Background

Priming doses of alcohol are associated with increased desire to drink and disinhibitory effects on subsequent control over drinking. Despite the importance of alcohol priming in the cue-reactivity literature, the effects of priming on brain responses to alcohol cues remains unclear. Furthermore, evidence suggests this relationship may be moderated by OPRM1 genotype.

Methods

Twenty individuals with alcohol dependence (six females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent two functional magnetic resonance imaging (fMRI) sessions, before and after a priming dose of alcohol, each including a gustatory alcohol cue reactivity paradigm and self-reported craving measures.

Results

Self-reported alcohol craving generally increased and remained higher for alcohol versus water cue presentations across pre- and post-priming scans. Compared to alcohol cues delivered during the post-priming scan, alcohol cues delivered pre-priming were associated with greater activation in regions including the hippocampus, amygdala, inferior frontal gyrus, temporal cortex, and occipital cortex. Controlling for alcoholism severity increased statistical significance of activation in these regions. Follow-up analyses revealed a positive correlation between alcoholism severity and pre- versus post-priming alcohol cue-reactivity primarily in frontal regions. OPRM1 genotype was also found to moderate alcohol cue-reactivity across scans.

Conclusion

This study provides initial evidence of alcohol cue-elicited habituation in fronto-temporal regions, despite continued craving, following a priming dose of alcohol. Further, it provides preliminary evidence for moderating roles of alcoholism severity and OPRM1 genotype on priming-related changes in cue-reactivity, adding to our understanding of the function of alcohol priming in alcohol dependence.

Interactions between dopaminergic and opioidergic systems have been implicated in the reinforcing properties of drugs of abuse. The present study investigated the effects of opioid blockade, via naltrexone, on functional magnetic resonance imaging (fMRI) measures during methamphetamine cue-reactivity to elucidate the role of endogenous opioids in the neural systems underlying drug craving. To investigate this question, non-treatment seeking individuals with methamphetamine use disorder (N=23; 74% male, mean age=34.70 (SD=8.95)) were recruited for a randomized, placebo controlled, within-subject design and underwent a visual methamphetamine cue-reactivity task during two blood-oxygen-level dependent (BOLD) fMRI sessions following 3 days of naltrexone (50 mg) and matched time for placebo. fMRI analyses tested naltrexone-induced differences in BOLD activation and functional connectivity during cue processing. The results showed that naltrexone administration reduced cue-reactivity in sensorimotor regions and related to altered functional connectivity of dorsal striatum, ventral tegmental area, and precuneus with frontal, visual, sensory, and motor-related regions. Naltrexone also weakened the associations between subjective craving and precuneus functional connectivity with sensorimotor regions and strengthened the associations between subjective craving and dorsal striatum and precuneus connectivity with frontal regions. In conclusion, this study provides the first evidence that opioidergic blockade alters neural responses to drug cues in humans with methamphetamine addiction and suggests that naltrexone may be reducing drug cue salience by decreasing the involvement of sensorimotor regions and by engaging greater frontal regulation over salience attribution.

Background

Endogenous opioids and striatal dopamine have been implicated in cue-induced alcohol craving and have been hypothesized to play a role in goal-directed, as opposed to habitual, alcohol use. This initial study examines dorsal and ventral striatal functional connectivity during alcohol-cue processing as a function of the A118G single-nucleotide polymorphism of the mu-opioid receptor (OPRM1) gene.

Methods

Seventeen individuals with alcohol dependence (6 females; 90% Caucasian; mean age = 29.4) underwent blood oxygen level-dependent functional magnetic resonance imaging, while performing an alcohol taste-cues task. Psychophysiological interaction analyses investigated associations of the OPRM1 genotype with ventral and dorsal striatum functional connectivity, using the ventral striatum and the caudate as the seed region, respectively.

Results

Compared to A-allele homozygotes, G-allele carriers of the OPRM1 gene showed (i) greater activation of the insula and orbitofrontal cortex and (ii) stronger negative fronto-striatal functional connectivity for both ventral and dorsal striatal seed regions during processing of alcohol versus water cues.

Conclusions

These preliminary findings suggest that, relative to A-allele homozygotes, G-allele carriers show unstable frontal regulation over reward and/or habit-driven inputs from the striatum resulting from greater reward sensitivity combined with limited self-control resources.

Decision-making strategies shift during normal aging and can profoundly affect wellbeing. Although overweighing losses compared to gains, termed "loss aversion," plays an important role in choice selection, the age trajectory of this effect and how it may be influenced by associated changes in brain structure remain unclear. We therefore investigated the relationship between age and loss aversion, and tested for its mediation by cortical thinning in brain regions that are susceptible to age-related declines and are implicated in loss aversion - the insular, orbitofrontal, and anterior and posterior cingulate cortices. Healthy participants (n = 106, 17-54 years) performed the Loss Aversion Task. A subgroup (n = 78) provided structural magnetic resonance imaging scans. Loss aversion followed a curvilinear trajectory, declining in young adulthood and increasing in middle-age, and thinning of the posterior cingulate cortex mediated this trajectory. The findings suggest that beyond a threshold in middle adulthood, atrophy of the posterior cingulate cortex influences loss aversion.

Importance

Various neuropsychiatric disorders, especially addictions, feature impairments in risky decision making; clarifying the neural mechanisms underlying this problem can inform treatment.

Objective

To determine how methamphetamine-dependent and control participants differ in brain activation during a risky decision-making task, resting-state functional connectivity within mesolimbic and executive control circuits, and the relationships between these measures.

Design, setting, and participants

A case-control, functional magnetic resonance imaging study of methamphetamine-dependent and healthy comparison participants at rest and when performing the Balloon Analogue Risk Task, which involves the choice to pump a balloon or to cash out in the context of uncertain risk. Conducted at a clinical research center at an academic institution, this study involved 25 methamphetamine-dependent and 27 control participants.

Main outcomes and measures

Parametric modulation of activation in the striatum and right dorsolateral prefrontal cortex (rDLPFC; ie, the degree to which activation changed as a linear function of risk and potential reward), both indexed by pump number, and resting-state functional connectivity, measured in the whole brain with seeds in the midbrain and rDLPFC. Relationships between these outcomes were also tested.

Results

Parametric modulation of cortical and striatal activation by pump number during risk taking differed with group. It was stronger in the ventral striatum but weaker in the rDLPFC in methamphetamine-dependent participants than control individuals. Methamphetamine-dependent participants also exhibited greater resting-state functional connectivity of the midbrain with the putamen, amygdala, and hippocampus (P < .05, whole brain, cluster corrected). This connectivity was negatively related to modulation of rDLPFC activation by risk level during risky decision making. In control participants, parametric modulation of rDLPFC activation by risk during decision making was positively related to resting-state functional connectivity of the rDLPFC with the striatum.

Conclusions and relevance

Maladaptive decision making by methamphetamine users may reflect circuit-level dysfunction, underlying deficits in task-based activation. Heightened resting-state connectivity within the mesocorticolimbic system, coupled with reduced prefrontal cortical connectivity, may create a bias toward reward-driven behavior over cognitive control in methamphetamine users. Interventions to improve this balance may enhance treatments for stimulant dependence and other disorders that involve maladaptive decision making.

Rationale

Heavy drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available.

Objective

The present study used a double-blind, randomized, 2 × 2 medication design, testing varenicline alone (VAR; 1 mg twice daily), naltrexone alone (NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on neural activation to cigarette cues in a sample (n = 40) of heavy drinking daily smokers (≥10 cigarettes/day).

Methods

All participants were tested after a 10-12-day titration period designed to reach steady state on the target medication. Participants underwent functional neuroimaging (fMRI) for examination of brain responses to visual smoking-related (vs. neutral) cues.

Results

Region of interest (ROI) analyses of brain responses to Cigarette vs. Neutral Cues indicated that the combination of VAR + NTX was associated with reduced activation of the bilateral anterior cingulate cortex as compared to placebo and to NTX alone. Exploratory whole-brain analyses also indicated significant differences in brain activation during cigarette cues in the active medications versus placebo condition. All medications suppressed left nucleus accumbens activation relative to placebo, suggesting the possibility that both medications, either alone or in combination, reduce neural signals associated with appetitive behavior.

Conclusions

Although preliminary, these neuroimaging findings indicate that clinical studies of the combination of VAR + NTX for heavy drinkers trying to quit smoking may be warranted.

Cigarette craving contributes substantially to the maintenance of tobacco use disorder. Behavioral strategies to regulate craving may facilitate smoking cessation but remain underexplored. We adapted an emotion-regulation strategy, using proximal/distal self-positioning, to the context of cigarette craving to examine craving regulation in 42, daily smokers (18-25 years old). After overnight abstinence from smoking, before and after smoking their first cigarette of the day, participants viewed videos of natural scenes presenting young adults who were either smoking cigarettes ("smoke") or not ("non-smoke"). Before each video, participants were instructed to imagine themselves either immersed in the scene ("close") or distanced from it ("far"). They rated their craving after each video. Task-based fMRI data are presented for a subsample of participants (N = 21). We found main effects of smoking, instruction, and video type on craving-lower ratings after smoking than before, following the "far" vs. "close" instructions, and when viewing non-smoke vs. smoke videos. Before smoking, "smoke" vs. "non-smoke" videos elicited activation in, orbitofrontal cortex, anterior cingulate, lateral parietal cortex, mid-occipital cortex, ventral striatum, dorsal caudate, and midbrain. Smoking reduced activation in anterior cingulate, left inferior frontal gyrus, and bilateral temporal poles. Activation was reduced in the ventral striatum and medial prefrontal cortex after the "far" vs. the "close" instruction, suggesting less engagement with the stimuli during distancing. The results indicate that proximal/distal regulation strategies impact cue-elicited craving, potentially via downregulation of the ventral striatum and medial prefrontal cortex, and that smoking during abstinence may increase cognitive control capacity during craving regulation.

Background

Negative emotional states contribute to cigarette smoking, and difficulties in regulating these states can hinder smoking cessation. Understanding the neural bases of these difficulties in smokers may facilitate development of novel therapies for Tobacco Use Disorder.

Methods

Thirty-seven participants (18 smokers, 19 nonsmokers; 16-21 years old) completed the Difficulties in Emotion Regulation Scale (DERS), which is comprised of 6 subscales (lack of emotional clarity, lack of emotional awareness, limited access to emotion regulation strategies, nonacceptance of emotional responses, difficulties engaging in goal-directed behaviors, and impulse control difficulties) that combine to provide a total score. Participants also underwent functional magnetic resonance imaging to determine resting-state functional connectivity of the amygdala. Separate ANOVAs were used to determine group differences in self-reports on the DERS. Voxel-wise linear mixed models were performed to determine whether group influenced relationships between whole-brain functional connectivity of the amygdala and scores on the DERS.

Results

Compared with nonsmokers, smokers reported greater difficulties in emotion regulation, denoted by higher total scores on the DERS. Group differences were observed on a subscale of lack of emotional clarity, but no other subscale differences on the DERS were observed. Nonsmokers exhibited a greater negative correlation than smokers between lack of emotional clarity scores and connectivity of the amygdala with the left inferior frontal gyrus. Finally, this amygdala-to-left inferior frontal gyrus connectivity was weaker in smokers than in nonsmokers.

Conclusions

These findings suggest that difficulties in emotion regulation in smokers are at least partially due to lack of emotional clarity. Given the role of the inferior frontal gyrus in understanding emotional states, strengthening connectivity between the amygdala and the inferior frontal gyrus may improve emotional clarity to help smokers regulate their negative emotions, thereby improving their ability to quit smoking.

Importance

Various neuropsychiatric disorders, especially addictions, feature impairments in risky decision making; clarifying the neural mechanisms underlying this problem can inform treatment.

Objective

To determine how methamphetamine-dependent and control participants differ in brain activation during a risky decision-making task, resting-state functional connectivity within mesolimbic and executive control circuits, and the relationships between these measures.

Design, setting, and participants

A case-control, functional magnetic resonance imaging study of methamphetamine-dependent and healthy comparison participants at rest and when performing the Balloon Analogue Risk Task, which involves the choice to pump a balloon or to cash out in the context of uncertain risk. Conducted at a clinical research center at an academic institution, this study involved 25 methamphetamine-dependent and 27 control participants.

Main outcomes and measures

Parametric modulation of activation in the striatum and right dorsolateral prefrontal cortex (rDLPFC; ie, the degree to which activation changed as a linear function of risk and potential reward), both indexed by pump number, and resting-state functional connectivity, measured in the whole brain with seeds in the midbrain and rDLPFC. Relationships between these outcomes were also tested.

Results

Parametric modulation of cortical and striatal activation by pump number during risk taking differed with group. It was stronger in the ventral striatum but weaker in the rDLPFC in methamphetamine-dependent participants than control individuals. Methamphetamine-dependent participants also exhibited greater resting-state functional connectivity of the midbrain with the putamen, amygdala, and hippocampus (P < .05, whole brain, cluster corrected). This connectivity was negatively related to modulation of rDLPFC activation by risk level during risky decision making. In control participants, parametric modulation of rDLPFC activation by risk during decision making was positively related to resting-state functional connectivity of the rDLPFC with the striatum.

Conclusions and relevance

Maladaptive decision making by methamphetamine users may reflect circuit-level dysfunction, underlying deficits in task-based activation. Heightened resting-state connectivity within the mesocorticolimbic system, coupled with reduced prefrontal cortical connectivity, may create a bias toward reward-driven behavior over cognitive control in methamphetamine users. Interventions to improve this balance may enhance treatments for stimulant dependence and other disorders that involve maladaptive decision making.