K. Doherty et al.

    Urges to smoke during the first month of abstinence: relationship to relapse and predictors

    Psychopharmacology (Berl.)

    (1995)
  • E.F. Domino et al.

    Denicotinized versus average nicotine tobacco cigarette smoking differentially releases striatal dopamine

    Nicotine Tob. Res.

    (2013)
  • M.P. Epping-Jordan et al.

    Dramatic decreases in brain reward function during nicotine withdrawal

    Nature

    (1998)
  • T.R. Franklin et al.

    Limbic activation to cigarette smoking cues independent of nicotine withdrawal: a perfusion fMRI study

    Neuropsychopharmacology

    (2007)
  • T.R. Franklin et al.

    Menstrual cycle phase at quit date predicts smoking status in an NRT treatment trial: a retrospective analysis

    J. Womens Health (Larchmt.)

    (2008)
  • T. Franklin et al.

    Effects of varenicline on smoking cue-triggered neural and craving responses

    Arch. Gen. Psychiatry

    (2011)
  • Cited by (10)

    • Exploration of the influence of body mass index on intra-network resting-state connectivity in chronic cigarette smokers

      2021, Drug and Alcohol Dependence
      Citation Excerpt :

      A laboratory-developed smoking history questionnaire assessed smoking history, which included the Fagerström Test for Cigarette Dependence (FTCD; (Fagerström, 2012) to measure severity and duration of nicotine dependence. The CWQ is a nine-item measure that measures cigarette craving and subjective withdrawal symptoms (Franklin et al., 2007, 2018; Ketcherside et al., 2020). Ratings are acquired while participants are in the scanner, both immediately before and following the smoking and nonsmoking stimulus presentations.

    • Attenuated cerebral blood flow in frontolimbic and insular cortices in Alcohol Use Disorder: Relation to working memory

      2021, Journal of Psychiatric Research
      Citation Excerpt :

      This inverse relation between smoking and PCASL-determined CBF replicates our previous studies (Pfefferbaum et al., 2011; Sullivan et al., 2013). It echoes a pattern of frontal and temporal CBF increases observed in smokers who were abstinent for 4 h compared with participants who smoked as usual before doing a perfusion scan (Franklin et al., 2018). That study indicated that CBF correlated positively with craving indices, suggesting that smoking abstinence induced craving and heightened CBF, which was detected in orbitofrontal cortex, anterior and posterior ventral insula, posterior cingulum, and superior temporal gyrus.

    • Severity of negative mood and anxiety symptoms occurring during acute abstinence from tobacco: A systematic review and meta-analysis

      2020, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      However, several studies proposed that tobacco withdrawal symptoms may emerge as soon as 4 hrs post-quit (e.g. Hendricks et al., 2006). This has been further supported by recent neuroimaging findings that revealed disrupted neural processes in the mesocorticolimbic network following 4 hrs of smoking abstinence (Franklin et al., 2018). Furthermore, little is known about possible sex differences related to the experience of specific mood symptoms.

    • Impaired cognitive performance under psychosocial stress in cannabis-dependent men is associated with attenuated precuneus activity

      2020, Journal of Psychiatry and Neuroscience
      Citation Excerpt :

      However, both acute nicotine administration and abstinence-induced nicotine craving may affect stress processing and underlying neural mechanisms. 37 Nicotine craving is reported to peak around 3 to 6 hours after the last cigarette, and a recent study reported craving-associated neural activity changes after 4 hours of abstinence.38 As a trade-off, participants were allowed to smoke as usual, but underwent a 1.5-hour supervised abstinence period before the start of the experimental paradigm. 20,29

    View all citing articles on Scopus
    View full text