Two models were run, evaluating percent heavy drinking days and the average number of drinks per week in the 4 weeks following the intervention or matched-control. Both models controlled for age, sex, cigarette smoking status, positive urine THC, and baseline percent heavy drinking days or average drinks per week depending on the drinking outcome model. Z-statistic images were thresholded with cluster-based corrections for multiple comparisons based on the theory of Gaussian Random Fields with a cluster-forming threshold of Z > 2.3 and a corrected cluster-probability threshold of p < 0.05 . This study examined the effect of a brief intervention on drinking outcomes, neural alcohol cue-reactivity, and the ability of neural alcohol cue-reactivity to predict drinking outcomes. Results did not find an effect of the brief intervention on alcohol use in this sample, and the intervention was not associated with differential neural alcohol cue reactivity. Exploratory secondary analyses revealed inverse relationships between differential neural activity in the precuneus and medial frontal gyrus in relation to alcohol-related outcomes, but these relationships were across conditions. The lack of main effect of intervention on either drinking outcomes or on neural alcohol cue reactivity is contrary to the study hypothesis whereby individuals assigned to the brief intervention condition were expected to show greater reductions in alcohol use compared to a no-intervention control condition . In the present study, reductions in alcohol use were observed for both conditions and it appears that simply participating in an alcohol research study at an academic medical center prompted notable behavioral changes. Reductions in drinking following study participation may be attributable to assessment reactivity, in which participants curb drinking after completing alcohol-related assessments and interviews . This phenomenon has been well-documented across several assessment modalities ,vertical grow tables including the AUDIT and TLFB interviews, which were used in the present study. In addition, recent studies have highlighted the fact that single session interventions, while efficacious in relatively large RCTS, have modest effect sizes .

As such, the present study may have been under powered to detect small effects sizes, which may account for the null findings regarding intervention effects on drinking outcomes. Future studies are encouraged to recruit larger samples of non-treatment seeking participants to better detect small effects. Furthermore, this finding should be considered in light of the sample, which was comprised of non-treatment seekers from the community, which is not the typical sample evaluated in brief intervention research. However, non-treatment seeking individuals with similar alcohol use characteristics are open to participating in brief interventions . Also of note the drinking outcomes in this study were evaluated using variables derived from the TLFB as the primary outcome measure. There is some evidence that some individuals under-report substance use when the TLFB is administered by an interviewer rather than a computer , potentially due to a social desirability bias in which participants wish to appear favorably to the interviewer. In the present study, the TLFB assessment was conducted by a trained research assistant and not the clinician who delivered the brief intervention in order to reduce this bias. However, the TLFB is a retrospective self-report measure and as such is subject to limitations including inaccuracies in participant recall. Alcohol use was also not biologically verified in this study. In light of the null findings regarding intervention effects on drinking in this study, it is perhaps not surprising that intervention condition was not associated with differences in neural cue reactivity in this sample. While it has been argued that neuroimaging techniques may be sensitive to mechanisms of behavior change , in the present study, neural processing of alcohol taste cues was no more sensitive to intervention effects than traditional measures of drinking outcomes. It should be noted however, that the alcohol taste cues task used in this study was abbreviated from its original version in order to increase the number of trials without substantially increasing scan duration. Additionally, the current version of the task used water as a control condition, while the original version employed an appetitive control condition in the form of litchi juice.

While the present version was recently validated in a separate sample , it may not have recruited the reward circuitry in response to alcohol cues as robustly as its previous iteration. Importantly, it should be noted that across both conditions, exposure to alcohol taste resulted in increased activation in frontal and limbic regions, compared to water taste, suggesting the task was fundamentally internally valid. Nevertheless, the magnitude of the activation may have been more limited due to the combination of the shortened trial duration and use of a non-appetitive control thus hindering efforts to detect intervention effects on neural processing of alcohol cues. Considered together, both factors likely posed significant challenges to the primary aims of the study, which fundamentally represented an interaction effect between treatment type and cue type. Given this, large magnitude main effects for both experimental factor would be optimal to bring the interaction into sharpest relief. Thus, the relatively modest effect size of the intervention and the sufficient but potentially smaller effects in the neuroimaging paradigm constrained the experimental tests. Future studies using neuroimaging to understanding brief interventions will require at least substantially larger sample sizes for a detectable clinical effect and potentially different neuroimaging paradigms. Regarding the prediction of drinking outcomes, the most compelling finding in the present study is that activation to alcohol tastes in the precuneus and medial frontal gyrus was negatively associated with percent heavy drinking days. The effect was such that individuals who had greater neural reactivity to alcohol taste in the precuneus and prefrontal cortex had fewer percent heavy drinking days in four weeks following the fMRI scan. Likewise, across groups, activation to alcohol tastes in the precuneus was negatively associated with average drinks per week. This pattern of results suggests that greater activation of the precuneus and frontal cortex during neural processing of alcohol taste cues, compared to control cues, predicts less drinking in the subsequent month. This effect was found across conditions, control and experimental, and is generally consistent with previous work suggesting that the precuneus is sensitive to changes in cue reactivity and possibly to changes in addiction severity .

The precuneus has also been implicated in a meta-analytic review of functional neuroimaging studies of alcohol cue reactivity . Thus the implication of precuneus activation as a predictor of subsequent drinking in the real world extends this line of research and suggests that this region may serve as an intervention target, particularly with regard to the salience of alcohol cues. Although the vast majority of neuromodulation studies to address motivation in addiction have focused on the frontal lobes , and dorsolateral prefrontal cortex in particular, recent investigations have shifted attention to the precuneus , with some success. This prospect is particularly exciting in the context of psychological interventions. The precuneus has been functionally implicated in self-related cognition , which in many cases is essential for behavioral interventions to have an impact. For example, in the context of a brief intervention, a person must encode the factual information provided and square it with their own self perceptions. Furthermore, in the current study’s intervention, participants were specifically asked what they wanted to do next and this necessarily demands meaningful self-related cognitive processing to generate behavior change. To illustrate this by contrast, we would have no expectation that a brief intervention would have a meaningful impact for a hypothetical individual who had no capacity to think abstractly about him or herself . Thus, self-related cognition is a necessary elementary information processing capacity for this type of intervention to be useful and the current study suggests that the extent to which this was engaged was associated with a more favorable outcome. Of course, this interpretation requires considerable caution because it is inherently conjecture and the precuneus has been implicated in a number of other cognitive functions. A recent review of psychosocial interventions for addiction medicine identified increased recruitment of self-referential processing regions, including the precuneus and medial prefrontal cortex, in response to targeted motivational interventions . Additionally, in cannabis users, greater precuneus activation during a motivational interviewing intervention was associated with a reduction in cannabis problems at follow-up ; further indicating that activation of self-referential processing circuitry may be important for treatment response. Other psychological interventions, including cue-extinction and episodic future thinking training,vertical grow trays may be successful at increasing self-related cognition through precuneus activation. Precuneus activation has been demonstrated in cigarette smokers who were told to engage in self-focused coping during a cue-exposure task , indicating the interventions targeting self-focused coping during exposure to drug cues may effectively activate this brain region. Exposure to episodic future thinking activates the precuneus and mPFC and results in alcohol dependent individuals increasing their valuation of future monetary rewards while lowering demand intensity for alcohol rewards . Frontoparietal circuitry, including the precuneus, is activated when participants make voluntary choices to cognitively reappraise craving responses or freely view craving cues . Of note, the precuneus is not neuroanatomically uniform, with distinct functional subregions according to both the anterior-posterior and dorsal-ventral axes, and distinct patterns of functional connectivity by subregion . The current study reveals associations for the precuneus in general, but cannot speak to subregional activation. In sum, the current study sought to examine whether a brief intervention would reduce both drinking and alcohol motivation as measured by neural reactivity to alcohol cues and neither hypothesis was supported.

This conclusion, however, must be tempered by effect size considerations for both the intervention and the paradigm, as well as the apparently substantial reactivity effects present in the control condition. Each of these has important methodological implications for future studies of the neural mechanisms of alcohol-related behavior change. In addition, independent of intervention, exploratory analyses revealed differential neural reactivity that predicted more favorable outcomes, particularly in the precuneus, suggesting that is a promising neural substrate warranting further study in this line of inquiry. The worldwide crisis related to the non-medical use of opioids continues, as reflected in high rates of deaths that are associated with prescription opioids, recreational drugs such as heroin and increasingly illicit supplies of fentanyl and analogs . The number of individuals seeking treatment for opioid dependence is high . Improvement in understanding the risk factors for opioid addiction, as well as the behavioral and neurobiological consequences of opioid exposure, may enhance the discovery of new or improved avenues for therapy. Pre-clinical models in, e.g., laboratory rats, have been critical to advancing understanding but have been mostly limited to the examination of opioids delivered by parenteral injection, the insertion of subcutaneous pellets or pumps, or by oral dosing. Many humans use opioids by the inhalation route and indeed, one of the original public health crises related to non-medical use of opioids in the modern era was associated with the inhalation of vapor created by heating opium . The inhalation route might induce differences in the speed of brain entry, first pass metabolism, sequestration and release from non-brain tissues, etc. compared with these laboratory approaches. There is even some indication that inhalation use of heroin may come before a switch to injection use , perhaps due to perceptions of safety or cultural factors. This may be true with respect to, e.g., disease transmission associated with intravenous injection practices but may involve other risks. For example, inhalation heroin users who develop leukoencephalopathy may be at increased risk for mortality compared with those who inject heroin . Prior studies have shown that the inhalation of heroin produces effects in animal models. Lichtman and colleagues reported anti-nociceptive effects of volatilized heroin and otheropioids in mice using a heated glass pipe approach and a tail-withdrawal assay and Carrol and colleagues demonstrated that monkeys would self-administer volatilized heroin . There has, however, been no subsequent broad adoption of either of these techniques, possibly due to the difficulty of creating and maintaining what appear to be one-off apparatus/devices constructed by the respective lab groups. The recent advent of e-cigarette style devices presents the possibility of delivering a wide range of drugs other than nicotine, including opioids, via vapor inhalation. These devices are widely available , offer significant translational appeal and can be easily adapted to use with laboratory rodents using commonly available sealed-top housing chambers, standard laboratory house vacuum, and simple plumbing.