Treatment seeking cigarette smokers have heightened craving when exposed to cigarette-related cues in a laboratory setting, regardless of whether or not they attempt to resist the urge to smoke. The extent of this heightened craving was consistent with prior functional brain imaging research demonstrating cigarette cue-induced craving (Brody et al 2002
; McBride et al 2006
; Wilson et al 2005
). However, patterns of regional brain activation (and deactivation) were clearly different depending on whether or not subjects attempted to resist craving.
Consistent with prior research (Smolka et al 2005
; Wilson et al 2005
; Lee et al 2005
), exposure to visual cigarette cues when subjects allowed themselves to crave (compared with the neutral cue condition) activated primary (left lateral occipital gyrus) and secondary (left cuneus, precuneus, and lingual and angular gyri, and bilateral supramarginal gyri) visual processing centers that also are activated during heightened visual attention (Makino et al 2004
; Servos et al 2002
; Roland and Gulyas 1995
) and recognition of familiar objects (Sugiura et al 2005
) and memories (Yonelinas et al 2005
). The retrosplenial cortex also showed activation in this analysis, possibly related to its role in memory formation (Ranganath et al 2005
), (including recall of autobiographical (Steinvorth et al 2005
) and emotionally salient events (Maddock 1999
)). While these results do overlap with regions found to activate in previous studies, we did not find activation in the prefrontal cortex or ACC, as has been reported previously when comparing cigarette-related with neutral cue states, possibly because subjects in this study may have experienced greater arousal when asked to resist craving with corresponding lower levels of arousal when not asked to resist.
For the cigarette cue resist compared to the neutral cue condition, activation was also found in secondary visual processing centers (bilateral precuneus, left angular gyrus, and bilateral supramarginal gyri) and retrosplenial cortex (bilaterally), but these clusters were larger than those found in the preceding analysis. This analysis also revealed activation of the dorsal ACC (a region associated with response conflict (Liu et al 2004
), decision-making (Paulus et al 2005
; Rushworth et al 2004
; Turk et al 2004
), regulation of anxiety-related behavior (Kalin et al 2005
), and planning (Lazeron et al 2000
)) and the PCC (a region associated with responses to anxiety-provoking video (Fredrikson et al 1997
), and recognition of words in an emotionally negative context (Maratos et al 2001
)). Deactivations were found with resisting craving in the sensorimotor cortices (bilateral post-central and right pre-central gyri) and cuneus bilaterally.
For the central analysis of this study comparing responses to the cigarette cues with versus without resisting cigarette craving, greater MR signal was found with resisting craving in regions involved in decision-making/planning (left dorsal and perigenual ACC) and attentional motivation (left PCC), along with a secondary visual processing center (left precuneus). Lower MR signal was found in a visual processing center (left cuneus) and in motor cortex (right post-central gyrus). The dorsal ACC activation and visual cortical deactivation found here are consistent with examinations of brain function during cognitive reappraisal and cognitive modulation of emotion (Pessoa et al 2002
; Ochsner et al 2004
; Ray et al 2005
; Kalisch et al 2006
). Engagement of the ACC, which is implicated in conflict avoidance and attentional control (Barch et al 2001
; Braver et al 2001
; Liu et al 2004
), may reflect the active direction of attention away from the hypersalient smoking stimuli as an effortful process that is contrary to automatic patterns of attention. Taken together, these findings suggest that actively suppressing the urge to smoke involves a redistribution of resources from sensory and motor areas to limbic (and related) brain areas.
While results here are in agreement with prior work, two aspects of the central study comparison were surprising, namely that subjects reported slightly (and non-significantly) more craving and that brain activation (particularly in the ACC and PCC) was greater when subjects were actively trying to resist the urge to smoke than when they allowed themselves to crave. These findings may be partly accounted for by the “white bear” effect, where subjects paradoxically think more strongly about a topic that they are instructed to suppress (Wegner et al 1987
; Enticott and Gold 2002
). While control instructions, such as asking subjects to actively try to crave during the cigarette cue crave presentation or to resist craving during the neutral cue presentation, would control for the intention aspects of the results, the present study sought to simulate real-life situations. And indeed, subjects did report that study conditions mimicked naturally-occurring situations.
Craving levels positively correlated with MR signal in the same decision-making (dorsal ACC), attentional processing (PCC), sensorimotor (left pre-central gyrus) and secondary visual processing (precuneus, right lingual and fusiform gyri, and bilateral supramarginal gyri) regions as in the preceding analyses, as well as regions that mediate (Kimbrell et al 1999
; Goldin et al 2005
; Kuchinke et al 2005
) and interpret (Menon et al 2000
; Kesler-West et al 2001
; Drexler et al 2000
) emotional stimuli (anterior insula and inferior frontal gyri bilaterally) and a region associated with sustained attention and episodic memory (left middle frontal gyrus (Cabeza and Nyberg 2000
)). Negative correlations were found in visual and auditory processing centers, as well as left motor cortex.
One limitation of this study was the absence of a non-smoking control group exposed to the same cues as the smokers studied here. However, in our prior work (Brody et al 2002
), non-smokers demonstrated neither cigarette craving nor changes in mood/anxiety associated with presentation of cigarette-related cues. Also, since the primary analysis here was the examination of cigarette cue exposure with and without resisting craving, the use of non-smoking control subjects would not be expected to help in the central interpretation of this study. The main strengths of this report include a relatively large sample size for a study of this type, the control of cue presentation through specialized MR-compatible equipment, and the fact that cues (e.g.- video of chore performance with or without smoking) and states (allowing oneself to crave versus resisting craving while watching similar cues) were matched closely.
In conclusion, we report significant differences in brain function when treatment-seeking smokers are exposed to cigarette-related cues and are actively resisting craving versus allowing themselves to crave. During craving resistance, activation was found in brain regions involved in decision-making, regulation of anxiety-related behaviors, and heightened attention, while deactivation was found in primary visual and motor cortices. Similar activations and deactivations were found when comparing the cigarette cue resistance to the neutral cue condition. Additionally, exposure to cigarette cues without craving resistance was found to activate visual processing centers when compared with neutral cue exposure. These results identify regions that may mediate the effects of existing Tobacco Dependence treatments and that may be targets for medication development. For example, enhanced catecholiminergic (Passerin et al 2000
; Schweimer et al 2005
), acetylcholinergic (Jacobsen et al 2004
; Gozzi et al 2006
; Choi et al 2006
), and cannabinoid (Mathew et al 1997
; Mathew et al 1999
; O'Leary et al 2002
) neurotransmission activate the ACC, including activation during effortful decision-making (Schweimer et al 2005
), while enhanced GABA (Passerin et al 2000
; Mintzer et al 2001
) neurotransmission diminishes ACC activation. Currently available medications for Tobacco Dependence, such as the catecholamine reuptake blocker bupropion HCl (Ascher et al 1995
; Horst and Preskorn 1998
) and nicotine replacement (acetylcholine agonist) therapy may exert their therapeutic effects at least partly through enhancement of ACC activation with concomitant improvement in the ability to resist craving, while medications that alter cannabinoid and GABAergic neurotransmission are currently under investigation as potential treatments for Tobacco Dependence. Thus, the present study may help elucidate the brain mediation of existing Tobacco Dependence treatments and suggests potential neurotransmitter system targets for medication development.