: Emerging evidence suggests that opioid receptor antagonists, such as naltrexone, are effective pharmacotherapies for alcohol, opioid, and possibly stimulant use disorders. It is posited that naltrexone exerts its effects, in part, by increasing functional connectivity between neural reward circuitry and frontal systems implicated in executive function. Yet no studies had examined whether executive function moderates these effects.
Adolescent traumatic brain injury (TBI) has long-term effects on brain functioning and behavior, impacting neural activity under cognitive load, especially in the reward network. Adolescent TBI is also linked to risk-taking behaviors including alcohol misuse. It remains unclear how TBI and neural functioning interact to predict alcohol experimentation during adolescence. Using Adolescent Brain Cognitive Development (ABCD) study data, this project examined if TBI at ages 9-10 predicts increased odds of alcohol sipping at ages 11-13 and if this association is moderated by neural activity during the Emotional EN-Back working memory task at ages 11-13. Logistic regression analyses showed that neural activity in regions of the fronto-basal ganglia network predicted increased odds of sipping alcohol by ages 11-13 (p < .05). TBI and left frontal pole activity interacted to predict alcohol sipping (OR = 0.507, 95% CI [0.303 - 0.846], p = .009) - increased activity predicted decreased odds of alcohol sipping for those with a TBI (OR = 0.516, 95% CI [0.314 - 0.850], p = .009), but not for those without (OR = 0.971, 95% CI [0.931 -1.012], p = .159). These findings suggest that for youth with a TBI, increased BOLD activity in the frontal pole, underlying working memory, may be uniquely protective against the early initiation of alcohol experimentation. Future work will examine TBI and alcohol misuse in the ABCD cohort across more time points and the impact of personality traits such as impulsivity on these associations.
Objective: Subjective responses to alcohol represent a biologically based, genetically moderated, and clinically informative marker of alcoholism risk; however, the physiology underlying this phenotype remains unclear. This study tested whether subjective responses during alcohol administration predict neural responses to alcohol cues in the scanner and whether these neural responses differ between OPRM1 genotypes. Method: Twenty alcohol-dependent individuals were recruited (10 G-allele carriers; 6 women; Mage = 29.4) for a within-subjects alcohol administration in the laboratory and a functional magnetic resonance imaging session consisting of an alcohol taste cues task. Laboratory assessments of alcohol high, liking, craving, and positive and negative reinforcement during alcohol administration were entered as predictors of neural response to the presentation of alcohol cues versus water cues in the scanner and further tested for OPRM1 genotype moderation (whole-brain cluster-corrected at Z > 1.96, p < .05). Results: Alcohol craving during alcohol administration predicted less neural activity, whereas alcohol reinforcement predicted greater neural activity to alcohol cues versus water cues in regions including the precuneus, posterior cingulate gyrus, and lingual gyrus. Alcohol high predicted greater neural activity to alcohol cues in regions including the precuneus and anterior cingulate cortex. OPRM1 genotype was found to moderate these relationships. No results were observed for alcohol liking. Conclusions: This study provides initial evidence that subjective responses to alcohol, namely craving, high, and the reinforcing properties of alcohol, predict neural markers of alcohol cue reactivity. These results support the validity of laboratory and neuroimaging measures of subjective responses to alcohol and offer an integration of these methods in a sample of alcohol-dependent individuals.
Background Acute alcohol consumption is associated with temporarily increased regional cerebral blood flow (CBF). The extent of this increase appears to be moderated by individual differences in the level of response (LR) to alcohol's subjective effects. The low LR phenotype is a known risk factor for the development of alcohol problems. This study investigates how the low LR phenotype relates to the relationship between alcohol‐related changes in CBF and alcohol problems 5 years later. Methods Young adults (ages 18 to 25) were selected based on their LR to alcohol and underwent a neuroimaging protocol including arterial spin labeling and functional scans. These participants were recontacted ~5 years later and assessed on alcohol outcomes. A final sample of 107 subjects (54 low and 53 high LR subjects) was included in the analyses. Whole‐brain analysis revealed 5 clusters of significant alcohol‐induced, versus placebo‐induced, CBF changes that were consistent with a previous report. Peak alcohol–placebo CBF response was extracted from these regions and, along with the LR group, submitted to a hierarchical linear regression predicting alcohol problems. Analyses controlled for age, sex, and baseline alcohol problems. Results In the regression analysis, greater alcohol–placebo CBF difference in the right middle/superior/inferior frontal gyri and bilateral anterior cingulate gyri clusters predicted greater future alcohol problems for the low LR group, whereas this relationship was not found to be significant in the high LR group. Conclusions This study demonstrates a clinically important relationship between CBF and future alcohol problems, particularly in individuals with a low LR phenotype. These initial results help to elucidate the neurobiological pathways involved in the development of alcohol use disorders for individuals with low LR.
Objective: Co-use of cannabis and nicotine and tobacco products (NTPs) in adolescence/young adulthood is common and associated with worse outcomes than the use of either substance in isolation. Despite this, little is known about the unique contributions of co-use to neurostructural microstructure during this neurodevelopmentally important period. This study sought to investigate the interactive effects of nicotine and cannabis co-use on white matter fiber tract microstructure in emerging adulthood. Method: A total of 111 late adolescent (16–22 years old) nicotine (NTP; n = 55, all past-year cannabis users) and non–nicotine users (non-NTP; n = 56, 61% reporting cannabis use in the past year) completed demographic and clinical interviews and a neuroimaging session comprising anatomical and diffusion-weighted imaging scans. Group connectometry analysis identified white matter tracts significantly associated with the interaction between nicotine group and past-year cannabis use according to generalized fractional anisotropy (GFA). Results: Nicotine Group × Cannabis Use interactions were observed in the right and left cingulum and left fornix tracts (false discovery rate = 0.053), where greater cannabis use was associated with increased GFA in the cingulum and left fornix, but only when co-used with nicotine. Conclusions: This report represents the first group connectometry analysis in late adolescent/young adult cannabis and/or NTP users. Results suggest that co-use of cannabis and NTPs results in a structurally distinct white matter phenotype as compared with cannabis use only, although to what extent this may change over time with more chronic nicotine and cannabis use remains to be examined in future work.
Background Craving is a clinically important phenotype for the development and maintenance of nicotine addiction. Virtual reality (VR) paradigms are successful in eliciting cue-induced subjective craving and may even elicit stronger craving than traditional picture-cue methods. However, few studies have leveraged the advances of this technology to improve the assessment of craving. Objective This report details the development of a novel, translatable VR paradigm designed to both elicit nicotine craving and assess multiple eye-related characteristics as potential objective correlates of craving. Methods A VR paradigm was developed, which includes three Active scenes with nicotine and tobacco product (NTP) cues present, and three Neutral scenes devoid of NTP cues. A pilot sample (N=31) of NTP users underwent the paradigm and completed subjective measures of nicotine craving, sense of presence in the VR paradigm, and VR-related sickness. Eye-gaze fixation time (“attentional bias”) and pupil diameter toward Active versus Neutral cues, as well as spontaneous blink rate during the Active and Neutral scenes, were recorded. Results The NTP Cue VR paradigm was found to elicit a moderate sense of presence (mean Igroup Presence Questionnaire score 60.05, SD 9.66) and low VR-related sickness (mean Virtual Reality Sickness Questionnaire score 16.25, SD 13.94). Scene-specific effects on attentional bias and pupil diameter were observed, with two of the three Active scenes eliciting greater NTP versus control cue attentional bias and pupil diameter (Cohen d=0.30-0.92). The spontaneous blink rate metrics did not differ across Active and Neutral scenes. Conclusions This report outlines the development of the NTP Cue VR paradigm. Our results support the potential of this paradigm as an effective laboratory-based cue-exposure task and provide early evidence of the utility of attentional bias and pupillometry, as measured during VR, as useful markers for nicotine addiction.
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.
Abstract Background Incentive salience processes are important for the development and maintenance of addiction. Eye characteristics such as gaze fixation time, pupil diameter, and spontaneous eyeblink rate (EBR) are theorized to reflect incentive salience and may serve as useful biomarkers. However, conventional cue exposure paradigms have limitations that may impede accurate assessment of these markers. Objective This study sought to evaluate the validity of these eye-tracking metrics as indicators of incentive salience within a virtual reality (VR) environment replicating real-world situations of nicotine and tobacco product (NTP) use. Methods NTP users from the community were recruited and grouped by NTP use patterns: nondaily (n=33) and daily (n=75) use. Participants underwent the NTP cue VR paradigm and completed measures of nicotine craving, NTP use history, and VR-related assessments. Eye-gaze fixation time (attentional bias) and pupillometry in response to NTP versus control cues and EBR during the active and neutral VR scenes were recorded and analyzed using ANOVA and analysis of covariance models. Results Greater subjective craving, as measured by the Tobacco Craving Questionnaire–Short Form, following active versus neutral scenes was observed ( F 1,106 =47.95; P <.001). Greater mean eye-gaze fixation time ( F 1,106 =48.34; P <.001) and pupil diameter ( F 1,102 =5.99; P =.02) in response to NTP versus control cues were also detected. Evidence of NTP use group effects was observed in fixation time and pupillometry analyses, as well as correlations between these metrics, NTP use history, and nicotine craving. No significant associations were observed with EBR. Conclusions This study provides additional evidence for attentional bias, as measured via eye-gaze fixation time, and pupillometry as useful biomarkers of incentive salience, and partially supports theories suggesting that incentive salience diminishes as nicotine dependence severity increases.
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