When abstinent <1 h, smokers showed a greater change in BOLD signal in the right precentral sulcus, including the FEF, in the incongruent than in the congruent condition of the Stroop Task. This difference between the two task conditions was not observed after smokers smoked a cigarette, nor was it exhibited by nonsmokers in either test. Literature regarding selective attention indicates that activity of the FEF (including the adjacent regions around the precentral sulcus) mediates shifts of attention and discrimination between targets and distracters (Astafiev et al, 2003
; Hopfinger et al, 2000
). For example, FEF neurons in monkeys are activated during discrimination between targets and distracters (Bichot and Schall, 1999
; Thompson and Bichot, 2005
); and the FEF is activated by distracters while human subjects perform an oddball task (Bledowski et al, 2004
). This activation is believed to reflect discrimination of distracters from targets and diversion of attention from distracters (Bledowski et al, 2004
). Previous fMRI studies found that activity in the FEF is associated with the diversion of attention in space (Astafiev et al, 2003
; Hopfinger et al, 2000
), the shifting of attention between objects at the same location, and between features of the same object (Liu et al, 2003
; Serences et al, 2004
Activity of FEF neurons mediates selection, generation, and inhibition of responses after peripheral cues (Astafiev et al, 2003
; Connolly et al, 2002
; Merriam et al, 2001
). The successful performance of the incongruent condition requires inhibition of the interference introduced by the semantic meaning of the word during signal perception, and perhaps also inhibition of the tendency to respond to the semantic meaning during response selection (MacLeod, 1991
; Mead et al, 2002
). The activity in the FEF observed in the present study may reflect either or both of these types of inhibition. Our study did not, however, distinguish between potential effects of brief abstinence or smoking on these types of inhibition.
Relative to young adults, aged subjects have deficits in inhibition of distracters on a selective attention task (Maylor and Lavie, 1998
). They also exhibit larger differences in the activity in the right FEF between the incongruent and congruent conditions than young adults while they perform the Stroop Task during fMRI (Langenecker et al, 2004
), suggesting that aging is associated with reduced functional efficiency of the FEF during performance of the Stroop task. The observed interaction in the present study reflects greater activity in the more difficult condition of smokers only and only in the test block before acute smoking. It suggests that the inhibitory function of the right FEF is compromised in smokers abstinent for only 45–60 min; and that this compromise is counteracted by smoking a cigarette.
In the present study, smokers did not report severe withdrawal and craving symptoms immediately before the first test. They also did not show significant differences in withdrawal and craving scores between the first and second tests. Therefore, it is unlikely that the effect of cigarette smoking on the BOLD signal at the right FEF and adjacent precentral sulcus of smokers is due to the relief of subjective nicotine withdrawal or craving for cigarettes. Our findings suggest that chronic smoking, short abstinence (45–60 min) from cigarette smoking, conditions that existed before the initiation of smoking, or any combination of these factors, impaired the functional efficiency of the right FEF of nicotine-dependent smokers on selective attention tasks, and that acute smoking a cigarette ameliorated this functional deficit. This acute reversal effect of cigarette smoking on the function of FEF may be one of several factors that help maintain smoking behavior.
In a previous study, smokers, who abstained from cigarette smoking for about 45 min, showed less activation in the parietal cortex and striatum than nonsmokers while they performed a continuous performance task; and that this hypoactivation in smokers was reversed after application of transdermal nicotine (21 mg, >3 h) (Lawrence et al, 2002
). In that study and in ours, smokers who were abstinent from cigarette smoking <60 min, exhibited abnormal brain activation while performing attentional tasks; and this abnormality was reversed by either cigarette smoking or nicotine administration. The two studies, however, show different directions of effects. We found that, before cigarette smoking, smokers showed higher task-related activity than nonsmokers (see ) although this difference did not reach our a priori
threshold for statistical significance. Notably the two studies used different tasks, and the abnormalities in activation were in different brain regions.
Acetylcholine enhances both bottom-up signal detection and top-down control of signal processing, thereby facilitating the processing of goal-related signals, suppressing the processing of distracters, and increasing the signal/noise ratio in the cortex (for review, see Sarter et al (2005)
). Such actions could increase the functional efficiency of cortex, reducing cortical activity (ie, BOLD signal) required for demanding attentional tasks. When delivered through cigarette smoking, nicotine mimics the action of acetylcholine by binding to nicotinic acetylcholine receptors (nAChRs) and promoting acetylcholine release. By this action, cigarette smoking may have reduced BOLD signal at the right FEF and adjacent precentral sulcus in the incongruent condition after cigarette smoking in our study. The same mechanism may explain why nicotine administration decreased task related BOLD signals in the frontal and parietal cortices of nonsmokers performing a selective attention task (Thiel et al, 2005
It is plausible that reduced functional efficiency in the brain following brief abstinence from smoking ad libitum
until the afternoon of testing may reflect desensitization of nAChRs. About 70% of α
2 nAChRs in cultured cells are desensitized after brief exposure to 10 nM (1.6 ng/ml) (Paradiso and Steinbach, 2003
). By comparison, smoking one cigarette can elevate arterial plasma nicotine concentrations above 180 nM (30 ng/ml) for more than 20 min (Gourlay and Benowitz, 1997
). In addition, positron emission tomographic assessment of in vivo
nAChR occupancy in smokers indicated that smoking just one cigarette can produce >88% occupancy of α
2* nAChRs for at least 4 h after smoking (Brody et al, 2006
). To the extent that nAChRs in human brain respond to nicotine with desensitization as shown in vitro
, smoking ad libitum
until 45–60 min before testing could render central nAChRs less responsive to stimulation by endogenous acetylcholine, and thereby decrease functional efficiency. If smokers in this study had a large proportion of their cerebral α
2* nAChRs desensitized at the time of testing, the positive effect of smoking one cigarette on selective attention could reflect activation of a population α
2* (or other) nAChRs that are resistant to desensitization. Alternatively, the effect may reflect non-nicotine components of tobacco smoke or of the smoking experience.
In the present study, we did not find significant improvement in task performance of smokers after they each smoked a cigarette. At the same time, we observed a decrease in BOLD signal in the incongruent condition of the Stroop task, suggesting improved functional efficiency in the right FEF and adjacent pre-central sulcus. A possible reason for the inconsistency between fMRI and behavioral findings is a greater sensitivity of neuroimaging methods as compared with purely behavioral tests, as observed previously (Bolla et al, 2003
; Eldreth et al, 2004
; Goldberg and Weinberger, 2004
Consistent with our hypothesis and relevant literature (Banich et al, 2000
; Brown et al, 1999
; Langenecker et al, 2004
; Taylor et al, 1997
; Zysset et al, 2001
), both test groups showed larger increases of BOLD signal from rest in the left IFG during the incongruent than during the congruent condition. Neuroimaging studies have indicated that the left IFG mediates inhibition in verbal working memory (Jonides et al, 1998
). Studies using the Stop-signal task found that the right IFG is the main cortical site involved inhibition of motor responses (Aron et al, 2003
; Aron and Poldrack, 2006
). The findings of different brain regions mediating inhibition in different tasks suggest that the inhibition, or cognitive control, involves multiple brain areas, and the exact location is task dependent.
There are limitations in this study. First, as the sample size is small, the results should be considered as preliminary. In addition, as CO and nicotine from cigarette smoking may have complex effects on cerebral perfusion (Domino et al, 2004
; Ghatan et al, 1998
; Rose et al, 2003
), they may affect BOLD signal, which is an essential feature of fMRI signal. Nicotine administration, however, did not alter the coupling between the BOLD signal and activity of the visual cortex in response to photic stimulation in a previous study (Jacobsen et al, 2002
), suggesting that this potential confound may not contribute to our findings. In our study, significant interaction between subject groups and tests was only observed in the right precentral sulcus and the adjacent FEF, which previous work implicated as contributing to selective attention and response selection. This selective effect is not easily explained by nonspecific effects of CO and/or nicotine on cerebral perfusion. Lastly, our study does not separate the effects of nicotine from other effects of the smoking experience (physical and emotional). Answering this question would require a larger sample and assay of plasma nicotine.
Our findings suggest that nicotine-dependent smokers have impaired functional efficiency in the right FEF and adjacent precentral sulcus, as evidenced by greater BOLD signal changes when tested in the incongruent than in the congruent condition of the Stroop Task. Nonsmokers did not show this difference between conditions. As smoking a cigarette removed the difference in smokers, it appears that smoking after even brief abstinence can improve functional efficiency. This effect appears to reflect normalization of deficient function rather than a facilitation of brain function beyond the level exhibited by healthy nonsmokers. To the extent that such recovery reflects effects of nicotine per se, smokers might achieve this improvement with products that deliver nicotine through routes other than smoking.