There was a minimum wash-out period between medication conditions of 7 days, with a range of 7-10 days. Regarding medication adherence, naltrexone and placebo capsules were packaged with 50mg of riboflavin. A visual inspection of riboflavin content under ultraviolet light indicated that all urine samples tested positive for riboflavin content. Participants completed a modified version of the Alcohol Taste Cues Task in the scanner . Within each task trial, participants initially viewed a visual cue for 2 seconds, followed by a fixation cross . The word “Taste” then appeared, corresponding to oral delivery of the indicated liquid at the start of the trial . Participants were also instructed to press a button on a button box to indicate the point at which the bolus of liquid was swallowed and this information was used to model motion associated with swallowing. There were two runs of this task, with 50 trials per run. Red or white wine, based on participant preference, was used as the alcohol stimulus; previous work from our group has demonstrated that this paradigm has been used to effectively elicit alcohol-related neural activation . Carbonated alcohol, such as beer, could not be systematically administered with the paradigm apparatus and was not offered as a drink option to participants. Visual stimuli and response collection were programmed using MATLAB and Psychtoolbox ,cannabis indoor greenhouse and visual stimuli were presented using MRI compatible goggles.
Participants completed an oral alcohol self-administration paradigm on day 5 of medication titration. At the start of this session, participants were required to test negative for substance use and to have a BrAC of 0.00 g/dl. Female participants were also required to test negative on a pregnancy test. Participants fasted for two hours prior to the session and were given a standardized meal before the alcohol administration. Participants initially completed an intravenous alcohol administration discussed in the primary manuscript . After completing the alcohol infusion paradigm and reaching a target BrAC of 0.06 g/dl, the IV was removed and, after a standardized period of five minutes, participants subsequently began an oral self-administration session at the testing center. Notably, the alcohol dose of 0.06 g/dl prior to the self-administration period was higher than the typical 0.03 g/dl priming dose implemented in self-administration tasks During the self-administration period, participants were provided 4 mini-drinks of their preferred alcoholic beverage and allowed to watch a movie over a 1-hour period. The 4 mini-drinks allowed participants to consume up to 0.04 g/dl alcohol in total, and were individualized by participant gender, weight, height, and alcohol content. Participants were also told that they would receive 1 dollar for each drink remaining at the end of the session. At the end of the session, participants were provided a meal and required to stay at the testing center until their BrAC dropped below 0.02 g/dl or to 0.00 g/dl if driving. For the taste cues paradigm, information regarding image acquisition parameters and preprocessing steps are available in Supplementary Materials and are derived from the primary manuscript . The main contrast of interest was the difference in activation corresponding to alcohol taste delivery and water delivery across the two task runs , for each within-subject medication condition. Consistent with previous studies examining relationships among ventral striatum activity, subjective response to alcohol, and drinking behavior , an anatomical bilateral ventral striatum region of interest was defined using the Harvard-Oxfordatlas in standard MNI space and was transformed into participants’ respective native space using FSL’s FLIRT .
This ROI was selected because ventral striatum is most consistently elicited in alcohol cue and taste reactivity paradigms, as well as most frequently associated with behavioral measures and treatment response . ROI selection was limited to one due to insufficient power to detect incremental model improvement with multiple ROIs. The mean contrast estimate values were extracted from this region for each subject and used in mixed models for group-level analysis . The self-administration paradigm yielded two outcome measures: latency to first drink , and total number of drinks consumed during the session . To examine the relationship between alcohol taste-induced neural activation and self-administration, multilevel mixed poisson and cox proportional hazard models were the primary analyses for total number of drinks and latency to first drink, respectively. Frailty models were fitted using a penalized partial likelihood approach available in SAS 9.4 . Primary analyses examined effects of variables of interest, including medication condition , alcohol consumption , and OPRM1. Due to concerns of overparameterization given the limited sample size, additional covariates of interest were individually included in separate models to determine whether main effects of ventral striatum would be altered. Alpha corrections were not utilized in this exploratory study due to limited sample size and constrained power. Tests of proportional hazards are included in Supplementary Materials and Figures S1a-S1d. Survival plots for latency to first drink, controlling for covariates within the final model , were generated to further explore ventral striatum activation in predicting latency to first drink. Of note, a dichotomous median-split ventral striatum variable was created for ease of visualization of these relationships, but ventral striatum activation was included as a continuous variable in all models. The distribution of latencies to first drink was non-normal.
Across medication conditions, 52% of individuals refrained from drinking throughout the paradigm, 29% consumed a drink within the first three minutes of the paradigm, and 19% of individuals consumed their first drink at some point during the remainder of the session. Cox regressions for latency to first drink indicated a significant effect of ventral striatum activation, Wald χ2 = 2.88, p = 0.05, such that those with lower ventral striatum activation exhibited longer latencies to first drink . Significant covariates included medication condition, Wald χ2 = 5.99, p = 0.01, such that naltrexone was associated with longer latency to first drink. OPRM1 was also significant, Wald χ2 = 3.31, p = 0.03, such that Asn40Asn homozygotes exhibited shorter latency to first drink. Other covariates of interest were not associated with latency to first drink . There were also no interactions of medication X gender on self-administration outcomes. This study examined the relationship between alcohol cue-induced ventral striatum activation and alcohol self-administration in the laboratory. Results from this heavy-drinking sample of East Asians indicated that higher ventral striatum activation was associated with a shorter latency to first self-administered drink. Similarly, ventral striatum activation was positively associated with the total number of drinks consumed during the self-administration paradigm in this sample. These results remained significant after controlling for severity of drinking patterns, OPRM1, and medication condition. Overall, this is the first study to examine whether neuroimaging outcomes of interest can predict responses within laboratory paradigms commonly used in the alcohol literature. This foundational work adds important validity to the hypothesized interplay between neural bases of alcohol craving and behavioral measures of alcohol seeking,cannabis growing equipment namely alcohol self-administration in the human laboratory. These associations contribute to a growing literature on the translational value of neuroimaging paradigms in alcohol treatment, particularly in elucidating potential mechanisms through which self-administration paradigms in AUD research are related to real world alcohol consumption . Such work is aligned with current efforts in behavioral treatments utilizing neuroimaging to study mechanisms of behavior change for substance use disorders; identifying those individuals with severe orbitofrontal cortex deficits, for instance, may be useful in guiding them away from treatments focused on increasing the salience of future negative consequences of substance use . In a similar fashion, adjunctive fMRI has been used to train individuals with substance use disorders through resonance-based breathing to reduce visual processing of drug cues and increase activation in areas implicated in internally directed cognition . Elucidating the translational value of these various experimental paradigms is strongly indicated, as AUD medications can exhibit differential results based on the utilized paradigm and such variability may in turn inform precision medicine efforts. Expanding the study of interexperimental paradigms may also shed light on aspects of alcohol consumption unique to individual paradigms. For instance, a greater understanding of individuals’ experiences in the transition between the first and subsequent drinks may be an important point of clinical interventions when discussing naltrexone use. While the primary aim of this study was not focused on genetic determinants of self administration, it is notable that genotypes encoding the binding potential of mu-opioid receptors were associated with self-administration outcomes.
While it is theorized that individuals with at least one copy of the G-allele for OPRM1 exhibit greater vulnerability to developing AUD, meta-analyses have been mixed, with findings that such an association may not be reliable , are population specific , or that G-allele confers a modest protective effect on general substance dependence in Europeanancestry cohorts . In this study, G-allele carriers of OPRM1 exhibited lower total consumption relative to A-allele carriers at a statistical trend level, as well as slower latency to first drink. This finding is consistent with the primary analyses for this data , which indicated that G-allele carriers of OPRM1 also reported less severe drinking history and lower AUDIT scores compared to Asn40 homozygotes and may, in turn, help to explain these findings. In sum, we accounted for genetic factors in these analyses given their theoretical and practical salience , particularly in this population . And while the genetic findings are notable and largely consistent with the literature, the primary focus on the study is on the fMRI to human laboratory association. This is the area in which the present analyses make a substantive contribution to the literature by supporting a long hypothesized, yet rarely tested, association between brain and behavior. Finally, this study identified significant effects of naltrexone in increasing latency to first drink and decreasing total alcohol consumption. Notably, while these contrast the primary study results from which the data are derived the current study is a secondary analysis of a sub-sample of participants who had completed both neuroimaging sessions. While inclusion of VS activation may have helped to improve model fit, the primary study had greater power in order to test pharmacogenetic effects. For these reasons, while it is possible that consideration of neuroimaging outcomes help elucidate AUD pharmacotherapy effects, replication using larger samples is warranted. On balance, this study should be interpreted in light of its strengths and limitations. Strengths included assessment of multiple experimental procedures used in the medication development literature and consideration of multiple psychiatric and genetic predictors of self-administration in the statistical analyses. Another strength is the test of hypothesis at the within subjects level of analysis. As argued by Curran and Bauer , several psychological processes which are inherently within-person processes, such as the relationship between how one’s brain processes alcohol cues and how much s/he wants to drink in the future, are presumed to be explained in between-subjects models, when in fact, within-subject analyses provide a more representative test of the process at hand . Thus, a within-subjects approach represents a more robust, and methodologically adequate, test of the association between brain and behavior. One of the most important limitations of the current study is a constrained sample and power; given the exploratory nature of this study, alpha corrections were not implemented. A limitation of the taste cues fMRI paradigm used in this study is that it was modified to reduce trial duration in order to increase the number of trials for analysis; in contrast to the original task , a whole-brain analysis of the task did not elicit significant clusters of mesocorticolimbic, including ventral striatum, activation. Therefore, replication using other tasks that more strongly elicit ventral striatum activation are needed, both to induce significant enough variability to test medication effects and also to translate such effects into another subsequent experimental modality. Variations of the Monetary Incentive Delay task that administer beer may be particularly useful in disentangling whether anticipation, relative to receipt, of alcohol taste are differently discriminant in predicting self-administration Relatedly, the taste cues paradigm was limited to the choice of red or white wine, which did not always correspond with participants’ drink of choice; while this correspondence was not a significant covariate in self-administration outcomes, administering drink of choice may increase external validity of the imaging task. Another potential weakness is that medication effects from the primary manuscripts were null; future studies are needed to corroborate that medication effects are consistent across paradigms, particularly in identifying significant such effects.