Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence

Abstract

Environments associated with prior drug use provoke craving and drug taking, and set the stage for lapse/relapse. Although the neurobehavioral bases of environment-induced drug taking have been investigated with animal models, the influence of drug-environments on brain function and behavior in clinical populations of substance users is largely unexplored. Adult smokers (n=40) photographed locations personally associated with smoking (personal smoking environments; PSEs) or personal nonsmoking environment (PNEs). Following 24-h abstinence, participants underwent fMRI scanning while viewing PSEs, PNEs, standard smoking and nonsmoking environments, as well as proximal smoking (eg, lit cigarette) and nonsmoking (eg, pencil) cues. Finally, in two separate sessions following 6-h abstinence they viewed either PSEs or PNEs while cue-induced self-reported craving and smoking behavior were assessed. Viewing PSEs increased blood oxygen level-dependent signal in right posterior hippocampus (pHPC; F(2,685)=3.74, p<0.024) and bilateral insula (left: F(2,685)=6.87, p=0.0011; right: F(2,685)=5.34, p=0.005). In the laboratory, viewing PSEs, compared with PNEs, was associated with higher craving levels (F(2,180)=18.32, p<0.0001) and greater ad lib smoking (F(1,36)=5.01, p=0.032). The effect of PSEs (minus PNEs) on brain activation in right insula was positively correlated with the effect of PSEs (minus PNEs) on number of puffs taken from a cigarette (r=0.6, p=0.001). Our data, for the first time in humans, elucidates the neural mechanisms that mediate the effects of real-world drug-associated environments on drug taking behavior under conditions of drug abstinence. These findings establish targets for the development and evaluation of treatments seeking to reduce environment provoked relapse.

Trial registration: ClinicalTrials.gov NCT01840111.

Figures

Figure 1

Example cues and differential effects of viewing personal and standard smoking and nonsmoking environments on brain activation—regions of interest (ROI) analysis. (a) Depiction of samples of smoking and nonsmoking, proximal and environment cues. (b–d) Bar graphs represent mean % BOLD signal change in response to viewing smoking and nonsmoking cues for each category in right posterior and anterior hippocampus (pHPC and aHPC in Panels b and d, respectively) and left insula (INS; (c)). Error bars represent SEM. Viewing personal smoking environments (PSEs) was associated with selectively increased BOLD signal in right pHPC and bilateral INS (see text and Supplementary Figure S3 for additional statistical detail).

Figure 2

Differential effects of viewing personal and standard smoking and nonsmoking environments on brain activation—whole-brain, voxel-wise analysis. Selected whole-brain, voxel-wise analyses were carried out. (a) BOLD signal was greater in response to viewing personal smoking environments, compared with personal nonsmoking environments (PSE>PNE) in brain areas including bilateral parietal cortex, right temporal gyrus, right insula, right striatum, right supramarginal gyrus, cerebellum, and brainstem. (b) Activation in response to smoking compared with nonsmoking cues was greater for personal compared with standard environments (personal>standard) in left insula. (c) Activation in response to smoking environments (relative to nonsmoking environments) compared with proximal smoking cues (relative to nonsmoking cues; environments>proximal) was observed in bilateral lateral occipital cortex, right temporal cortex, and right precuneus. All contrasts were evaluated at a cluster-corrected threshold of z=3.1, p<0.05. The location of the a priori INS ROIs are noted in Panels a and b by a light blue circle.

Figure 3

Differential effects of viewing personal smoking and nonsmoking environments on craving, smoking behavior and breath carbon monoxide. The effects of viewing personal smoking and nonsmoking environments are shown for craving, smoking behavior measures (no. of cigarettes smoked; no. of puffs) and boost in breath CO levels. Viewing personal smoking compared with nonsmoking environment cues (PSE vs PNE) resulted in significantly greater cue-provoked craving, higher number of puffs taken, and an increase in breath CO boost.

Figure 4

Association between task-related insula activation and the effects of personal smoking environments on smoking behavior. Shown is a positive association between the effects of exposure to personal smoking environments (minus nonsmoking environments) on right insula (INS) activation and on log-transformed number of puffs. This effect was observed after controlling for severity of nicotine dependence (as measured by the FTND) (r=0.60, p=0.001). Although not identified as an outlier, the removal of one participant with a relatively large decrease in smoking reduces the correlation to r=0.54, p=0.005, two-tailed.

Figure 5

Functional Network Including the pHPC and INS ROIs. An exploratory dual regression analysis on BOLD signal acquired during the task resulted in one component (IC 7; 4.01% of total variance) that included the a priori INS and pHPC ROIs. Areas in red were positively associated with the component and include hippocampus, insula, parahippocampal cortex, superior temporal gyrus, and lingual gyrus; blue areas were negatively associated with the component and include the dorsal striatum. A priori INS and pHPC ROIs are depicted in green. A correlation between PSE-induced increases in number of puffs and intrinsic connectivity of this component with the left INS ROI (r=0.41, p=0.03) was observed. Although not identified as an outlier, the removal of one participant with a relatively large decrease in smoking reduces the correlation to a trend (r=0.34, p=0.09, two-tailed).