Dorsolateral prefrontal and orbitofrontal cortex interactions during self-control of cigarette craving Takuya Hayashia,b,c,d,1, Ji Hyun Koa,e, Antonio P. Strafellaa,e, and Alain Daghera,1 aMcConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4; bRIKEN Center for Molecular Imaging Science, Kobe, Hyogo 650-0047, Japan; cHuman Brain Research Center, Graduate School of Medicine, Kyoto University, and dCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and eDepartment of Medicine (Neurology), University of Toronto, Toronto, ON, Canada M5S 1A8 Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved January 4, 2013 (received for review July 17, 2012) Drug-related cues induce craving, which may perpetuate drug use parietal cortices and subcortical areas (18, 19), but none has or trigger relapse in addicted individuals. Craving is also under the investigated the neural substrates of the incorporation of contex- influence of other factors in daily life, such as drug availability and tual information into craving. A metaanalysis of the cue reactivity self-control. Neuroimaging studies using drug cue paradigms have neuroimaging literature suggested that prefrontal cortical areas are shown frontal lobe involvement in this contextual influence on onlyactivatedwhendruguseisavailablesoonafterthescanning cue reactivity, but have not clarified how and which frontal area procedure (18), but did not specify how context is processed within accounts for this phenomenon. We explored frontal lobe contribu- prefrontal circuitry. Recent studies suggest involvement of dorsal tions to cue-induced drug craving under different intertemporal drug or medial prefrontal cortex in cognitive control of craving (20, 21), availability conditions by combining transcranial magnetic stimula- although causal roles of these areas has not been demonstrated. tion and functional magnetic resonance imaging in smokers. We We hypothesize that cue-induced craving is a reflection of the hypothesized that the dorsolateral prefrontal cortex (DLPFC) regu- current net value of the drug for the addicted individual, as a func- lates craving during changes in intertemporal availability. Subjective tion of drug cues and drug-related context, and may be encoded in craving was greater when cigarettes were immediately available, and the medial orbitofrontal cortex (mOFC). This is based on recent this effect was eliminated by transiently inactivating the DLPFC with findings that the mOFC encodes subjective value for available goods transcranial magnetic stimulation. Functional magnetic resonance after accounting for variables such as temporal delay, risk, and cost imaging demonstrated that the signal most proportional to subjec- (22–25). We also hypothesized that information regarding the im- tive craving was located in the medial orbitofrontal cortex across all mediacy of drug availability may be processed in circuitry including contexts, whereas the DLPFC most strongly encoded intertemporal the dorsolateral prefrontal cortex (DLPFC). This hypothesis derives availability information. The craving-related signal in the medial from recent literature on the critical role of the DLPFC in inter- orbitofrontal cortex was attenuated by inactivation of the DLPFC, temporal choice (26, 27) and self-control (28, 29). Specifically, our particularly when cigarettes were immediately available. Inactivation hypothesis arises from our previous work in smokers performing of the DLPFC also reduced craving-related signals in the anterior a cigarette cue task, in which craving-related signals were greater in cingulate and ventral striatum, areas implicated in transforming value an area of left DLPFC when cigarettes were available immediately signals into action. These findings indicate that DLPFC builds up value compared with when they were available later (30). In the current signals based on knowledge of drug availability, and support a model study, we tested this hypothesis using a within-subject design of wherein aberrant circuitry linking dorsolateral prefrontal and orbito- behavior and functional magnetic resonance imaging (fMRI) with frontal cortices may underlie addiction. or without transient focal inactivation of the left DLPFC. Cortical inactivation was achieved using 1-Hz transcranial magnetic stimu- decision making | smoking | nicotine | expectancy | temporal discounting lation (TMS), which is known to transiently inhibit the targeted cortex (31). The results of behavioral and neuroimaging data, ddiction can be placed within the framework of decision combined with inactivation of the DLPFC, shed light on the ways in Amaking (1, 2). Drug cues such as the sight or smell of cig- which cues and context are combined to drive smoking behavior. arettes can trigger craving and drug seeking (3, 4). Behavioral economists propose that drug cues increase the marginal utility Results × of the drug, favoring the decision to consume (3, 5, 6). Indeed, The fMRI study comprised a within-subject 2 2 factorial design “ ” “ ” cue-induced craving reflects the subjective value of drug use (7) with factors of cigarette availability and TMS, as illustrated A Materials and Methods SI Text S1 and predicts drug-seeking behaviors (8, 9), but is also amenable in Fig. 1 (detailed in and ). to self-control (6, 10). Cue-induced craving is affected by a vari- Each subject underwent four sessions of the fMRI smoking cue ety of contexts and events that impact self-control, such as per- reactivity task on different days, with the order of sessions ran- ceived drug availability (11–14), expectancy (15), stress (16), or domized and counterbalanced across subjects. The cue reactivity intention to seek treatment (17). However, the mechanism by task comprised a block design that included two types of videos, one of individuals engaged in cigarette smoking, and a control which craving is under the regulation of self-control is poorly video of persons engaged in nonsmoking behavior (30). The two understood both at behavioral (17) and neural levels (1, 18). The perceived opportunity to use a drug increases the craving response to drug cues and may itself be viewed as a conditioned fl Author contributions: T.H., A.P.S., and A.D. designed research; T.H., J.H.K., and A.D. per- cue (17). Recent studies indicate that cigarette craving is in u- formed research; T.H. contributed new reagents/analytic tools; T.H. and A.D. analyzed enced to a greater degree by cognitive expectancy to smoke than data; and T.H. and A.D. wrote the paper. by nicotine withdrawal (11–13). For example, flight attendants on The authors declare no conflict of interest. fl nonsmoking ights reported higher craving urges immediately This article is a PNAS Direct Submission. before landing, when smoking was about to be permitted, in- Freely available online through the PNAS open access option. dependently of the duration of abstinence (11). The evidence, See Commentary on page 4165. however, is that expectancy only invokes craving in the presence of 1To whom correspondence may be addressed. E-mail: [email protected] or alain@ a conditioned smoking cue (12, 15). bic.mni.mcgill.ca. Neuroimaging studies in addiction have revealed cue-related This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. responses in numerous brain areas, including frontal, visual, and 1073/pnas.1212185110/-/DCSupplemental. 4422–4427 | PNAS | March 12, 2013 | vol. 110 | no. 11 www.pnas.org/cgi/doi/10.1073/pnas.1212185110 Downloaded by guest on October 1, 2021 from our TMS paradigm (at least 30–60 min) (31, 34). Exhaled CO monitoring 4 h later confirmed that participants complied with SEE COMMENTARY the instructions of cigarette availability. Behavioral Data. Subjects indicated their current level of craving (Q1, “I’m craving a cigarette right now”) after each video using a visual analog scale. Relative craving was significantly affected by the interaction of availability and TMS [F(1,9) = 6.3, P < 0.05] (Fig. 1B), but there was no significant effect of availability or TMS. Relative craving differed between the two availability levels in sham TMS [T(9) = 2.8, P < 0.05] but not in true TMS [T(9) = 1.4, P = 0.2]. These findings indicate that craving is amenable to modulation by cues and contextual information (intertemporal cigarette availability), and that inactivation of the DLPFC with TMS eliminated the effect of cigarette availability on craving. Detailed behavioral data are provided in SI Text S2. Neural Activity Associated with Cue-Induced Craving. There was significantly greater blood oxygen level-dependent (BOLD) ac- tivity during the smoking compared with the control video in several brain areas including the bilateral DLPFC, medial pre- frontal cortex, frontal pole, ventral striatum, and temporal, pa- rietal, and visual cortices (Fig. S1A and Table S1), in keeping with our previous study (30). We then looked for brain areas where activity correlated with subjective cigarette craving. We identified relatively localized areas of the prefronto-striatal circuitry, with the greatest effect size located in the mOFC, followed by the left DLPFC and ventral striatum (cluster-corrected P < 0.05; Fig. 2A COGNITIVE SCIENCES and Table S2). The mOFC BOLD signal correlated only with PSYCHOLOGICAL AND craving and was not influenced by any of intention to smoke, ir- ritability, boredom, or by cue alone (Table S2). Intention to smoke correlated with BOLD signal