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Craving is a hallmark of drug dependence, including dependence on nicotine. Many studies have examined the neural substrates of cravings elicited by smoking-related cues. Less is known about the neural basis of unprovoked, abstinence-induced cravings, despite the contributions of such cravings to smoking relapse. To fill this gap, we used arterial spin labeled ASL perfusion magnetic resonance imaging to characterize the neural substrates of abstinence-induced cravings to smoke.

These data suggest that increased activation in the brain's visuospatial and reward circuitry underlies abstinence-induced cravings to smoke, and thereby, may be important in relapse. Cravings are a prominent feature of models of drug dependence, including nicotine, and a target of medication development efforts Nestler, ; Lerman et al.

However, not all forms of craving are equivalent with respect to the proximal causes or consequences. A second form of craving develops rapidly after smoking cessation, in the absence of smoking-related cues Jarvik et al. The brain circuitry that underlies cue-elicited cravings to smoke has been explored extensively using positron emission tomography PET and functional magnetic resonance imaging fMRI Brody, Compared with neutral cues, smoking-related cues produce increased activation in the brain's visual attention and reward circuitry Brody et al.

Some of these regions e. However, these studies varied with respect to the abstinence status of smokers, and only one McClernon et al. Thus, much less is known about how nicotine abstinence affects regional brain activation or about the neural circuitry underlying abstinence-induced cravings to smoke. Predictions about the neural basis of abstinence-induced cravings can be generated based on previous neurobiological evidence.

Other regions of interest suggested by previous research include those important in neural plasticity, learning, and memory e. To explore the neural basis of abstinence-induced cravings, smokers in the present study were scanned, using arterial spin labeled ASL perfusion magnetic resonance imaging MRI , on two separate occasions: during a resting state of smoking satiety 1 h after cigarette consumption versus a resting abstinent state at least 12 h after cigarette consumption.

The cerebral blood flow CBF changes associated with smoking abstinence compared with satiety were further examined for correlations with subjective abstinence-induced craving.

Fifteen smokers, 18—55 years old, who smoked at least 10 cigarettes per day for the last 6 months were recruited through newspaper advertisements. Eligible participants were required to abstain from psychotropic medications for 14 d before the session and throughout the study i. The experiment used a within-subject design with two imaging sessions occurring 1—3 weeks apart: 1 smoking as usual and 2 overnight 12—14 h abstinent.

Both sessions occurred before 12 noon for standardization and the order of sessions was counterbalanced across participants. For both sessions, subjects were instructed to refrain from alcohol or other drugs for at least 24 h before the session, to abstain from food for 2 h before the session, and to abstain from caffeine for at least 1 h before the session. For the smoking as usual session, participants were asked to smoke one of their own brand cigarettes before entering the clinic.

After arrival to the clinic, participants completed self-report questionnaires below and provided a carbon monoxide CO breath sample. This sample was used to verify overnight abstinence for the abstinence session. All participants self reported no smoking for the past 14 h. We used a criterion of 15 ppm, because reduced lung function in long term smokers produces variability in ability to clear CO overnight. CO level at the satiety session was also used to control for recent tobacco exposure in the analyses.

At baseline, participants completed standard demographic assessments and measures of smoking history. The Fagerstrom Test for Nicotine Dependence Fagerstrom and Schneider, , a six-item validated scale, was also administered. In addition, we assessed total withdrawal scores Hughes et al. ASL perfusion MRI provides a noninvasive and comparatively inexpensive method for quantifying CBF during a task condition or a resting state using magnetically labeled arterial blood water as an endogenous tracer Detre et al.

The magnetic tracer has a decay rate of T1, the longitudinal relaxation time for blood water or brain tissue, which is sufficiently long 1—2 s at 3 tesla to allow perfusion of the microvasculature to be detected.

Tissue perfusion is quantified by pairwise comparison with separate images acquired with control labeling, using an appropriate model Alsop et al. An unlimited number of CBF measurements can be made, enhancing power for time series based statistical analysis. In addition, ASL perfusion measurements both at rest and during task activation have been demonstrated to be highly reproducible across intervals varying from a few minutes to 7 weeks Floyd et al.

High-resolution structural MR images were acquired in both sessions for CBF image spatial normalization, using a T1-weighted three-dimensional 3D magnetization-prepared rapid acquisition gradient echo MP-RAGE sequence with slices, 1. These data were acquired before a longer scanning protocol that included fMRI. During the perfusion scan, participants were instructed to lie quietly in the scanner. Because we were interested in cravings during a resting state, and because cognitive tasks are known to change CBF Xu et al.

They were reminded not to fall asleep during the scan. For each session, ASL image pairs were realigned to the mean of all control images to correct for head movements, and spatially smoothed with a 3D isotropic Gaussian kernel with full-width at half-maximum of 10 mm. One subject was excluded because of excessive motion, resulting in a sample size of For each session, the mean control image was coregistered to the structural image acquired in the same session using the mutual information based coregistration algorithm provided by SPM5.

The same coregistration parameters were also used to coregister the CBF maps to the structural image. Each subject's normalized mean control images were segmented using SPM5.

The segmented gray matter masks were averaged and the overlap of all subjects' gray matter was pulled out and used as a final mask for calculating global CBF of each session. Contrast analysis between the abstinence and smoking session was conducted on each subject's normalized CBF images using a general linear model first level analysis.

A random effect analysis using one-sample t testing Holmes and Friston, on the parametric maps of the first level contrast was used to generate a statistical parametric map of the T statistic at each voxel for population inference second-level analysis. Another multiple regression with the total withdrawal score difference abstinence minus satiety , CO scores of the smoking session, and gender as covariates was performed to examine correlations between CBF changes and changes in total withdrawal symptoms.

Two-sample t tests were applied to test 1 whether there is a significant main effect of session i. Gender and the CO scores of the smoking session were included as nuisance covariates.

Multiple comparison corrections were then performed using the familywise error FWE theory and based on the small volume correction SVC Worsley et al. The small volume was chosen using a sphere located in the center of the corresponding regions. Fifty percent of participants had at least some college education. The average age was The average Fagerstrom Test for Nicotine Dependence score was 4. As expected, the nicotine abstinence manipulation produced significant differences in cravings across the two sessions [average craving scores of 3.

X , Y , and Z refer to the left—right sagittal , anterior—posterior coronal , and the inferior—superior axial orientations, respectively, and are color coded in yellow, turquoise, and blue.

The location of each slice is marked by lines with different colors and the corresponding X or Z value. Figure 1 shows the main regional CBF effects of abstinence versus satiety. Statistical map of the regional CBF changes caused by abstinence vs satiety. The two blue lines superposed on the medial sagittal slice indicate the locations of the two left axial slices.

Figure 2 shows the correlation between abstinence-induced absolute CBF changes and abstinence-induced craving changes the difference in scores between abstinence and satiety sessions.

Association of abstinence-induced craving with regional CBF changes. An axial slice bottom row shows suprathreshold clusters in the amygdala and the hippocampus. Suprathreshold correlation clusters in the occipital cortex, midbrain, and the anterior cingulate were also shown in the sagittal slice bottom row. Based on a previous study Tanabe et al. Figure 3 shows the correlation between abstinence-induced CBF changes and total withdrawal score changes i.

Association of abstinence-induced global withdrawal scores with regional CBF changes. Significant correlations of CBF change with change in withdrawal symptoms were found in the right dorsolateral prefrontal cortex, caudate, right hippocampus, and the right medial temporal gyrus.

The present study examined effects of abstinence from smoking on resting CBF, as well as the correlation between abstinence-induced changes in resting CBF and changes in cravings to smoke.

The ACC and OFC are paralimbic regions that have been implicated in drug-seeking behavior Kalivas and Volkow, , partly via their roles in reward-related decision-making and cognitive control Rushworth et al. As with abstinence-induced craving in the present study, ACC and OFC activation have been linked with cue-induced craving in previous research Brody et al.

These same regions are activated after delivery of nicotine vs placebo Stein et al. Together, these findings support an important role for the ACC and OFC in nicotine dependence, and perhaps specifically in craving responses that are known to promote relapse. The hippocampus and amygdala, which play important roles in associative learning and synaptic plasticity Tronson and Taylor, , are also implicated in abstinence-induced cravings in the present study.

The ventral striatum, also associated with abstinence-induced craving in the present study, is activated by smoking related cues as well David et al. The ventral striatum has been implicated in the anticipation and immediate response to rewards, particularly among individuals scoring high on a trait measure of impulsivity Hariri et al.

Correlations observed in the present study between abstinence-induced cravings and insula activation are consistent with the role of this region in awareness of interoceptive cues Damasio et al. Finally, the thalamus, rich in nAChRs that stimulate dopamine release Brody et al.

Previously, Tanabe and colleagues Tanabe et al. In contrast, we observed a positive correlation between the increase of CBF in the thalamus during abstinence and the abstinence-induced craving. To address these differences, we also analyzed data on a global withdrawal symptom scale, finding CBF increases in the right DLPFC, hippocampus, and medial temporal gyrus, but not thalamus. The greater sensitivity of craving scores, compared with global withdrawal scores, for correlations with CBF changes during abstinence is noteworthy.

Increased cravings to smoke post cessation consistently predict relapse, particularly in the first weeks of quitting Doherty et al. Global assessments of withdrawal that encompass somatic, cognitive, and affective symptoms Hughes, tend to be less robust predictors of relapse. For example, increased withdrawal symptoms have been shown to predict relapse during cessation treatment in some studies Piasecki et al.

This is further supported by data showing that the extent to which smoking cessation treatments reduce withdrawal does not necessarily correlate with their efficacy Jorenby et al.

Thus, global measures of abstinence symptoms may not only be less sensitive measures in neuroimaging studies of smoking behavior, but also appear to have reduced prognostic value compared with measures of specific constructs e. The present study has several strengths, including the within-subject design and the abstinence manipulation.

However, there are potential limitations as well. First, on the day of the satiety session, participants smoked their last cigarette 45—60 min before the scanning session. This time lag was introduced because smoking a cigarette immediately before the scan would make it difficult to disentangle the effects of acute nicotine delivery. Nonetheless, it is possible that some participants may have experienced minor abstinence symptoms during the smoking session. However, craving scores between the two sessions were significantly different, suggesting that the abstinence manipulation was effective.

Third, physiological assessments were not performed during scanning, and we cannot rule out the possibility that a subject fell asleep, despite our urging to the contrary. Fourth, with only two sessions examined in this study and no control group, it was not possible to determine the intersession test—retest reliability of ASL perfusion for our data.

However, the effects reported in the present study were much larger than the mean differences observed between two time points 7 weeks apart in a previous CASL reproducibility study Hermes et al.

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The best way to get people to quit smoking is to offer them cash, a new study suggests. Research published Wednesday in the New England Journal of Medicine compared the effectiveness of different programs for getting people to quit.

Some were offered advice on smoking cessation and access to a motivational text-messaging service. Some also got free cessation aids, like nicotine patches. Another group got that, plus free e-cigarettes. The two groups who were offered cash saw a significant jump in their success rates after six months — about double that of the e-cigarette group.

Andrew Pipe, a smoking cessation researcher at the Ottawa Heart Institute and professor of medicine at the University of Ottawa. What smokers will value is offers of assistance. Other studies that have looked at money as an incentive have also seen quite a bit of success, he said.

Just 2. Only a tiny fraction of people responded to opt out, so that left a lot of people who may not have actively participated. Among people who were engaged with the study, Women might want to time it with their period, study suggests. But the money has to come from somewhere. Want to discuss? Please read our Commenting Policy first. World Canada Local. The best incentive to quit smoking? Free money. Full Menu Search Menu. Close Local your local region National.

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